JP7449843B2 - セストリン-gator2相互作用のモジュレーターおよびその使用 - Google Patents
セストリン-gator2相互作用のモジュレーターおよびその使用 Download PDFInfo
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- JP7449843B2 JP7449843B2 JP2020195185A JP2020195185A JP7449843B2 JP 7449843 B2 JP7449843 B2 JP 7449843B2 JP 2020195185 A JP2020195185 A JP 2020195185A JP 2020195185 A JP2020195185 A JP 2020195185A JP 7449843 B2 JP7449843 B2 JP 7449843B2
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
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- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
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- C07C2601/14—The ring being saturated
Description
本発明は、セストリン-GATOR2相互作用をモジュレートし、これにより間接的に、mTORC1活性を選択的にモジュレートするために有用な化合物および方法に関する。本発明はまた、本発明の化合物を含む薬学的に許容される組成物および様々な障害の処置において前記組成物を使用する方法も提供する。
ラパマイシン複合体1(mTORC1)タンパク質キナーゼの機構的標的は、増殖因子、細胞ストレス、ならびに栄養素およびエネルギーレベルなどの、多様な環境的合図を感じるマスター成長調節因子である。mTORC1は、活性化されると、mRNA翻訳および脂質合成などの同化作用を賦活する基質をリン酸化し、オートファジーなどの異化作用を制限する。mTORC1の調節異常は、とりわけ、糖尿病、てんかん、神経変性、免疫応答、骨格筋成長の抑制およびがんを含めた、幅広い範囲の疾患において発生する(Howellら、(2013年)Biochemical Society transactions 41巻、906~912頁;Kimら、(2013年) Molecules and cells 35巻、463~473頁;LaplanteおよびSabatini、(2012年) Cell 149巻、274~293頁)。
27頁)。Rag GTPアーゼは、mTORC1の細胞内局在化を制御しており、アミノ酸は、Rheb GTPアーゼがやはり生存しているリソソーム表面にmTORC1の動員を促進する(Buergerら、(2006年) Biochemical and Biophysical Research Communications 344巻、869~880頁;Dibbleら、(2012年) Molecular cell 47巻、535~546頁;Saitoら、(2005年) Journal of Biochemistry 137巻、423~430頁;Sancakら、(2008年) Science(New York、NY)320巻、1496~1501頁)。Rag GTPアーゼの上流経路のいくつ
かの正の構成成分が特定されている。Ragulator複合体は、Rag GTPアーゼをリソソーム表面に局在化させて、液胞型ATPアーゼと一緒になって、RagA/B上でのGDPのGTPへの交換を促進する(Bar-Peledら、(2012年) Cell 150巻、1196~1208頁;Sancakら、(2010年) Cell 141巻、290~303頁;Zoncuら、(2011年)Science Signaling 334巻、678~683頁)。別個のFLCN-FNIP複合体が、RagC/D上で作用し、GTPのGDPへの加水分解を刺激する(Tsunら、2013年)。RagA/BがGTPにロードされ、RagC/DがGDPにロードされると、それらのヘテロ二量体が結合して、そのアクチベータであるRheb GTPアーゼに接触することができるようになる、リソソーム表面にmTORC1を動員する。
451~460頁;Peetersら、(2003年) Human genetics 112巻、573~580頁)。セストリン2は、mTORC1のシグナル伝達を阻害し、TSCの上流のAMPKを活性化して、TSCと相互作用する(BudanovおよびKarin、(2008年) Cell 134巻、451~460頁)ことが提唱されているが、後の研究により、AMPKの非存在下で、セストリン2によりmTORC1が阻害されることが見出され(Pengら、(2014年) Cell 159巻(1号):122~33頁)、このことは、GATOR2複合体が、セストリン2に応答して、mTORC1をモジュレートする際に果たす重要な役割をさらに強調するものである。
セストリン-GATOR2複合体のモジュレートは、間接的に、mTORC1活性を選択的にモジュレートするための潜在的な治療標的となる。
本発明の化合物および薬学的に許容されるその組成物は、セストリン-GATOR2モジュレーターとして有効であることが今や見出された。このような化合物は、一般式I:
1.本発明のある特定の実施形態の一般的な説明:
本発明の化合物およびその組成物は、セストリン-GATOR2モジュレーターとして有用である。ある特定の実施形態では、本発明は、式Iの化合物:
R1は、HまたはC1~6アルキルであり、
R2は、R、-(CH2)n-フェニル、-C(O)R、-SO2Rまたは-C(O)N(R)2であり、
nは、0、1または2であり、
Rはそれぞれ独立して、水素、-CN、あるいは飽和もしくは不飽和C1~6脂肪族、フェニル、4~7員の飽和もしくは部分不飽和の単環式炭素環式環、1~4個のヘテロ原子を有する5~6員の単環式ヘテロアリール環、または窒素、酸素もしくは硫黄から独立して選択される1~2個のヘテロ原子を有する4~8員の飽和または部分飽和の複素環式環から選択される、任意選択で置換されている基であり、
R3は、環A、-C(O)R、-C(O)OR、-C(O)N(R)2、-SO3H、-SO2N(R)2、-S(O)R、-S(O)環A、-ORまたは-B(OR)2であり、この場合、同一ホウ素上の2つのOR基はそれらの介在原子と一緒になって、ホウ素および2個の酸素に加えて、窒素、酸素もしくは硫黄から独立して選択される0~3個のヘテロ原子を有する、5~8員の飽和もしくは部分不飽和の単環式環を形成するか、またはR3とR4が一緒になって、窒素、酸素もしくは硫黄から選択される0~1個のヘテロ原子を有する、任意選択で置換されている5~6員環を形成し、
Lは、共有結合、または1~9つのフルオロ基により任意選択で置換されている直鎖もしくは分枝状C1~6アルキレン鎖であり、
環Aは、フェニル、または窒素、酸素もしくは硫黄から独立して選択される1~4個のヘテロ原子を有する、任意選択で置換されている5~6員のヘテロアリール環から選択される、任意選択で置換されている環であり、
R4は、R、-CF3、-OR、-N(R)2、-Si(R)3もしくは-SRであるか、またはR3とR4が一緒になって、窒素、酸素もしくは硫黄から選択される0~1個のヘテロ原子を有する、任意選択で置換されている5~6員環を形成し、
R5は、HまたはC1~4アルキルである)
を提供する。
2.化合物および定義:
周期表に従って特定される。さらに有機化学の一般原理は、「Organic Chemistry」、Thomas Sorrell、University Science Books、Sausalito:1999年、および「March's Advanced Organic Chemistry」、第5版、編:Smith, M.B.および March, J.、John Wiley & Sons、New York:2001年に記載されており、それらの全内容が参照により本明細書に組み込まれている。
。用語「アリール」は、用語「アリール環」と互換的に使用することができる。本発明のある特定の実施形態では、「アリール」とは、以下に限定されないが、1つまたは複数の置換基を有していてもよい、フェニル、ビフェニル、ナフチル、アントラシルなどを含む、芳香族環系を指す。同様に、本明細書において使用されている用語「アリール」の範囲内には、芳香族環が、インダニル、フタルイミジル、ナフトイミジル、フェナントリジニルまたはテトラヒドロナフチルなどの1つまたは複数の非芳香族環に縮合している基も含まれる。
チアゼピニル、モルホリニルおよびキヌクリジニルが含まれる。用語「複素環」、「ヘテロシクリル」、「ヘテロシクリル環」、「複素環式基」、「複素環式部分」および「複素環式ラジカル」は、本明細書において互換的に使用され、ヘテロシクリル環が、インドリニル、3H-インドリル、クロマニル、フェナントリジニルまたはテトラヒドロキノリニルなどの、アリール、ヘテロアリールまたは脂環式環のうちの1つまたは複数に縮合している基も含む。ヘテロシクリル基は、単環式または二環式とすることができる。用語「ヘテロシクリルアルキル」は、ヘテロシクリルによって置換されているアルキル基を指し、この場合、アルキル部分およびヘテロシクリル部分は、独立して、任意選択で置換されている。
(OR°)2;-SiR°3;-(C1~4直鎖または分枝状アルキレン)O-N(R°)2;または-(C1~4直鎖または分枝状アルキレン)C(O)O-N(R°)2であり、R°はそれぞれ、以下に定義されている通り置換されていてもよく、独立して、水素、C1~6脂肪族、-CH2Ph、-O(CH2)0~1Ph、-CH2-(5~6員のヘテロアリール環)、または窒素、酸素もしくは硫黄から独立して選択される0~4個のヘテロ原子を有する5~6員の飽和環、部分不飽和環またはアリール環であるか、または上の定義であっても、R°の2つの独立した出現がそれらの介在原子(複数可)と一緒になって、窒素、酸素もしくは硫黄から独立して選択される0~4個のヘテロ原子を有する、3~12員の飽和、部分不飽和もしくはアリールの一環式または二環式環を形成し、これは、以下において定義されている通り置換されていてもよい。
R* 2))2~3S-を含み、R*のそれぞれ独立した出現は、水素、以下に定義されている通り置換されていてもよいC1~6脂肪族、あるいは窒素、酸素もしくは硫黄から独立して選択される0~4個のヘテロ原子を有する非置換の5~6員の飽和環、部分不飽和環またはアリール環から選択される。「任意選択で置換されている」基の置換可能なビシナル炭素に結合している好適な二価置換基には、以下:-O(CR* 2)2~3O-が含まれ、R*のそれぞれ独立した出現は、水素、以下に定義されている通り置換されていてもよいC1~6脂肪族、あるいは窒素、酸素もしくは硫黄から独立して選択される0~4個のヘテロ原子を有する非置換の5~6員の飽和環、部分不飽和環またはアリール環から選択される。
C(NH)NR† 2または-N(R†)S(O)2R†が含まれ、R†はそれぞれ、独立して、水素、以下に定義されている通り置換されていてもよいC1~6脂肪族、非置換-OPh、あるいは窒素、酸素もしくは硫黄から独立して選択される0~4個のヘテロ原子を有する、非置換の5~6員の飽和環、部分不飽和環またはアリール環であるか、あるいは上の定義であっても、R†の2つの独立した出現は、それらの介在原子(複数可)と一緒になって、窒素、酸素もしくは硫黄から独立して選択される0~4個のヘテロ原子を有する、非置換の3~12員の飽和、部分不飽和もしくはアリールの単環式環または二環式環を形成する。
らは、参照により本明細書に組み込まれている、J. Pharmaceutical Sciences、1977年、66巻、1~19頁に、薬学的に許容される塩を詳細に記載している。本発明の化合物の薬学的に許容される塩は、好適な無機酸および有機酸ならびに無機塩基および有機塩基から誘導されるものを含む。薬学的に許容される非毒性の酸付加塩の例は、塩酸、臭化水素酸、リン酸、硫酸および過塩素酸などの無機酸により形成されるアミノ基の塩、または酢酸、シュウ酸、マレイン酸、酒石酸、クエン酸、コハク酸またはマロン酸などの有機酸により形成されるアミノ基の塩であるか、あるいはイオン交換などの当技術分野において使用される他の方法を使用することによる。他の薬学的に許容される塩には、アジピン酸塩、アルギン酸塩、アスコルビン酸塩、アスパラギン酸塩、ベンゼンスルホン酸塩、安息香酸塩、重硫酸塩、ホウ酸塩、酪酸塩、樟脳酸塩、カンファースルホン酸塩、クエン酸塩、シクロペンタンプロピオン酸塩、二グルコン酸塩、ドデシル硫酸塩、エタンスルホン酸塩、ギ酸塩、フマル酸塩、グルコヘプトン酸塩、グリセロリン酸塩、グルコン酸塩、ヘミ硫酸塩、ヘプタン酸塩、ヘキサン酸塩、ヨウ化水素酸塩、2-ヒドロキシ-エタンスルホン酸塩、ラクトビオン酸塩、乳酸塩、ラウリン酸塩、ラウリル硫酸塩、リンゴ酸塩、マレイン酸塩、マロン酸塩、メタンスルホン酸塩、2-ナフタレンスルホン酸塩、ニコチン酸塩、硝酸塩、オレイン酸塩、シュウ酸塩、パルミチン酸塩、パモ酸塩、ペクチン酸塩、過硫酸塩、3-フェニルプロピオン酸塩、リン酸塩、ピバル酸塩、プロピオン酸塩、ステアリン酸塩、コハク酸塩、硫酸塩、酒石酸塩、チオシアン酸塩、p-トルエンスルホン酸塩、ウンデカン酸塩、吉草酸塩などが含まれる。
