JP6215832B2 - アミノピリミジンキナーゼ阻害剤 - Google Patents
アミノピリミジンキナーゼ阻害剤 Download PDFInfo
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- JP6215832B2 JP6215832B2 JP2014539984A JP2014539984A JP6215832B2 JP 6215832 B2 JP6215832 B2 JP 6215832B2 JP 2014539984 A JP2014539984 A JP 2014539984A JP 2014539984 A JP2014539984 A JP 2014539984A JP 6215832 B2 JP6215832 B2 JP 6215832B2
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- alkyl
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- heteroaryl
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 235000021081 unsaturated fats Nutrition 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 125000005863 α-amino(C1-C4)alkanoyl group Chemical group 0.000 description 1
- 125000005853 β-dimethylaminoethyl group Chemical group 0.000 description 1
Classifications
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- 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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- A61K31/505—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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- A61K31/535—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
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- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Description
Xは、−N(R7)2、−N(R7)(R2)、または−N(H)−R3−R6であり;
R’は、H、メチル、(C2−C4)アルキル、またはベンジルであり;
R2は、H、−CH2OP(=O)(OH)2、−CH2O(P=O)(OR8)2、−(C=O)OCHR8O(C=O)CH3、または−(C=O)OCH2O(P=O)(OH)2であり;
R3は、−C(=NR)−または−(C(R)2)n−であり;
R5は、1,4−シクロヘキサンジイル、1,4−フェニレン、1,4−シクロヘプタンジイル、1,4−シクロオクタンジイル、1,5−シクロオクタンジイル、1,4−ビシクロ[2.2.1]ヘプタンジイル、1,4−ビシクロ[2.2.2]オクタンジイル、および1,5−ビシクロ[3.3.1]ノナンジイルからなる群から選択され;
R6は、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル、アリール、ヘテロアリール、アルコキシ、ヒドロキシ、ペルフルオロアルキル、トリフルオロメトキシおよびハロゲン化物からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;
R7は、H、−C(=NR)R、−(C(R)2)nR、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル、アリール、ヘテロアリール、アルコキシ、ヒドロキシ、ペルフルオロアルキル、トリフルオロメトキシおよびハロゲン化物からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;または
