JP6699909B2 - メチル/フルオロ−ピリジニル−メトキシ置換ピリジノン−ピリジニル化合物及びフルオロ−ピリミジニル−メトキシ置換ピリジノン−ピリジニル化合物 - Google Patents
メチル/フルオロ−ピリジニル−メトキシ置換ピリジノン−ピリジニル化合物及びフルオロ−ピリミジニル−メトキシ置換ピリジノン−ピリジニル化合物 Download PDFInfo
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- JP6699909B2 JP6699909B2 JP2016518047A JP2016518047A JP6699909B2 JP 6699909 B2 JP6699909 B2 JP 6699909B2 JP 2016518047 A JP2016518047 A JP 2016518047A JP 2016518047 A JP2016518047 A JP 2016518047A JP 6699909 B2 JP6699909 B2 JP 6699909B2
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- methoxy
- hydroxypropan
- dimethyl
- chloro
- bromo
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- -1 fluoro-pyrimidinyl-methoxy Chemical group 0.000 title claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 145
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 52
- 239000003112 inhibitor Substances 0.000 claims description 47
- 150000003839 salts Chemical class 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 102000004127 Cytokines Human genes 0.000 claims description 20
- 108090000695 Cytokines Proteins 0.000 claims description 20
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 19
- 125000001246 bromo group Chemical group Br* 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 18
- 206010025323 Lymphomas Diseases 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 16
- 208000035475 disorder Diseases 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 201000001320 Atherosclerosis Diseases 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 9
- 208000023275 Autoimmune disease Diseases 0.000 claims description 8
- 208000027866 inflammatory disease Diseases 0.000 claims description 8
- 208000037976 chronic inflammation Diseases 0.000 claims description 7
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 241000282472 Canis lupus familiaris Species 0.000 claims description 5
- 206010016654 Fibrosis Diseases 0.000 claims description 5
- 230000001154 acute effect Effects 0.000 claims description 5
- 230000004761 fibrosis Effects 0.000 claims description 5
- 239000003018 immunosuppressive agent Substances 0.000 claims description 5
- 229940043355 kinase inhibitor Drugs 0.000 claims description 5
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 5
- 102000016289 Cell Adhesion Molecules Human genes 0.000 claims description 4
- 108010067225 Cell Adhesion Molecules Proteins 0.000 claims description 4
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims description 4
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 4
- 239000002955 immunomodulating agent Substances 0.000 claims description 4
- 229940121354 immunomodulator Drugs 0.000 claims description 4
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 3
- 230000000879 anti-atherosclerotic effect Effects 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- FRXIFMCHMAFYRO-UHFFFAOYSA-N 3,4-dimethyl-1-pyridin-4-ylpyridin-2-one Chemical compound O=C1C(C)=C(C)C=CN1C1=CC=NC=C1 FRXIFMCHMAFYRO-UHFFFAOYSA-N 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- JNHJDKZWINPQMW-UHFFFAOYSA-N 1-(2-pyridin-2-ylpyridin-4-yl)pyridin-2-one Chemical compound N1(C(C=CC=C1)=O)C1=CC(=NC=C1)C1=NC=CC=C1 JNHJDKZWINPQMW-UHFFFAOYSA-N 0.000 claims 1
- HODBZIYISFGYNB-UHFFFAOYSA-N 3-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-[2-[2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl]-5-methylpyridin-4-yl]-6-methylpyridin-2-one Chemical compound CC1=CN=C(C=2C(=CN=C(N=2)C(C)(C)O)C)C=C1N(C(C=1Br)=O)C(C)=CC=1OCC1=NC=C(F)C=C1F HODBZIYISFGYNB-UHFFFAOYSA-N 0.000 claims 1