体(例えば、鏡像異性体、ジアステレオマー異性体および幾何(または立体構造)異性体)、例えば、各不斉中心に関するRおよびS立体配置、ZおよびE二重結合異性体、ならびにZおよびE立体構造異性体を含むことがやはり意図される。したがって、単一の立体化学異性体、ならびに本発明の化合物の鏡像異性体、ジアステレオマー異性体および幾何(または立体構造)異性体混合物が、本発明の範囲内にある。特に明記しない限り、本発明の化合物のすべての互変異性体が、本発明の範囲内にある。さらに、特に明記しない限り、本明細書において図示されている構造は、1個または複数の同位体富化原子が存在していることしか違いのない化合物も含まれることがやはり意図されている。例えば、ジュウテリウムもしくはトリチウムによる水素の置きかえ、または13Cもしくは14C富化炭素による炭素の置きかえを含めた、本発明の構造を有する化合物は、本発明の範囲内にある。このような化合物は、例えば、分析用手段として、生物アッセイにおけるプローブとして、または本発明による治療剤として有用である。
3.例示的な実施形態の説明:
R1は、HまたはC1~6アルキルであり、
R2は、R、-(CH2)n-フェニル、-C(O)R、-SO2Rまたは-C(O)N(R)2であり、
nは、0、1または2であり、
Rはそれぞれ独立して、水素、-CN、あるいは飽和もしくは不飽和C1~6脂肪族、フェニル、4~7員の飽和もしくは部分不飽和の単環式炭素環式環、1~4個のヘテロ原子を有する5~6員の単環式ヘテロアリール環、または窒素、酸素もしくは硫黄から独立し
て選択される1~2個のヘテロ原子を有する4~8員の飽和または部分飽和の複素環式環から選択される、任意選択で置換されている基であり、
R3は、環A、-C(O)R、-C(O)OR、-C(O)N(R)2、-SO3H、-SO2N(R)2、-S(O)R、-S(O)環A、-ORまたは-B(OR)2であり、この場合、同一ホウ素上の2つのOR基はそれらの介在原子と一緒になって、ホウ素および2個の酸素に加えて、窒素、酸素もしくは硫黄から独立して選択される0~3個のヘテロ原子を有する、5~8員の飽和もしくは部分不飽和の単環式環を形成するか、またはR3とR4が一緒になって、窒素、酸素もしくは硫黄から選択される0~1個のヘテロ原子を有する、任意選択で置換されている5~6員環を形成し、
Lは、共有結合、または1~9つのフルオロ基により任意選択で置換されている直鎖もしくは分枝状C1~6アルキレン鎖であり、
環Aは、フェニル、または窒素、酸素もしくは硫黄から独立して選択される1~4個のヘテロ原子を有する、任意選択で置換されている5~6員のヘテロアリール環から選択される、任意選択で置換されている環であり、
R4は、R、-CF3、-OR、-N(R)2、-Si(R)3もしくは-SRであるか、またはR3とR4が一緒になって、窒素、酸素もしくは硫黄から選択される0~1個のヘテロ原子を有する、任意選択で置換されている5~6員環を形成し、
R5は、HまたはC1~4アルキルである)を提供する。
、R4は、シクロプロピルである。一部の実施形態では、R4は、シクロブチルである。一部の実施形態では、R4は、sec-ブチルである。一部の実施形態では、R4は、メトキシルである。一部の実施形態では、R4は、メチルチオイルである。一部の実施形態では、R3とR4は一緒になって、窒素、酸素または硫黄から選択される、0~1個のヘテロ原子を有する、任意選択で置換されている5~6員環を形成する。一部の実施形態では、R4は、以下の表1に図示されているものから選択される。一部の実施形態では、R4は、以下の表2に図示されているものから選択される。
Qは、-C(R’)2-または-NH-であり、
RxおよびRyはそれぞれ、水素であるか、またはRxとRyは一緒になって、=Oを形成し、
Rはそれぞれ独立して、水素、-CN、あるいはC1~6脂肪族、フェニル、4~7員の飽和もしくは部分不飽和の単環式炭素環式環、1~4個のヘテロ原子を有する5~6員の単環式ヘテロアリール環、または窒素、酸素もしくは硫黄から独立して選択される1~2個のヘテロ原子を有する4~8員の飽和または部分飽和の複素環式環から選択される、任意選択で置換されている基であり、
R’はそれぞれ独立して、水素、ハロゲン、-CN、あるいはC1~6脂肪族、フェニル、4~7員の飽和もしくは部分不飽和の単環式炭素環式環、1~4個のヘテロ原子を有する5~6員の単環式ヘテロアリール環、または窒素、酸素もしくは硫黄から独立して選択される1~2個のヘテロ原子を有する4~8員の飽和または部分飽和の複素環式環から選択される、任意選択で置換されている基であり、
Lは、共有結合、または1~9つのフルオロ基により任意選択で置換されている直鎖もしくは分枝状C1~6アルキレン鎖であり、
R4’は、R、-CF3、-OR、-N(R)2、-Si(R)3または-SRであり、R5’は、H、-ORまたはC1~4アルキルである)を提供する。
R1は、HまたはC1~6アルキルであり、
R2は、R、-(CH2)n-フェニル、-C(O)R、-SO2Rまたは-C(O)N(R)2であり、
R4’’はそれぞれ、独立して、R、ハロゲンまたは-CF3であり、
Rはそれぞれ独立して、水素、-CN、あるいは飽和もしくは不飽和C1~6脂肪族、フェニル、4~7員の飽和もしくは部分不飽和の単環式炭素環式環、1~4個のヘテロ原子を有する5~6員の単環式ヘテロアリール環、または窒素、酸素もしくは硫黄から独立して選択される1~2個のヘテロ原子を有する4~8員の飽和または部分飽和の複素環式環から選択される、任意選択で置換されている基であり、
L1は、共有結合、または1~9つのフルオロ基により任意選択で置換されている直鎖もしくは分枝状C1~6アルキレン鎖である)
を提供する。
、L1は、共有結合である。一部の実施形態では、L1は、1~9つのフルオロ基により任意選択で置換されている直鎖または分枝状C1~6アルキレン鎖である。一部の実施形態では、L1は、以下の表1に図示されているものから選択される。
5.使用、製剤および投与
薬学的に許容される組成物
水素カリウム、塩化ナトリウム、亜鉛塩、コロイド状シリカ、マグネシウムトリシリケート、ポリビニルピロリドン、セルロースをベースとする物質、ポリエチレングリコール、カルボキシメチルセルロースナトリウム、ポリアクリレート、ワックス、ポリエチレン-ポリオキシプロピレン-ブロックポリマー、ポリエチレングリコールおよび羊毛脂が含まれる。
。これらの油性溶液剤または懸濁剤はまた、カルボキシメチルセルロースなどの長鎖アルコール希釈剤もしくは分散剤、または乳剤および懸濁剤を含めた、薬学的に許容される剤形の製剤化において一般に使用される類似の分散化剤を含有していてもよい。Tween、Spanおよび他の乳化剤などの他の一般的に使用される界面活性剤、または薬学的に許容される固体、液体もしくは他の剤形の製造に一般に使用される生物学的利用能増強剤もまた、製剤化のために使用されてもよい。
化合物および薬学的に許容される組成物の使用
ッセイすることができる。in vitroアッセイは、セストリン-GATOR2相互作用の阻害または活性化を決定するアッセイを含む。代替的なin vitroアッセイは、阻害剤またはアクチベータが、セストリンのGATOR2への結合を低下させるまたは増加させる能力を定量するものである。セストリン-GATOR2相互作用の阻害剤またはアクチベータとして本発明において利用される化合物をアッセイするための詳細条件は、以下の実施例に説明されている。
悪性腫瘍、ならびに大部分の結腸がん、腎細胞癌、前立腺がんおよび/または睾丸腫瘍、肺の非小細胞癌、小腸のがんおよび食道のがんなどの悪性腫瘍を含む腺癌を含む。
ており、呼吸系の癌、胃腸系の癌、尿生殖器系の癌、睾丸癌、乳癌、前立腺癌、内分泌腺系の癌および黒色腫を含めた、上皮または内分泌腺組織の悪性腫瘍を指す。一部の実施形態では、がん(cancer)は、腎癌または黒色腫である。例示的な癌腫には、子宮頸部、肺、前立腺、胸部、頭頸部、結腸および卵巣の組織から形成されるものが含まれる。この用語はまた、例えば、癌性組織および肉腫組織からなる悪性腫瘍を含む、癌肉腫も含む。「腺癌」とは、腺組織から誘導される、または腫瘍細胞が認識可能な腺構造を形成する、癌腫を指す。
細胞増殖性障害
がん
、松果体腫、血管芽細胞腫、聴神経腫、乏突起神経膠腫、神経鞘腫、髄膜腫、黒色腫、神経芽細胞腫および網膜芽細胞腫)など)が含まれる。一部の実施形態では、がんは、黒色腫または乳がんである。
他の増殖性疾患
他の障害
号):2214~24頁;Efeyanら、(2012年)Trends Mol Med.9月;18巻(
9号):524~533頁を参照されたい)。したがって、一部の実施形態では、本発明は、リボソーム病を処置することを必要とする患者において、リボソーム病を処置する方法であって、前記患者に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。ある特定の実施形態では、本発明は、リボソーム病を処置することを必要とする患者において、ダイアモンド-ブラックファン貧血、5q症候群、シュワッハマン-ダイアモンド症候群、X連鎖先天性角化不全症、軟骨毛髪形成不全症またはトリーチャーコリンズ症候群から選択されるリボソーム病を処置する方法であって、前記患者に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
る。(Xuら、(2016年)BMC Genomics 17巻:25頁を参照されたい)。したが
って、一部の実施形態では、本発明は、コヒーシン病(例えば、ロバーツ症候群およびコルネリアデランゲ症候群)を処置することを必要とする患者において、コヒーシン病(例えば、ロバーツ症候群およびコルネリアデランゲ症候群)を処置する方法であって、前記患者に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
脊柱損傷、切断、変性疾患、被験体にとって回復にベッドでの療養を必要とする状態、集中ケアユニットでの滞在、または長期入院による、筋萎縮を反転させるか、または筋萎縮を阻止する。(Gordonら、(2013年)Int J Biochem Cell Biol. 10月;45巻(10号):2147~57頁;Legerら、(2009年) Muscle Nerve. 7月;
40巻(1号):69~78頁を参照されたい)。したがって、一部の実施形態では、本発明は、筋萎縮を反転または阻止することを必要とする患者において、骨折、重症な火傷、脊柱損傷、切断、変性疾患、被験体にとって回復にベッドでの療養を必要とする状態、集中ケアユニットでの滞在、または長期入院による、筋萎縮を反転または阻止する方法であって、前記患者に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
):6318~6331頁;Gurpurら、(2009年) Am J Pathol. 3月;174巻(3号):999~1008頁;Chauhanら、(2013年)Neurosci Res. 9月~
10月;77巻(1~2号):102~9頁);Chingら、(2013年) Hum Mol Genet. 3月15日;22巻(6号):1167~79頁を参照されたい)。したがって
、一部の実施形態では、本発明は、疾患、状態または障害を処置することを必要とする患者において、サルコペニア、筋除神経、筋ジストロフィー、炎症性ミオパチー、脊髄性筋萎縮症(SMA)、筋萎縮性側索硬化症(ALS)または重症筋無力症などの骨格筋萎縮をもたらす疾患、状態または障害を処置する方法であって、前記患者に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
の治療抵抗性がんを有するか、またはそれに罹患している(KimおよびGuan、(2015