2つのR7 とそれらが結合している窒素とが一緒になって、−O−、−N(R)−および−S−からなる群より選択される1個の追加ヘテロ原子を必要に応じて環に含む、窒素含有ヘテロシクリルを指し;
R8は、H、アルキル、ベンジル、t−ブチル、アリール、またはヘテロアリールであり;
Rは、Hまたは(C1−C4)アルキルであり、
nは、1、2または3である。)
Xは、−N(R7)2、−N(R7)(R2)、または−N(H)−R3−R4であり;
R’は、H、メチル、(C2−C4)アルキル、またはベンジルであり;
R1は、1,4−シクロヘキサンジイルおよび1,4−フェニレンからなる群から選択され;
R2は、H、−CH2OP(=O)(OH)2、−CH2O(P=O)(OR8)2、−(C=O)OCHR8O(C=O)CH3、または−(C=O)OCH2O(P=O)(OH)2であり;
R3は、−C(=NR)−または−(C(R)2)n−であり;
R4は、アリールおよびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、ハロゲン化物、アルキル、ペルフルオロアルキル、アリール、ヘテロアリール、およびヘテロシクリルからなる群から選択され、任意のアリールまたはヘテロアリール置換基は、それ自体、場合により、ペルフルオロアルキルまたはジオキソランで置換され;
R7は、H、−C(=NR)R、−(C(R)2)nR、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル(ベンジルを含むがこれに限定されない)、アリール(フェニルを含むがこれに限定されない)、ヘテロアリール(ピリジル、イミダゾリル、チアゾリル、フリル、およびチオニルを含むがこれらに限定されない)、アルコキシ(メトキシを含むがこれに限定されない)、ヒドロキシ、ペルフルオロアルキル(トリフルオロメチルを含むがこれに限定されない)、トリフルオロメトキシ、ならびにハロゲン化物(フッ化物および塩化物を含むがこれらに限定されない)からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;または
2つのR7 とそれらが結合している窒素とが一緒になって、−O−、−N(R)−および−S−からなる群より選択される1個の追加ヘテロ原子を必要に応じて環に含む、窒素含有ヘテロシクリルを指し;
R8は、H、アルキル、ベンジル、t−ブチル、アリール、またはヘテロアリールであり;
Rは、Hまたは(C1−C4)アルキルであり、
nは、1、2または3である。)
R2は、H、−CH2OP(=O)(OH)2、−CH2O(P=O)(OR8)2、−(C=O)OCHR8O(C=O)CH3、または−(C=O)OCH2O(P=O)(OH)2であり;
R3は、−C(=NR)−または−(C(R)2)n−であり;
Rは、Hまたは(C1−C4)アルキルであり;
nは、1、2または3であり;
R6は、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル(ベンジルを含むがこれに限定されない)、アリール(フェニルを含むがこれに限定されない)、ヘテロアリール(ピリジル、イミダゾリル、チアゾリル、フリル、およびチオニルを含むがこれらに限定されない)、アルコキシ(メトキシを含むがこれに限定されない)、ヒドロキシ、ペルフルオロアルキル(トリフルオロメチルを含むがこれに限定されない)、トリフルオロメトキシ、ならびにハロゲン化物(フッ化物および塩化物を含むがこれらに限定されない)からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;
R8は、H、アルキル、ベンジル、t−ブチル、アリール、またはヘテロアリールである。)
R3は、−C(=NR)−または−(C(R)2)n−であり;
Rは、Hまたは(C1−C4)アルキルであり;
nは、1、2または3であり;
R4は、アリールおよびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、ハロゲン化物、アルキル、ペルフルオロアルキル、アリール、ヘテロアリール、およびヘテロシクリルからなる群から選択され、任意のアリールまたはヘテロアリール置換基は、それ自体、場合により、ペルフルオロアルキルまたはジオキソランで置換される。)
R’は、H、メチル、(C2−C4)アルキル、またはベンジルであり;