- HBXTXPFNZZNJQU-UHFFFAOYSA-N 3-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-[2-[2-(2-hydroxypropan-2-yl)pyrimidin-4-yl]-5-methylpyridin-4-yl]-6-methylpyridin-2-one Chemical compound CC1=CN=C(C=2N=C(N=CC=2)C(C)(C)O)C=C1N(C(C=1Br)=O)C(C)=CC=1OCC1=NC=C(F)C=C1F HBXTXPFNZZNJQU-UHFFFAOYSA-N 0.000 claims 1
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- SBOOSBGAMKNLCO-UHFFFAOYSA-N 3-bromo-4-[(3-fluoro-5-methylpyridin-2-yl)methoxy]-1-[2-[2-(2-hydroxypropan-2-yl)pyrimidin-4-yl]-5-methylpyridin-4-yl]-6-methylpyridin-2-one Chemical compound FC1=CC(C)=CN=C1COC1=C(Br)C(=O)N(C=2C(=CN=C(C=2)C=2N=C(N=CC=2)C(C)(C)O)C)C(C)=C1 SBOOSBGAMKNLCO-UHFFFAOYSA-N 0.000 claims 1
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- WYKFYAOQEJRERX-UHFFFAOYSA-N 3-bromo-4-[(4-fluoropyridin-3-yl)methoxy]-1-[2-[2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl]-5-methylpyridin-4-yl]-6-methylpyridin-2-one Chemical compound CC1=CN=C(C=2C(=CN=C(N=2)C(C)(C)O)C)C=C1N(C(C=1Br)=O)C(C)=CC=1OCC1=CN=CC=C1F WYKFYAOQEJRERX-UHFFFAOYSA-N 0.000 claims 1
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- RKEYNJVMSQBDIX-UHFFFAOYSA-N 3-bromo-4-[(5-fluoro-3-methylpyridin-2-yl)methoxy]-1-[2-[6-(2-hydroxypropan-2-yl)-3-methylpyridin-2-yl]-5-methylpyridin-4-yl]-6-methylpyridin-2-one Chemical compound CC1=CC(F)=CN=C1COC1=C(Br)C(=O)N(C=2C(=CN=C(C=2)C=2C(=CC=C(N=2)C(C)(C)O)C)C)C(C)=C1 RKEYNJVMSQBDIX-UHFFFAOYSA-N 0.000 claims 1
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- BREYXCQWCCNVPT-UHFFFAOYSA-N 3-bromo-4-[(5-fluoropyridin-2-yl)methoxy]-1-[2-[6-(2-hydroxypropan-2-yl)-3-methylpyridin-2-yl]-5-methylpyridin-4-yl]-6-methylpyridin-2-one Chemical compound CC1=CC=C(C(C)(C)O)N=C1C1=CC(N2C(C(Br)=C(OCC=3N=CC(F)=CC=3)C=C2C)=O)=C(C)C=N1 BREYXCQWCCNVPT-UHFFFAOYSA-N 0.000 claims 1
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Description
本出願は、2013年6月7日出願の、仮特許出願第61/832,736号の利益及び優先権を主張する非仮特許出願であり、当該仮特許出願の開示全体が参照により本明細書に組込まれる。
ノイド及び一酸化窒素のそれぞれの主要な源であるCOX2及びiNOSといった重要な炎症性酵素の誘導の原因でもある。さらに、p38MAPK経路は、MMP2、MMP9及びMMP13を包含するマトリックスメタロプロテアーゼ(MMP)の発現を制御する。
に特異的に依存するであろう阻害剤のための結合ポケットをさらに提供し得る。
した。これらの疾患に加え、このサイトカインの生合成及び活性におけるp38MAPK経路に関する重要な役割をもとに、複数のIL−ip介在疾患がp38阻害剤の影響を受け得る。これらの疾患としては、とりわけ、クリオピリン関連周期性障害(CAPS)のファミリー、慢性痛風、糖尿病、スチル病、家族性地中海熱が挙げられる。
許文献7に記載されている。当該出願に記載される化合物は、ジ−フルオロフェニル−メトキシ−ピリミジノン−フェニル化合物を包含し、ここで、フェニル断片は、カルボニル架橋によってピペラジニル又はモルホリニルラジカルで置換されている。
上記の化合物は、次の詳細な説明でより十分に説明される。
化合物の説明における一般名の使用を、明確にするためにここで定義する。
じ意味で使用する。
リル、ベンゾオキサゾリル、ベンズイミダゾリル、イソインドリル、ベンゾトリアゾリル、プリニル、チアナフテニル及びピラジニルが挙げられる。ヘテロアリールの連結は、芳香族環を介して生じ得、又は、ヘテロアリールが二環式又は三環式であり、環の1つが芳香族ではなく、若しくは、ヘテロ原子を一切含まない場合は、非芳香族環又はヘテロ原子を一切含んでいない環によって生じ得る。「ヘテロアリール」はまた、ヘテロアリールを含んでいるいずれかの窒素のN−オキシド誘導体を包含することが理解される。
結合の同じ側にラジカル原子(「シス」)、又は、二重結合の反対側にラジカル原子(「トランス」)をそれぞれ有する幾何異性の形態を指す。
本開示は、式(I)の構造を有する化合物:
又はその薬剤的に許容できる塩を提供し、ここで:
XはCH又はNであり;
R1はH、C1−C6アルキル、フルオロ、クロロ、ブロモ、シアノ又は−CF3から成る群から選択され;
R2はH、メチル、シアノ又はフルオロから成る群から選択され;
R3は:
から成る群から選択され;
R4はH、メチル、OH及び−O−CH3から成る群から選択され;
R5はH又はC1−C3アルキルであり;
mは1又は2であり;
nは0又は1であり;
pは1であり;及び、
qは0又は1である。
又はその薬剤的に許容できる塩が提供され、ここで:
XはCH又はNであり;
R1はH、C1−C6アルキル、フルオロ、クロロ、ブロモ、シアノ又は−CF3から成る群から選択され;
R2はH、メチル、シアノ又はフルオロから成る群から選択され;
R4はH、メチル、OH及び−OCH3から成る群から選択され;
R5はH又はC1−C3アルキルであり;
mは1又は2であり;及び、
nは0又は1である。
又はその薬剤的に許容できる塩が提供され、ここで:
XはCH又はNであり;
R1はH、C1−C6アルキル、フルオロ、クロロ、ブロモ、シアノ又は−CF3から成る群から選択され;
R2はH、メチル、シアノ又はフルオロから成る群から選択され;
R4はH、メチル、OH及び−OCH3から成る群から選択され;