年)J Clin Invest. 1月;125巻(1号):25~32頁を参照されたい)。したがって、一部の実施形態では、本発明は、オートファジーを予防することを必要とする患者において、オートファジーの誘発に依存性の治療抵抗性がんを有するか、またはそれに罹患している患者における、オートファジーを予防する方法であって、前記患者に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
1号):131~9頁を参照されたい)。したがって、一部の実施形態では、本発明は、運動後の強化を増加する、および/または筋肉量を増加させる方法を提供する。一部の実施形態では、本方法は、本方法を必要とする被験体において、非経口の全栄養素の一部と
して、または機能的な電気的刺激を促進するための、物理的治療法と併せて実施され、前記被験体に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む。
7頁を参照されたい)。したがって、一部の実施形態では、本発明は、食物摂取を低減することを必要とする被験体において、食物摂取を低減する方法であって、前記被験体に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
)Biotechnol Bioeng. 2月16日 doi:10.1002/bit.25951を
参照されたい)。したがって、一部の実施形態では、本発明は、バイオリアクターからの治療用組換えタンパク質の製造における生産性を向上する方法であって、前記製造に、提供される化合物または薬学的に許容されるその組成物を添加するステップを含む方法を提供する。
8~897頁;O'Brienら(2011年)Eur J Immunol.;41巻:3361~337
0頁;Delgoffeら、(2009年)Immunity. 6月19日;30巻(6号):832~
44頁;Chi、(2012年)Nat Rev Immunol. 4月20日;12巻(5号):32
5~338頁;Pollizziら、(2015年)J Clin Invest.;125巻(5号):2090~2108頁;Aliら、(2015年)Front Immunol.;6巻:355頁;Katholnigら、(2013年)Biochem Soc Trans. 8月;41巻(4号):927~33頁;Wangら、(2013年)Proc Natl Acad Sci USA. 12月10日;110巻(50号):E4894~903頁;YangおよびChi、(2013年)J Clin Invest. 12月
;123巻(12号):5165~78頁を参照されたい)。したがって、一部の実施形態では、本発明は、免疫細胞におけるmTORC1を活性化して、その抗腫瘍活性を促進および/または維持する方法を提供する。一部の実施形態では、本発明は、養子免疫伝達前に、免疫細胞において、in vitroでmTORC1を増加させる方法を提供する。一部の実施形態では、本発明は、in vivoで他の標的免疫療法戦略と共投与した場合に、免疫細胞においてmTORC1を増加させる方法を提供する。ある特定の実施形態では、免疫細胞は、ナイーブなT細胞、CD4+またはCD8+T細胞、Th1、Th2、TRegおよびTh17細胞、樹状細胞、NK細胞およびマクロファージを含み、前記免疫細胞に、提供される化合物または薬学的を許容されるその組成物を添加するステップを含む。
形態では、本発明は、網膜色素変性および眼の神経変性の他の形態を処置することを必要とする被験体において、網膜色素変性および眼の神経変性の他の形態を処置する方法であって、前記被験体に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
巻(19号):6367~78頁;Norrmenら、(2014年)Cell Rep. 10月23
日;9巻(2号):646~60頁;Love(2006年) J Clin Pathol. 11月;59巻(11号):1151~1159頁を参照する)。したがって、一部の実施形態では、本発明は、髄鞘再生およびニューロンの活性を促進する方法ことを必要とする被験体において、脱髄を特徴とする、損傷後または疾患における、髄鞘再生およびニューロンの活性を促進する方法であって、前記被験体に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。一部の実施形態では、本発明は、多発性硬化症を処置することを必要とする被験体において、多発性硬化症を処置する方法であって、前記被験体に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。一部の実施形態では、本発明は、パーキンソン病を処置することを必要とする被験体において、パーキンソン病を処置する方法であって、前記被験体に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
multiple sclerosis)を処置する方法であって、前記被験体に、提供される化合物ま
たは薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
よびニーマンピック病を処置する方法であって、前記被験体に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
05号、394~397頁を参照されたい)。したがって、一部の実施形態では、本発明は、自閉症の形態を処置または予防することを必要とする被験体において、自閉症の形態を処置または予防する方法であって、前記被験体に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
巻(4号):559~561頁を参照されたい)。したがって、一部の実施形態では、本発明は、樹状突起形成およびシナプス形成を増加させることを必要とする被験体において、樹状突起棘の減少およびシナプスの喪失によって特徴付けられる神経変性疾患における樹状突起形成およびシナプス形成を増加させる方法であって、前記被験体に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。一部の実施形態では、本発明は、アルツハイマー病、筋萎縮性側索硬化症、脳卒中または緑内障を処置することを必要とする被験体において、アルツハイマー病、筋萎縮性側索硬化症、脳卒中または緑内障を処置する方法であって、前記被験体に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
7巻(308号):ra4を参照されたい)。したがって、一部の実施形態では、本発明は、疾患を処置することを必要とする被験体において、アルツハイマー病、筋萎縮性側索硬化症、統合失調症、レット症候群、脆弱X症候群、パーキンソン病、ハンチントン病、脳卒中および緑内障などの疾患を処置する方法であって、前記被験体に、提供される化合物または薬学的に許容されるその組成物を投与するステップを含む方法を提供する。
、口腔に(bucally)投与することができる。ある特定の実施形態では、本発明の化合物
は、所望の治療効果を得るため、1日に1回または複数回、1日あたり、被験体の体重あたり約0.01mg/kg~約50mg/kg、および好ましくは約1mg/kg~約25mg/kgの投与量レベルで、経口または非経口投与することができる。
剤が含まれる。活性化合物に加えて、液体剤形は、例えば、水または他の溶媒などの当技術分野において一般に使用される不活性希釈剤、エチルアルコール、イソプロピルアルコール、炭酸エチル、酢酸エチル、ベンジルアルコール、安息香酸ベンジル、プロピレングリコール、1,3-ブチレングリコール、ジメチルホルムアミド、油(特に、綿実油、落花生油、コーン油、胚芽油、オリーブ油、ヒマシ油およびゴマ油)、グリセロール、テトラヒドロフルフリルアルコール、ポリエチレングリコール、およびソルビタンの脂肪酸エステル、ならびにそれらの混合物などの可溶化剤および乳化剤を含有することができる。不活性な希釈剤に加えて、本経口用組成物はまた、湿潤剤、乳化剤および懸濁化剤、甘味剤、着香剤および芳香剤などのアジュバントを含むことができる。
このような固形剤形では、活性化合物は、少なくとも1つの不活性な、薬学的に許容される賦形剤または担体(クエン酸ナトリウムまたはリン酸二カルシウムなど)、および/またはa)充填剤もしくは増量剤(デンプン、ラクトース、スクロース、グルコース、マンニトールおよびケイ酸など)、b)結合剤(例えば、カルボキシメチルセルロース、アルギネート、ゼラチン、ポリビニルピロリジノン、スクロースおよびアカシアなど)、c)保湿剤(グリセロールなど)、d)崩壊剤(寒天、炭酸カルシウム、バレイショデンプンまたはタピオカデンプン、アルギン酸、ある特定のシリケートおよび炭酸ナトリウムなど)、e)溶解遅延剤(パラフィンなど)、f)吸収促進剤(第四級アンモニウム化合物など)、g)湿潤剤(例えば、セチルアルコールおよびモノステアリン酸グリセロールなど)、h)吸収剤(カオリンおよびベントナイトクレイなど)、およびi)滑沢剤(タルク、ステアリン酸カルシウム、ステアリン酸マグネシウム、固体ポリエチレングリコール、ラウリル硫酸ナトリウム)、およびそれらの混合物と混合される。カプセル剤、錠剤および丸剤の場合、これらの剤形はまた、緩衝化剤を含むことがある。
中に充填剤として用いられてもよい。
BioPharma製)など)、AZD6244(AstraZeneca製)、PD
181461(Pfizer製)およびロイコボリンが含まれる。用語「アロマターゼ阻害剤」は、本明細書で使用する場合、エストロゲン生成、例えば、それぞれ基質であるアンドロステンジオンおよびテストステロンのエストロンおよびエストラジオールへの変換を阻害する化合物に関する。この用語には、以下に限定されないが、ステロイド、とりわけアタメスタン、エキセメスタンおよびフォルメスタン、および、特に非ステロイド、とりわけアミノグルテチミド、ログレチミド、ピリドグルテチミド、トリロスタン、テストラクトン、ケトコナゾール、ボロゾール、ファドロゾール、アナストロゾールおよびレトロゾールが含まれる。エキセメスタンは、商標名Aromasin(商標)で販売されている。フォルメスタンは、商標名Lentaron(商標)で販売されている。ファドロゾールは、商標名Afema(商標)で販売されている。アナストロゾールは、商標名Arimidex(商標)で販売されている。レトロゾールは、商標名Femara(商標)またはFemar(商標)で販売されている。アミノグルテチミドは、商標名Orimeten(商標)で販売されている。アロマターゼ阻害剤である化学治療剤を含む本発明の組合せは、乳房腫瘍などのホルモン受容体陽性腫瘍の処置に、特に有用である。
イド;コチシンおよびエポチロンおよびそれらの誘導体を含めた、微小管安定化化合物、微小管脱安定化化合物および微小管重合阻害剤に関する。パクリタキセルは、商標名Taxol(商標)で販売されている。ドセタキセルは、商標名Taxotere(商標)で販売されている。ビンブラスチン硫酸塩は、商標名Vinblastin R.P(商標)で販売されている。ビンクリスチン硫酸塩は、商標名Farmistin(商標)で販売されている。
