JP6266639B2 - IL−12、IL−23および/またはIFNαの調節に有用なアルキルアミド置換ピリミジン化合物 - Google Patents
IL−12、IL−23および/またはIFNαの調節に有用なアルキルアミド置換ピリミジン化合物 Download PDFInfo
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- JP6266639B2 JP6266639B2 JP2015541885A JP2015541885A JP6266639B2 JP 6266639 B2 JP6266639 B2 JP 6266639B2 JP 2015541885 A JP2015541885 A JP 2015541885A JP 2015541885 A JP2015541885 A JP 2015541885A JP 6266639 B2 JP6266639 B2 JP 6266639B2
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- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
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- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
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- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
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- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
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Description
本発明は、Tyk−2に作用してシグナル伝達阻害を起こすことにより、IL−12、IL−23および/またはIFNαの調節に有用である化合物に関する。ここに提供されるのは、アルキルアミド置換ピリミジン化合物、該化合物を含む組成物およびその使用方法である。本発明は、さらに、哺乳動物におけるIL−12、IL−23および/またはIFNαの調節と関係する状態の処置に有用である、少なくとも1個の本発明の化合物を含む医薬組成物に関する。
共通p40サブユニットを共有するヘテロ二量体サイトカイン類であるインターロイキン(IL)−12およびIL−23は、活性化抗原提示細胞により産生され、そして自己免疫において重要な役割を有するT細胞系譜の二つのエフェクターであるTh1およびTh17細胞の分化および増殖に重要である。IL−23はp40サブユニットと独特のp19サブユニットからなる。IL−23RとIL−12Rβ1からなるヘテロ二量体受容体を介して作用するIL−23は、IL−17A、IL−17F、IL−6およびTNF−αのような炎症誘発性サイトカイン類を産生するTh17細胞の生存および増殖に必須である(McGeachy, M.J. et al., “The link between IL-23 and Th17 cell-mediated immune pathologies”, Semin. Immunol., 19:372-376 (2007))。これらのサイトカイン類は、リウマチ性関節炎、多発性硬化症、炎症性腸疾患および狼瘡を含む多数の自己免疫性疾患の病理生物学に介在することで重要である。IL−12は、IL−23と共通したp40サブユニットに加えてp35サブユニットを含み、IL−12Rβ1とIL−12Rβ2からなるヘテロ二量体受容体を介して作用する。IL−12はTh1細胞発達ならびにMHC発現、B細胞のIgGサブクラスへのクラススイッチおよびマクロファージの活性化の刺激により免疫に重要な役割を有するサイトカインであるIFNγの分泌に必須である(Gracie, J.A. et al., “Interleukin-12 induces interferon-gamma-dependent switching of IgG alloantibody subclass”, Eur. J. Immunol., 26:1217-1221 (1996); Schroder, K. et al., “Interferon-gamma: an overview of signals, mechanisms and functions”, J. Leukoc. Biol., 75(2):163-189 (2004))。