R5はH又はC1−C3アルキルであり;
mは1又は2であり;及び、
nは0又は1である。
げられる:
又はその薬剤的に許容できる塩が提供され、ここで:
XはCH又はNであり;
R1はH、C1−C6アルキル、フルオロ、クロロ、ブロモ、シアノ又は−CF3から成る群から選択され;
R2はH、メチル、シアノ又はフルオロから成る群から選択され;
R4はH、メチル、OH及び−OCH3から成る群から選択され;
R5はH又はC1−C3アルキルであり;
pは1であり;及び、
qは0又は1である。
極性溶媒中で式Yの化合物を化合物Zに接触させて混合物を形成すること;
混合物を十分な温度で、及び、十分な時間の間加熱すること;並びに、
約2未満のpKaを有する酸の存在下で、式Wの構造を有する反応生成物を形成することを含み:
ここで、R10はブロモ又はクロロのいずれかである。別の実施形態では、極性溶媒はジオキサンである。別の実施形態では、温度は約70℃〜約105℃の範囲である。別の実施形態では、反応生成物を形成するのに十分な時間は2〜約6時間の範囲である。別の実施形態では、酸は硫酸である。別の実施形態では、R10はクロロである。別の実施形態では、R10はブロモである。
本発明の化合物は、以下で詳細を記す一般的な合成スキーム及び実験手順で例示される方法を用いて調製され得る。これらの一般的な合成スキーム及び実験手順は例示の目的で提示され、限定することは意図されていない。本発明の化合物を調製するために用いる出発材料は市販されており、又は、当該技術分野では公知の通常の方法を用いて調製され得る。
スキーム1:
れる場合はN−ブロモスクシンイミド)を用いて1eをハロゲン化することで、2fを提供する。2fのN,N−ジメチルホルムアミドジメチルアセタールとの反応によるin situエナミン形成によって、中間体が提供され、当該中間体は次いで、DMFといった溶媒中で2−ヒドロキシ−2−メチルプロピオンアミジンと反応させ、ピリミジノン2gを得る。2gをTFA又はHClといった酸で処理することでベンジル基を脱保護し、2hが提供される。フェノール2hを所望するベンジルハライド置換基(R3CH2Br又はR3CH2Cl)でアルキル化することで、所望するピリジノン2iが提供される。
スキーム2
中間体
中間体I:2−クロロメチル−3,5−ジフルオロ−ピリジンの調製
氷水浴を用いて冷やしたエタノール(5mL)中の3,5−ジフルオロピリジン−2−カルボン酸の懸濁液(2.0g、12.6mmol)に、滴下しながら塩化チオニル(2mL)を添加した。溶液を60℃で3時間加熱した。反応物を周囲温度まで戻し、真空中で濃縮し、エチルエステル、塩酸塩を黄色の油状物質(2.5g)として得た。
工程B:(3,5−ジフルオロ−ピリジン−2−イル)−メタノールの調製
氷水浴を用いて冷やしたエタノール(10mL)中のパートAの3,5−ジフルオロ−ピリジン−2−カルボン酸エチルエステルの溶液(2.5g、12.6mmol)に、小分けして水素化ホウ素ナトリウム(1.43g、37.8mmol)を添加した。溶液を0℃で30分間撹拌し、周囲温度で2時間撹拌した。反応物を0℃まで戻し、飽和塩化アンモニウムを滴下して加えた。溶媒を真空中で除去し、結果として得られる残渣を酢酸エチルと水で分けた。有機層を飽和塩化アンモニウム、水及びブラインで洗浄し、硫酸マグネシウム上で乾燥させた。スラリーをろ過及び濃縮し、アルコールを黄色の油状物質(1.8g)として得た:MS(ES)m/e146(M+H)。
ジクロロメタン(20mL)中のパートBの(3,5−ジフルオロ−ピリジン−2−イル)−メタノールの溶液(1.8g、12.3mmol)に、N,N−ジメチルホルムアミドを3滴添加し、氷水浴を用いて冷やした。塩化チオニル(2mL)を滴下して添加し、溶液を周囲温度で1時間撹拌した。溶液を真空中で濃縮し、淡褐色液体としてクロロ化合物(1.75g)を得た。
混合物を酢酸エチルと水で分けた。有機層を水及びブラインで洗浄し、硫酸マグネシウム上で乾燥させた。溶液を真空中で濃縮し、茶色の油状物質を得た。順相クロマトグラフィー(酢酸エチル/ヘプタン)によって、アルキル化生成物を淡黄色固体(4.6g)として得た:MS(ES)m/e371(M+H)。
びブラインで洗浄し、硫酸マグネシウム上で乾燥させた。溶液を真空中で濃縮した。残渣をジクロロメタンに懸濁し、結果として得られた白色の固体を真空ろ過によって回収し、塩素化脱保護生成物(1.16g)を得た:MS(ES)m/e293(M+H)。
(393mg、2.85mmol)を添加した。スラリーを75℃で18時間加熱した。スラリーを周囲温度まで戻し、酢酸エチルと水で分けた。有機層をブラインで洗浄し、硫酸マグネシウム上で乾燥させた。溶液を濃縮し、順相クロマトグラフィー(酢酸エチル/ヘプタン)を用いて精製し、表題化合物を淡黄色の固体(255mg、46%)として得た:MS(ES)m/e514(M+H)。
本開示は、ある状態を有する、又はある状態を有しやすい対象のそのような状態を治療する方法をさらに提供し、当該方法は、対象に治療上有効な量の1つ以上の上記化合物を投与することによってである。1つの実施形態では、治療は予防療法である。別の実施形態では、治療は対症療法である。別の実施形態では、回復療法である。
本発明に従って治療され得る状態としては、限定はしないが、自己免疫性障害、慢性炎症性障害、急性炎症性障害、自己炎症性障害、疼痛、アテローム性動脈硬化症、糖尿病、線維症、代謝疾患、がん、腫瘍、白血病、リンパ腫等が挙げられる。
ューロパシー、自己免疫性卵巣不全、自己免疫性精巣炎、自己免疫性血小板減少症、反応性関節炎、強直性脊椎炎、シリコーン移植関連自己免疫疾患、シェーグレン症候群、家族性地中海熱、全身性エリテマトーデス、血管炎症候群(例えば巨細胞性動脈炎、ベーチェット病及びウェジナー肉芽腫症といった)、白斑、自己免疫疾患の二次的な血液学的兆候(例えば貧血といった)、薬剤誘発性自己免疫、橋本甲状腺炎、下垂体炎、特発性血小板紫斑病、金属誘発性自己免疫、重症筋無力症、天疱瘡、自己免疫性難聴(例えばメニエール病が挙げられる)、グッドパスチャー症候群、グレーブス病、HW関連自己免疫症候群及びギラン−バレー病が挙げられる;炎症性状態の例としては、限定はしないが、敗血症、敗血症性ショック、エンドトキシンショック、エンドトキシン誘発性毒素ショック、グラム陰性菌敗血、エンドトキシンショック症候群、糸球体腎炎、腹膜炎、間質性膀胱炎、乾癬、アトピー性皮膚炎、酸素過剰誘発性炎症、喘息、慢性閉塞性肺疾患(COPD)、血管炎、移植片対宿主反応(すなわち、移植片対宿主疾患)、同種移植片拒絶(例えば、急性同種移植片拒絶及び慢性同種移植片拒絶)、初期の移植拒絶(例えば、急性同種移植片拒絶反応)、再潅流傷害、急性疼痛、慢性疼痛、神経因性疼痛、結合組織炎、膵臓炎、慢性感染症、脳膜炎、脳炎、心筋炎、歯肉炎、手術後の外傷、組織傷害、外傷性脳損傷、肝炎、全腸炎、副鼻腔炎、ぶどう膜炎、眼炎症、視神経炎、胃潰瘍、食道炎、腹膜炎、歯膜炎、皮膚筋炎、胃炎、筋炎、多発性筋痛、肺炎並びに気管支炎が挙げられる。線維症;限定はしないが、肥満、ステロイド耐性、耐糖能障害、メタボリックシンドロームを包含する代謝疾患。いくつかの実施形態では、本明細書に記載する方法を用いて腫瘍を患っている当該方法が必要な患者を治療し得る。これらの状態の例としては、限定はしないが、血管新生、多発性骨髄腫、白血病、B細胞リンパ腫、T細胞リンパ腫、マスト細胞腫瘍、リンパ腫、ホジキン病、骨がん、口/咽頭癌、食道癌、喉頭癌、胃癌、腸癌、結腸癌、直腸癌、肺癌、肝臓癌、膵臓癌、神経がん、脳がん、頭頚部癌、喉癌、卵巣癌、子宮癌、前立腺癌、精巣癌、膀胱癌、腎臓癌、乳癌、小細胞肺癌、黒色腫、皮膚癌、奇形腫、横紋筋肉腫、神経膠腫、転移性及び骨障害が挙げられる。いくつかの実施形態では、調節不全p38に関わる疾患としては、限定はしないがアテローム性動脈硬化症、アテローム性硬化症冠動脈の再狭窄、急性冠動脈症候群、心筋梗塞、移植心冠動脈病変及び脳卒中を包含する心血管及び脳血管障害;炎症性又はアポトーシス性要素を有する中枢神経系障害、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、筋萎縮性側索硬化症、脊髄損傷、ニューロン虚血並びに末梢神経障害が挙げられる。患者という用語は、上記の状態を有するヒト及び非ヒト動物の双方を指す。非ヒト動物は、限定はしないが、イヌ及びネコの種といったペット動物であり得る。
