JP6853833B2 - エストロゲン受容体調節物質の組合せ - Google Patents
エストロゲン受容体調節物質の組合せ Download PDFInfo
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- JP6853833B2 JP6853833B2 JP2018561709A JP2018561709A JP6853833B2 JP 6853833 B2 JP6853833 B2 JP 6853833B2 JP 2018561709 A JP2018561709 A JP 2018561709A JP 2018561709 A JP2018561709 A JP 2018561709A JP 6853833 B2 JP6853833 B2 JP 6853833B2
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- 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
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Steroid Compounds (AREA)
Description
本出願は、2016年5月26日に出願された米国仮出願第62/342,126号の利益を主張し、その内容の全体があらゆる目的において本明細書に組み込まれる。
酸素を意味する。
(A)オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、非置換アルキル、非置換ヘテロアルキル、非置換アリール、非置換ヘテロアリール、ならびに
(B)以下から選択される少なくとも1つの置換基で置換されたアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール:
(i)オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、非置換アルキル、非置換ヘテロアルキル、非置換アリール、非置換ヘテロアリール、ならびに
(ii)以下から選択される少なくとも1つの置換基で置換されたアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール:
(a)オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、非置換アルキル、非置換ヘテロアルキル、非置換アリール、非置換ヘテロアリール、及び
(b)以下から選択される少なくとも1つの置換基で置換されたアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール:オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、非置換アルキル、非置換ヘテロアルキル、非置換アリール、非置換ヘテロアリール。
R1は、独立的に、水素、ハロゲン、−NR2R3、−CXa 3、−CN、−SO2Cl、−SOn1R10、−SOv1NR2R3、−NHNR2R3、−ONR2R3、−NHC=(O)NHNR2R3、−NHC=(O)NR2R3、−N(O)m1、−C(O)R9、−C(O)−OR9、−C(O)NR2R3、−OR10、−NR2SO2R10、−NR2C=(O)R9、−NR2C(O)−OR9、−NR2OR9、−OCXa 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールである。R2は、独立的に、水素、ハロゲン、−CXb 3、−CN、−SO2Cl、−SOn2R14、−SOv2NR11R12、−NHNH2、−ONR11R12、−NHC=(O)NHNH2、−NHC=(O)NR11R12、−N(O)m2、−NR11R12、−C(O)R13、−C(O)−OR13、−C(O)NR11R12、−OR14、−NR11SO2R14、−NR11C=(O)R13、−NR11C(O)−OR13、−NR11OR13、−OCXb 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールである。R3は、独立的に、水素、ハロゲン、−CXc 3、−CN、−SO2Cl、−SOn3R18、−SOv3NR15R16、−NHNH2、−ONR15R16、−NHC=(O)NHNH2、−NHC=(O)NR15R16、−N(O)m3、−NR15R16、−C(O)R17、−C(O)−OR17、−C(O)NR15R16、−OR18、−NR15SO2R18、−NR15C=(O)R17、−NR15C(O)−OR17、−NR15OR17、−OCXc 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールである。R2及びR3置換基は任意選択で連結して、置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよい。Lは、独立的に、結合、−NR4−、−NR4C(O)−、−C(O)NR4−、−O−、−S−、−C(O)−、−S(O)−、−S(O)2−、置換もしくは非置換アルキレン、置換もしくは非置換ヘテロアルキレン、置換もしくは非置換シクロアルキレン、置換もしくは非置換ヘテロシクロアルキレン、置換もしくは非置換アリーレン、置換もしくは非置換ヘテロアリーレン、または置換もしくは非置換スピロ環式リンカーである。R4は、独立的に、水素、ハロゲン、−CXd 3、−CN、−SO2Cl、−SOn4R22、−SOv4NR19R20、−NHNH2、−ONR19R20、−NHC=(O)NHNH2、−NHC=(O)NR19R20、−N(O)m4、−NR19R20、−C(O)R21、−C(O)−OR21、−C(O)NR19R20、−OR22、−NR19SO2R22、−NR19C=(O)R21、−NR19C(O)−OR21、−NR19OR21、−OCXd 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールである。R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、及びR22は、独立的に、水素、ハロゲン、−CX3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCX3、−OCHX2、−CF3、−OCF3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、同じ窒素原子に結合したR11及びR12置換基は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキルまたは置換もしくは非置換ヘテロアリールを形成してもよく、同じ窒素原子に結合したR15及びR16置換基は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキルまたは置換もしくは非置換ヘテロアリールを形成してもよく、同じ窒素原子に結合したR19及びR20置換基は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよい。記号nは0〜5の整数である。記号m1、m2、m3、m4、v1、v2、v3、及びv4は独立的に1または2である。記号n1、n2、n3、及びn4は独立的に0〜4の整数である。記号X、Xa、Xb、Xc、及びXdは独立的に−Cl、−Br、−I、または−Fである。
諸実施形態において、このような構造においてアスタリスクで示される−CH3は、非置換C1−C5アルキルで置き換えることができる。
5が引き受け、m5の定義はm51、m52、m53、m54、及び/またはm55が引き受け、v1の定義はv11、v12、v13、v14、及び/またはv15が引き受け、v2の定義はv21、v22、v23、v24、及び/またはv25が引き受け、v3の定義はv31、v32、v33、v34、及び/またはv35が引き受け、v4の定義はv41、v42、v43、v44、及び/またはv45が引き受け、v5の定義はv51、v52、v53、v54、及び/またはv55が引き受け、n1の定義はn11、n12、n13、n14、及び/またはn15が引き受け、n2の定義はn21、n22、n23、n24、及び/またはn25が引き受け、n3の定義はn31、n32、n33、n34、及び/またはn35が引き受け、n4の定義はn41、n42、n43、n44、及び/またはn45が引き受け、n5の定義はn51、n52、n53、n54、及び/またはn55が引き受け、Xの定義はX1、X2、X3、X4、及び/またはX5が引き受け、Xaの定義はXa1、XaX2、Xa3、Xa4、及び/またはXa5が引き受け、Xbの定義はXb1、Xb2、Xb3、Xb4、及び/またはXb5が引き受け、Xcの定義はXc1、Xc2、Xc3、Xc4、及び/またはXc5が引き受け、Xdの定義はXd1、Xd2、Xd3、Xd4、及び/またはXd5が引き受け、Xeの定義はXe1、Xe2、Xe3、Xe4、及び/またはXe5が引き受ける。R1、R2、R3、R4、R5、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、m1、m2、m3、m4、m5、v1、v2、v3、v4、v5、n1、n2、n3、n4、n5、X、Xa、Xb、Xc、Xd、及びXeの定義内で使用される変数、及び/または複数の場合に出現し、かつ異なっている変数も同様に、より明快に各群を区別するために適切にラベル付けすることができる。