本発明は、Tyk2介在シグナル伝達の阻害によりIL−12、IL−23および/またはIFNαのモジュレーターとして有用な、下記式(I)の化合物に関する。
本発明はまた薬学的に許容される担体および本発明の化合物の少なくとも1個を含む医薬組成物を提供する。
本発明はまた治療に使用するための本発明の化合物も提供する。
ここに提供されるのは、式(I)
R1は場合により0〜7個のR1aで置換されていてよいC1−3アルキルであり;
R1aは各々独立して水素、重水素、F、Cl、Br、CF3またはCNであり;
R2はC1−6アルキルまたは−(CH2)r−3〜14員炭素環であり、各基は0〜4個のR2aで置換されており;
R2aは各々独立して水素、=O、ハロ、OCF3、CN、NO2、−(CH2)rORb、−(CH2)rSRb、−(CH2)rC(O)Rb、−(CH2)rC(O)ORb、−(CH2)rOC(O)Rb、CH2)rNR11R11、−(CH2)rC(O)NR11R11、−(CH2)rNRbC(O)Rc、−(CH2)rNRbC(O)ORc、−NRbC(O)NR11R11、−S(O)pNR11R11、−NRbS(O)pRc、−S(O)pRc、0〜3個のRaで置換されているC1−6アルキル、C1−6ハロアルキル、0〜3個のRaで置換されているC2−6アルケニル、0〜3個のRaで置換されているC2−6アルキニル、0〜1個のRaで置換された−(CH2)r−3〜14員炭素環または0〜2個のRaで置換されている炭素原子またはN、OおよびS(O)pから選択される1〜4個のヘテロ原子を含む−(CH2)r−5〜7員ヘテロ環であり;
R3はC3−10シクロアルキル、C6−10アリールまたはN、OおよびSから選択される1〜4個のヘテロ原子を含む5〜10員ヘテロ環であり、各基は0〜4個のR3aで置換されており;
R3aは各々独立して水素、=O、ハロ、OCF3、CF3、CHF2、CN、NO2、−(CH2)rORb、−(CH2)rSRb、−(CH2)rC(O)Rb、−(CH2)rC(O)ORb、−(CH2)rOC(O)Rb、−(CH2)rNR11R11、−(CH2)rC(O)NR11R11、−(CH2)rNRbC(O)Rc、−(CH2)rNRbC(O)ORc、−NRbC(O)NR11R11、−S(O)pNR11R11、−NRbS(O)pRc、−S(O)pRc、0〜3個のRaで置換されているC1−6アルキル、0〜3個のRaで置換されているC2−6アルケニル、0〜3個のRaで置換されているC2−6アルキニル、C1−6ハロアルキル、0〜3個のRaで置換された−(CH2)r−3〜14員炭素環または0〜3個のRaで置換された炭素原子およびN、OおよびS(O)pから選択される1〜4個のヘテロ原子を含む−(CH2)r−5〜10員ヘテロ環であるか;
または2個のR3aは、それらが結合している原子と一体となって、縮合環を形成し、該環はフェニルならびに炭素原子およびN、SまたはOから選択される1〜4個のヘテロ原子を含む5〜7員ヘテロ環から選択され、該縮合環はRa1で置換されており;
R4およびR5は独立して水素、0〜1個のRfで置換されているC1−4アルキル、0〜3個のRdで置換されている(CH2)r−フェニルまたは炭素原子およびN、OおよびS(O)pから選択される1〜4個のヘテロ原子を含む−(CH2)−5〜7員ヘテロ環であり;
R11は各々独立して水素、0〜3個のRfで置換されているC1−4アルキル、CF3、0〜1個のRfで置換されているC3−10シクロアルキル、0〜3個のRdで置換されている(CH)r−フェニルまたは0〜3個のRdで置換されている炭素原子およびN、OおよびS(O)pから選択される1〜4個のヘテロ原子を含む−(CH2)r−5〜7員ヘテロ環であり;
Rbは各々独立して水素、0〜3個のRdで置換されているC1−6アルキル、C1−6ハロアルキル、0〜2個のRdで置換されているC3−6シクロアルキルまたは0〜3個のRfで置換されている炭素原子およびN、OおよびS(O)pから選択される1〜4個のヘテロ原子を含む−(CH2)r−5〜7員ヘテロ環または0〜3個のRdで置換されている(CH2)r−フェニルであり;