本発明に従って治療される適切な対象には、哺乳動物対象が包含される。本発明に従った哺乳動物としては、限定はしないが、ヒト、イヌ、ネコ、ウシ、ヤギ、ウマ、ヒツジ、ブタ、げっ歯動物、ウサギ、霊長動物等が挙げられ、子宮内の哺乳動物を包含する。対象はいずれかの性別及びいずれかの発達段階であり得る。
本発明の化合物は概して、治療上有効な量で投与される。
上記の状態の治療のために、本明細書で記載する化合物は以下のように投与され得る:
本発明の化合物は、化合物が胃腸管に入る、又は、口から直接血流へ吸収される(例えば、口腔又は舌下投与)よう嚥下することを包含する経口で投与され得る。
本発明の化合物は、血流、筋肉又は内臓器官へ直接投与され得る。非経口投与に適した手段としては、静脈内、筋肉内、皮下、動脈内、腹腔内、髄腔内、頭蓋内等が挙げられる。非経口投与に適したデバイスとしては、注射器(針及び針無しの注射器)及び点滴方法が挙げられる。
本発明の化合物は、皮膚に局所的又は経皮的に投与され得る。この局所投与の製剤はとしては、ローション、溶液、クリーム、ゲル、ハイドロゲル、軟膏、泡状物質、インプラント、パッチ等が挙げられ得る。局所投与製剤のための薬剤的に許容可能な担体としては、水、アルコール、鉱油、グリセリン、ポリエチレングリコール等が挙げられ得る。局所投与はまた、電気穿孔、イオン泳動、音波泳動等によって実施され得る。
本発明の化合物は、単独で、又は、他の薬剤的に活性な化合物と組合せて用いて、上記した状態といった状態を治療し得る。本発明の化合物及び他の薬剤的に活性な化合物は、同時(同一の剤形又は異なる剤形のいずれかで)又は順次投与され得る。したがって、1つの実施形態では、本発明は、対象に治療上有効な量の1つ以上の本発明の化合物及び1つ以上の追加の薬剤的に活性な化合物を投与することで状態を治療する方法を含む。
態では、したがって、本明細書に記載する投与レジメンから逸脱する。
ORAL、SANDIMMUNE)、タクロリムス及びシクロフォスファミド(CYTOXAN)、CD20遮断剤(RITUXIMAB)、腫瘍壊死因子(TNF)遮断剤(例えば、エタネルセプト(ENBREL)、インフリキシマブ(REMICADE)及びアダリムマブ(HUMIRA)、アバタセプト(CTLA4−Ig)及びインターロイキン−1受容体拮抗薬(例えばアナキンラ(KINERET))、インターロイキン6阻害剤(例えば、ACTEMRA)、インターロイキン17阻害剤(例えば、AIN457)、ヤヌスキナーゼ阻害剤(例えば、TASOCITINIB)、Syk阻害剤(例えばR788)、クロロキン及びその誘導体。
PRAK誘導リン酸化の遮断における、阻害剤効力を比較する酵素アッセイで評価する。化合物の活性化リン酸化−p38αを阻害する能力を、p38α/MK2及びp38α/PRAKカスケードアッセイ形式を用いて評価する。p38αのキナーゼ活性を、GST−MK2又はGST−PRAKをリン酸化するその能力によって決定する。p38αによるMK2又はPRAKの活性化を、蛍光標識したMK2/PRAK特異性ペプチド基質、Hsp27ペプチド(FITC−KKKALSRQLSVAA)のリン酸化を測定することで定量化する。Hsp27ペプチドのリン酸化を、IMAP技術(モレキュラーデバイス(Molecular Devices)社、カリフォルニア州、サニーベール)を用いて数量化する。キナーゼ反応を、20mMのHEPES、pH7.5、10mMのMgCl2、0.01%Triton X−100、0.01%BSA、1mMのDTT及び2%DMSO中の384ウェルプレート(グライナー(Greiner)社、781280)で実行する。阻害剤濃度は0.02〜30,000nMの間でばらつき、一方で、Hsp27ペプチド基質及びMgATPはそれぞれ1μM及び10μMで一定に保たれる。活性化p38αを、カスケード反応での1nMの非リン酸化GST−MK2との反応のために30pMの最終濃度まで添加する。p38α/PRAKカスケードに関しては、非活性化GST−PRAKを10nMで一定に保つ一方で、p38αを200pMの最終濃度まで添加する。キナーゼ反応を室温でインキュベートし、IMAP結合溶液の添加によって120分後にクエンチした。これらの条件下で、およそ20%の基質Hsp27ペプチドがリン酸化される。反応をHsp27ペプチド及びMgATPの添加によって開始するプリインキュベーション実験を除いて、反応は活性化p38αの添加によって開始される。p38αの阻害剤とのプリインキュベーション、又はp38αの非活性化GST−MK2若しくは非活性化GST−PRAK及び阻害剤とのプリインキュベーションを、ATP及びHsp27ペプチドを添加して触媒作用を開始する前に、2×最終アッセイ濃度で、室温にて、240分間実施する。p38α化合物阻害活性効力を、p38α/MK2カスケードアッセイの用量反応IC50値又はKi値から定量化する一方で、基質選択性を、p38α/PRAK:p38α/MK2のIC50値の割合として算出する。本明細書に記載され、本アッセイで評価される式(I)の種化合物は、自己免疫疾患及びリンパ腫といったp38キナーゼ介在疾患の治療で治療効果を提供することが予想される。
とが示されている。したがって、p38MAPK経路の阻害は、炎症促進性サイトカインの生合成を減少させることで炎症応答を低下させるだろう。本実験では、TNFα、IL−6及びIL−1β(炎症促進性サイトカイン)の生合成を半分阻害するのに必要な本発明の化合物の量を示す。これは、自己免疫状態、リンパ腫及び関節リウマチを包含する多くの疾患の治療を助ける効果である炎症の低下に役立つ本発明の化合物の有効性を反映する。p38阻害剤のサイトカイン生産を遮断する効力及び効能の評価は、ヒトU937細胞株を用いて実行される。U937ヒト前単球細胞株を、アメリカ合衆国培養細胞系統保存機関(American Type Culture Collection)(メリーランド州、ロックビル)から取得する。これらの細胞は、Burnette(Burnetteら、(2009).SD0006:a potent, selective and orally available inhibitor of p38 kinase,Pharmacology 84(1):42−60)が説明する通り、単球/マクロファージ表現型に分化する。分化したU937細胞を、完全な培地の96ウェルの組織培養プレート(200,000個の細胞/ウェル)に播種する。24時間後、細胞を60分間、化合物の存在下又は不在下で前処理し、次いで、LPS(0.1μg/mL)で4時間刺激する。次いで、培養培地を、ELISAによるTNFα、IL−6又はIL−1βの量の決定のために回収する。4パラメーターロジスティックモデルを用いて、及び、最良の最小二乗法へのあてはめを繰り返した後にIC50の値を求め、サイトカイン濃度を組み換えタンパク質の標準曲線から推定する。本明細書に記載され、本アッセイで評価される式(I)の種化合物は、リンパ腫又は炎症といったp38キナーゼ介在疾患の治療で治療効果を提供することが予想される。
胞株を、アメリカ合衆国培養細胞系統保存機関(メリーランド州、ロックビル)から取得する。これらの細胞は、Burnette(Burnetteら、(2009).SD0006:a potent,selective and orally available inhibitor of p38 kinase,Pharmacology