R2は、H、−CH2OP(=O)(OH)2、−CH2O(P=O)(OR8)2、−(C=O)OCHR8O(C=O)CH3、または−(C=O)OCH2O(P=O)(OH)2であり;
R3は、−C(=NR)−または−(C(R)2)n−であり;
Rは、Hまたは(C1−C4)アルキルであり、
nは、1、2または3であり;
R6は、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル(ベンジルを含むがこれに限定されない)、アリール(フェニルを含むがこれに限定されない)、ヘテロアリール(ピリジル、イミダゾリル、チアゾリル、フリル、およびチオニルを含むがこれらに限定されない)、アルコキシ(メトキシを含むがこれに限定されない)、ヒドロキシ、ペルフルオロアルキル(トリフルオロメチルを含むがこれに限定されない)、トリフルオロメトキシ、ならびにハロゲン化物(フッ化物および塩化物を含むがこれらに限定されない)からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;
R8は、H、アルキル、ベンジル、t−ブチル、アリール、またはヘテロアリールである。)
R’は、H、メチル、(C2−C4)アルキル、またはベンジルであり;
R2は、H、−CH2OP(=O)(OH)2、−CH2O(P=O)(OR8)2、−(C=O)OCHR8O(C=O)CH3、または−(C=O)OCH2O(P=O)(OH)2であり;
R3は、−C(=NR)−または−(C(R)2)n−であり;
Rは、Hまたは(C1−C4)アルキルであり、
nは、1、2または3であり;
R6は、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル(ベンジルを含むがこれに限定されない)、アリール(フェニルを含むがこれに限定されない)、ヘテロアリール(ピリジル、イミダゾリル、チアゾリル、フリル、およびチオニルを含むがこれらに限定されない)、アルコキシ(メトキシを含むがこれに限定されない)、ヒドロキシ、ペルフルオロアルキル(トリフルオロメチルを含むがこれに限定されない)、トリフルオロメトキシ、ならびにハロゲン化物(フッ化物および塩化物を含むがこれらに限定されない)からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;
R8は、H、アルキル、ベンジル、t−ブチル、アリール、またはヘテロアリールである。)
本明細書で使用する用語の定義は、化学分野および製薬分野で各用語について認められている現在の最先端技術の定義を包含することを意図する。適切な場合には、図を提供する。定義は、特に、個別にまたはより大きなグループの一部として特定の場合に限定されない限り、これらは、本明細書全体で使用するような用語に適用する。
R50、R51およびR52は、それらが、環構造中に4〜8個の原子を有する複素環と完全に結合しているN原子と共に、それぞれ独立して、水素、アルキル、アルケニル、−(CH2)m−R61、または−(CH2)m−R50および−(CH2)m−R51を表し;R61は、アリール、シクロアルキル、シクロアルケニル、複素環または多環を表し、mは0または1〜8個の範囲の整数である。他の実施形態において、R50およびR51(ならびに場合によりR52)は、それぞれ独立して、水素、アルキル、アルケニル、または−(CH2)m−R61を表す。したがって、「アルキルアミン」という用語は、それに結合した置換アルキルまたは非置換アルキルを有する、上記に定義されるアミン基を含み、すなわち、R50およびR51の少なくとも一方はアルキル基である。
本発明の態様は、カゼインキナーゼ1および/もしくはカゼインキナーゼ2ならびに/またはPIMキナーゼを阻害する化合物に関する。例えば、実施形態は、式1の化合物またはその薬学的に許容される塩に関する:
Xは、−N(R7)2、−N(R7)(R2)、または−N(H)−R3−R6であり;
R’は、H、メチル、(C2−C4)アルキル、またはベンジルであり;
R2は、H、−CH2OP(=O)(OH)2、−CH2O(P=O)(OR8)2、−(C=O)OCHR8O(C=O)CH3、または−(C=O)OCH2O(P=O)(OH)2であり;
R3は、−C(=NR)−または−(C(R)2)n−であり;
R5は、1,4−シクロヘキサンジイル、1,4−フェニレン、1,4−シクロヘプタンジイル、1,4−シクロオクタンジイル、1,5−シクロオクタンジイル、1,4−ビシクロ[2.2.1]ヘプタンジイル、1,4−ビシクロ[2.2.2]オクタンジイル、および1,5−ビシクロ[3.3.1]ノナンジイルからなる群から選択され;