Rcは0〜3個のRfで置換されているC1−6アルキル、0〜3個のRfで置換されている(CH2)r−C3−6シクロアルキル、0〜3個のRfで置換されている(CH2)r−フェニルであるか;または
Rdは各々独立して水素、F、Cl、Br、OCF3、CF3、CN、NO2、−ORe、−(CH2)rC(O)Rc、−NReRe、−NReC(O)ORc、C1−6アルキルまたは0〜3個のRfで置換されている(CH2)r−フェニルであり;
Reは各々独立して水素、C1−6アルキル、C3−6シクロアルキルおよび0〜3個のRfで置換されている(CH2)r−フェニルから選択され;
Rfは各々独立して水素、ハロ、CN、NH2、OH、C3−6シクロアルキル、CF3、O(C1−6アルキル)または炭素原子およびN、OおよびS(O)pから選択される1〜4個のヘテロ原子を含む−(CH2)r−5〜7員ヘテロアリールであり;
pは0、1または2であり;
rは0、1、2、3または4である。〕
の化合物またはその立体異性体、互変異性体、薬学的に許容される塩、溶媒和物もしくはプロドラッグから選択される少なくとも1個の化学物質である。
R1は0〜7個のR1aで置換されているC1−3アルキルであり;
R1aは各々独立して水素または重水素であり;
R2はC1−6アルキル、C3−6シクロアルキルまたはフェニルであり、各基はR2aから選択される0〜4個の基で置換されており;
R2aは各々独立して水素、ハロ、CN、−(CH2)rORb、−(CH2)rC(O)Rb、−(CH2)rC(O)NR11R11、−S(O)pNR11R11、0〜3個のRaで置換されているC1−6アルキル、C1−6ハロアルキル、0〜1個のRaで置換された−(CH2)r−3〜14員炭素環または0〜2個のRaで置換されている炭素原子およびN、OおよびS(O)pから選択される1〜4個のヘテロ原子を含む−(CH2)r−5〜7員ヘテロ環であり;
R3はC3−10シクロアルキル、C6−10アリールまたはN、OおよびSから選択される1〜4個のヘテロ原子を含む5〜10員ヘテロ環であり、各基は0〜4個のR3aで置換されており;
R3aは各々独立して水素、ハロ、OCF3、CF3、CHF2、CN、−(CH2)rORb、−(CH2)rSRb、−(CH2)rC(O)Rb、−(CH2)rNR11R11、−(CH2)rC(O)NR11R11、−(CH2)rNRbC(O)Rc、−S(O)pNR11R11、−NRbS(O)pRc、−S(O)pRc、0〜3個のRaで置換されているC1−6アルキル、C1−6ハロアルキル、0〜3個のRaで置換された−(CH2)r−3〜14員炭素環または0〜3個のRaで置換された炭素原子およびN、OおよびS(O)pから選択される1〜4個のヘテロ原子を含む−(CH2)r−5〜10員ヘテロ環であるか;
または2個のR3aは、それらが結合している原子と一体となって、縮合環を形成し、該環は、0〜3個のRa1で置換されているフェニルまたは炭素原子およびN、SまたはOから選択される1〜4個のヘテロ原子を含む5〜7員ヘテロ環を形成し;
R11は各々独立して水素、0〜3個のRfで置換されているC1−4アルキルまたは0〜1個のRfで置換されているC3−10シクロアルキルであり;
RaおよびRa1は各々独立して水素、=O、F、−(CH2)rORbまたは0〜3個のRfで置換されているC1−6アルキルであり;
Rbは各々独立して水素、0〜3個のRdで置換されているC1−6アルキル、C1−6ハロアルキル、0〜2個のRdで置換されているC3−6シクロアルキルまたは0〜3個のRfで置換されている炭素原子およびN、OおよびS(O)pから選択される1〜4個のヘテロ原子を含む−(CH2)r−5〜7員ヘテロ環または0〜3個のRdで置換されている(CH2)r−フェニルであり;
Rcは0〜3個のRfで置換されているC1−6アルキルであり;
Rdは各々独立して水素、ハロ(F)または−OHであり;
Rfは各々独立して水素、ハロ、CN、OHまたはO(C1−6アルキル)であり;
pは0、1または2であり;
rは0、1または2である。〕
式(I)の化合物またはその立体異性体、互変異性体、薬学的に許容される塩、溶媒和物もしくはプロドラッグが提供される。