84(1):42−60)が説明する通り、単球/マクロファージ表現型に分化する。浮遊細胞(T75cm2の組織培養フラスコ内で1ミリリットル当たりおよそ50万個)を10%のウシ胎仔血清(FBS)と抗生物質を含むRPMIで成長させる。1日目に、フォルボール12−ミリステート13−アセテート(PMA、20ng/ml)を培養フラスコに添加し、細胞を一晩37℃/5%CO2でインキュベートする。2日目に、細胞を遠心分離し、PMA無しの新しい培地で再懸濁することで、細胞を洗浄する。付着した細胞をかきとり、遠心分離し、1ミリリットル当たり100万個の密度である新しい培地で再懸濁することで、付着した細胞を3日目に回収する。PMAで分化したU937細胞を次いで96ウェルの平底組織培養プレート(100ml/ウェル)の各ウェルに配分し、1ウェル当たり100,000個の細胞を回復させ、一晩インキュベートする。アッセイの日に、新しい培地(50ml/ウェル)をプレートに添加し、続いて化合物(25ml/ウェル、濃度応答)を1時間添加する。細胞を100mlの最終アッセイ体積で、LPS(100ng/ml)で刺激する。30分後、完全な溶解緩衝液(50ml/ウェル、MSD Tris溶解緩衝液、プロテアーゼ阻害剤及びホスファターゼ阻害剤を補充)を添加し、プレートを振盪機上に4℃で30分間置き、−20℃で冷凍保存する。細胞溶解物(25ml/ウェル)を解凍し、リン酸化Hsp27/合計Hsp27又はリン酸化JNK/合計JNKの決定のためにアッセイプレートからメソスケール(Meso Scale)検出プレートへ移す。
。血漿を慎重に別の96ウェルの丸底プレートに写し、アッセイ培地(10%ウシ胎仔血清(FBS)と抗生物質を含むDMEM)で2倍に希釈する。最後に、希釈した血漿(25ml/ウェル)を、IL−1、IL−6又はTNFαの決定のためにMeso Scale検出プレートへ移す。
Chemical)社、ミシガン州、アンアーバー)で定量化する。本明細書に記載され、本アッセイで評価される式(I)の種化合物は、リンパ腫又は関節リウマチといったp38キナーゼ介在疾患の治療で治療効果を提供することが予想される。
子(TF)を生産することを証明するものである。96ウェル形式では、付着したHUVEC(5継代以下)を1時間、参照として非選択性p38阻害剤又は対照のための媒体を含む段階希釈した化合物で処理する。Hsp27リン酸化に関して、細胞を次いで500pg/mLのIL−1βで0.5時間刺激し、培地を除去し、細胞を溶解し、溶解物内のリン酸化Hsp27を酵素結合免疫吸着測定(ELISA)(ライフテクノロジー(Life Technologies)社、カリフォルニア州、カールスバッド)で定量化する。TF放出の手順は、IL−1β刺激が5時間続く以外はELISAベースアッセイ(アメリカン・ダイアグノスティカ(American Diagnostica)社、コネチカット州、スタンフォード)と同様である。TF阻害IC50:HSP27リン酸化阻害IC50の割合をこれらの細胞における基質選択性指数として定義する。本明細書に記載され、本アッセイで評価される式(I)の種化合物は、リンパ腫及び自己炎症性疾患といったp38キナーゼ介在疾患の治療で治療効果を提供することが予想される。
ことが予想される。
Claims (19)
- R3が3,5−ジフルオロピリジン−2−イル、3−フルオロピリジン−2−イル、5−フルオロ−3−メチルピリジン−2−イル、6−フルオロピリジン−2−イル、6−フルオロ−4−メチルピリジン−2−イル、3−フルオロ−5−メチルピリジン−2−イル及び5−フルオロピリジン−2−イルから成る群から選択される請求項2に記載の化合物又はその薬剤的に許容できる塩。
- 前記化合物が:
3−ブロモ−4−((3,5−ジフルオロピリジン−2−イル)メトキシ)−6’’−(
2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−クロロ−4−((3,5−ジフルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((3,5−ジフルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((3,5−ジフルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((3,5−ジフルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−クロロ−4−((3,5−ジフルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((3,5−ジフルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((3,5−ジフルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オンから成る群から選択される、請求項4に記載の化合物又はその薬剤的に許容できる塩。 - 前記化合物が:
3−クロロ−4−((5−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((3−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((5−フルオロ−3−メチルピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((6−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((6−フルオロ−4−メチルピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((3−フルオロ−5−メチルピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((5−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((5−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((5−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−クロロ−4−((5−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((5−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((5−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((5−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((3−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((3−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((3−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−クロロ−4−((3−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((3−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((3−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((3−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((5−フルオロ−3−メチルピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((5−フルオロ−3−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((5−フルオロ−3−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−クロロ−4−((5−フルオロ−3−メチルピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((5−フルオロ−3−メチルピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−