る化合物;i)イマチニブまたはニロチニブ(AMN107)などのN-フェニル-2-ピリミジン-アミン誘導体などのc-Ablファミリーメンバーおよびその遺伝子融合産物の活性を標的とする、低下させるまたは阻害する化合物などの、c-Ablファミリーメンバー、その遺伝子融合産物(例えば、BCR-Ablキナーゼ)および変異体の活性を標的とする、低下させるまたは阻害する化合物;PD180970;AG957;NSC680410;ParkeDavis製のPD173955;またはダサチニブ(BMS-354825);j)タンパク質キナーゼC(PKC)のメンバー、ならびにセリン/トレオニンキナーゼのRafファミリー、MEK、SRC、JAK/pan-JAK、FAK、PDK1、PKB/Akt、Ras/MAPK、PI3K、SYK、TYK2、BTKおよびTECファミリーのメンバー、ならびに/またはミドスタウリンなどのスタウロスポリン誘導体を含めたサイクリン依存性キナーゼファミリー(CDK)のメンバーの活性を標的とする、低下させるまたは阻害する化合物;さらなる化合物の例は、UCN-01、サフィンゴール、BAY43-9006、ブリオスタチン1、ペリホシン;リモフォシン;RO318220およびRO320432;GO6976;lsis3521;LY333531/LY379196;イソキノリン化合物;FTI;PD184352またはQAN697(P13K阻害剤)またはAT7519(CDK阻害剤)を含む;k)タンパク質-チロシンキナーゼ阻害剤の活性を標的とする、低下させるまたは阻害する化合物などの、タンパク質-チロシンキナーゼ阻害剤の活性を標的とする、低下させるまたは阻害する化合物は、メシル酸イマチニブ(Gleevec(商標))またはチルホスチン(tyrphostin)(チルホスチンA23/RG-50810;AG99;チルホスチンAG213;チルホスチンAG1748;チルホスチンAG490;チルホスチンB44;チルホスチンB44(+)鏡像異性体;チルホスチンAG555;AG494;チルホスチンAG556、AG957など)、およびアダホスチン(4-{[(2,5-ジヒドロキシフェニル)メチル]アミノ}-安息香酸アダマンチルエステル;NSC680410、アダホスチン)を含む;l)上皮増殖因子受容体ファミリーの活性を標的とする、低下させるまたは阻害する化合物などの、受容体チロシンキナーゼの上皮増殖因子ファミリー(ホモまたはヘテロ二量体としての、EGFR1 ErbB2、ErbB3、ErbB4)およびその変異体の活性を標的とする、低下させるまたは阻害する化合物は、とりわけEGF受容体、ErbB2、ErbB3およびErbB4などのEGF受容体チロシンキナーゼファミリーメンバーを阻害するか、またはEGFもしくはEGF関連リガンドに結合する化合物、タンパク質または抗体、CP358774、ZD1839、ZM105180;トラスツズマブ(Herceptin(商標))、セツキシマブ(Erbitux(商標))、イレッサ、タルセバ、OSI-774、Cl-1033、EKB-569、GW-2016、E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3またはE7.6.3および7H-ピロロ-[2,3-d]ピリミジン誘導体である;m)c-Metの活性を標的とする、低下させるまたは阻害する化合物、とりわけc-Met受容体のキナーゼ活性を阻害する化合物などのc-Met受容体の活性を標的とする、低下させるまたは阻害する化合物、またはc-Metの細胞外ドメインを標的とするかもしくはHGFに結合する抗体、n)以下に限定されないが、PRT-062070、SB-1578、バリシチニブ、パクリチニブ、モメロチニブ、VX-509、AZD-1480、TG-101348、トファシチニブおよびルキソリチニブを含めた、1つまたは複数のJAKファミリーメンバー(JAK1/JAK2/JAK3/TYK2および/またはpan-JAK)のキナーゼ活性を標的とする、低下させるまたは阻害する化合物、o)以下に限定されないが、ATU-027、SF-1126、DS-7423、PBI-05204、GSK-2126458、ZSTK-474、ブパルリシブ、ピクトレリシブ、PF-4691502、BYL-719、ダクトリシブ、XL-147、XL-765およびイデラリシブを含めた、PI3キナーゼ(PI3K)のキナーゼ活性を標的とする、低下させるまたは阻害する化合物、および;およびq)以下に限定されないが、シクロパミン、ビスモデギブ、イトラコナゾール、エリスモデギブおよびIPI-926(サリデギブ)を含めた、ヘッジホッグタンパク質(Hh)またはスムーズンド受
容体(SMO)経路のシグナル伝達作用を標的とする、低下させるまたは阻害する化合物などを含む。
、US8138347、WO2002088112、WO2007084786、WO2007129161、WO2006122806、WO2005113554およびWO2007044729に見出すことができる。
マブ(Herceptin(商標))、トラスツズマブ-DM1、アービタックス(erbitux)、ベバシズマブ(Avastin(商標))、リツキシマブ(Rituxan(登録商標))、PRO64553(抗CD40)および2C4抗体を含む。抗体とは、インタクトなモノクローナル抗体、ポリクローナル抗体、少なくとも2つのインタクトな抗体および抗体断片から形成される多重特異的抗体を意味し、それらが所望の生物活性を示すことに限る。
プトプリン(とりわけ、ALLに対してara-Cと組み合わせて)、および/もしくはペントスタチンを含めた、ピリミジンまたはプリンヌクレオシドアナログを指す。リボヌクレオチドレダクターゼ阻害剤は、とりわけ、ヒドロキシ尿素または2-ヒドロキシ-1H-イソインドール-1,3-ジオン誘導体である。
ナル抗体;Angiostatin(商標);Endostatin(商標);アントラニル酸アミド;ZD4190;ZD6474;SU5416;SU6668;ベバシズマブ;またはrhuMAbおよびRHUFabなどの抗VEGF抗体もしくは抗VEGF受容体抗体、マクゴンなどのVEGFアプタマー;FLT-4阻害剤、FLT-3阻害剤、VEGFR-2 IgGI抗体、アンジオザイム(RPI4610)およびベバシズマブ(Avastin(商標))が含まれる。
サゾンなどの化合物を指す。
ernational(例えばIMS World Publications)から入手することができる。
の相互の期間内に投与することができる。
以下の実施例に図示されている通り、ある例示的な実施形態では、化合物は、以下の一般手順に従って調製する。一般方法は、本発明のある化合物の合成を図示しているが、以下の一般的な方法および当業者に公知の他の方法は、本明細書に記載されているすべての化合物、ならびにこれらの化合物のそれぞれの部分クラスおよび種に適用することができることが認識される。
4A MS:4Åモレキュラーシーブ
AcOH:酢酸
ACN:アセトニトリル
Anhyd:無水
Aq:水性、水溶液
Bn:ベンジル
Boc:tert-ブトキシカルボニル
CbzCl:クロロギ酸ベンジル
Cbz-OSU:N-(ベンジルオキシカルボニルオキシ)スクシンイミド
Cu(OAc)2:酢酸銅(II)
d:日数、日間
DAST:三フッ化ジエチルアミノ硫黄
DBU:1,8-ジアゾビシクロ[5.4.0]ウンデカ-7-エン
DCE:1,2-ジクロロエタン
DCM:ジクロロメタン
DEA:ジエチルアミン
DIBAL-H:水素化ジイソブチルアルミニウム
DIPEA:N,N-ジイソプロピルエチルアミン
DMA:N,N-ジメチルアセトアミド
DMAP:4-ジメチルアミノピリジン
DMF:N,N-ジメチルホルムアミド
DMSO-ジメチルスルホキシド
DPPA:ジフェニルホスホリルアジド
EDC:1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩
ee:鏡像異性体過剰率
ESI:エレクトロスプレーイオン化
Et3N:トリエチルアミン
Et2O:ジエチルエーテル
EtOAc:酢酸エチル
EtOH:エタノール
Fmoc:フルオレニルメチルオキシカルボニル
Fmoc-OSu:N-(9-フルオレニルメトキシカルボニルオキシ)スクシンイミドh:時間
HATU:1-[ビス(ジメチルアミノ)メチレン]-1H-1,2,3-トリアゾロ[4,5-b]ピリジニウム3-オキシドヘキサフルオロホスフェート
HCOONH4:ギ酸アンモニウム
HPLC:高速液体クロマトグラフィー
IBX:2-ヨードオキシ安息香酸
IPA:イソプロピルアルコール
KOAc:酢酸カリウム
M:モル濃度
Me:メチル
MeOH:メタノール
mins:分
mL:ミリリットル
mM:ミリモル濃度
mmol:ミリモル
MTBE:メチルtert-ブチルエーテル
NaBH3CN:シアノ水素化ホウ素ナトリウム
Na2CO3:炭酸ナトリウム
NaHCO3:炭酸水素ナトリウム
NMP:N-メチルピロリジン
NMR:核磁気共鳴
oC:摂氏度
PBS:リン酸緩衝食塩水
Pd/C:パラジウム炭素
Pd(OH)2/C:パールマン触媒
PE:石油エーテル
PhNH2:アニリン
PPh3:トリフェニルホスフィン
Rel:相対
rt:室温
sat:飽和
SFC:超臨界流体クロマトグラフィー
SOCl2:塩化チオニル
TBAB:臭化テトラ-n-ブチルアンモニウム
tBuOK:カリウムtert-ブトキシド
TEA:トリエチルアミン
Tf:トリフルオロメタンスルホネート
TfAA:トリフルオロメタンスルホン酸無水物
TFA:トリフルオロ酢酸(trifluoracetic acid)
TIPS:トリイソプロピルシリル
THF:テトラヒドロフラン
TMSCN:シアン化トリメチルシリル
pTSA:パラ-トルエンスルホン酸
TsOH:p-トルエンスルホン酸
塩[I-2]および(R)-2-アミノ-7,7,7-トリフルオロヘプタン酸塩酸塩[I-3]。
ステップ1:1,1,1-トリフルオロ-5-ヨードペンタン:
ステップ2:(S)-tert-ブチル2-(ジフェニルメチレンアミノ)-7,7,7-トリフルオロヘプタノエートおよび(R)-tert-ブチル2-(ジフェニルメチレ
ンアミノ)-7,7,7-トリフルオロヘプタノエート:
J = 8.0 Hz, 2H), 7.43-7.46 (m, 3H), 7.38-7.39 (m, 1H), 7.31-7.34 (m, 2H), 7.15-7.17 (m, 2H), 3.91 (dd, J = 5.5 Hz, 7.5 Hz, 1H), 2.00-2.05 (m, 2H), 1.88-1.92 (m, 2H), 1.31-1.52 (m, 13H).
J = 7.0 Hz, 2H), 7.43-7.46 (m, 3H), 7.38-7.39 (m, 1H), 7.31-7.34 (m, 2H), 7.15-7.17 (m, 2H), 3.92 (dd, J = 5.5 Hz, 7.5 Hz, 1H), 2.00-2.05 (m, 2H), 1.88-1.92 (m, 2H), 1.31-1.52 (m, 13H).
2H), 1.83-1.90 (m, 2H), 1.40-1.56 (m, 4H).
トリフルオロヘプタン酸塩酸塩(I-3)が白色固体(91.6mg、0.39mmol、82%)として得られた。ESI-MS(EI+、m/z):200.1[M+H]+。1H NMR (500 MHz, D2O) δ 3.92 (t, J = 6.0 Hz, 1H), 2.09 - 2.14
(m, 2H), 1.82 - 1.89 (m, 2H), 1.39 - 1.55 (m, 4H).
(m, 2H).
(m, 2H).
5,5-トリフルオロペンタンニトリル(6.7g、粗製)の溶液を17時間、95℃に加熱した。この溶液を濃縮乾固し、ACN(50mL)により希釈し、得られた溶液をろ過し(100mL)、pHを飽和NaHCO3溶液により3~4に調整して、この混合物をろ過して乾燥すると、2-(ベンジルアミノ)-5,5,5-トリフルオロペンタン酸(3.5g、13.4mmol、3ステップで43%)が白色固体として得られた。ESI-MS(EI+、m/z):262.1[M+H]+。
4.05-4.10 (m, 1H), 2.34-2.41 (m, 1H), 2.21-2.29 (m, 1H), 1.84-1.97 (m, 2H).
1H), 7.71 (d, J = 8.0 Hz, 1H), 7.30-7.39 (m, 5H), 5.05 (s, 2H), 4.05-4.10 (m, 1H), 2.34-2.41 (m, 1H), 2.21-2.29 (m, 1H), 1.84-1.97 (m,
2H).
H(20mL)中混合物を水素下、室温で2時間、撹拌した。この混合物をろ過し、フィルターケーキをMeOH(20mL)により洗浄した。このろ液を濃縮すると、(S)-2-アミノ-5,5,5-トリフルオロペンタン酸(I-6)(200mg、1.17mmol、71%)が白色固体として得られた。ESI-MS(EI+、m/z):172.1[M+H]+。1H-NMR (400 MHz, DMSO-d6): δ 8.38 (s, 3H), 4.05 (d,
J = 4.4 Hz, 1H), 2.34-2.55 (m, 2H), 1.95-20.9 (m, 2H).
J = 4.4 Hz, 1H), 2.34-2.55 (m, 2H), 1.95-20.9 (m, 2H).
移動相:n-ヘキサン(0.1%DEA):EtOH(0.1%DEA)=90:10)により精製すると、(S)-2-(ベンジルオキシカルボニルアミノ)-6,6,6-トリフルオロヘキサン酸(232mg、0.73mmol、29%)および(R)-2-(ベンジルオキシカルボニルアミノ)-6,6,6-トリフルオロヘキサン酸(250mg、0.78mmol、31.3%)が白色固体として得られた。ESI-MS(EI+、m/z):342.0[M+Na]+。
Hz, 1H), 7.38-7.32 (m, 5H), 5.04 (s, 2H), 4.00-3.96 (m, 1H), 2.28-2.19 (m, 2H), 1.80-1.51 (m, 4H).