R3aが各々独立して水素、Ph、CN、NH2、OCF3、ORb、ハロ、シクロアルキル、C(O)NR11R11、S(O)2NR11R11、C(O)Rb、SOpRc、NRbSOpRc、NRbC(O)Rc、ハロアルキル(CF3)、CN、0〜3個のRaで置換されている炭素原子およびN、SまたはOから選択される1〜4個のヘテロ原子を含む5〜7員ヘテロ環および0〜3個のRaで置換されているC1−6アルキルであるか;または
第一のR3aと第二のR3aが、それらが結合している原子と一体となって炭素原子およびN、SまたはOから選択される1〜4個のヘテロ原子を含む縮合5〜7員ヘテロ環またはフェニルを形成し;
R11が各々独立して水素、シクロプロピルまたは0〜1個のRfで置換されているC1−4アルキルであり;
Raが各々独立してハロ(F)またはORbであり;
Rbが各々独立して水素、0〜3個のRfで置換されている炭素原子およびN、SまたはOから選択される1〜4個のヘテロ原子を含む5〜7員ヘテロ環または0〜3個のRdで置換されているC1−6アルキルであり;
Rdが各々独立してハロ(F)またはOHであり;
Rcが0〜3個のRfで置換されているC1−6アルキルであり;
Rfが各々独立して水素、ハロ(F)またはOHであり;
pが2である、
式(I)の化合物またはその立体異性体、互変異性体、薬学的に許容される塩、溶媒和物もしくはプロドラッグを提供する。
R3が
R3aaがS(O)pRc、ORb、クロロ、F、CN、NH2、C(O)NR11R11、NRbSOpRc、NRbC(O)Rc、0〜3個のRaで置換されているC1−6アルキルまたは0〜3個のRaで置換されているN、OおよびSから選択される1〜3個のヘテロ原子を含む5〜6員ヘテロアリールであり;
R3ab、R3acまたはR3adが独立して水素、Cl、F、Br、CN、ORb、0〜3個のRaで置換されているC1−6アルキル;C(O)NR11R11、C(O)Rb、S(O)pRcまたは0〜3個のRaで置換されているN、OおよびSから選択される1〜3個のヘテロ原子を含む4〜7員ヘテロ環であり;
RaがORbまたはハロであり;
Rbが水素、0〜2個のRdで置換されているC1−6アルキル、N、OおよびSから選択される1〜3個のヘテロ原子を含む5〜7員ヘテロシクロであり;
R11が各々独立して水素、0〜3個のRfで置換されているシクロプロピルまたは0〜3個のRfで置換されているC1−4アルキルであり;
Rbが水素または0〜2個のRdで置換されているC1−6アルキルであり;
Rcが0〜3個のRfで置換されているC1−6アルキルであり;
Rdが各々独立してFまたはOHであり;
Rfがハロ(好ましくはF)であり;
pが0〜2である、
式(I)の化合物またはその立体異性体、互変異性体、薬学的に許容される塩、溶媒和物もしくはプロドラッグが提供される。
本発明はまた本発明の化合物を製造するための方法および中間体も提供する。
他の態様において、式(I)の化合物は実施例の化合物または実施例化合物の組み合わせまたはここでの他の態様から選択される。
他の態様において、化合物は下記アッセイの少なくとも一つでIC50<1000nMを有する。
次は、本明細書および添付する特許請求の範囲で使用する用語の定義である。ここに示す基または用語の最初の定義は、特に断らない限り、個々にまたは他の基の一部として、明細書および特許請求の範囲をとおしてその基または用語に適用される。
用語“ハロアルキル”は、1個以上のハロ置換基を有する置換アルキルをいう。例えば、“ハロアルキル”はモノ、ジおよびトリフルオロメチルを含む。
用語“ハロアルコキシ”は、1個以上のハロ置換基を有するアルコキシ基をいう。例えば、“ハロアルコキシ”はOCF3を含む。
用語“不飽和”を環または基に関して使用するとき、該環または基は完全不飽和でも一部不飽和でもよい。
a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985)およびWidder, K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press (1985);
b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and Development, pp. 113-191, Harwood Academic Publishers (1991);および
c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992)