式(I):
一態様において、必要とする対象における過剰増殖性障害を処置する方法であって、対象に、有効量の、本明細書で開示する組成物、または本明細書で開示するキットの化合物及びさらなる薬剤(例えば、CDK4阻害物質もしくはCDK6阻害物質)を投与することを含む方法が提供される。したがって、諸実施形態において、当該方法は、本明細書で提供する化合物、例えば式Iの化合物及びその実施形態、ならびに追加の薬阻害物質またはさらなる薬剤、例えばCDK4阻害物質またはCDK6阻害物質を投与することを含む。
一態様において、必要とする対象におけるエストロゲン受容体活性を阻害する方法が提供される。当該使用は、対象に、有効量の、本明細書で開示する組成物、または本明細書で開示するキットの化合物もしくはその医薬的に許容される塩、さらなる薬剤(例えば、CDK4阻害物質もしくはCDK6阻害物質)を投与することを含む。したがって、諸実施形態において、当該方法は、本明細書で提供する化合物、例えば式Iの化合物及びその実施形態、ならびに追加の薬阻害物質またはさらなる薬剤、例えばCDK4阻害物質またはCDK6阻害物質を投与することを含む。
実施形態1。組成物であって、
CDK4阻害物質またはCDK6阻害物質、及び
次式を有する化合物
(式中、
R1は、独立的に、水素、ハロゲン、−NR2R3、−CXa 3、−CN、−SO2Cl、−SOn1R10、−SOv1NR2R3、−NHNR2R3、−ONR2R3、−NHC=(O)NHNR2R3、−NHC=(O)NR2R3、−N(O)m1、−C(O)R9、−C(O)−OR9、−C(O)NR2R3、−OR10、−NR2SO2R10、−NR2C=(O)R9、−NR2C(O)−OR9、−NR2OR9、−OCXa 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
Lは、独立的に、結合、−NR4−、−NR4C(O)−、−C(O)NR4−、−O−、−S−、−C(O)−、−S(O)−、−S(O)2−、置換もしくは非置換アルキレン、置換もしくは非置換ヘテロアルキレン、置換もしくは非置換シクロアルキレン、置換もしくは非置換ヘテロシクロアルキレン、置換もしくは非置換アリーレン、置換もしくは非置換ヘテロアリーレン、または置換もしくは非置換スピロ環式リンカーであり、
R2は、独立的に、水素、ハロゲン、−CXb 3、−CN、−SO2Cl、−SOn2R14、−SOv2NR11R12、−NHNH2、−ONR11R12、−NHC=(O)NHNH2、−NHC=(O)NR11R12、−N(O)m2、−NR11R12、−C(O)R13、−C(O)−OR13、−C(O)NR11R12、−OR14、−NR11SO2R14、−NR11C=(O)R13、−NR11C(O)−OR13、−NR11OR13、−OCXb 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R3は、独立的に、水素、ハロゲン、−CXc 3、−CN、−SO2Cl、−SOn3R18、−SOv3NR15R16、−NHNH2、−ONR15R16、−NHC=(O)NHNH2、−NHC=(O)NR15R16、−N(O)m3、−NR15R16、−C(O)R17、−C(O)−OR17、−C(O)NR15R16、−OR18、−NR15SO2R18、−NR15C=(O)R17、−NR15C(O)−OR17、−NR15OR17、−OCXc 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R2及びR3置換基は、任意選択で連結して、置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
R4は、独立的に、水素、ハロゲン、−CXd 3、−CN、−SO2Cl、−SOn4R22、−SOv4NR19R20、−NHNH2、−ONR19R20、−NHC=(O)NHNH2、−NHC=(O)NR19R20、−N(O)m4、−NR19R20、−C(O)R21、−C(O)−OR21、−C(O)NR19R20、−OR22、−NR19SO2R22、−NR19C=(O)R21、−NR19C(O)−OR21、−NR19OR21、−OCXd 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、及びR22は、独立的に、水素、ハロゲン、−CX3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCX3、−OCHX2、−CF3、−OCF3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、同じ窒素原子に結合したR11及びR12置換基は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキルまたは置換もしくは非置換ヘテロアリールを形成してもよく、同じ窒素原子に結合したR15及びR16置換基は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキルまたは置換もしくは非置換ヘテロアリールを形成してもよく、同じ窒素原子に結合したR19及びR20置換基は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
nは0〜5の整数であり、
m1、m2、m3、m4、v1、v2、v3、及びv4は独立的に1または2であり、
n1、n2、n3、及びn4は独立的に0〜4の整数であり、
X、Xa、Xb、Xc、及びXdは独立的に−Cl、−Br、−I、または−Fである)
R5は、独立的に、水素、ハロゲン、−CXe 3、−CN、−SO2Cl、−SOn5R26、−SOv5NR23R24、−NHNH2、−ONR23R24、−NHC=(O)NHNH2、−NHC=(O)NR23R24、−N(O)m5、−NR23R24、−C(O)R25、
−C(O)−OR25、−C(O)NR23R24、−OR26、−NR23SO2R26、−NR23C=(O)R25、−NR23C(O)−OR25、−NR23OR25、−OCXe 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R23、R24、R25、及びR26は、独立的に、水素、ハロゲン、−CX3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCX3、−OCHX2、−CF3、−OCF3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、同じ窒素原子に結合したR23及びR24置換基は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
m5及びv5は独立的に1または2であり、
n5は独立的に0〜4の整数であり、
Xeは独立的に−Cl、−Br、−I、または−Fである)
R5は、独立的に、水素、ハロゲン、−CXe 3、−CN、−SO2Cl、−SOn5R26、−SOv5NR23R24、−NHNH2、−ONR23R24、−NHC=(O)NHNH2、−NHC=(O)NR23R24、−N(O)m5、−NR23R24、−C(O)R25、−C(O)−OR25、−C(O)NR23R24、−OR26、−NR23SO2R26、−NR23C=(O)R25、−NR23C(O)−OR25、−NR23OR25、−OCXe 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R23、R24、R25、及びR26は、独立的に、水素、ハロゲン、−CX3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCX3、−OCHX2、−CF3、−OCF3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、同じ窒素原子に結合したR23及びR24置換基は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
m5及びv5は独立的に1または2であり、