Hz, 1H), 7.38-7.30 (m, 5H), 5.04 (s, 2H), 4.00-3.96 (m, 1H), 2.33-2.15 (m, 2H), 1.82-1.51 (m, 4H).
2H), 1.70-1.57 (m, 2H).
2H), 1.71-1.54 (m, 2H).
(m, 3H), 0.85~0.90 (m, 6H).
MHz, MeOD): δ 7.24-7.32 (m, 5H), 4.44 (t, J = 7.5 Hz, 1H), 3.58
(s, 2H), 1.64-1.68 (m, 3H), 0.96 (d, J = 6.0 Hz, 3H), 0.91 (d, J
= 6.0 Hz, 3H).
4.08-4.09 (m, 1H), 2.87-2.89 (m, 1H), 2.65-2.66 (m, 1H), 1.91-1.95 (m, 1H), 1.62~1.71 (m, 3H), 0.88~0.94 (m, 12H).
(q, J = 6.0 Hz, 1H), 2.68 (dd, J = 7.5 Hz, 12.0 Hz, 1H), 1.92~1.99 (m, 1H), 1.65~1.78 (m, 3H), 0.88~0.96 (m, 12H).
= 6.5 Hz, 2H), 7.47-7.57 (m, 3H), 4.69 (dd, J = 4.0 Hz, 11.0 Hz,
1H), 1.75-1.84 (m, 3H), 1.01 (dd, J = 6.5 Hz, 10.5 Hz, 6H).
C18 21*250mm 10μm、移動相:A:0.1%トリフルオロ酢酸;B:アセトニトリル)により精製すると、(S)-ベンジル2-イソブチルアミド-4-メチルペンタノエート(300mg、1.03mmol、81%)が白色固体として得られた。MS(EI+、m/z):292.2[M+H]+。
9.5 Hz, 1H), 2.69-2.74 (m, 1H), 2.05 (d, J = 12.5 Hz, 1H), 1.97 (d, J = 12.5 Hz, 1H), 1.74 - 1.67 (m, 2H), 1.57 - 1.51 (m, 2H), 1.50 - 1.44 (m, 1H), 1.36 - 0.99 (m, 5H), 0.87 (dt, J = 10.5 Hz,
J = 20.5 Hz, 6H).
6H).
5H), 4.30 (dd, J = 13.5 Hz, 37.0 Hz, 2H), 3.75 (dd, J = 7.5 Hz,
15.5 Hz, 1H), 1.65 (dt, J = 6.5 Hz, 13.5 Hz, 1H), 1.45 (t, J = 7.2 Hz, 2H), 0.85 (dd, J = 1.5 Hz, 6.5 Hz, 6H).
(dq, J = 6.5 Hz, 13.0 Hz, 1H), 1.54 - 1.46 (m, 2H), 0.91 - 0.82
(m, 6H).
12.82 (s, 1H), 7.56 (d, J = 9.0 Hz, 1H), 3.82 (dd, J = 8.0 Hz,
15.5 Hz, 1H), 2.88 (s, 3H), 1.72 (dt, J = 6.5 Hz, 13.0 Hz, 1H),
1.48 (t, J = 7.0 Hz, 2H), 0.89 (t, J = 7.0 Hz, 6H).
J = 7.5 Hz, 1H), 3.31 (dd, J = 5.0 Hz, 8.5 Hz, 1H), 1.80-1.71 (m, 1H), 1.50-1.44 (m, 1H), 1.35-1.29 (m, 1H), 0.90 (dd, J = 6.5 Hz,
14.0 Hz, 6H).
(m, 2H), 1.26-1.36 (m, 3H), 0.96 (dd, J = 6.0 Hz, 20.5 Hz, 6H).
δ 12.61 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.62 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.4 Hz, 2H), 3.63 (dd,
J = 8.5 Hz, 14.5 Hz, 1H), 1.53 (td, J = 6.5 Hz, 13.5Hz, 1H), 1.41 - 1.31 (m, 2H), 0.79 (d, J = 6.6 Hz, 3H), 0.66 (d, J = 6.5 Hz, 3H).
8.0 Hz, 2H), 3.99 (d, J = 8.4 Hz, 1H), 2.87 (q, J = 6.0 Hz, 1H), 1.72~1.86 (m, 2H), 1.62~1.68 (m, 1H), 0.85~1.03 (m, 6H).
により冷却した、(S)-2-アミノ-4-メチルペンタン酸(1.0g、7.62mmol)のアセトン(20mL)および飽和Na2CO3(20mL)中溶液を滴下して加えた。1時間後、この溶液を6M HCl溶液によりpH2に調整し、EtOAc(40×2)により抽出して、ブライン(80mL)により洗浄し、得られた溶液をろ過(80mL×3)して乾燥(Na2SO4)し、ろ過して真空で濃縮した。粗生成物をクロマトグラフィー(シリカ、MeOH/DCM=1/20)により精製すると、(S,E)-2-(4-メトキシ-4-オキソブタ-2-エナミド)-4-メチルペンタン酸(I-45)(1.0g、4.11mmol、53%)が黄色油状物として得られた。ESI-MS(EI+、m/z):244.2[M+H]+。1H-NMR (400 MHz, CDCl3): δ 7.32 (d, J = 15.2 Hz, 1H), 7.05 (d, J = 15.2 Hz, 1H), 6.85-6.89 (m,
2H), 7.30-7.46 (m, 1H), 3.82 (s, 1H), 1.63-1.78 (m, 3H), 0.97 (d, J = 4.8 Hz, 6H).
0M、69mL、69.0mmol)を滴下して加え、この混合物を-78℃で30分間、撹拌した。TLCによって確認した後に、この反応物を飽和クエン酸によりクエンチし、Et2Oにより抽出した。抽出物を飽和クエン酸、ブラインにより洗浄してNa2SO4で乾燥し、減圧下で濃縮すると、油状のアルデヒドである2,2-ジフルオロ-3-メチルブタナール(4.2g)が得られ、これを精製することなく、次のステップに直ちに使用した。
Hz, 3 H).
mg、0.24mmol)のMeOH(15mL)中溶液に、室温でHCOONH4(77mg、1.22mmol)およびPd/C(100mg)を加えた。この混合物を60℃で2時間、撹拌した。反応混合物をろ過して濃縮すると、粗生成物が得られ、これを逆相シリカゲルクロマトグラフィーにより精製すると、(S)-2-アミノ-3,3-ジフルオロ-4-メチルペンタン酸(I-47)(14mg、34%)が白色固体として得られた。1H-NMR (500 MHz, D2O): δ 4.27 (dd, J = 24.0, 3.5 Hz, 1 H), 2.55-2.42 (m, 1 H), 1.04 (d, J = 7.0 Hz, 3 H), 0.993 (d, J = 6.5
Hz, 3 H).
ステップ1:(S)-tert-ブチル4-メチル-1-(メチルスルホンアミド)-1-オキソペンタン-2-イルカルバメート:
ステップ2:(S)-2-アミノ-4-メチル-N-(メチルスルホニル)ペンタンアミド塩酸塩[I-147]:
ステップ1:(S)-tert-ブチル4,4-ジメチル-1-(N-メチルメチルスルホンアミド)-1-オキソペンタン-2-イルカルバメート:
ステップ2:(S)-2-アミノ-N,4,4-トリメチル-N-(メチルスルホニル)ペンタンアミド塩酸塩[I-193]:
ステップ1:tert-ブチル4-フルオロ-4-メチル-1-(メチルスルホンアミド)-1-オキソペンタン-2-イルカルバメート:
ステップ2:2-アミノ-4-フルオロ-4-メチル-N-(メチルスルホニル)ペンタンアミド塩酸塩[I-192]。
ステップ1:(S)-メチル2-((S)-2-(tert-ブトキシカルボニルアミノ)-4,4-ジメチルペンタンアミド)-4-メチルペンタノエート:
ステップ2:(S)-メチル2-((S)-2-アミノ-4,4-ジメチルペンタンアミド)-4-メチルペンタノエート塩酸塩[I-190]。
塩酸塩[I-122]。
ステップ1:(S)-メチル2-アミノ-4,4-ジメチルペンタノエート塩酸塩[I-122]:
ステップ1:(R)-メチル2-アミノ-4,4-ジメチルペンタノエート塩酸塩[I-123]:
(34.2mg、0.17mmol、50%)として得られた。ESI-MS(EI+、m/z):160.1[M+H]+。1H-NMR (500 MHz, CD3OD): δ 4.02-4.04 (m, 1H), 3.86 (s, 3H), 1.97-2.02 (m, 1H), 1.64-1.68 (m, 1H), 1.03 (s,
9H).
ステップ1:2-(tert-ブトキシカルボニルアミノ)-5,5,5-トリフルオロ-4-メチルペンタン酸:
ステップ2:2,5-ジオキソピロリジン-1-イル2-(tert-ブトキシカルボニルアミノ)-5,5,5-トリフルオロ-4-メチルペンタノエート:
ニルアミノ)-5,5,5-トリフルオロ-4-メチルペンタノエート(400mg)が白色固体として得られた。ESI-MS(EI+、m/z):282.9[M-100]+。
ステップ3:tert-ブチル1-シアナミド-5,5,5-トリフルオロ-4-メチル-1-オキソペンタン-2-イルカルバメート:
ステップ4:2-アミノ-N-シアノ-5,5,5-トリフルオロ-4-メチルペンタンアミド塩酸塩[I-205]:
3H).
ステップ2:1-メチルシクロブタンカルバルデヒド:
ステップ3:(Z)-tert-ブチル2-(tert-ブトキシカルボニルアミノ)-3-(1-メチルシクロブチル)アクリレート:
ステップ4:tert-ブチル2-(tert-ブトキシカルボニルアミノ)-3-(1-メチルシクロブチル)プロパノエート:
。この混合物をろ過し、ろ液を濃縮乾固すると、tert-ブチル2-(tert-ブトキシカルボニルアミノ)-3-(1-メチルシクロブチル)プロパノエート(600mg、粗製)が無色油状物として得られた。ESI-MS(EI+、m/z):158.2[M-156]+。
ステップ5:2-アミノ-3-(1-メチルシクロブチル)プロパン酸[I-206]:
1H NMR (500 MHz, D2O) δ 3.91 (t, J = 7.5 Hz, 1H), 2.06-2.02 (m, 1H), 1.88-1.64 (m, 7H), 1.15 (s, 3H).
2-アミノ-3-(1-メチルシクロブチル)プロパン酸の手順は、実施例8と同じとした。
ステップ6:2-(ベンジルオキシカルボニルアミノ)-3-(1-メチルシクロブチル)プロパン酸:
3(3mL)中混合物を室温で5時間、撹拌した。この溶液を分取HPLC(Boston C18 21*250mm 10μm、移動相:A:0.1%トリフルオロ酢酸;B:アセトニトリル)により精製すると、2-(ベンジルオキシカルボニルアミノ)-3-(1-メチルシクロブチル)プロパン酸(160mg、0.54mmol)が白色固体として得られた。MS(EI+、m/z):292.0[M+H]+。
ステップ7:(S)-2-(ベンジルオキシカルボニルアミノ)-3-(1-メチルシクロブチル)プロパン酸:
ステップ8:(S)-2-アミノ-3-(1-メチルシクロブチル)プロパン酸[I-93]:
δ 3.76-3.79 (t, 1H), 1.96-2.00 (m, 1H), 1.61-1.86 (m, 7H), 1.11 (s, 3H).