を参照のこと。
本発明の化合物は、遺伝子転写を含むIL−23刺激およびIFNα刺激細胞機能を調節する。本発明の化合物により調節され得る他のタイプの細胞機能は、IL−12刺激応答を含むが、これに限定されない。
プローブ置換アッセイ
プローブ置換アッセイを次のとおり行う。385ウェルプレートにおいて、試験化合物を組み換えにより発現させたヒトTyk2のアミノ酸575〜869に対応するHisタグ付タンパク質(配列を下に示す)2.5nMで、40nM ((R)−N−(1−(3−(8−メチル−5−(メチルアミノ)−8H−イミダゾ[4,5−d]チアゾロ[5,4−b]ピリジン−2−イル)フェニル)エチル)−2−([3H]メチルスルホニル)ベンズアミド)(製造は下に記載)および80μg/mL 銅Hisタグシンチレーション近接アッセイビーズ(Perkin Elmer, Catalog #RPNQ0095)と共に、100μg/mL ウシ血清アルブミンおよび5%DMSOを含む50mM HEPES、pH7.5中、30分、室温でインキュベートした。Tyk2に結合した放射標識プローブ(製造は下に記載)の量をシンチレーション計数により定量し、試験化合物による阻害を、無阻害剤(0%阻害)または無Tyk2(100%阻害)のウェルとの比較により計算した。IC50値は、放射標識プローブ結合を50%阻害するのに必要な試験化合物濃度と定義する。
MGSSHHHHHH SSGETVRFQG HMNLSQLSFH RVDQKEITQL SHLGQGTRTN VYEGRLRVEG SGDPEEGKMDDEDPLVPGRD RGQELRVVLK VLDPSHHDIA LAFYETASLM SQVSHTHLAF VHGVCVRGPE NIMVTEYVEHGPLDVWLRRE RGHVPMAWKM VVAQQLASAL SYLENKNLVH GNVCGRNILL ARLGLAEGTS PFIKLSDPGVGLGALSREER VERIPWLAPE CLPGGANSLS TAMDKWGFGA TLLEICFDGE APLQSRSPSE KEHFYQRQHRLPEPSCPQLA TLTSQCLTYE PTQRPSFRTI LRDLTRL。
安定に統合させたSTAT依存性ルシフェラーゼレポーターを有するKit225 T細胞を、10%熱不活性化FBS(Gibco)および100U/mL PenStrep(Gibco)を含むRPMI(Gibco)に播種した。次いで細胞を20ng/mL ヒト組み換えIL−23または200U/mL ヒト組み換えIFNα(PBL InterferonSource)のいずれかで5〜6時間刺激した。ルシフェラーゼ発現を、製造者の指示に従いSTEADY-GLO(登録商標)Luciferase Assay System(Promega)を使用して測定した。阻害データを無阻害剤対照ウェルを0%阻害とし、非刺激対照ウェルを100%阻害として比較することにより計算した。用量応答曲線を作成して、非線形回帰分析から導かれる細胞応答の50%阻害に必要な濃度(IC50)を決定した。
本発明の化合物は、有機化学の当業者が利用可能な多くの方法により合成し得る。本発明の化合物を製造するための一般的合成スキームを下に記載する。これらのスキームは例であり、ここに開示する化合物を製造するために当業者が使用できる可能な方法を制限することを意図しない。本発明の化合物を製造するための異なる方法が当業者には明らかである。さらに、合成における種々の工程を、所望の化合物または化合物群を得るために別の順序で実施してよい。一般的スキームに記載した方法により製造した本発明の化合物を、下の製造例および実施例の章に記載する。
NaHCO3(水性)=飽和重炭酸ナトリウム水溶液
塩水=飽和塩化ナトリウム水溶液
DCM=ジクロロメタン
DIEA=N,N−ジイソプロピルエチルアミン
DMAP=4−(N,N−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
EDC=N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド塩酸塩
EtOAc=酢酸エチル
HOAT=1−ヒドロキシ−7−アザベンゾトリアゾール
HOBT=1−ヒドロキシベンゾトリアゾール水和物
rt=周囲の室温(一般に約20〜25℃)
TEA=トリエチルアミン
TFA=トリフルオロ酢酸
THF=テトラヒドロフラン