n5は独立的に0〜4の整数であり、
Xeは独立的に−Cl、−Br、−I、または−Fである)
CDK4阻害物質またはCDK6阻害物質、及び
次式を有する化合物
(式中、
R1は、独立的に、水素、ハロゲン、−NR2R3、−CXa 3、−CN、−SO2Cl、−SOn1R10、−SOv1NR2R3、−NHNR2R3、−ONR2R3、−NHC=(O)NHNR2R3、−NHC=(O)NR2R3、−N(O)m1、−C(O)R9、−C(O)−OR9、−C(O)NR2R3、−OR10、−NR2SO2R10、−NR2C=(O)R9、−NR2C(O)−OR9、−NR2OR9、−OCXa 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
Lは、独立的に、結合、−NR4−、−NR4C(O)−、−C(O)NR4−、−O−、−S−、−C(O)−、−S(O)−、−S(O)2−、置換もしくは非置換アルキレン、置換もしくは非置換ヘテロアルキレン、置換もしくは非置換シクロアルキレン、置換もしくは非置換ヘテロシクロアルキレン、置換もしくは非置換アリーレン、置換もしくは非置換ヘテロアリーレン、または置換もしくは非置換スピロ環式リンカーであり、
R2は、独立的に、水素、ハロゲン、−CXb 3、−CN、−SO2Cl、−SOn2R14、−SOv2NR11R12、−NHNH2、−ONR11R12、−NHC=(O)NHNH2、−NHC=(O)NR11R12、−N(O)m2、−NR11R12、−C(O)R13、−C(O)−OR13、−C(O)NR11R12、−OR14、−NR11SO2R14、−NR11C=(O)R13、−NR11C(O)−OR13、−NR11OR13、−OCXb 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R3は、独立的に、水素、ハロゲン、−CXc 3、−CN、−SO2Cl、−SOn3R18、−SOv3NR15R16、−NHNH2、−ONR15R16、−NHC=(O)NHNH2、−NHC=(O)NR15R16、−N(O)m3、−NR15R16、−C(O)R17、−C(O)−OR17、−C(O)NR15R16、−OR18、−NR15SO2R18、−NR15C=(O)R17、−NR15C(O)−OR17、−NR15OR17、−OCXc 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R2及びR3置換基は、任意選択で連結して、置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
R4は、独立的に、水素、ハロゲン、−CXd 3、−CN、−SO2Cl、−SOn4R22、−SOv4NR19R20、−NHNH2、−ONR19R20、−NHC=(O)NHNH2、−NHC=(O)NR19R20、−N(O)m4、−NR19R20、−C(O)R21、−C(O)−OR21、−C(O)NR19R20、−OR22、−NR19SO2R22、−NR19C=(O)R21、−NR19C(O)−OR21、−NR19OR21、−OCXd 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、及びR22は、独立的に、水素、ハロゲン、−CX3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCX3、−OCHX2、−CF3、−OCF3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、同じ窒素原子に結合したR11及びR12置換基は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキルまたは置換もしくは非置換ヘテロアリールを形成してもよく、同じ窒素原子に結合したR15及びR16置換基は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキルまたは置換もしくは非置換ヘテロアリールを形成してもよく、同じ窒素原子に結合したR19及びR20置換基は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
nは0〜5の整数であり、
m1、m2、m3、m4、v1、v2、v3、及びv4は独立的に1または2であり、
n1、n2、n3、及びn4は独立的に0〜4の整数であり、
X、Xa、Xb、Xc、及びXdは独立的に−Cl、−Br、−I、または−Fである)
37:153−159.97.Brunner N,et al.(1993).Eur.J.Cancer 29A:562−569.98.Wu X,J et al.(2009).Cancer Res 69:1722−7.99.Dubik D,et al.(1987).Cancer Res.47,6517−6521.100.Navarro F,et al.(2003).Fertility Sterility 79:1409−1415.101.Greb R,O.et al.(1997).Hum Reprod 12:1280−1292.102.Wu W,et al.(2007).Mol Cancer Therap 6:471−483.103.Li D,et al.(2002).Oncogene.21:2805−14.104.Pegram M,et al.(2004).J Natl Cancer Inst 96:739−49.105.Pietras RJ,Szego CM(1977).Nature 265:69−72.106.Pietras R,et al.(1998).Oncogene 17:2235−49.107.Chou T,Talalay P(1984).Adv Enzyme Regul.22:27−55.108.Pegram,M.,et al.(1999).Oncogene,18:2241−2251.109.Verrier F,et al.(2001).J Virol 75:9177−9186.110.Chou TC(2002).J Virol 76:10577;author reply:10578.111.Geyer CE,et al.(2006) N Engl J Med 355:2733−2743.112.Osborne C,et al.(1995).J Natl Cancer Inst 87:746−60.113.Mah V,et al.(2007).Cancer Res 67:10484−90.114.Kobayashi N,et al.(2008).Cancer Res 68:3066−73.115.Reckamp K,et al.(2008).J Thorac Oncol 3:117−24.116.Detre S,et al.(2003).Cancer Res 63:6516−22.1.Ma C,et al.(2009).Oncology 23:133−142.2.Hurvitz S,Pietras R(2008).Cancer 113:2385−97.3.Early Breast Cancer Trialists’ Collaborative Group(1998).Lancet 351:1451−67.4.McGuire WL,Clark G(1992).N.Engl.J.Med.,326:1756−1762.5.Ali S,Coombes R(2002).Nature Rev Cancer 21:101−113.6.Prat A,Baselga J(2008).Nat Clin Pract Oncol 5:531−542.7.Hoffmann J,et al.(2004).J Natl Cancer Inst 96:210−218.8.O’Brien J,et al.(2006).J Biol Chem 281:26683−92.9.Pietras RJ,et al.(2007).Clin Cancer Res 13:4672−4676.10.Syed F,et al.(2007).Endocrinology 148:1902−10.11.Massarweh S,et al.(2008).Cancer Res 68:826−33.12.Lipton A et al.(2003) J Clin Oncol 21:1967−1972.13.Ellis MJ et al.(2006) J Clin Oncol 24:3019−3025.14.Pietras,R,et al.(1995).Oncogene 10:2435−2446.15.Marquez DC,Pietras RJ(2001).Oncogene 20:5420−30.16.Marquez DC,et al.(2006).Mol Cell Endocrinol.246:91−100.17.Mintz P,et al.(2008).Cancer 113:1489−1495.18.Madak−Erdogan Z,et al.