ステップ1:tert-ブチル2-(ジフェニルメチレンアミノ)-3-(トリメチルシリル)プロパノエート:
S(8.47mL、8.47mmol)を滴下して加えた。この溶液を-78℃で1時間、撹拌した。(ヨードメチル)トリメチルシラン(1.8g、8.47mmol)を滴下して加えた。この溶液を-78℃~室温で、一晩、撹拌した。この溶液をブライン(25mL*2)により洗浄して乾燥(Na2SO4)し、濃縮してクロマトグラフィー(シリカ、酢酸エチル/石油エーテル=1/30)により精製すると、tert-ブチル2-(ジフェニルメチレンアミノ)-3-(トリメチルシリル)プロパノエート(2.3g、6.04mmol、71%)が黄色固体として得られた。ESI-MS(EI+、m/z):382.3[M+H]+。
ステップ2:2-アミノ-3-(トリメチルシリル)プロパン酸塩酸塩[I-204]:
8.33 (br, 1H), 3.75 (m, 1H), 1.00-1.14 (m, 2H), 0.06 (s, 9H).
ステップ1:(S)-2-アミノ-3-(トリメチルシリル)プロパン酸塩酸塩[I-201]:
I-200]。
ステップ1:(R)-2-アミノ-3-(トリメチルシリル)プロパン酸塩酸塩[I-200]:
ステップ1:(S)-2-アミノ-4-フルオロ-4-メチルペンタン酸[I-194]:
3.79 (m, 1H), 2.19-2.26 (m, 1H), 1.97-2.05 (m, 1H), 1.42 (d, Jz=3.5
Hz, 3H), 1.37 (d, Jz=4.0 Hz, 3H).
ステップ1:(S)-tert-ブチル1-シアノ-3,3-ジメチルブチルカルバメート:
ステップ2:(S)-tert-ブチル3,3-ジメチル-1-(2H-テトラゾール-5-イル)ブチルカルバメート:
ープとして得られた。ESI-MS(EI+、m/z):214.3[M+H-56]+。
ステップ3:((S)-3,3-ジメチル-1-(2H-テトラゾール-5-イル)ブタン-1-アミン[I-94]:
C18 21*250mm 10μm、移動相:A:0.1%トリフルオロ酢酸;B:アセトニトリル)により直接、精製すると、(S)-3,3-ジメチル-1-(2H-テトラゾール-5-イル)ブタン-1-アミン2,2,2-トリフルオロ酢酸塩[I-94]が白色固体として得られた(30mg、0.11mmol、9%、3ステップ)。MS(EI+、m/z):170.2[M+H]+。1H NMR (500 MHz, CD3OD) δ 8.18 (br, 3H), 4.48 (m, 1H), 2.14 (m, 1H), 1.73 (dd, Jz=3.5, 16.5 Hz 1H), 0.72 (s, 9H).
を加えた。この混合物を室温まで温め、この温度で17時間、撹拌した。この反応混合物を水(300mL)に注ぎ入れ、EA(200mL×2)により抽出し、有機相を水(200mL×3)およびブライン(100mL)により洗浄して乾燥(Na2SO4)し、この溶液を濃縮して、粗製物をSGCにより精製すると、明黄色液体(8.0g、81%)が得られた。
1H NMR (500 MHz, CDCl3) δ 9.77 (s, 1H), 7.36-7.26 (m, 5H), 4.53 (s, 2 H), 3.8-3.83 (m, 2H), 2.71-2.68 (m, 2H).
1H NMR (500 MHz, CDCl3) δ 7.38-7.29 (m, 5H), 4.51 (t, J= 12 Hz, 2
H), 4.23-4.19 (m, 1H), 3.59-3.57 (m, 2H), 2.04-2.01 (m, 1H), 1.78-1.73 (m, 1H), 0.13 (s, 9H).
1H NMR (500 MHz, CDCl3) δ 7.38-7.29 (m, 5H), 4.53 (t, J= 12 Hz, 2
H), 3.78-3.74 (m, 1H), 3.66-3.57 (m, 2H), 3.5 (s, 3H), 2.03-1.96 (m, 1H), 1.78-1.57 (m, 1H).
1H NMR (500 MHz, メタノール-d4) δ 4.23-4.19 (m, 1H), 3.96-3.88 (m, 1H), 3.64-3.6 (m, 3H), 2.29-2.22 (m, 1H), 2.04-1.97 (m, 1H).
サン酸(0.6g、2.3mmol、3ステップで30%)が白色固体として得られた。ESI-MS(EI+、m/z):264.4[M+H]+。
1.51 (m, 2H), 0.97 (d, J = 14.9 Hz, 6H), 0.92 (dd, J = 6.8, 3.6
Hz, 6H).
-ジメチルヘキサン酸[I-191]。
J = 15.0 Hz, J = 5.0 Hz, 1H), 1.42 (dd, J = 15.0 Hz, J = 7.0
Hz, 1H), 1.23-1.28 (m, 2H), 0.87 (d, (dd, J = 4.5 Hz, 6H), 0.80 (t, J = 7.5 Hz, 3H).
J = 15.0 Hz, J = 5.0 Hz, 1H), 1.42 (dd, J = 15.0 Hz, J = 7.0
Hz, 1H), 1.23-1.28 (m, 2H), 0.87 (d, (dd, J = 4.5 Hz, 6H), 0.80 (t, J = 7.5 Hz, 3H).
カゲルクロマトグラフィーにより精製すると、2-アミノ-6,6,6-トリフルオロ-4-メチルヘキサン酸[I-177](45mg、84%)が白色固体として得られた。ESI-MS(EI+、m/z):200.2[M+H]+;1H NMR (500 MHz, DMSO) δ 3.15 (d, J = 5.7 Hz, 1H), 2.39 - 2.24 (m, 1H), 2.19 - 1.96
(m, 2H), 1.82 - 1.66 (m, 1H), 1.63 - 1.35 (m, 1H), 0.98 (dd, J = 16.5, 6.2 Hz, 3H).
ステップ1:5-(ベンジルオキシメチル)-2,2-ジメチル-1,3-ジオキサン:
ステップ2:2-(ベンジルオキシメチル)プロパン-1,3-ジオール:
20mL)により希釈し、ブライン(15mL)により洗浄して乾燥し、蒸発させると、粗製無色油状物(780mg、100%)が得られた。ESI-MS(EI+、m/z):197[M+H]+。
ステップ3:((3-フルオロ-2-(フルオロメチル)プロポキシ)メチル)ベンゼン:
4H), 3.57 (d, J = 6.2 Hz, 2H), 2.50 - 2.34 (m, 1H).
ステップ4:3-フルオロ-2-(フルオロメチル)プロパン-1-オール:
ステップ5:3-フルオロ-2-(フルオロメチル)プロピルトリフルオロメタンスルホネート:
ステップ6:tert-ブチル2-(ジフェニルメチレンアミノ)-5-フルオロ-4-(フルオロメチル)ペンタノエート:
物(22mg、6.9%)が白色固体として得られた。ESI-MS(EI+、m/z):388[M+H]+。1H NMR (500 MHz, DMSO) δ 7.56 - 7.45 (m, 6H), 7.41 (t, J = 7.4 Hz, 2H), 7.18 (d, J = 6.3 Hz, 2H), 4.50 - 4.17
(m, 4H), 3.91 (dd, J = 7.7, 5.5 Hz, 1H), 2.11 - 1.97 (m, 1H), 1
.87 (dd, J = 12.7, 5.5 Hz, 2H), 1.38 (s, 9H).
ステップ7:(S)-2-アミノ-5-フルオロ-4-(フルオロメチル)ペンタン酸塩酸塩:
ステップ1:(S)-3-アミノ-5,5-ジメチル-ジヒドロフラン-2(3H)-オン[I-187]:
- 2.48 (m, 1H), 2.13 (t, J = 11.7 Hz, 1H), 1.45 (s, 3H), 1.40 (s, 3H).
4)し、ろ過して真空で濃縮し、クロマトグラフィー(シリカ、酢酸エチル/石油エーテルを0%から5%)によって精製すると、ジエチル2-(1,1-ジフルオロプロパン-2-イリデン)マロネート(60.9g、258mmol、86%)が無色液体として得られた。ESI-MS(EI+、m/z):237.0[M+H]+。1H-NMR (500 MHz, CDCl3): δ 6.97 (t, J = 55.5 Hz, 1H), 4.25-4.33 (m, 4H), 2.03 (s, 3H), 1.29-1.34 (m, 6H).
m 5um;溶媒、MeOH(0.2%メタノールアンモニア)]によって精製すると、(S)-2-(ベンジルオキシカルボニルアミノ)-5,5-ジフルオロ-4,4-ジメチルペンタン酸(400mg、1.27mmol、26%、2ステップ)および(R)-2-(ベンジルオキシカルボニルアミノ)-5,5-ジフルオロ-4,4-ジメチルペンタン酸(380mg、1.21mmol、25%、2ステップ)が2つの無色油状物として得られた。ESI-MS(EI+、m/z):316.0。
6.0 Hz, 1H), 2.07 (dd, J = 15.5 Hz, J = 5.5 Hz, 1H), 1.77 (dd,
J = 15.5 Hz, J = 6.5 Hz, 1H), 0.96 (d, J = 9.5 Hz, 6H).
eOH(0.2%メタノールアンモニア)]により精製すると、(S)-2-(ベンジルアミノ)-5,5-ジフルオロ-4,4-ジメチルペンタンアミド(400mg、1.48mmol、31%)および(R)-2-(ベンジルアミノ)-5,5-ジフルオロ-4,4-ジメチルペンタンアミド(380mg、1.41mmol、30%)が2つの無色液体として得られた。ESI-MS(EI+、m/z):253.0[M+H]+。
MHz, MeOD-d4): δ 5.66 (t, J = 56.5 Hz, 1H), 3.95 (dd, J = 8.0 Hz, J = 5.0 Hz, 1H), 2.14 (dd, J = 10.0 Hz, J = 8.0 Hz, 1H), 1.83 (dd, J = 14.5 Hz, J = 5.5 Hz, 1H), 1.12 (d, J = 15.0 Hz, 6H).
ーのバイオタージにより精製すると、(S)-メチル2-((S)-2-アミノ-5,5-ジフルオロ-4,4-ジメチルペンタンアミド)-4-メチルペンタノエート(45mg、69%)が白色固体として得られた。ESI-MS(EI+、m/z):309.0。
1H-NMR (500 MHz, DMSO-d6): 9.11 (d, J = 7 Hz, 1H), 8.41 (s, 3H), 5.81 (t, J = 56.5 Hz, 1H), 4.34-4.31 (m, 1H), 3.89-3.81 (m, 1H), 3.62 (s, 3H), 1.98-1.93 (m, 1H), 1.76-1.73 (m, 1H), 1.65-1.54 (m, 3H), 0.93-0.81 (m, 12H).
1H-NMR (500 MHz, DMSO-d6): 9.18 (d, J = 7 Hz, 1H), 8.38 (s, 3H), 5.79 (t, J = 56.5 Hz, 1H), 4.37-4.32 (m, 1H), 3.85-3.78 (m, 1H), 3.58 (s, 3H), 1.97-1.92 (m, 1H), 1.77-1.72 (m, 1H), 1.61-1.51 (m, 3H), 0.94-0.82 (m, 12H).
ロ-4-メチルペンタン酸(150mg、0.47mmol)およびPd/C(75mg)のMeOH(15mL)中溶液を、室温で3時間、撹拌した。この反応混合物をろ過して濃縮すると、(2S,4R)-2-アミノ-5,5,5-トリフルオロ-4-メチルペンタン酸(51.7mg、59%)が白色固体として得られた。ESI-MS(EI+、m/z):186.2[M+H]+。1H-NMR (500 MHz, MeOD): δ 3.64-3.60 (m,
1H), 2.77-2.71 (br, 1H), 2.24-2.18 (m, 1H),1.76-1.69 (m, 1H),1.25 (d,
J = 7.0 Hz, 3 H).