R6は、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル(ベンジルを含むがこれに限定されない)、アリール(フェニルを含むがこれに限定されない)、ヘテロアリール(ピリジル、イミダゾリル、チアゾリル、フリル、およびチオニルを含むがこれらに限定されない)、アルコキシ(メトキシを含むがこれに限定されない)、ヒドロキシ、ペルフルオロアルキル(トリフルオロメチルを含むがこれに限定されない)、トリフルオロメトキシおよびハロゲン化物(フッ化物および塩化物を含むがこれらに限定されない)からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;
R7は、H、−C(=NR)R、−(C(R)2)nR、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル、アリール、ヘテロアリール、アルコキシ、ヒドロキシ、ペルフルオロアルキル、トリフルオロメトキシ、およびハロゲン化物からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;または
2つのR7 とそれらが結合している窒素とが一緒になって、−O−、−N(R)−および−S−からなる群より選択される1個の追加ヘテロ原子を必要に応じて環に含む、窒素含有ヘテロシクリルを表し;
R8は、H、アルキル、ベンジル、t−ブチル、アリール、またはヘテロアリールであり;
Rは、Hまたは(C1−C4)アルキルであり、
nは、1、2または3である。)
Xは、−N(R7)2、−N(R7)(R2)、または−N(H)−R3−R4であり;
R’は、H、メチル、(C2−C4)アルキル、またはベンジルであり;
R1は、1,4−シクロヘキサンジイルおよび1,4−フェニレンからなる群から選択され;
R2は、H、−CH2OP(=O)(OH)2、−CH2O(P=O)(OR8)2、−(C=O)OCHR8O(C=O)CH3、または−(C=O)OCH2O(P=O)(OH)2であり;
R3は、−C(=NR)−または−(C(R)2)n−であり;
R4は、アリールおよびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、ハロゲン化物、アルキル、ペルフルオロアルキル、アリール、ヘテロアリール、およびヘテロシクリルからなる群から選択され、任意のアリールまたはヘテロアリール置換基は、それ自体、場合により、ペルフルオロアルキルまたはジオキソランで置換され;
R7は、H、−C(=NR)R、−(C(R)2)nR、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル(ベンジルを含むがこれに限定されない)、アリール(フェニルを含むがこれに限定されない)、ヘテロアリール(ピリジル、イミダゾリル、チアゾリル、フリル、およびチオニルを含むがこれらに限定されない)、アルコキシ(メトキシを含むがこれに限定されない)、ヒドロキシ、ペルフルオロアルキル(トリフルオロメチルを含むがこれに限定されない)、トリフルオロメトキシ、ならびにハロゲン化物(フッ化物および塩化物を含むがこれらに限定されない)からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;または
2つのR7 とそれらが結合している窒素とが一緒になって、−O−、−N(R)−および−S−からなる群より選択される1個の追加ヘテロ原子を必要に応じて環に含む、窒素含有ヘテロシクリルを表し;
R8は、H、アルキル、ベンジル、t−ブチル、アリール、またはヘテロアリールであり;
Rは、Hまたは(C1−C4)アルキルであり、
nは、1、2または3である。)
R2は、H、−CH2OP(=O)(OH)2、−CH2O(P=O)(OR8)2、−(C=O)OCHR8O(C=O)CH3、または−(C=O)OCH2O(P=O)(OH)2であり;
R3は、−C(=NR)−または−(C(R)2)n−であり;
Rは、Hまたは(C1−C4)アルキルであり;
nは、1、2または3であり;