(2008).Mol Endocrinol 22:2116−2127.19.Hammes S,Levin E(2007).Endocr Rev 28:726−41.20.Weinberg O,et al.(2005).Drug Resistance Updates 8:219−233.21.Early Breast Cancer Trialists’ Collaborative Group(2005).Lancet 365:1687−1717.22.Dowsett M,et al.(2005).Breast Cancer Res Treat.93 Suppl 1:S11−18.23.The Breast International Group 1−98 Collaborative Group(2005).N Engl J Med 353:2747−2757.24.ATAC Trialists’ Group(2005).Lancet 365:60−62.25.Wakeling AE,et al.(1991).Cancer Res 51:3867−73.26.Wakeling A,et al.(2001).Clin.Cancer Res.7:4350s−4355s.27.Wijayaratne,A.L.and McDonnell,D.P.(2001) J.Biol.Chem.276,35684−356892 28.Robertson J,et al.(2009).J Clin Oncol 27:4530−5.29.Osborne CK,et al.(2002) J Clin Oncol 20:3386−3395.30.Haas A,Siepmann T(1997).FASEB J.11,1257−1268.31.Lange,C.A.,et al.(2000).Proc.Natl Acad.Sci.97,1032−1037.32.Alarid,E.T.,et al.(1999).Mol.Endocrinol.13,1522−1534.33.Nawaz,Z.,et al.(1999) Proc.Natl Acad.Sci.USA 96:1858−1862.34.Wang Y,et al.(2009).J.Biochem.145:331−343.35.Kim TK,Maniatis T(1996).Science 273,1717−1719.36.Ring A,Dowsett M(2004) Endocr Relat Cancer 11:643−658.37.Pike AC,et al.2001 Structure(Camb) 9:145−153.38.Dauvois S,et al.(1992).Proc.Natl.Acad.Sci.U.S.A.89:4037−4041.39.Clemons MJ,et al.(2014).Breast Cancer Res Treat.146:153−62.40.Di Leo A,et al.(2014).J Natl Cancer Inst.106 337−44.41.Robertson JF,et al.(2012).Breast Cancer Res Treat.136:503−11.42.Estevez L,et al.(2013).Cancer Treat Rev.39:136−41.43.Di Leo A,et al.(2010).J Clin Oncol 28:4594−600.44.Pietras RJ,et al.(2005).Steroids,70:372−81.45.Shah KN,Faridi,JS(2011).J Steroid Biochem Mol Biol 125:219−225.46.Robertson JFR GE,et al.(2004).Breast Cancer Res Treat 88:S236−S7.47.Wakeling AE,et al.(1991).Cancer Res 51:3867−73.48.Michel van Kruchten,et al.(2014).Proc American Assoc Clin Oncol Annual Meeting:588.1) Laszlo Kurti,et al..Org.Lett.,2008,10,5247−5250.2) Chongsoo Lim,et al.Tetrahedron Lett.,2006,47,6417−6420.3) David C.Labaree,et al.J.Med.Chem.2003,46,1886−1904.1.At website:www.cancer.org/research/ cancerfactsstatistics/ cancerfactsfigures2014/index(estimate of the American Cancer Society for 2014).2.D.J.Kojetin,et al.Endocrine−Related Cancer 2008,15,851−870.A.K.Shiau,et al.Cell,1998,95,927−937.3.D.C.Labaree,et al.Med.Chem.2003,46,1886−1904.R.Tedesco,et al.J.Org.Chem.1995,60,5316−5318.4.Nose,A.;Kudo,T.Chem.Pharm.Bull.1988,36,1529−1533.Osby,J.O.;Ganem,B.Tetrahedron Lett.1985,26,6413−6416.
1.The Coronary Drug Project.Findings leading to discontinuation of the 2.5−mg day estrogen group.The coronary Drug Project Research Group.JAMA.1973 Nov 5;226(6):652−7.PubMed PMID:4356847;2.Patrone C,Cassel TN,Pettersson K,Piao YS,Cheng G,Ciana P,Maggi A,Warner M,Gustafsson JA,Nord M.Regulation of postnatal lung development and homeostasis by estrogen receptor beta.Mol Cell Biol.2003 Dec;23(23):8542−52.PubMed PMID:14612399;PubMed Central PMCID:PMC262653;3.Olivo−Marston SE,Mechanic LE,Mollerup S,Bowman ED,Remaley AT,Forman MR,Skaug V,Zheng YL,Haugen A,Harris CC.Serum estrogen and tumor−positive estrogen receptor−alpha are strong prognostic classifiers of non−small−cell lung cancer survival in both men and women.Carcinogenesis.2010 Oct;31(10):1778−86.doi:10.1093/carcin/bgq156.Epub 2010 Aug 20.PubMed PMID:20729390;PubMed Central PMCID:PMC2981456;4.Kazmi N,Marquez−Garban DC,Aivazyan L,Hamilton N,Garon EB,Goodglick L,Pietras RJ.The role of estrogen,progesterone and aromatase in human non−small−cell lung cancer.Lung Cancer Manag.2012 Dec;1(4):259−272.PubMed PMID:23650476;PubMed Central PMCID:PMC3643508;5.Garon EB,Pietras RJ,Finn RS,Kamranpour N,Pitts S,Marquez−Garban DC,Desai AJ,Dering J,Hosmer W,von Euw EM,Dubinett SM,Slamon DJ.Antiestrogen fulvestrant enhances the antiproliferative effects of epidermal growth factor receptor inhibitors in human non−small−cell lung cancer.J Thorac Oncol.2013 Mar;8(3):270−8.doi:10.1097/JTO.0b013e31827d525c.PubMed PMID:23399957;PubMed