= 7.0 Hz, 3 H).
使用した手順は、実施例187において使用されているものと同じとした。
J = 5.5 Hz, 1H), 2.23 (dd, J = 15.5 Hz, J = 5.5 Hz, 1H), 1.90
(dd, J = 15.5 Hz, J = 6.0 Hz, 1H), 1.13 (d, J = 8.5 Hz, 6H).
1H-NMR (500 MHz, MeOD-d4): 4.47 (t, J = 7.5 Hz, 1H), 3.99-3.97 (m, 1H), 3.77 (s, 3H), 2.33-2.28 (m, 1H), 1.95-1.91 (m, 1H), 1.69-1.68 (m, 3H), 1.24-1.17 (m, 6H), 1.00-0.94 (m, 6H).
使用した手順は、実施例188において使用されているものと同じとした。
手順および特性決定:
(実施例189)(S)-メチル2-((S)-2-アミノ-5,5,5-トリフルオロ-4,4-ジメチルペンタンアミド)-4-メチルペンタノエート[I-189]:1H-NMR (500 MHz, MeOD-d4): 4.52 (t, J = 7.5 Hz, 1H), 4.02-3.99 (m, 1H), 3.73 (s, 3H), 2.35-2.30 (m, 1H), 1.95-1.91 (m, 1H), 1.78-1.67 (m,
3H), 1.25 (s, 3H), 1.17 (s, 3H), 1.01-0.97 (m, 6H).
ステップ1:tert-ブチル2-(ジフェニルメチレンアミノ)-6-フルオロヘキサノエート:
ステップ2:(S)-2-アミノ-6-フルオロヘキサン酸[I-108]:
ステップ2:(R)-2-アミノ-6-フルオロヘキサン酸[I-109]:
Hz, 1H), 4.410 (t, J = 6.0 Hz, 1H), 3.823 (t, J = 6.0 Hz, 1H),
1.906-1.827 (m, 2H), 1.722-1.639 (m, 2H) , 1.485-1.399 (m, 2H).
状物として得られた。ESI-MS(EI+、m/z):254.1[M+H]+。
ル)ペンタノエート(100mg、0.30mmol)、HCOONH4(92mg、1.5mmol)およびPd/C(10%、20mg)のMeOH(10mL)中混合物を1時間、65℃に加熱した。この混合物をろ過し、ろ液を濃縮して、逆相シリカゲルクロマトグラフィーにより精製すると、メチル2-アミノ-5,5,5-トリフルオロ-4-(トリフルオロメチル)ペンタノエートトリフルオロ酢酸(76mg、0.21mmol、70%)が白色固体として得られた。ESI-MS(EI+、m/z):254.1[M+H]+。1H NMR (500 MHz, MeOD-d4) δ 4.26 (dd, J = 7.5 Hz, J =
6.0 Hz, 1H), 3.91 (m, 4H), 2.49 (dd, J = 8.5 Hz, J = 5.0 Hz, 1H), 2.33-2.37 (m, 1H).
HCl溶液により3~4に調整し、この溶液をEtOAc(50mL×2)により抽出してブライン(50mL)により洗浄し、乾燥(Na2SO4)して、ろ過して真空で濃縮し、粗生成物を逆相シリカゲルクロマトグラフィー、次に、キラル分取HPLC[カラム、CC4 4.6*250mm 5um;溶媒、MeOH(0.2%メタノールアンモニア)]によって精製すると(S)-2-(ベンジルオキシカルボニルアミノ)-5,5,5-トリフルオロ-4-(トリフルオロメチル)ペンタン酸(27mg、0.072mmol、5%、2ステップ)および(R)-2-(ベンジルオキシカルボニルアミノ)-5,5,5-トリフルオロ-4-(トリフルオロメチル)ペンタン酸(22mg、0.059mmol、4%、2ステップ)が2つの無色油状物として得られた。ESI-MS(EI+、m/z):396.0[M+Na]+。
(40mL)中溶液に、氷浴下、IBX(7.35g、26.3mmol)を加えた。この混合物を室温まで温め、一晩、撹拌した。この反応混合物を水(200mL)に注ぎ入れ、Et2O(100mL×2)により抽出し、有機相を水(100mL×3)およびブライン(100mL)により洗浄して乾燥(Na2SO4)し、この溶液を次のステップに使用した。
得られた。ESI-MS(EI+、m/z):342.2[M+H]+。
5mmol)およびPd/C(10%、10mg)のMeOH(5mL)中混合物を1時間、60℃に加熱した。この混合物をろ過し、ろ液を濃縮して、逆相シリカゲルクロマトグラフィーにより精製すると、2-アミノ-N-シクロペンチル-3,3-ジフルオロ-N,4-ジメチルペンタンアミド(16.3mg、0.066mmol、49%)が白色固体として得られた。ESI-MS(EI+、m/z):249.2 1H NMR (500 MHz, MeOD-d4) δ 5.26 (dd, J = 15.5 Hz, J = 6.0 Hz, 0.5H), 5.08 (dd, J = 16.5 Hz, J = 5.0 Hz, 1H), 4.28-4.31 (m, 0.5H), 2.97 (d, J
= 48.5 Hz, 3H), 2.38 (m, 1H), 1.65-1.99 (m, 8H), 11.16 (dt, J = 6.5 Hz, J = 3.0 Hz, 6H).
ステップ1:3-ヒドロキシ-N-メトキシ-N,2,2-トリメチルプロパンアミド:
ステップ2:3-フルオロ-N-メトキシ-N,2,2-トリメチルプロパンアミド:
ステップ3:3-フルオロ-2,2-ジメチルプロパナール:
ステップ5:tert-ブチル2-(tert-ブトキシカルボニルアミノ)-5-フルオロ-4,4-ジメチルペンタノエート:
(Z)-tert-ブチル2-(tert-ブトキシカルボニルアミノ)-5-フルオロ-4,4-ジメチルペンタ-2-エノエート(190mg、0.60mmol)およびPd/C(10%、30mg)のIPA(15mL)中混合物を、水素下、室温で17時間、撹拌した。この混合物をろ過して濃縮すると、tert-ブチル2-(tert-ブトキシカルボニルアミノ)-5-フルオロ-4,4-ジメチルペンタノエート(200mg、粗製)が無色液体として得られた。ESI-MS(EI+、m/z):342.2[M+Na]+。
ステップ6:2-アミノ-5-フルオロ-4,4-ジメチルペンタン酸トリフルオロ酢酸:
tert-ブチル2-(tert-ブトキシカルボニルアミノ)-5-フルオロ-4,4-ジメチルペンタノエート(200mg、粗製)の6M HCl(20mL)およびジオキサン(10mL)中溶液を17時間、50℃に加熱した。この混合物を真空で濃縮し、水(30mL)により希釈し、Et2O(20mL×2)により抽出して、ろ液を真空
で濃縮し、逆相シリカゲルクロマトグラフィーにより精製すると、2-アミノ-5-シクロペンチルペンタン酸トリフルオロ酢酸塩(31.7mg、0.11mmol、19%)が白色固体として得られた。ESI-MS(EI+、m/z):164.2[M+H]+。1H-NMR (500 MHz, D2O): δ 4.16 (d, J = 47.5 Hz, 1H), 3.97 (t, J
= 5.5 Hz, 1H), 2.03 (dd, J = 15.5 Hz, J = 5.5 Hz, 1H), 1.71 (dd, J = 15.5 Hz, J = 6.0 Hz, 1H), 0.91 (dd, J = 15.0 Hz, J = 2.0 Hz, 6H).
ペンタン酸:
Hz, J = 9.5 Hz, 1H),1.94 (dd, J = 15.0 Hz, J = 3.0 Hz, 1H), 1.38 (dd, J = 9.5 Hz, J = 5.0 Hz, 6H).
より抽出した。有機相を水(30mL×2)およびブライン(50mL)により洗浄して乾燥(Na2SO4)し、ろ過して真空で濃縮すると、2-(ベンジルアミノ)-5,5,5-トリフルオロ-4-メチルペンタンニトリル(2.6g、粗製)が褐色油状物として得られ、これを次のステップに使用した。ESI-MS(EI+、m/z):257.3[M+H]+。
NMR (500 MHz, DMSO-d6) δ 4.67-4.93 (m, 1H), 2.31 - 2.41 (m, 1H),
2.00-2.12 (m, 2H), 0.99 (dd, J = 16.8, J = 6.4 Hz, 6H).