下に示す製造は、市販されていない反応材の合成であり、本発明の式(I)の化合物の製造のために用いた。表およびスキームにおける全てのキラル化合物は、特に断らない限りラセミ体である。
分析的HPLCを、次の方法を使用して、Shimadzu LC10AS液体クロマトグラフで行った。
メチル2,4−ジクロロピリミジン−5−カルボキシレート(140mg、0.68mmolを含むバイアルに、アセトニトリル(1mL)、ジイソプロピルエチルアミン(0.24mL、1.4mmol)および2−(メチルチオ)アニリン(94mg、0.68mmol)を添加した。反応物を70℃で90分加熱し、室温に冷却し、溶媒を減圧下に除去した。残存固体をジクロロメタン(DCM)に再溶解し、ヘキサンの添加により析出させた。生成物を濾過により集め、ヘキサンで濯ぎ、さらに精製することなく使用した。集めた物質(220mg)は約50%純度であった。LC保持時間1.08分[J]. マススペクトロメトリー(“MS”)(E+) m/z: 310 (MH+)
粗製の中間体1(100mg、<0.32mmol)の1−メチル−2−ピロリドン(NMP、1mL)溶液に、シクロプロピルメタンアミン(23mg、0.32mmol)を添加し、反応物を100℃で90分加熱した。反応物を室温に冷却し、水で希釈し、生成物を酢酸エチル(×3)で抽出した。合わせた有機層を水(×2)および塩水(×1)で洗浄し、硫酸ナトリウムで乾燥し、濾過し、濃縮し、自動化クロマトグラフィー(5〜20%EtOAc/ヘキサン)で精製して、中間体2(22mg、19%収率)を得た。LC保持時間0.88分[J]. MS(E+) m/z: 345 (MH+)
中間体2(23mg、0.067mmolを酢酸(AcOH、0.17mL)に溶解し、過酸化水素(30%水溶液、140μL、1.34mmol)およびタングステン酸ナトリウム二水和物(22mg、0.067mmol)を連続的に添加した。反応は過酸化の兆しなく、30分後に収量した。反応物を水および酢酸エチルで希釈し、層を分離し、水層を酢酸エチルで1回抽出した。合わせた有機層を飽和重亜硫酸ナトリウム水溶液で1回および水で1回洗浄した。合わせた有機層を硫酸ナトリウムで乾燥し、濾過し、減圧下濃縮して、スルホン生成物である中間体3(25mg、83%純度、84%収率)を得た。LC保持時間0.79分[J]. MS(E+) m/z: 377 (MH+)
メチル2,4−ジクロロピリミジン−5−カルボキシレート(1.30g、6.28mmol)を含むバイアルに、アセトニトリル(10mL)、ジイソプロピルエチルアミン(2.19mL、12.56mmol)および2−アミノベンズアミド(855mg、6.28mmol)を添加した。反応物を70℃で60分加熱し、室温に冷却して、生成物を固体として析出させた。固体を濾別し、アセトニトリルで濯ぎ、集め、乾燥して、中間体4を粗製の固体として得た(2.3g、90%純度)。分析的に純粋なサンプルを、自動化シリカゲルクロマトグラフィー(40〜85%EtOAc/ヘキサン)を使用して得た。1H NMR (400MHz, MeOD/クロロホルム-d) δ 8.85 - 8.77 (m, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.58 - 7.48 (m, 1H), 7.25 (t, J=7.6 Hz, 1H), 4.04 - 3.98 (m, 3H). LC保持時間0.76分[J]. MS(E+) m/z: 307 (MH+)
中間体4(200mg、0.65mmol)のNMP(1mL)溶液に、4−フルオロアニリン(72mg、0.65mmol)を添加し、バイアルを密閉し、100℃で1時間加熱した。反応物を室温に冷却し、酢酸エチルおよび水で希釈し、中間体5を溶液から析出させた。固体を濾過により集め、酢酸エチルで濯ぎ、乾燥して、中間体5を白色固体として得た(125mg、45%収率)。1H NMR (400MHz, DMSO-d6) δ 11.40 (s, 1H), 9.87 (br. s., 1H), 8.72 (s, 1H), 8.29 - 7.93 (m, 2H), 7.73 - 7.57 (m, 3H), 7.54 - 7.38 (m, 2H), 7.19 (t, J=7.3 Hz, 1H), 7.05 (t, J=8.5 Hz, 2H), 3.84 (s, 3H). LC保持時間0.72分[J]. MS(E+) m/z: 382 (MH+)