Central PMCID:PMC3573351;6.Marquez−Garban DC,Mah V,Alavi M,Maresh EL,Chen HW,Bagryanova L,Horvath S,Chia D,Garon E,Goodglick L,Pietras RJ.Progesterone and estrogen receptor expression and activity in human non−small cell lung cancer.Steroids.2011 Aug;76(9):910−20.doi:10.1016/j.steroids.2011.04.015.Epub 2011 May 8.PubMed PMID:21600232;PubMed Central PMCID:PMC3129425;7.Mah V,Marquez D,Alavi M,Maresh EL,Zhang L,Yoon N,Horvath S,Bagryanova L,Fishbein MC,Chia D,Pietras R,Goodglick L.Expression levels of estrogen receptor beta in conjunction with aromatase predict survival in non−small cell lung cancer.Lung Cancer.2011 Nov;74(2):318−25.doi:10.1016/j.lungcan.2011.03.009.Epub 2011 Apr 20.PubMed PMID:21511357;PubMed Central PMCID:PMC3175023;8.Marquez−Garban DC,Chen HW,Goodglick L,Fishbein MC,Pietras RJ.Targeting aromatase and estrogen signaling in human non−small cell lung cancer.Ann N Y Acad Sci.2009 Feb;1155:194−205.doi:10.1111/j.1749−6632.2009.04116.x.PubMed PMID:19250205;PubMed Central PMCID:PMC2782616;9.Mah V,Seligson DB,Li A,Marquez DC,Wistuba II,Elshimali Y,Fishbein MC,Chia D,Pietras RJ,Goodglick L.Aromatase expression predicts survival in women with early−stage non small cell lung cancer.Cancer Res.2007 Nov 1;67(21):10484−90.PubMed PMID:17974992;PubMed Central PMCID:PMC3581354;10.Marquez−Garban DC,Chen HW,Fishbein MC,Goodglick L,Pietras RJ.Estrogen receptor signaling pathways in human non−small cell lung cancer.Steroids.2007 Feb;72(2):135−43.Epub 2007 Feb 5.PubMed PMID:17276470;11.Weinberg OK,Marquez−Garban DC,Fishbein MC,Goodglick L,Garban HJ,Dubinett SM,Pietras RJ.Aromatase inhibitors in human lung cancer therapy.Cancer Res.2005 Dec 15;65(24):11287−91.PubMed PMID:16357134;12.Pietras RJ,Marquez DC,Chen HW,Tsai E,Weinberg O,Fishbein M.Estrogen and growth factor receptor interactions in human breast and non−small cell lung cancer cells.Steroids.2005 May−Jun;70(5−7):372−81.Epub 2005 Mar 25.PubMed PMID:15862820;13.Siegfried JM,Lin Y,Diergaarde B,Lin HM,Dacic S,Pennathur A,Weissfeld JL,Romkes M,Nukui T,Stabile LP.Expression of PAM50 Genes in Lung Cancer:Evidence that Interactions between Hormone Receptors and HER2/HER3 Contribute to Poor Outcome.Neoplasia.2015 Nov;17(11):817−25.doi:10.1016/j.neo.2015.11.002.PubMed PMID:26678909;PubMed Central PMCID:PMC4681883;14.Siegfried JM,Stabile LP.Estrongenic steroid hormones in lung cancer.Semin Oncol.2014 Feb;41(1):5−16.doi:10.1053/j.seminoncol.2013.12.009.Epub 2013 Dec 12.Review.PubMed PMID:24565577;PubMed Central PMCID:PMC4001725;15.Stabile LP,Dacic S,Land SR,Lenzner DE,Dhir R,Acquafondata M,Landreneau RJ,Grandis JR,Siegfried JM.Combined analysis of estrogen receptor beta−1 and progesterone receptor expression identifies lung cancer patients with poor outcome.Clin Cancer Res.2011 Jan 1;17(1):154−64.doi:10.1158/1078−0432.CCR−10−0992.Epub 2010 Nov 9.PubMed PMID:21062926;PubMed Central PMCID:PMC3064257;16.Hershberger PA,Stabile LP,Kanterewicz B,Rothstein ME,Gubish CT,Land S,Shuai Y,Siegfried JM,Nichols M.Estrogen receptor beta(ERbeta) subtype−specific ligands increase transcription,p44/p42 mitogen activated protein kinase(MAPK) activation and growth in human non−small cell lung cancer cells.J Steroid Biochem Mol Biol.2009 Aug;116(1−2):102−9.doi:10.1016/j.jsbmb.2009.05.004.Epub 2009 May 19.PubMed PMID:19460433;PubMed Central PMCID:PMC2722836;17.Stabile LP,Lyker JS,Gubish CT,Zhang W,Grandis JR,Siegfried JM.Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non−small cell lung cancer shows enhanced antiproliferative effects.Cancer Res.2005 Feb 15;65(4):1459−70.PubMed PMID:15735034;18.Stabile LP,Davis A