細胞を成長させた。
ることである。さらに、この方法は、セストリン2へのロイシンの結合を拮抗する化合物、およびロイシンに応答して、GATOR2からセストリン2が解離するの阻止する化合物を特定する。
ストリン2の欠損は、100%活性を表すように正規化する。化合物は、2連でアッセイし、各化合物の活性は、ロイシン活性の割合として定量し、平均する。試験化合物から定量したデータの一覧表示を表3に示す。アッセイを繰り返して試みると、水と比べて、ロイシンの平均活性は20%の標準偏差となった。したがって、25μMにおいて、2連のどちらもGATOR2に結合したセストリン2の量が少なくとも40%低下した化合物は、統計的に有意と見なされ、ロイシン模倣体と称した。一部の化合物では、Flag-WDR24に結合したセストリン2の量が増加した(表3中のロイシンのネガティブ活性率として示す)。-40%未満のロイシン活性を示した化合物もやはり、適合した(hits)と見なされ、ロイシンアンタゴニストと称した。
年)に記載されている通り、ロイシンの添加の10~90分後にシグナル伝達を測定すると、mTORC1が活性化される。したがって、ロイシン模倣体として特定された化合物が、同様の様式で、mTORC1を活性化するかどうかを試験する同様のアッセイを設計した。簡潔に言うと、10%ウシ胎児血清および抗生物質を補給したDMEM中で、800,000個のHEK293T細胞を6ウェルプレートの各ウェルでプレート培養した。翌日、細胞をロイシンを含まない改変DMEM(Thermo Scientific)または血清を含まない改変DMEMに1時間、置き、次いで、10分間より長いある期間、所与の濃度でロイシン模倣体を添加(n=3)した。次に、細胞を溶解して、SDS-PAGEの処理を行い、Kang,S.A.ら、Science 341巻(6144号):364~374頁(2013年)に記載されている通り、mTORC1基質であるリン酸化S6キナーゼ(Thr389)、およびリン酸化4EBP1(Thr37/46)(Cell Signaling Technology)、および負荷対照(ベータ-アクチン、Santa Cruz Biotechnology)を対象とする抗体を用いてウエスタンブロット法を行った。次に、LI-COR(登録商標)イメージングプラットフォームを使用して、リン酸化基質に対応するバンドの強度を、アクチンのバンドに対して正規化した。化合物により処置されていないロイシン飢餓細胞に対して、mTORC1シグナル伝達を著しく増加させる(スチューデントt検定、p<0.05)化合物は、細胞において活性があると見なした。ポジティブ対照として、ロイシン飢餓細胞に、ロイシンを60分間、100μMで加えた。
物は、細胞においてロイシン増強剤であると見なした。対照として、ロイシンを添加する前に、ロイシン飢餓細胞を予め水により処置した。あるいは、潜在的なロイシンアンタゴニストは、上記と同じであるが、ロイシン飢餓および刺激のない方法で、HEK293T細胞においてアッセイした。十分量の培養条件下で、化合物を処置した際に、mTORC1のシグナル伝達のベースラインが減衰するかどうかを決定するため、ウエスタンブロットを行った。
ources/Images/44-176283MAN_SureFire_TGR70S_p70_pT389.pdf)に従ってアッセイした。化合物により処置されてい
ないロイシン飢餓細胞に対して、mTORC1のシグナル伝達を著しく増加させる(スチューデントt検定、p<0.05)化合物は、mTORC1アクチベータであると見なした。化合物により処置されていないロイシン飢餓細胞に対して、mTORC1のシグナル伝達を著しく低下させる(スチューデントt検定、p<0.05)化合物は、細胞において阻害剤であると見なした。ポジティブ対照として、ロイシンは、化合物処置と等しい期間、ロイシン飢餓細胞に100uMで添加した。
形質転換させた。細胞を37℃で、0.6ODまで成長させて、次に、18℃で12~14時間、0.2mM IPTGによりタンパク質産生を誘発させた。6,000gで遠心分離することにより細胞を採集し、溶解緩衝液(50mMリン酸カリウム、pH8.0、500mM NaCl、30mMイミダゾール、1mM DTT、10μg/ml ベンゾナーゼおよび1mM PMSF)に再懸濁し、音波照射により溶解した。この溶解物を10,000gで20分間、遠心分離することにより清澄化した。可溶化画分からセストリン2タンパク質を単離し、Hisタグの親和性捕捉、次いで、イオン交換およびサイズ排除クロマトグラフィーによりほぼ100%の純度にした。サーマルシフトアッセイに関しては、セストリン2タンパク質を希釈緩衝液(10mM Tris HCl pH7.4、150mM NaCl、1mM DTT、0.1mM EDTA)中で、2mg/mlまで希釈した。サーマルシフトアッセイを行う前に、2μlのセストリン2タンパク質を、96ウェルプレートのウェルあたり、8μlのROX色素(Thermo Fisher)、1μLのビヒクルまたは化合物、および14μLの希釈緩衝液と合わせ、化合物を結合させるため、1時間、氷の上でインキュベートした。次に、Agilent MX3005pでサーマルシフトアッセイを行い、各化合物を、10μM、100μMおよび1000μMの3連でアッセイした。ロイシンとのインキュベートにより、セストリン2の溶融温度が、用量依存様式で、2.16から11.61摂氏度にシフトした。ビヒクルと共にインキュベートしたセストリン2の、サーマルシフトの繰り返し測定値のCV%変動に基づいて、2度またはそれより多い正方向へのシフトを、統計的に有意であると見なす。
、Cell Reports 9巻:1~8頁(2014年)に記載されている通り、化合物のイン
キュベート後に、試料に、1.5時間、CST抗セストリン2抗体を用いた免疫沈降を施し、次いで、プロテインA-セファロースと共に、30分間のインキュベートした。セファロースコンジュゲート抗体-タンパク質複合体を遠心分離により沈殿させて、試料間の全セストリン2タンパク質レベルが等しいことを決定するため、ウサギポリクローナル抗セストリン2抗体(Protein Tech、#10795-1-AP)を用いて、フロースルーに2回の免疫沈降を施した。免疫沈降試料に、SDS-PAGE、次いで、SIGMA(カタログ番号WH0083667M3)からのマウスモノクローナル抗セストリン2抗体を用いるウエスタンブロットを行った。CSTに由来する抗セストリン2抗体により免疫沈降させた試料を用いる免疫ブロットの場合、ロイシン結合により、セストリン2に対応するバンドの強度が50%またはそれより大きな、かなりの低下が誘発された
が、Protein Tech抗体により免疫沈降した試料を用いた免疫ブロットの場合、セストリン2の変化はもたらされなかった。やはり測定されたこの型のアッセイにより、化合物とのインキュベートにより誘発されるセストリン2の不安定性が増加した。このアッセイは、同じ方法で行ったが、セストリン2を脱安定化する(サーマルシフトアッセイによって測定される)化合物は、CST抗体を使用して免疫沈降させたセストリン2に対応する免疫ブロットバンド強度の増加をもたらした。
胞に由来する溶解物を用いて、ALPHAlisaを行った。細胞をベースとする処置は、多重ウェルプレートで行い、ALPHAlisa反応あたり、15μLの溶解物(1mg/mlの全タンパク質)を、ビオチン化抗体10μL、抗体/受容体ビーズミックス12.5μLおよびストレプトアジピンドナービーズミックス12.5μLと組み合わせて使用した。
は、DMSOに対して、5.1~10倍のシフトを実現し、「G」と表示されている活性を有する化合物は、DMSOに対して、10.1~14倍のシフトを実現した。
(項目1)
式Iの化合物:
R 1 は、HまたはC 1~6 アルキルであり、
R 2 は、R、-(CH 2 ) n -フェニル、-C(O)R、-SO 2 Rまたは-C(O)N(R) 2 であり、
nは、0、1または2であり、
Rはそれぞれ独立して、水素、-CN、あるいは飽和もしくは不飽和C 1~6 脂肪族、フェニル、4~7員の飽和もしくは部分不飽和の単環式炭素環式環、1~4個のヘテロ原子を有する5~6員の単環式ヘテロアリール環、または窒素、酸素もしくは硫黄から独立して選択される1~2個のヘテロ原子を有する4~8員の飽和または部分飽和の複素環式環から選択される、任意選択で置換されている基であり、
R 3 は、環A、-C(O)R、-C(O)OR、-C(O)N(R) 2 、-SO 3 H、-SO 2 N(R) 2 、-S(O)R、-S(O)環A、-ORまたは-B(OR) 2 であり、この場合、同一ホウ素上の2つのOR基はそれらの介在原子と一緒になって、前記ホウ素および2個の酸素に加えて、窒素、酸素もしくは硫黄から独立して選択される0~3個のヘテロ原子を有する、5~8員の飽和もしくは部分不飽和の単環式環を形成するか、またはR 3 とR 4 が一緒になって、窒素、酸素もしくは硫黄から選択される0~1個のヘテロ原子を有する、任意選択で置換されている5~6員環を形成し、
Lは、共有結合、または1~9つのフルオロ基により任意選択で置換されている直鎖もしくは分枝状C 1~6 アルキレン鎖であり、
環Aは、フェニル、または窒素、酸素もしくは硫黄から独立して選択される1~4個のヘテロ原子を有する、任意選択で置換されている5~6員のヘテロアリール環から選択される、任意選択で置換されている環であり、
R 4 は、R、-CF 3 、-OR、-N(R) 2 、-Si(R) 3 もしくは-SRであるか、またはR 3 とR 4 が一緒になって、窒素、酸素もしくは硫黄から選択される0~1個のヘテロ原子を有する、任意選択で置換されている5~6員環を形成し、
R 5 は、HまたはC 1~4 アルキルである)であって、
前記式Iの化合物は、表2に図示されているもの以外である、式Iの化合物。
(項目2)
R 1 がHである、項目1に記載の化合物。
(項目3)
R 1 がC 1~6 アルキルである、項目1に記載の化合物。
(項目4)
R 2 が、-(CH 2 ) n -フェニルである、項目1に記載の化合物。
(項目5)
R 2 が、-C(O)R、-SO 2 Rまたは-C(O)N(R) 2 である、項目1に記載の化合物。
(項目6)
R 2 が、メチル、-(CH 2 )-フェニルまたは-C(O)CH 3 である、項目1に記載の化合物。
(項目7)
R 3 が、-C(O)R、-C(O)OR、-C(O)N(R) 2 、-SO 3 H、-SO 2 N(R) 2 、-S(O)R、-S(O)環A、-ORまたは-B(OR) 2 である、項目1から6のいずれかに記載の化合物。
(項目8)
前記化合物が、式II:
(項目9)
環Aが、任意選択で置換されているフェニルである、項目8に記載の化合物。
(項目10)
環Aが、窒素、酸素または硫黄から独立して選択される1~4個のヘテロ原子を有する、任意選択で置換されている5員のヘテロアリール環である、項目8に記載の化合物。
(項目11)
環Aが、1~2個の窒素原子を有する、任意選択で置換されている6員のヘテロアリール環である、項目8に記載の化合物。
(項目12)
環Aが、イミダゾリル、イソオキサゾリル、1H-ピロリル、ピラゾリル、オキサゾリル、テトラゾリル、チアゾリル、トリアゾリル、ピリジルまたはピリミジニルから選択される、任意選択で置換されている環である、項目8に記載の化合物。
(項目13)
Lが共有結合である、項目1から12のいずれか一項に記載の化合物。
(項目14)
Lが、1~4つのフルオロ基により任意選択で置換されている直鎖または分枝状C 1~6 アルキレン鎖である、項目1から12のいずれか一項に記載の化合物。
(項目15)
Lが、メチレン、n-ブチレニル、エチレニルまたはn-プロピレニルである、項目14に記載の化合物。
(項目16)
R 4 が、-CF 3 、-ORまたは-SRである、項目1から15のいずれか一項に記載の化合物。
(項目17)
R 4 が、イソプロピル、tert-ブチル、シクロプロピル、シクロブチル、sec-ブチル、メトキシルまたはメチルチオイルである、項目16に記載の化合物。
(項目18)
R 5 がHである、項目1から17のいずれか一項に記載の化合物。
(項目19)
R 5 がメチルである、項目1から17のいずれか一項に記載の化合物。
(項目20)
式IIIの化合物:
Qが、-C(R’) 2 -または-NH-であり、
R x およびR y はそれぞれ、水素であるか、またはR x とR y は一緒になって、=Oを形成し、
Rはそれぞれ独立して、水素、-CN、あるいはC 1~6 脂肪族、フェニル、4~7員の飽和もしくは部分不飽和の単環式炭素環式環、1~4個のヘテロ原子を有する5~6員の単環式ヘテロアリール環、または窒素、酸素もしくは硫黄から独立して選択される1~2個のヘテロ原子を有する4~8員の飽和または部分飽和の複素環式環から選択される、任意選択で置換されている基であり、
R’はそれぞれ独立して、水素、ハロゲン、-CN、あるいはC 1~6 脂肪族、フェニル、4~7員の飽和もしくは部分不飽和の単環式炭素環式環、1~4個のヘテロ原子を有する5~6員の単環式ヘテロアリール環、または窒素、酸素もしくは硫黄から独立して選択される1~2個のヘテロ原子を有する4~8員の飽和または部分飽和の複素環式環から選択される、任意選択で置換されている基であり、
Lは、共有結合、または1~9つのフルオロ基により任意選択で置換されている直鎖もしくは分枝状C 1~6 アルキレン鎖であり、
R 4’ は、R、-CF 3 、-OR、-N(R) 2 、-Si(R) 3 または-SRであり、R 5’ は、H、-ORまたはC 1~4 アルキルである)。
(項目21)
Qが、-NH-、-CH 2 -または-CHF-である、項目20に記載の化合物。
(項目22)
R x およびR y がそれぞれ、水素であるか、またはR x とR y が一緒になって、=Oを形成する、項目20に記載の化合物。
(項目23)
R 5’ が、Hまたは-OHである、項目20から22のいずれか一項に記載の化合物。(項目24)
(項目25)
Lが、-CH 2 -である、項目20から24のいずれか一項に記載の化合物。
(項目26)
項目1から25のいずれか一項に記載の化合物、および薬学的に許容される担体、アジュバントまたはビヒクルを含む、薬学的に許容される組成物。
(項目27)
追加の治療剤と組み合わせた、項目26に記載の組成物。
(項目28)
前記追加の治療剤が、抗増殖性化合物である、項目27に記載の組成物。
(項目29)
セストリン-GATOR2相互作用をモジュレートして、これにより生物試料中で間接的に、mTORC1活性を選択的にモジュレートする方法であって、前記生物試料を項目1から25のいずれか一項に記載の化合物に接触させるステップを含む方法。
(項目30)
セストリン-GATOR2相互作用をモジュレートして、これにより患者において、間接的に、mTORC1活性を選択的にモジュレートする方法であって、前記患者に項目26に記載の組成物を投与するステップを含む方法。
(項目31)
mTORC1によって媒介される障害を処置することを必要とする患者において、mTORC1によって媒介される障害を処置する方法であって、前記患者に項目26に記載の組成物を投与するステップを含む方法。
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