中間体5(120mg、0.315mmol)のメタノール(2mL)およびTHF(10mL)溶液に、水酸化ナトリウム(水中1M、0.63mL、0.63mmol)を添加し、反応物を6時間還流した。溶媒を、残存する水を除去するためにDCM共沸を使用して、減圧下に除去した。得られた固体をDCM/MeOHに溶解し、塩酸(ジオキサン中4M、0.75mL、3.0mmol)を添加した。溶媒を減圧下に除去し、DCMから3回再濃縮して、中間体6をHCl塩として得た(130mg、77%収率)。1H NMR (400MHz, DMSO-d6) δ 8.63 (d, J=8.1 Hz, 1H), 8.54 - 8.45 (m, 2H), 7.35 - 7.25 (m, 4H), 6.93 (t, J=7.0 Hz, 1H), 6.82 - 6.61 (m, 3H). LC保持時間0.66分[J]. MS(E+) m/z: 368 (MH+)
中間体6(20mg、0.54mmol)、(ベンゾリアゾール−1−イルオキシ)トリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスフェート(BOP、24mg、0.054mmol)、トリエチルアミン(21μL、0.15mmol)およびメタンアミン塩酸塩(6.7mg、0.099mmol)をDMF(1mL)中で併せ、室温で1時間撹拌した。反応物をDMFで希釈し、濾過し、分取HPLCを使用して精製して、2(6.9mg、26%収率)をTFA塩として得た。1H NMR (500MHz, DMSO-d6) δ 11.68 (s, 1H), 9.70 (br. s., 1H), 8.55 (s, 1H), 8.36 (d, J=4.5 Hz, 1H), 8.10 (d, J=18.3 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.62 (dd, J=8.4, 5.0 Hz, 2H), 7.54 (dd, J=7.7, 1.2 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.25 - 7.11 (m, 2H), 7.06 - 6.97 (m, 2H), 2.76 (d, J=4.0 Hz, 3H). LC保持時間1.27分[E]. MS(E+) m/z: 381 (MH+)
Claims (9)
- 次の式(I):
R1は場合により0〜7個のR1aで置換されていてよいC1−3アルキルであり;
R1aは各々独立して水素、重水素、F、Cl、Br、CF3またはCNであり;
R2は
R 3 は
R 3aa はS(O) p R c 、OR b 、クロロ、F、CN、NH 2 、C(O)NR 11 R 11 、NR b SO p R c 、NR b C(O)R c 、0〜3個のR a で置換されているC 1−6 アルキルまたは0〜3個のR a で置換されているN、OおよびSから選択される1〜3個のヘテロ原子を含む5〜6員ヘテロアリールであり;
R 3ab 、R 3ac またはR 3ad は独立して水素、Cl、F、Br、CN、OR b 、0〜3個のR a で置換されているC 1−6 アルキル;C(O)NR 11 R 11 、C(O)R b 、S(O) p R c または0〜3個のR a で置換されているN、OおよびSから選択される1〜3個のヘテロ原子を含む4〜7員ヘテロ環であり;
R a はOR b またはハロであり;
R b は水素、0〜2個のR d で置換されているC 1−6 アルキル、N、OおよびSから選択される1〜3個のヘテロ原子を含む5〜7員ヘテロシクロであり;
R4およびR5は独立して水素、0〜1個のRfで置換されているC1−4アルキル、0〜3個のRdで置換されている(CH2)r−フェニルまたは炭素原子およびN、OおよびS(O)pから選択される1〜4個のヘテロ原子を含む−(CH2)−5〜7員ヘテロ環であり;
R 11 は各々独立して水素、0〜3個のR f で置換されているシクロプロピルまたは0〜3個のR f で置換されているC 1−4 アルキルであり;
Rcは0〜3個のRfで置換されているC1−6アルキルであり;
Rdは各々独立してFまたはOHであり;
Rfはハロであり;
pは0、1または2であり;
rは0、1、2、3または4である。〕