R6は、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル(ベンジルを含むがこれに限定されない)、アリール(フェニルを含むがこれに限定されない)、ヘテロアリール(ピリジル、イミダゾリル、チアゾリル、フリル、およびチオニルを含むがこれらに限定されない)、アルコキシ(メトキシを含むがこれに限定されない)、ヒドロキシ、ペルフルオロアルキル(トリフルオロメチルを含むがこれに限定されない)、トリフルオロメトキシ、ならびにハロゲン化物(フッ化物および塩化物を含むがこれらに限定されない)からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;
R8は、H、アルキル、ベンジル、t−ブチル、アリール、またはヘテロアリールである。)
R3は、−C(=NR)−または−(C(R)2)n−であり;
Rは、Hまたは(C1−C4)アルキルであり;
nは、1、2または3であり;
R4は、アリールおよびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、ハロゲン化物、アルキル、ペルフルオロアルキル、アリール、ヘテロアリール、およびヘテロシクリルからなる群から選択され、任意のアリールまたはヘテロアリール置換基は、それ自体、場合により、ペルフルオロアルキルまたはジオキソランで置換される。)
R’は、H、メチル、(C2−C4)アルキル、またはベンジルであり;
R2は、H、−CH2OP(=O)(OH)2、−CH2O(P=O)(OR8)2、−(C=O)OCHR8O(C=O)CH3、または−(C=O)OCH2O(P=O)(OH)2であり;
R3は、−C(=NR)−または−(C(R)2)n−であり;
Rは、Hまたは(C1−C4)アルキルであり、
nは、1、2または3であり;
R6は、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル(ベンジルを含むがこれに限定されない)、アリール(フェニルを含むがこれに限定されない)、ヘテロアリール(ピリジル、イミダゾリル、チアゾリル、フリル、およびチオニルを含むがこれらに限定されない)、アルコキシ(メトキシを含むがこれに限定されない)、ヒドロキシ、ペルフルオロアルキル(トリフルオロメチルを含むがこれに限定されない)、トリフルオロメトキシ、ならびにハロゲン化物(フッ化物および塩化物を含むがこれらに限定されない)からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;
R8は、H、アルキル、ベンジル、t−ブチル、アリール、またはヘテロアリールである。)
R’は、H、メチル、(C2−C4)アルキル、またはベンジルであり;
R2は、H、−CH2OP(=O)(OH)2、−CH2O(P=O)(OR8)2、−(C=O)OCHR8O(C=O)CH3、または−(C=O)OCH2O(P=O)(OH)2であり;
R3は、−C(=NR)−または−(C(R)2)n−であり;
Rは、Hまたは(C1−C4)アルキルであり、
nは、1、2または3であり;
R6は、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群から選択され、これらのいずれも、場合によりモノ置換または二置換され、存在する場合、これらの置換基は、独立して、アルキル、アルキルアリール、アラルキル(ベンジルを含むがこれに限定されない)、アリール(フェニルを含むがこれに限定されない)、ヘテロアリール(ピリジル、イミダゾリル、チアゾリル、フリル、およびチオニルを含むがこれらに限定されない)、アルコキシ(メトキシを含むがこれに限定されない)、ヒドロキシ、ペルフルオロアルキル(トリフルオロメチルを含むがこれに限定されない)、トリフルオロメトキシ、ならびにハロゲン化物(フッ化物および塩化物を含むがこれらに限定されない)からなる群から選択され、任意のアリールまたはヘテロアリール置換基は、場合により、アルキル、ハロゲン化物、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで置換されていてもよく;
R8は、H、アルキル、ベンジル、t−ブチル、アリール、またはヘテロアリールである。)
は、特定の化合物のE−異性体を表す。別の実施形態において、
は、特定の化合物のZ−異性体を表す。さらに別の実施形態において、
は、特定の化合物のE−異性体およびZ−異性体の混合物を表す。