L,Gubish CT,Hopkins TM,Luketich JD,Christie N,Finkelstein S,Siegfried JM.Human non−small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen.Cancer Res.2002 Apr 1;62(7):2141−50.PubMed PMID:11929836;19.Finn RS,Aleshin A,Slamon DJ.Targeting the cyclin−dependent kinases(CDK) 4/6 in estrogen receptor−positive breast cancers.Breast Cancer Res.2016 Feb 9;18(1):17.doi:10.1186/s13058−015−0661−5.PubMed PMID:26857361;PubMed Central PMCID:PMC4746893;20.Finn RS,Dering J,Conklin D,Kalous O,Cohen DJ,Desai AJ,Ginther C,Atefi M,Chen I,Fowst C,Los G,Slamon DJ.PD 0332991,a selective cyclin D kinase 4/6 inhibitor,preferentially inhibits proliferation of luminal estrogen receptor−positive human breast cancer cell lines in vitro.Breast Cancer Res.2009;11(5):R77.doi:10.1186/bcr2419.PubMed PMID:19874578;PubMed Central PMCID:PMC2790859;21.Goldman JW,Shi P,Reck M,Paz−Ares L,Koustenis A,Hurt KC.Treatment Rationale and Study Design for the JUNIPER Study:A Randomized Phase III Study of Abemaciclib With Best Supportive Care Versus Erlotinib With Best Supportive Care in Patients With Stage IV Non−Small−Cell Lung Cancer With a Detectable KRAS Mutation Whose Disease Has Progressed After Platinum−Based Chemotherapy.Clin Lung Cancer.2016 Jan;17(1):80−4.doi:10.1016/j.cllc.2015.08.003.Epub 2015 Aug 18.PubMed PMID:26432508;22.Vidula N,Rugo HS.Cyclin−Dependent Kinase 4/6 Inhibitors for the Treatment of Breast Cancer:A Review of Preclinical and Clinical Data.Clin Breast Cancer.2016 Feb;16(1):8−17.doi:10.1016/j.clbc.2015.07.005.Epub 2015 Jul 26.Review.PubMed PMID:26303211;23.Chazin VR,Kaleko M,Miller AD,Slamon DJ.Transformation mediated by the human HER−2 gene independent of the epidermal growth factor receptor.Oncogene.1992 Sep;7(9):1859−66.PubMed PMID:1354348;24.Marquez DC,Chen HW,Curran EM,Welshons WV,Pietras RJ.Estrogen receptors in membrane lipid rafts and signal transduction in breast cancer.Molecular and cellular endocrinology.2006 Feb 26;246(1−2):91−100.PubMed PMID:16388889;25.Marquez−Garban DC,Chen HW,Fishbein MC,Goodglick L,Pietras RJ.Estrogen receptor signaling pathways in human non−small cell lung cancer.Steroids.2007 Feb;72(2):135−43.PubMed PMID:17276470;26.Lai A,Kahraman M,Govek S,Nagasawa J,Bonnefous C,Julien J,et al.Identification of GDC−0810(ARN−810),an Orally Bioavailable Selective Estrogen Receptor Degrader(SERD) that Demonstrates Robust Activity in Tamoxifen−Resistant Breast Cancer Xenografts.Journal of medicinal chemistry.2015 Jun 25;58(12):4888−904.PubMed PMID:25879485;27.Schroder AL,Pelch KE,Nagel SC.Estrogen modulates expression of putative housekeeping genes in the mouse uterus.Endocrine.2009 Apr;35(2):211−9.PubMed PMID:19219570
Claims (20)
- 過剰増殖性障害を処置するための医薬の製造における、CDK4/6阻害物質及び式(I)の化合物またはその医薬的に許容される塩の使用であって、
前記式(I)の化合物が、
R1は、独立的に、水素、ハロゲン、−NR2R3、−CXa 3、−CN、−SO2Cl、−SOn1R10、−SOv1NR2R3、−NHNR2R3、−ONR2R3、−NHC(O)NHNR2R3、−NHC(O)NR2R3、−N(O)m1、−C(O)R9、−C(O)−OR9、−C(O)NR2R3、−OR10、−NR2SO2R10、−NR2C(O)R9、−NR2C(O)−OR9、−NR2OR9、−OCXa 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
Lは、独立的に、結合、−NR4−、−NR4C(O)−、−C(O)NR4−、−O−、−S−、−C(O)−、−S(O)−、−S(O)2−、置換もしくは非置換アルキレン、置換もしくは非置換ヘテロアルキレン、置換もしくは非置換シクロアルキレン、置換もしくは非置換ヘテロシクロアルキレン、置換もしくは非置換アリーレン、置換もしくは非置換ヘテロアリーレン、または置換もしくは非置換スピロ環式リンカーであり、
R2は、独立的に、水素、ハロゲン、−CXb 3、−CN、−SO2Cl、−SOn2R14、−SOv2NR11R12、−NHNH2、−ONR11R12、−NHC(O)NHNH2、−NHC(O)NR11R12、−N(O)m2、−NR11R12、−C(O)R13、−C(O)−OR13、−C(O)NR11R12、−OR14、−NR11SO2R14、−NR11C(O)R13、−NR11C(O)−OR13、−NR11OR13、−OCXb 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R3は、独立的に、水素、ハロゲン、−CXc 3、−CN、−SO2Cl、−SOn3R18、−SOv3NR15R16、−NHNH2、−ONR15R16、−NHC(O)NHNH2、−NHC(O)NR15R16、−N(O)m3、−NR15R16、−C(O)R17、−C(O)−OR17、−C(O)NR15R16、−OR18、−NR15SO2R18、−NR15C(O)R17、−NR15C(O)−OR17、−NR15OR17、−OCXc 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R2及びR3は任意選択で連結して、置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
R4は、独立的に、水素、ハロゲン、−CXd 3、−CN、−SO2Cl、−SOn4R22、−SOv4NR19R20、−NHNH2、−ONR19R20、−NHC(O)NHNH2、−NHC(O)NR19R20、−N(O)m4、−NR19R20、−C(O)R21、−C(O)−OR21、−C(O)NR19R20、−OR22、−NR19SO2R22、−NR19C(O)R21、−NR19C(O)−OR21、−NR19OR21、−OCXd 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、及びR22は、独立的に、水素、ハロゲン、−CX3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC(O)NHNH2、−NHC(O)NH2、−NHSO2H、−NHC(O)H、−NHC(O)−OH、−NHOH、−OCX3、−OCHX2、−CF3、−OCF3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