5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((5−フルオロ−3−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((5−フルオロ−3−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((6−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((6−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((6−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−クロロ−4−((6−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((6−フルオロピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((6−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((6−フルオロピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((6−フルオロ−4−メチルピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((6−フルオロ−4−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((6−フルオロ−4−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−クロロ−4−((6−フルオロ−4−メチルピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((6−フルオロ−4−メチルピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((6−フルオロ−4−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((6−フルオロ−4−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((3−フルオロ−5−メチルピリジン−2−イル)メトキシ)−2’
−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((3−フルオロ−5−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((3−フルオロ−5−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−クロロ−4−((3−フルオロ−5−メチルピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((3−フルオロ−5−メチルピリジン−2−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((3−フルオロ−5−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;及び
3−ブロモ−4−((3−フルオロ−5−メチルピリジン−2−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オンから成る群から選択される、請求項3に記載の化合物又はその薬剤的に許容できる塩。 - 前記化合物が:
3−クロロ−4−((4−フルオロピリジン−3−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((4−フルオロピリジン−3−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((4−フルオロピリジン−3−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((4−フルオロピリジン−3−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−クロロ−4−((4−フルオロピリジン−3−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((4−フルオロピリジン−3−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((4−フルオロピリジン−3−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;及び
3−ブロモ−4−((4−フルオロピリジン−3−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オンから成る群から選択される、請求項8に記載の化合物又はその薬剤的に許容できる塩。 - 前記化合物が:
3−クロロ−4−((5−フルオロピリミジン−4−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((5−フルオロピリミジン−4−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((5−フルオロピリミジン−4−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−ブロモ−4−((5−フルオロピリミジン−4−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−5’,6−ジメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;
3−クロロ−4−((5−フルオロピリミジン−4−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−ブロモ−4−((5−フルオロピリミジン−4−イル)メトキシ)−2’−(2−(2−ヒドロキシプロパン−2−イル)−5−メチルピリミジン−4−イル)−5’,6−ジメチル−2H−[1,4’−ビピリジン]−2−オン;
3−クロロ−4−((5−フルオロピリミジン−4−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オン;及び
3−ブロモ−4−((5−フルオロピリミジン−4−イル)メトキシ)−6’’−(2−ヒドロキシプロパン−2−イル)−3’’,5’,6−トリメチル−2H−[1,4’:2’,2’’−テルピリジン]−2−オンから成る群から選択される、請求項11に記載の化合物又はその薬剤的に許容できる塩。 - 治療上有効な量の請求項1〜12のいずれか1項に記載の化合物又はその薬剤的に許容できる塩及び薬剤的に許容可能な担体を含む医薬組成物。