を有する化合物またはその立体異性体もしくは薬学的に許容される塩。 - R4およびR5の両者が水素である、請求項1に記載の化合物またはその立体異性体もしくは薬学的に許容される塩。
- 次の式
R1は0〜7個のR1aで置換されているC1−3アルキルであり;
R1aは各々独立して水素または重水素であり;
R2は
R 3 は
R 3aa はS(O) p R c 、OR b 、クロロ、F、CN、NH 2 、C(O)NR 11 R 11 、NR b SO p R c 、NR b C(O)R c 、0〜3個のR a で置換されているC 1−6 アルキルまたは0〜3個のR a で置換されているN、OおよびSから選択される1〜3個のヘテロ原子を含む5〜6員ヘテロアリールであり;
R 3ab 、R 3ac またはR 3ad は独立して水素、Cl、F、Br、CN、OR b 、0〜3個のR a で置換されているC 1−6 アルキル;C(O)NR 11 R 11 、C(O)R b 、S(O) p R c または0〜3個のR a で置換されているN、OおよびSから選択される1〜3個のヘテロ原子を含む4〜7員ヘテロ環であり;
R a はOR b またはハロであり;
R b は水素、0〜2個のR d で置換されているC 1−6 アルキル、N、OおよびSから選択される1〜3個のヘテロ原子を含む5〜7員ヘテロシクロであり;
R 11 は各々独立して水素、0〜3個のR f で置換されているシクロプロピルまたは0〜3個のR f で置換されているC 1−4 アルキルであり;
Rcは0〜3個のRfで置換されているC1−6アルキルであり;
Rdは各々独立してFまたは−OHであり;
Rfは各々独立してハロであり;
pは0、1または2であり;
rは0、1または2である。〕
を有する、請求項1または2に記載の化合物またはその立体異性体もしくは薬学的に許容される塩。 - R3aaがORbである、請求項1〜3のいずれかに記載の化合物またはその立体異性体もしくは薬学的に許容される塩。
- R3aaがS(O)pRcまたはC(O)NR11R11である、請求項1〜3のいずれかに記載の化合物またはその立体異性体もしくは薬学的に許容される塩。
- 次の式(I):
R 1 は場合により0〜7個のR 1a で置換されていてよいC 1−3 アルキルであり;
R 1a は各々独立して水素、重水素、F、Cl、Br、CF 3 またはCNであり;
R 2 は
R 3 は
R 4 およびR 5 は独立して水素、0〜1個のR f で置換されているC 1−4 アルキル、0〜3個のR d で置換されている(CH 2 ) r −フェニルまたは炭素原子およびN、OおよびS(O) p から選択される1〜4個のヘテロ原子を含む−(CH 2 )−5〜7員ヘテロ環であり;
R c は0〜3個のR f で置換されているC 1−6 アルキル、0〜3個のR f で置換されている(CH 2 ) r −C 3−6 シクロアルキル、0〜3個のR f で置換されている(CH 2 ) r −フェニルであるか;または
R d は各々独立して水素、F、Cl、Br、OCF 3 、CF 3 、CN、NO 2 、−OR e 、−(CH 2 ) r C(O)R c 、−NR e R e 、−NR e C(O)OR c 、C 1−6 アルキルまたは0〜3個のR f で置換されている(CH 2 ) r −フェニルであり;
R e は各々独立して水素、C 1−6 アルキル、C 3−6 シクロアルキルおよび0〜3個のR f で置換されている(CH 2 ) r −フェニルから選択され;
R f は各々独立して水素、ハロ、CN、NH 2 、OH、C 3−6 シクロアルキル、CF 3 、O(C 1 − 6 アルキル)または炭素原子およびN、OおよびS(O) p から選択される1〜4個のヘテロ原子を含む−(CH 2 ) r −5〜7員ヘテロアリールであり;
pは0、1または2であり;
rは0、1、2、3または4である。〕
を有する化合物またはその立体異性体もしくは薬学的に許容される塩。 - R1がCH3、C2H5、CD3またはCD2CD3である、請求項1〜6のいずれかに記載の化合物またはその立体異性体もしくは薬学的に許容される塩。
- 請求項1〜7のいずれかに記載の1個以上の化合物および薬学的に許容される担体または希釈剤を含む、医薬組成物。
- 炎症性疾患または自己免疫性疾患を治療するための、請求項8に記載の医薬組成物。
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