同じ窒素原子に結合したR11及びR12は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキルまたは置換もしくは非置換ヘテロアリールを形成してもよく、
同じ窒素原子に結合したR15及びR16は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキルまたは置換もしくは非置換ヘテロアリールを形成してもよく、
同じ窒素原子に結合したR19及びR20は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
nは0〜5の整数であり、
m1、m2、m3、m4、v1、v2、v3、及びv4は独立的に1または2であり、
n1、n2、n3、及びn4は独立的に0〜4の整数であり、および
X、Xa、Xb、Xc、及びXdは独立的に−Cl、−Br、−I、または−Fである)
の化合物である、使用。 - 前記過剰増殖性障害が、リンパ管平滑筋腫症またはがんである、請求項1に記載の使用。
- 前記過剰増殖性障害が、乳がん、肺がん、婦人科系がん、卵巣がん、子宮内膜がん、または前立腺がんである、請求項1に記載の使用。
- 前記過剰増殖性障害が、ER陽性乳がん、ER陰性乳がん、ホルモン感受性乳がん、ホルモン非感受性乳がん、トリプルネガティブ乳がん、HER−2陽性乳がん、転移性乳がん、またはそれらの2つ以上の組み合わせである、請求項1に記載の使用。
- 前記過剰増殖性障害が、エストロゲン受容体活性に関連する、請求項1〜4のいずれか1項に記載の使用。
- 前記CDK4/6阻害物質が、パルボシクリブ、リボシクリブ、アベマシクリブ、セリシクリブ、フラボピリドール、[4−アミノ−2−(1−メタンスルホニルピペリジン−4−イルアミノ)ピリミジン−5−イル](2,3−ジフルオロ−6−メトキシフェニル)メタノン、リビシクリブ(riviciclib)、ミルシクリブ、(Z)−1,3−ジヒドロ−3−(1H−イミダゾール−4−イルメチレン)−5−メトキシ−2H−インドール−2−オン、(4−ブトキシ−1H−ピラゾロ[3,4−b]ピリジン−5−イル)(2,6−ジフルオロ−4−メチルフェニル)−メタノン、3−[[6−(2−メトキシフェニル)−4−ピリミジニル]アミノ]ベンゼンメタンスルホンアミド、トランス−4−[[6−(エチルアミノ)−2−[[1−(フェニルメチル)−1H−インドール−5−イル]アミノ]−4−ピリミジニル]アミノ]−シクロヘキサノール、2−ブロモ−12,13−ジヒドロ−5H−インドロ[2,3−a]ピロロ[3,4−c]カルバゾール−5,7(6H)−ジオン、1,4−ジメトキシアクリジン−9(10H)−チオン、4−(((4−ヒドロキシ−5−プロポキシ−ピリジン−2−イルメチル)−アミノ)−メチレン)−6−ヨード−4H−イソキノリン−1,3−ジオン、リュビジン(Ryuvidine)、ファスカプリシン、4−[5−クロロ−3−(1−メチルエチル)−1H−ピラゾール−4−イル]−N−[5−[4−(ジメチルアミノ)−1−ピペリジニル]−2−ピリジニル]−2−ピリミジンアミン、2−ヒドロキシ−1−[2−[[9−(4−メチルシクロヘキシル)ピリド[4,5]ピロロ[1,2−d]ピリミジン−2−イル]アミノ]−7,8−ジヒドロ−5H−1、6−ナフチリジン−6−イル]エテノン、5−[4−[[(5−メチル−2−フラニル)メチル]アミノ]−6−キナゾリニル]−2−フランメタノール、4−(2,6−ジクロロベンズアミド)−N−(ピペリジン−4−イル)−1H−ピラゾール−3−カルボキサミド、プルバラノールB、スタウロスポリン、または9,10,11,12−テトラヒドロ−9,12−エポキシ−1H−ジインドロ[1,2,3−fg:3’、2’、1’−kl]ピロロ[3,4−i][1、6]ベンゾジアゾシン−1,3(2H)−ジオンである、請求項1〜5のいずれか1項に記載の使用。
- 式(I)の化合物が、式(Ia):
R5は、独立的に、水素、ハロゲン、−CXe 3、−CN、−SO2Cl、−SOn5R26、−SOv5NR23R24、−NHNH2、−ONR23R24、−NHC(O)NHNH2、−NHC(O)NR23R24、−N(O)m5、−NR23R24、−C(O)R25、
−C(O)−OR25、−C(O)NR23R24、−OR26、−NR23SO2R26、−NR23C(O)R25、−NR23C(O)−OR25、−NR23OR25、−OCXe 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R23、R24、R25、及びR26は、独立的に、水素、ハロゲン、−CX3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC(O)NHNH2、−NHC(O)NH2、−NHSO2H、−NHC(O)H、−NHC(O)−OH、−NHOH、−OCX3、−OCHX2、−CF3、−OCF3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
同じ窒素原子に結合したR23及びR24は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
m5及びv5は独立的に1または2であり、
n5は独立的に0〜4の整数であり、
Xeは独立的に−Cl、−Br、−I、または−Fである)
の化合物またはその医薬的に許容される塩である、請求項1〜6のいずれか1項に記載の使用。 - 式(I)の化合物が、式(IIa):
R5は、独立的に、水素、ハロゲン、−CXe 3、−CN、−SO2Cl、−SOn5R26、−SOv5NR23R24、−NHNH2、−ONR23R24、−NHC(O)NHNH2、−NHC(O)NR23R24、−N(O)m5、−NR23R24、−C(O)R25、−C(O)−OR25、−C(O)NR23R24、−OR26、−NR23SO2R26、−NR23C(O)R25、−NR23C(O)−OR25、−NR23OR25、−OCXe 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R23、R24、R25、及びR26は、独立的に、水素、ハロゲン、−CX3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC(O)NHNH2、−NHC(O)NH2、−NHSO2H、−NHC(O)H、−NHC(O)−OH、−NHOH、−OCX3、−OCHX2、−CF3、−OCF3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
同じ窒素原子に結合したR23及びR24は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
m5及びv5は独立的に1または2であり、
n5は独立的に0〜4の整数であり、
Xeは独立的に−Cl、−Br、−I、または−Fである)
の化合物またはその医薬的に許容される塩である、請求項1〜6のいずれか1項に記載の使用。 - R5が独立的に、水素、ハロゲン、−CXe 3、または非置換アルキルである、請求項1〜8のいずれか1項に記載の使用。
- R5が独立的に、水素、−F、−CF3、または非置換メチルである、請求項9に記載の使用。
- Lが独立的に、結合または2〜8員ヘテロアルキレンである、請求項1〜10のいずれか1項に記載の使用。
- Lが独立に、結合、−NH−(置換または非置換(C1−C4)アルキレン)、または−NHC(O)−(置換または非置換(C1−C4)アルキレン)である、請求項11に記載の使用。
- R2が独立的に、ハロゲン、置換もしくは非置換(C1−C10)アルキル、または置換もしくは非置換2〜10員ヘテロアルキルである、請求項1〜12に記載の使用。
- R3が、水素、または独立に、ハロゲン、置換もしくは非置換(C1−C10)アルキル、もしくは置換もしくは非置換2〜10員ヘテロアルキルである、請求項1〜13に記載の使用。
- R2及びR3が連結して、非置換の3〜6員ヘテロシクロアルキルを形成する、請求項1〜12のいずれか1項に記載の使用。
- nが1または2である、請求項1〜15のいずれか1項に記載の使用。
- (i)CDK4/6阻害物質、及び
(ii)式(I)の化合物またはその医薬的に許容される塩
を含む医薬組成物であって、
前記式(I)の化合物が、
