JP6838796B2 - 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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- JP6838796B2 JP6838796B2 JP2020004547A JP2020004547A JP6838796B2 JP 6838796 B2 JP6838796 B2 JP 6838796B2 JP 2020004547 A JP2020004547 A JP 2020004547A JP 2020004547 A JP2020004547 A JP 2020004547A JP 6838796 B2 JP6838796 B2 JP 6838796B2
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- methoxy
- hydroxypropan
- dimethyl
- chloro
- bromo
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 132
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 52
- 239000012826 P38 inhibitor Substances 0.000 claims description 40
- -1 3,5-difluoropyridine-2-yl Chemical group 0.000 claims description 39
- 201000010099 disease Diseases 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000001246 bromo group Chemical group Br* 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 239000002158 endotoxin Substances 0.000 claims description 13
- 208000011580 syndromic disease Diseases 0.000 claims description 10
- 206010040070 Septic Shock Diseases 0.000 claims description 9
- 230000000735 allogeneic effect Effects 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 5
- 230000000737 periodic effect Effects 0.000 claims description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 206010016207 Familial Mediterranean fever Diseases 0.000 claims description 4
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 claims description 4
- 101710126825 NACHT, LRR and PYD domains-containing protein 3 Proteins 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 201000005569 Gout Diseases 0.000 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 3
- 230000009885 systemic effect Effects 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
- 208000023328 Basedow disease Diseases 0.000 claims description 2
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- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
- 206010063837 Reperfusion injury Diseases 0.000 claims description 2
- 206010040047 Sepsis Diseases 0.000 claims description 2
- 201000002661 Spondylitis Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
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- 239000007943 implant Substances 0.000 claims description 2
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- 230000036473 myasthenia Effects 0.000 claims description 2
- 210000002569 neuron Anatomy 0.000 claims description 2
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- 230000036303 septic shock Effects 0.000 claims description 2
- 208000020408 systemic-onset juvenile idiopathic arthritis Diseases 0.000 claims description 2
- 230000001256 tonic effect Effects 0.000 claims description 2
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- 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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- VTMMPUGRLAAPMR-UHFFFAOYSA-N 3-bromo-4-[(3-fluoropyridin-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=CC=C1F VTMMPUGRLAAPMR-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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- OPVIUBREJYFKPG-UHFFFAOYSA-N 3-bromo-4-[(6-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=C(F)C=CC=3)C=C2C)=O)=C(C)C=N1 OPVIUBREJYFKPG-UHFFFAOYSA-N 0.000 claims 1
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- KJKUSTKNNGORKD-UHFFFAOYSA-N 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-[2-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-5-methylpyridin-4-yl]-6-methylpyridin-2-one Chemical compound CC1=CN=C(C=2N=C(C=CC=2)C(C)(C)O)C=C1N(C(C=1Cl)=O)C(C)=CC=1OCC1=NC=C(F)C=C1F KJKUSTKNNGORKD-UHFFFAOYSA-N 0.000 claims 1
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- 231100000765 toxin Toxicity 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 125000000165 tricyclic carbocycle group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 229940063674 voltaren Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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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。