本発明の1つまたは複数の化合物は、本明細書に記載の疾患もしくは病状を治療または改善するための用量で、単独で、または適切な担体もしくは賦形剤(複数可)と混合された医薬組成物で哺乳類に投与することができる。これらの化合物の混合物は、単純な混合物として、または適切に処方される医薬組成物で患者に投与することもできる。例えば、本発明の一態様は、治療有効量の式1、式2、式3、式4、式5、もしくは式6の化合物、またはその薬学的に許容される塩、溶媒和物、その鏡像異性体もしくは立体異性体、および薬学的に許容される希釈剤もしく担体を含む医薬組成物に関する。
CK1およびそのサブタイプのCK2、Wnt経路、ならびに/またはTGFβ経路の活性を調節する方法を本明細書に提供する。病状および疾患を治療または予防する方法であって、その過程が、CK1(例えば、CK1γ)、CK2、Wnt経路、および/またはTGFβ経路の活性を調節することによって影響され得る方法も本明細書に提供する。このような方法は、典型的には、治療有効量の本発明の化合物または組成物を、それを必要とする被験体に投与することを含む。
本明細書で使用する「治療有効量」または「治療有効用量」は、完全にまたは部分的に、病状の進行を阻害するか、または少なくとも部分的に、病状の1つもしくは複数の症状を軽減する本発明の化合物または2つ以上のこのような化合物の組合せの量である。治療有効量は、予防的に有効な量でも有り得る。治療的に有効な量は、患者のサイズおよび性別、治療される病状、その病状の重症度ならびに求められる結果に依存するであろう。所与の患者について、治療有効量は、当業者に公知の方法によって決定することができる。
本発明の化合物および組成物(例えば、式1、式2、式3、式4、式5、または式6の化合物および組成物)は、必要に応じて、有効成分を含む1つもしくは複数の単位剤形を含み得るパックまたはディスペンサー装置に入っていてもよい。例えば、パックは、金属ホイルまたはブリスターパックなどのプラスチックホイルを含んでもよい。パックまたはディスペンサー装置には、投与のための取扱説明書を添付することができる。適合する医薬担体中に処方される本発明の化合物を含む組成物も調製し、適切な容器に入れ、示される病状の治療のためにラベルを貼ってもよい。使用のための取扱説明書も提供してもよい。
モノ−Bocジアミンの置換/脱保護
8mLの丸底バイアルに、boc保護アミン[sad123−119](34.5mg、46マイクロモル、1当量)、CH2C12(0.5mL)およびTFA(175μl、2.28ミリモル、50当量)を入れた。溶液を室温で15分間攪拌した。反応が完了したことをLC−MSが示した。溶媒を減圧濃縮した。残留物をDMSOに溶解し、逆相HPLC(0〜50、12分、2回注入)により精製し、所望の生成物18.3mgを白色固体として得た(73.8%、1 TFA塩)。LC−MS:0.58分、M+1=430。
メチルフラン−2−カルビミデート(carbimidate)塩酸塩の調製
予想されるプロドロッグ類似体
tert−ブチル(トランス−4−((4−((Z)−(2,4−ジオキソチアゾリジン−5−イリデン)メチル)ピリミジン−2−イル)アミノ)シクロヘキシル)カルバメートトリフルオロ酢酸(70.8mg、0.13ミリモル、1当量)を、DMF(1mL)に溶解し、鉱油中60%の水素化ナトリウム(63μL、0.36ミリモル、3当量)を一度に添加する。クロロメチルクロロホルメート(10.6mg、0.26ミリモル、2.0当量)を一度に加え、反応混合物を室温で45分間撹拌する。ジ−tert−ブチル(クロロメチル)ホスフェート(31μL、0.13ミリモル、1当量)を一度に加え、反応混合物を室温で1時間振盪する。次いで、反応混合物を50℃で振盪する。溶媒を蒸発させ、残留物をCH2Cl2に懸濁し、トリフルオロ酢酸(0.26mL、3.33ミリモル、25当量)で処理する。所望のリン酸塩を分取HPLC(基本法)により精製する。
アルデヒド類のカスタム合成のための一般的なボロン酸のカップリング
選択した細胞増殖阻害データ
CellTiter 96(登録商標)水性のMTS試薬粉末(カタログ番号:G11 12、プロメガ社、MTS試薬粉末の保管は、遮光し、4℃で乾燥させる。)
フェナジンメトサルフェート(PMS)(品番:P9625、シグマ社、PMS粉末の保管は、遮光し、4℃で乾燥させる)
PMS溶液の調製:
DPBS中0.92mg/mLのPMSを、0.2μmのフィルターに通して無菌の、遮光した容器に濾過滅菌する。−20℃で保管。
MTS溶液の調製:
(10枚の96ウェルプレートに十分な)MTS溶液21mLの調製のために、以下のプロトコルを勧める。
a.遮光した容器を選択するか、またはホイルで容器を包む。