R1は、独立的に、水素、ハロゲン、−NR2R3、−CXa 3、−CN、−SO2Cl、−SOn1R10、−SOv1NR2R3、−NHNR2R3、−ONR2R3、−NHC(O)NHNR2R3、−NHC(O)NR2R3、−N(O)m1、−C(O)R9、−C(O)−OR9、−C(O)NR2R3、−OR10、−NR2SO2R10、−NR2C(O)R9、−NR2C(O)−OR9、−NR2OR9、−OCXa 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
Lは、独立的に、結合、−NR4−、−NR4C(O)−、−C(O)NR4−、−O−、−S−、−C(O)−、−S(O)−、−S(O)2−、置換もしくは非置換アルキレン、置換もしくは非置換ヘテロアルキレン、置換もしくは非置換シクロアルキレン、置換もしくは非置換ヘテロシクロアルキレン、置換もしくは非置換アリーレン、置換もしくは非置換ヘテロアリーレン、または置換もしくは非置換スピロ環式リンカーであり、
R2は、独立的に、水素、ハロゲン、−CXb 3、−CN、−SO2Cl、−SOn2R14、−SOv2NR11R12、−NHNH2、−ONR11R12、−NHC(O)NHNH2、−NHC(O)NR11R12、−N(O)m2、−NR11R12、−C(O)R13、−C(O)−OR13、−C(O)NR11R12、−OR14、−NR11SO2R14、−NR11C(O)R13、−NR11C(O)−OR13、−NR11OR13、−OCXb 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R3は、独立的に、水素、ハロゲン、−CXc 3、−CN、−SO2Cl、−SOn3R18、−SOv3NR15R16、−NHNH2、−ONR15R16、−NHC(O)NHNH2、−NHC(O)NR15R16、−N(O)m3、−NR15R16、−C(O)R17、−C(O)−OR17、−C(O)NR15R16、−OR18、−NR15SO2R18、−NR15C(O)R17、−NR15C(O)−OR17、−NR15OR17、−OCXc 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R2及びR3置換基は、任意選択で連結して、置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
R4は、独立的に、水素、ハロゲン、−CXd 3、−CN、−SO2Cl、−SOn4R22、−SOv4NR19R20、−NHNH2、−ONR19R20、−NHC(O)NHNH2、−NHC(O)NR19R20、−N(O)m4、−NR19R20、−C(O)R21、−C(O)−OR21、−C(O)NR19R20、−OR22、−NR19SO2R22、−NR19C(O)R21、−NR19C(O)−OR21、−NR19OR21、−OCXd 3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、及びR22は、独立的に、水素、ハロゲン、−CX3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC(O)NHNH2、−NHC(O)NH2、−NHSO2H、−NHC(O)H、−NHC(O)−OH、−NHOH、−OCX3、−OCHX2、−CF3、−OCF3、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、
同じ窒素原子に結合したR11及びR12は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキルまたは置換もしくは非置換ヘテロアリールを形成してもよく、
同じ窒素原子に結合したR15及びR16は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキルまたは置換もしくは非置換ヘテロアリールを形成してもよく、
同じ窒素原子に結合したR19及びR20は、任意選択で連結して置換もしくは非置換ヘテロシクロアルキル、または置換もしくは非置換ヘテロアリールを形成してもよく、
nは0〜5の整数であり、
m1、m2、m3、m4、v1、v2、v3、及びv4は独立的に1または2であり、
n1、n2、n3、及びn4は独立的に0〜4の整数であり、及び
X、Xa、Xb、Xc、及びXdは独立的に−Cl、−Br、−I、または−Fである)
の化合物である、医薬組成物。 - 前記CDK4/6阻害物質が、パルボシクリブ、リボシクリブ、アベマシクリブ、セリシクリブ、フラボピリドール、[4−アミノ−2−(1−メタンスルホニルピペリジン−4−イルアミノ)ピリミジン−5−イル](2,3−ジフルオロ−6−メトキシフェニル)メタノン、リビシクリブ(riviciclib)、ミルシクリブ、(Z)−1,3−ジヒドロ−3−(1H−イミダゾール−4−イルメチレン)−5−メトキシ−2H−インドール−2−オン、(4−ブトキシ−1H−ピラゾロ[3,4−b]ピリジン−5−イル)(2,6−ジフルオロ−4−メチルフェニル)−メタノン、3−[[6−(2−メトキシフェニル)−4−ピリミジニル]アミノ]ベンゼンメタンスルホンアミド、トランス−4−[[6−(エチルアミノ)−2−[[1−(フェニルメチル)−1H−インドール−5−イル]アミノ]−4−ピリミジニル]アミノ]−シクロヘキサノール、2−ブロモ−12,13−ジヒドロ−5H−インドロ[2,3−a]ピロロ[3,4−c]カルバゾール−5,7(6H)−ジオン、1,4−ジメトキシアクリジン−9(10H)−チオン、4−(((4−ヒドロキシ−5−プロポキシ−ピリジン−2−イルメチル)−アミノ)−メチレン)−6−ヨード−4H−イソキノリン−1,3−ジオン、リュビジン(Ryuvidine)、ファスカプリシン、4−[5−クロロ−3−(1−メチルエチル)−1H−ピラゾール−4−イル]−N−[5−[4−(ジメチルアミノ)−1−ピペリジニル]−2−ピリジニル]−2−ピリミジンアミン、2−ヒドロキシ−1−[2−[[9−(4−メチルシクロヘキシル)ピリド[4,5]ピロロ[1,2−d]ピリミジン−2−イル]アミノ]−7,8−ジヒドロ−5H−1、6−ナフチリジン−6−イル]エテノン、5−[4−[[(5−メチル−2−フラニル)メチル]アミノ]−6−キナゾリニル]−2−フランメタノール、4−(2,6−ジクロロベンズアミド)−N−(ピペリジン−4−イル)−1H−ピラゾール−3−カルボキサミド、プルバラノールB、スタウロスポリン、または9,10,11,12−テトラヒドロ−9,12−エポキシ−1H−ジインドロ[1,2,3−fg:3’、2’、1’−kl]ピロロ[3,4−i][1、6]ベンゾジアゾシン−1,3(2H)−ジオンである、請求項18に記載の組成物。
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US4911920A (en) | 1986-07-30 | 1990-03-27 | Alcon Laboratories, Inc. | Sustained release, comfort formulation for glaucoma therapy |
FR2588189B1 (fr) | 1985-10-03 | 1988-12-02 | Merck Sharp & Dohme | Composition pharmaceutique de type a transition de phase liquide-gel |
JP2594486B2 (ja) | 1991-01-15 | 1997-03-26 | アルコン ラボラトリーズ インコーポレイテッド | 局所的眼薬組成物 |
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US5679788A (en) | 1993-06-17 | 1997-10-21 | Roussel Uclaf | 11 beta-substituted-19 nor-steroids |
US7528123B1 (en) | 1998-11-20 | 2009-05-05 | N.V. Organon | Estrogenic estra-1,3,5(10)-trienes with differential effects on the alpha and beta estrogen receptors, having a linear hydrocarbon chain of from 5-9 carbon atoms in position 11 |
US9315539B2 (en) | 2002-10-01 | 2016-04-19 | Yale University | 11 beta-short chain substituted estradiol analogs and their use in the treatment of menopausal symptoms and estrogen sensitive cancer |
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