ピロリル、ピリダジニル、ピラジニル、キノリニル、イソキノリニル、ベンゾフラニル、ジベンゾフラニル、ジベンゾチオフェニル、ベンゾチエニル、インドリル、ベンゾチアゾリル、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。
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。
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。
1dを得る。ピリジノン1dはR2及びX置換基次第で、3つの経路のうち1つを介して表題化合物へ転化され得る。例えば、R2がメチルの場合、パラジウム触媒の存在下での1dのビニルスズ試薬との反応によってメチルケトン1iが提供される。イソプロパノールといった溶媒中でN−クロロサクシニミド(又は対応するブロモが所望される場合はN−ブロモスクシンイミド)を用いる1iのハロゲン化によって、1jが提供される。1j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、ピリジノン1gを得る。又は、XがNである場合、そのハライドをエタノール中のパラジウム触媒の存在下で一酸化炭素と処理することで、1dはカルボキシル化され得、エステル1eを得る。水中水酸化リチウムでの1eのエステルを加水分解し、続いて、中間体カルボン酸をCDIで処理、次にワインレブ条件化でメトキシメチルアミン及びジイソプロピルエチルアミンといったアミン塩基で処理し、1hを得る。THFといった溶媒中でのワインレブアミド1hの所望するR2グリナード(Grinard)試薬との反応により、1iが提供される。ケトン1iは次いで1jに転化され、次いで、上記の通り、最終化合物1gに転化される。ピリジン又はピリミジンD環を準備する別の選択肢は、適切なパラジウム触媒を用いるスズキ条件下で1dを所望するボロン酸で反応させ、結合中間体を得ることであり、当該結合中間体は、次いで、NCS又はNBSを用いてハロゲン化され、1fが提供される。THFといった溶媒中で臭化メチルマグネシウムを1fに添加することで、表題化合物1gが提供される。
スキーム1:
在下におけるビニルスズ試薬と2dの反応によってメチルケトン2eが提供される。イソプロパノールといった溶媒中で、N−クロロサクシニミド(又は対応するブロモが所望される場合は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)。
ピリジニル−2−オンの調製
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。
びマトリックスメタロプロテアーゼが挙げられる。
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。
が挙げられ得る。
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。
る副作用の1つが発疹である場合、最初の治療剤と組合せて抗ヒスタミン剤を投与するのがふさわしい。又は、ほんの例として、p38阻害剤の治療上の有効性は、治療上の効果も有する他の治療剤(治療レジメンも含む)の投与によって強化される。いずれの場合も、治療されている疾患、障害又は状態に関わらず、患者が経験する全体的な効果は、単に2つの治療剤を加算したものであるか、又は、患者は相乗効果を経験するかのいずれかである。
患う危険がある場合、又は、アテローム性動脈硬化症に関する状態を患っている若しくは患う危険がある場合、本明細書に記載するp38阻害剤組成物は、アテローム性動脈硬化症若しくはアテローム性動脈硬化症に関する状態を治療するための1つ以上の剤又は方法と一緒に、いずれかの組合せで使用してもよい。アテローム性動脈硬化症又はアテローム性動脈硬化症に関する状態を治療する治療剤/治療の例としては、限定はしないが、次のうちいずれかが挙げられる:トルセトラピブ、アスピリン、ナイアシン、HMG CoA還元酵素阻害剤(例えば、アトルバスタチン、フルバスタチン、ロバスタチン、プラバスタチン、ロスバスタチン及びシンバスタチン)、コレセベラム、コレスチラミン、コレスチポール、ゲムフィブロジル、プロブコール及びクロファイブレート。
パ腫及び関節リウマチを包含する多くの疾患を治療するのに役立つ炎症応答の低下を手助けするのにどれだけ効果的であるかを測定するものである。化合物の、新規のMK2基質選択性阻害活性機構を、HSP−27由来のペプチド基質の、p38/MK2対p38/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。
るだろう。古典的p38阻害剤は、p38の基質の下流のリン酸化を遮断する一方で、JNKといった並行した経路の活性を上昇させる。異なるクラスのp38阻害剤のp38及びJNK経路制御に対する影響の評価を、2つの経路に関してそれぞれリン酸化HSP27及びリン酸化JNKを用いて行う。p38阻害剤のリン酸化タンパク質に影響を与え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(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。
158USP単位)を含むバキュテナー回収管内へ集め、プール化し、優しく振動し、96ウェルの丸底組織培養プレート(180ml/ウェル)の各ウェルに配分した。化合物(10ml/ウェル、濃度応答)を添加し、使い捨ての96ポリプロピレンのピンツールを用いて15〜20秒間優しく混合し、プレートを37℃/5%CO2で1時間インキュベートする。HWBを200mlの最終アッセイ体積で、LPS(100ng/ml)で刺激させる。3時間後、プレートを240xgで5分間回転し、赤血球をペレット化する。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。
静脈内皮細胞(HUVEC)を用い、Hsp27リン酸化(p38/MK2活性化のバイオマーカー)を阻害する一方、別のp38の下流基質であるMSKに関連している組織因子(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。
合物を静脈内注射した4時間後、LPS(E.coli血清型0111:B4、シグマアルドリッチ社)を投与する。最大TNFα及びIL−1β生産に対応する時間点である、LPS注射から90分後、心穿刺を介して血液を血清分離管で回収する。凝血後、血清を取り出し、−20℃で保存し、IL−1β及びTNFα量をELISA(前述のBurnette)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。
Claims (12)
- 式(I)の化合物:
又はその薬剤的に許容できる塩を含むp38阻害剤であって、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であり、
潰瘍性大腸炎、炎症性腸疾患、クローン病、乾癬、全身性エリテマトーデス、多発性硬化症、グレーブス病、重症筋無力症、骨障害、変形性関節症、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、エンドトキシンショック症候群、敗血症、関節炎、喘息、再潅流傷害、ニューロン虚血、脳卒中、慢性痛風、移植片対宿主疾患、同種移植片拒絶、糸球体腎炎、肺炎症、転移性黒色腫、多発性骨髄腫、慢性閉塞性肺疾患(COPD)、乾癬性関節炎、強直性脊椎炎、クリオピリン関連周期性症候群(CAPS)、スチル病、家族性地中海熱から成る群から選択される状態を治療するための、
前記p38阻害剤。 - 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p38阻害剤。
- 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p38阻害剤。 - 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p38阻害剤。 - 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p38阻害剤。 - 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p38阻害剤。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US201361832736P | 2013-06-07 | 2013-06-07 | |
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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 |
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CN116354935A (zh) * | 2021-12-29 | 2023-06-30 | 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 |
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