b.この容器にDPBS21mLを加える。
c.MTS試薬粉末42mgを秤量し、DPBSに加える。
d.15分間、またはMTSが完全に溶解するまで、磁気撹拌プレート上で中程度の速度で混合する。
e.MTS溶液のpHを測定する。最適なpHは、pH6.0〜6.5の間にある。溶液がpH6.5を超える場合は、1NのHClでpH6.5に調整する。
f.MTS溶液を0.2μmのフィルターを通して、無菌の遮光した容器に濾過滅菌する。
g.遮光して、−20℃でMTS溶液を保管する。
a.100μL量で培養した細胞を含む1枚の96ウェルプレートに十分な量の試薬を調製するために、MTS溶液およびPMS溶液を解凍する。MTS溶液の20mLサイズを完全に解凍するのに、室温で約90分間、または37℃の水浴中で10分かかるはずである(注:便宜上、最初に生成物を解凍する時は、PMS溶液1mLチューブの全内容物を、MTS溶液20mLのボトルに移すことができる。この混合物は、使用中、−20℃で保存すべきである。4℃でPMS溶液およびMTS溶液を保存する場合は、アッセイプレートに添加する直前まで、これらの溶液を混合してはいけない)。
b.無菌技術を用いて琥珀色の試薬瓶からMTS溶液2.0mLを取り出し、試験管に移す。
c.細胞を含む培養プレートへ添加する直前に、PMS溶液100μLをMTS溶液2.0mLに添加する。
d.合わせたMTS/PMS溶液の完全な混合を確実にするために、この試験官を穏やかに旋回させる。
スペクトラマックスプラス(SpectraMAX plus)マイクロプレート分光光度計モデル3011、モレキュラーデバイス社(米国カリフォルニア州);CO2水ジャケット付きインキュベーター(CO2 water jacketed incubator)、サーマ(米国)。倒立顕微鏡(Reverse microscope)、Chongguang XDS−1B、Chongqing Guangdian社(重慶、中華人民共和国)。
1.細胞を、それぞれ対数増殖期間中に採取し、血球計数器で計数した。細胞生存率は、トリパンブルー排除法により98%以上であった。
2.細胞濃度を、それぞれの培地で2.22×113もしくは1.11×113または5.56×104細胞/mLに調整した。
3.細胞懸濁液90μLを96ウェルプレートに添加し(それぞれの細胞濃度について3つ組)、最終的な細胞密度は、2×104もしくは1×104または5×103細胞/ウェルであった。5×103細胞/ウェルの密度を最初のテストに使用した。適切な細胞密度を決定し、最初の試験の結果に従って調整した。
4.翌日、試験品または陽性薬物を、20mMの濃度のストック溶液としてDMSOに溶解させた。
5.薬物溶液10μLを、それぞれのウェルに分注した(それぞれの薬物濃度について3つ組)。
6.プレートをさらに72時間培養し、次いで、MTSアッセイにより測定した。
7.MTS/PMS溶液を使用直前に調製した。この混合物20μLを、培地100μLを含む96ウェルアッセイプレートの各ウェルに入れた(最終反応量は120μlであった)。
8.プレートを、加湿した5%CO2雰囲気中、37℃で1〜4時間インキュベートした。
9.490nmの吸光度を、SpectraMAX Plusマイクロプレート分光光度計を用いて記録した。
グラフパッドプリズム(GraphPad Prism)バージョン5のソフトウェアを用いて、IC50を計算した。グラフの曲線を、非線形回帰モデルを用いてシグモイド型用量にフィットさせた。
結果を表2に示す。
本明細書に引用した米国特許および米国公開特許出願の全ては、参照により本明細書に組み込まれる。
本発明のいくつかの実施形態について本明細書に記載し、図示してきたが、当業者は、機能を実行し、かつ/または結果および/または本明細書に記載の利点の1つもしくは複数を得るための様々な他の手段ならびに/または構造を容易に予測するであろうし、そのような変化および/または変更のそれぞれは、本発明の範囲内にあると考えられる。より一般的には、当業者は、本明細書に記載の全てのパラメータ、寸法、物質、および立体配置が例示的であると意図され、実際のパラメータ、寸法、物質、および/または立体配置は、本発明の教示が用いられる特定の用途(複数可)に依存することを容易に理解するであろう。当業者は、本明細書に記載の本発明の特定の実施形態との多くの等価物を、日常的な実験のみを用いて認識するか、または確認することができるであろう。したがって、上記の実施形態は単なる例として提示されて、添付の特許請求の範囲およびその同等物の範囲内で、本発明が、具体的に記載および請求されるような方法よりもむしろ別の方法で実施され得ることを理解されたい。本発明は、本明細書に記載の個々の特徴、システム、物品、物質、キット、および/または方法を対象とする。さらに、2つ以上のそのような特徴、システム、物品、物質、キット、および/または方法の任意の組み合わせは、そのような特徴、システム、物品、物質、キット、および/または方法が相互に矛盾しない場合には、本発明の範囲内に含まれる。