- 抗炎症薬、抗アテローム硬化薬、免疫抑制薬、免疫調節薬、細胞分裂阻害薬、血管新生阻害剤、キナーゼ阻害剤、サイトカイン阻害薬及び細胞接着分子の阻害剤から成る群から選択される活性医薬成分を、治療上有効な量でさらに含む、請求項13に記載の医薬組成物。
- 自己免疫性障害、慢性炎症性障害、急性炎症性障害、自己炎症性障害、アテローム性動脈硬化症、糖尿病、線維症及びがんから成る群から選択される状態を治療するための請求項13又は14に記載の医薬組成物。
- イヌ及びヒトから選択される哺乳動物用である、請求項15に記載の医薬組成物。
- 前記がんがリンパ腫である、請求項16に記載の医薬組成物。
- ヒト用であり、前記状態が慢性炎症性障害である、請求項16に記載の医薬組成物。
- 前記慢性炎症性障害が、関節リウマチである、請求項18に記載の医薬組成物。
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Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3845529A1 (en) * | 2013-06-07 | 2021-07-07 | Aclaris Therapeutics, Inc. | Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds |
EP3502692A1 (en) | 2017-12-20 | 2019-06-26 | Aposcience AG | Potency assay for secretomes |
EP4003344A4 (en) * | 2019-07-31 | 2023-07-26 | Aclaris Therapeutics, Inc. | DEUTERED MK2 SIGNALING PATH INHIBITORS AND METHODS FOR THEIR USE |
MX2022011748A (es) | 2020-03-27 | 2022-12-02 | Aclaris Therapeutics Inc | Composiciones orales de inhibidor de ruta de mk2 para el tratamiento de condiciones inmunitarias. |
MX2023005884A (es) * | 2020-11-23 | 2023-06-26 | Aclaris Therapeutics Inc | Metodos para sintetizar compuestos de piridinona-piridinilo sustituidos. |
JP2024512154A (ja) | 2021-03-31 | 2024-03-18 | シンセラ, インコーポレイテッド | Mk2阻害剤及びその使用 |
CA3226158A1 (en) | 2021-07-09 | 2023-01-12 | Xinthera, Inc. | Pyridinone mk2 inhibitors and uses thereof |
WO2023001282A1 (zh) * | 2021-07-23 | 2023-01-26 | 南京明德新药研发有限公司 | 杂环取代的嘧啶衍生物 |
TW202315625A (zh) * | 2021-08-13 | 2023-04-16 | 大陸商深圳信立泰藥業股份有限公司 | 三聯吡啶二酮化合物或其鹽、包括其藥物組合物及其用途 |
CN116178345B (zh) * | 2021-10-19 | 2024-08-13 | 深圳信立泰药业股份有限公司 | 一种取代的嘧啶基-吡啶基-吡啶酮化合物及其制备方法与应用 |
WO2023125708A1 (zh) * | 2021-12-29 | 2023-07-06 | 上海美悦生物科技发展有限公司 | 一种p38 MAPK/MK2通路调节剂及其组合物、制备方法和用途 |
TWI836822B (zh) * | 2021-12-29 | 2024-03-21 | 大陸商上海美悦生物科技發展有限公司 | p38 MAPK/MK2通路調節劑及其組合物、製備方法和用途 |
CN118510776A (zh) * | 2022-01-14 | 2024-08-16 | 上海翰森生物医药科技有限公司 | 含五元环类衍生物、其制备方法和应用 |
AU2023207395A1 (en) | 2022-01-14 | 2024-07-11 | Jiangsu Hansoh Pharmaceutical Group Co., Ltd. | Pyridine-containing polycyclic derivative, and preparation method therefor and use thereof |
WO2023150709A2 (en) * | 2022-02-04 | 2023-08-10 | Aclaris Therapeutics, Inc. | Methods of synthesizing deuterated substituted pyridinone-pyridinyl compounds |
WO2023165554A1 (zh) * | 2022-03-03 | 2023-09-07 | 深圳信立泰药业股份有限公司 | 一种氘代三联吡啶二酮化合物或其盐及其制备方法与应用 |
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WO2024022412A1 (zh) * | 2022-07-28 | 2024-02-01 | 深圳信立泰药业股份有限公司 | 一种式(i)所示的三联吡啶二酮化合物晶型及其制备方法与应用 |
WO2024046327A1 (zh) * | 2022-08-30 | 2024-03-07 | 长春金赛药业有限责任公司 | p38α-MK2抑制剂化合物、药物组合物及其应用 |
WO2024077059A1 (en) * | 2022-10-05 | 2024-04-11 | Xinthera, Inc. | Crystalline forms of an mk2 inhibitor |
CN118047757A (zh) * | 2022-11-16 | 2024-05-17 | 上海美悦生物科技发展有限公司 | 吡啶氮氧化物类衍生物及其药物组合物、制备方法和用途 |
CN118344289A (zh) * | 2023-01-13 | 2024-07-16 | 上海美悦生物科技发展有限公司 | 苯基取代的杂芳基类化合物及其药物组合物、制备方法和用途 |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US789061A (en) * | 1904-07-11 | 1905-05-02 | Harrison G Post | Paper barrel. |
JP2002526482A (ja) | 1998-09-18 | 2002-08-20 | バーテックス ファーマシューティカルズ インコーポレイテッド | p38のインヒビター |
SK16482001A3 (sk) | 1999-05-21 | 2002-04-04 | Scios Inc. | Indolové deriváty ako inhibítory p38 kinázy |
EP1341782A2 (en) | 2000-11-20 | 2003-09-10 | Scios Inc. | Inhibitors of p38 kinase |
US7314752B2 (en) | 2001-07-19 | 2008-01-01 | Common Sense, Ltd. | Secretion-monitoring article |