Claims (13)
- 下記式6の化合物またはその薬学的に許容される塩:
R′は、H、メチル、(C2−C4)アルキル、またはベンジルであり;
R2は、H、−CH2OP(=O)(OH)2、−CH2O(P=O)(OR8)2、−(C=O)OCHR8O(C=O)CH3、または−(C=O)OCH2O(P=O)(OH)2であり;
R3は、−C(=NR)−または−(C(R)2)n−であり;
Rは、Hまたは(C1−C4)アルキルであり;
nは、1、2または3であり;
R6は、アルキル、アルキルアリール、アリール、アルキルヘテロアリール、アルキルヘテロアルキル、およびヘテロアリールからなる群より選択され、それらはいずれも、アルキル、アルキルアリール、アラルキル、アリール、ヘテロアリール、アルコキシ、ヒドロキシ、ペルフルオロアルキル、トリフルオロメトキシ、およびハロゲンからなる群より独立して選択される置換基で必要に応じてモノ置換または二置換されており、アリールまたはヘテロアリール置換基は、アルキル、ハロゲン、アルコキシ、ペルフルオロアルキル、またはジオキソラニルで必要に応じて置換されていてもよく;および
R8は、H、アルキル、ベンジル、t−ブチル、アリール、またはヘテロアリールである。 - R′がHである、請求項1記載の化合物。
- R′がメチルである、請求項1記載の化合物。
- R′がベンジルである、請求項1記載の化合物。
- R6が、アルキル、アリール、およびヘテロアリールからなる群より選択される、請求項1記載の化合物。
- R6が、フェニル、ビフェニル、ピリジル、ピリミジル、ナフチル、キノリニル、フラニル、およびチエニルからなる群より選択される、請求項5記載の化合物。
- R6がフェニルであり、前記置換基が、アルキル、アリール、ヘテロアリール、アルコキシ、ペルフルオロアルキル、ハロゲンからなる群より独立して選択され、アリールまたはヘテロアリール置換基は、アルキル、ハロゲン、アルコキシ、ペルフルオロアルキル、およびジオキソラニルからなる群より選択される置換基で置換されている、請求項6記載の化合物。
- R6がピリジルであり、前記置換基が、アルキル、アリール、ヘテロアリール、アルコキシ、ペルフルオロアルキル、ハロゲンからなる群より独立して選択され、アリールまたはヘテロアリール置換基は、アルキル、ハロゲン、アルコキシ、ペルフルオロアルキル、およびジオキソラニルからなる群より選択される置換基で置換されている、請求項6記載の化合物。
- R6がピリミジルであり、前記置換基が、アルキル、アリール、ヘテロアリール、アルコキシ、ペルフルオロアルキル、ハロゲンからなる群より独立して選択され、アリールまたはヘテロアリール置換基は、アルキル、ハロゲン、アルコキシ、ペルフルオロアルキル、およびジオキソラニルからなる群より選択される置換基で置換されている、請求項6記載の化合物。
- R6がナフチルであり、前記置換基が、アルキル、アリール、ヘテロアリール、アルコキシ、ペルフルオロアルキル、ハロゲンからなる群より独立して選択され、アリールまたはヘテロアリール置換基は、アルキル、ハロゲン、アルコキシ、ペルフルオロアルキル、およびジオキソラニルからなる群より選択される置換基で置換されている、請求項6記載の化合物。
- R6がキノリニルであり、前記置換基が、アルキル、アリール、ヘテロアリール、アルコキシ、ペルフルオロアルキル、ハロゲンからなる群より独立して選択され、アリールまたはヘテロアリール置換基は、アルキル、ハロゲン、アルコキシ、ペルフルオロアルキル、およびジオキソラニルからなる群より選択される置換基で置換されている、請求項6記載の化合物。
- 下記の構造式のいずれか1つにより表される化合物、またはその薬学的に許容される塩、もしくはそのシス/トランス異性体。
- 下記式で示される化合物、またはその薬学的に許容される塩。
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