BR0307631A (pt) | 2002-02-14 | 2004-12-21 | Pharmacia Corp | Piridinonas substituìdas como moduladores de p38 map-quinase |
EP1506189A1 (en) | 2002-04-26 | 2005-02-16 | Vertex Pharmaceuticals Incorporated | Pyrrole derivatives as inhibitors of erk2 and uses thereof |
GB0218630D0 (en) | 2002-08-10 | 2002-09-18 | Tanabe Seiyaku Co | Novel compounds |
CA2498111A1 (en) | 2002-09-11 | 2004-03-25 | Merck & Co., Inc. | Dihydroxypyridopyrazine-1,6-dione compounds useful as hiv integrase inhibitors |
US20070167621A1 (en) | 2003-04-03 | 2007-07-19 | Pharmacia Corporation | Substituted pyrimidinones |
US7183287B2 (en) | 2003-04-03 | 2007-02-27 | Pharmacia Corporation | Substituted pyrimidinones |
NL1026826C2 (nl) | 2003-08-13 | 2007-01-04 | Pharmacia Corp | Gesubstitueerde pyridinonen. |
JP2005255675A (ja) | 2004-02-09 | 2005-09-22 | Tanabe Seiyaku Co Ltd | 医薬組成物 |
CA2555176A1 (en) | 2004-02-11 | 2005-08-25 | Smithkline Beecham Corporation | Hiv integrase inhibitors |
US7576212B2 (en) * | 2004-12-09 | 2009-08-18 | Xention Limited | Thieno[2,3-B] pyridines as potassium channel inhibitors |
BRPI0607913A2 (pt) | 2005-04-08 | 2010-03-23 | Eisai R&D Man Co Ltd | agente terapÊutico para discinesia |
TW200740755A (en) | 2005-07-13 | 2007-11-01 | Bayer Cropscience Sa | Dihalogenation of N,O-disubstituted hydroxypyridones and their uses |
WO2007081901A2 (en) | 2006-01-05 | 2007-07-19 | The Scripps Research Institute | Pyrimidinone derivatives as protein kinase inhibitors |
UY30378A1 (es) | 2006-06-02 | 2008-01-02 | Janssen Pharmaceutica Nv | Nuevos derivados de piridinona n-aril y n-heteroaril sustituidos para usar en enfermedades mediadas por mch-1 |
WO2008008493A2 (en) | 2006-07-14 | 2008-01-17 | Amgen Inc. | Alkyne-substituted pyridone compounds and methods of use |
BRPI0719060A2 (pt) | 2006-11-24 | 2014-02-04 | Takeda Pharmaceutical | Composto, prodroga, agente farmacêutico, métodos para inibir um receptor de angiotensina ii e/ou ativar um receptor ativado com proliferador de peroxisoma, e para prevenir ou tratar doenças ou condições, e, uso de um composto |
JP2010512322A (ja) | 2006-12-07 | 2010-04-22 | ノバルティス アーゲー | 有機化合物 |
EP2166857A4 (en) | 2007-06-06 | 2011-03-30 | Xcovery Inc | KINASE INHIBITOR COMPOUNDS |
NZ582661A (en) | 2007-07-17 | 2012-03-30 | Bristol Myers Squibb Co | Method for modulating gpr119 g protein-coupled receptor and selected compounds |
PE20110136A1 (es) | 2008-06-27 | 2011-03-17 | Novartis Ag | Compuestos organicos |
WO2011003007A1 (en) | 2009-07-01 | 2011-01-06 | Albany Molecular Research, Inc. | Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine mch-1 antagonists, methods of making, and use thereof |
US8618299B2 (en) | 2009-07-01 | 2013-12-31 | Albany Molecular Research, Inc. | Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof |
US9073925B2 (en) | 2009-07-01 | 2015-07-07 | Albany Molecular Research, Inc. | Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof |
CN103391718A (zh) | 2010-12-06 | 2013-11-13 | 汇合生命科学股份有限公司 | 取代的吡啶酮-吡啶基化合物 |
WO2013086208A1 (en) * | 2011-12-06 | 2013-06-13 | Confluence Life Sciences, Inc. | Substituted pyrimidinone-phenyl-pyrimidinyl compounds |
EP3845529A1 (en) * | 2013-06-07 | 2021-07-07 | Aclaris Therapeutics, Inc. | Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds |
USD789061S1 (en) * | 2015-11-04 | 2017-06-13 | Salomon S.A.S. | Upper of a footwear article |
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