JP2013528205A - 尿素誘導体、および特に呼吸器の疾患の治療におけるその治療的使用 - Google Patents
尿素誘導体、および特に呼吸器の疾患の治療におけるその治療的使用 Download PDFInfo
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- JP2013528205A JP2013528205A JP2013513759A JP2013513759A JP2013528205A JP 2013528205 A JP2013528205 A JP 2013528205A JP 2013513759 A JP2013513759 A JP 2013513759A JP 2013513759 A JP2013513759 A JP 2013513759A JP 2013528205 A JP2013528205 A JP 2013528205A
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- 230000009385 viral infection Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
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Abstract
Description
本発明は、特に呼吸器の疾患の治療における抗炎症剤として有用な、p38 MAPK阻害剤である化合物および組成物に関する。
マイトジェン活性化タンパク質キナーゼ(MAPK)は、二重リン酸化によってその基質を活性化する、プロリン指向性セリン/スレオニンキナーゼのファミリーを構成する。ヒトのp38 MAPキナーゼには、4種類の既知のアイソフォーム、p38α、p38β、p38γおよびp38δがある。p38キナーゼは、サイトカイン抑制性抗炎症薬結合タンパク質(CSBP)、ストレス活性化タンパク質キナーゼ(SAPK)およびRKとしても知られ、転写因子(ATF−2、MAX、CHOPおよびC/ERPbなど)ならびに他のキナーゼ(MAPKAP−K2/3またはMK2/3など)のリン酸化(Steinら、Ann.Rep.Med Chem.、1996、31、289-298)および活性化を担い、それ自体は、物理的および化学的ストレス(例えば、紫外線、浸透圧ストレス)、炎症誘発性サイトカインならびに細菌性リポ多糖(LPS)によって活性化される(Herlaar E.& Brown Z.、Molecular Medicine Today、1999、5、439-47)。p38リン酸化の産物は、腫瘍壊死因子α(TNF α)およびインターロイキン(IL)−1、ならびにシクロオキシゲナーゼ−2(COX−2)を含めた、炎症性サイトカインの産生を媒介することが示されている。IL−1およびTNFαが、IL−6およびIL−8などの他の炎症誘発性サイトカインの産生を刺激することも知られている。
本発明の化合物は、p38αを含めたp38マイトジェン活性化タンパク質キナーゼ(「p38 MAPK」、「p38キナーゼ」または「p38」)の阻害剤であり、TNFαおよびIL−8の産生を含めた、サイトカインおよびケモカインの産生の阻害剤である。本発明の化合物は、炎症性疾患、特にアレルギー性および非アレルギー性気道疾患、より詳細には慢性閉塞性肺疾患(「COPD」)および喘息などの閉塞性または炎症性気道疾患の治療において、幾つもの治療用途を有する。したがって、本発明の化合物は、鼻または口による吸入による肺送達に特に適している。
本発明によると、式(I)の化合物または医薬として許容されるその塩が提供される:
R1は、式(IA)または(IB)または(IC)の基であり:
R4bは、C1〜C6アルキル、C3〜C6シクロアルキル、任意選択により置換されたフェニル、任意選択により置換された5員もしくは6員の単環式ヘテロアリール、または式(IIa)もしくは(IIb)の基であり;
R3bは、任意選択により置換されたC1〜C6アルキル;−NH2;モノ−またはジ−(C1〜C6)アルキルアミノ;モノ−またはジ−(C1〜C3)アルキル−X−(C1〜C3)アルキルアミノ(式中、Xは、O、S、またはNH;N−モルホリノ;N−ピペリジニル、N−ピペラジニルもしくはN−(C1〜C3)アルキルピペラジン−1−イル)であり;
Yは、−O−または−S(O)p−(式中、pは0、1または2)であり;
Aは、フェニル環に縮合した、5、6または7個の環原子を有する、任意選択により置換されたシクロアルキレン基であり;
R2は、式(IIIa)、(IIIb)、(IIIc)、(IIId)または(IIIe)の基であり:
qは、0、1、2または3であり;
Tは、−N=または−CH=であり;
R5は、HまたはFであり;
R7は、−CH3;−C2H5 −CH2OH、−CH2SCH3 −SCH3または−SC2H5であり;
R8は、−CH3または−C2H5であり、また
R6の各出現は、独立に、H、C1〜C6アルキル、ヒドロキシもしくはハロであるか;または、R6の単一の出現は、式(IVa)、(IVb)もしくは(IVc)の基であり
式(IVa)、(IVb)および(IVc)において、nおよびpは上で定義した通りであり;
また、R6において、式中
R61aおよびR61bは、H、アルキルであるか、または、R61aおよびR61bは、それらが結合した窒素とともに繋がり、NおよびOから選択されるさらなるヘテロ原子を任意選択により含有する4〜7員の複素環式環、例えば、ピペリジン、ピペラジンもしくはモルホリン環などを形成してもよい。
本明細書で使用される場合、用語「(Ca〜Cb)アルキル」(ここで、aおよびbは整数)は、aからb個の炭素原子を有する直鎖または分岐鎖のアルキル基を指す。よって、例えばaが1でbが6のとき、該用語には、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、sec−ブチル、t−ブチル、n−ペンチルおよびn−ヘキシルが含まれる。
本発明の幾つかの実施形態では、R1は、式(IA)または(IB)の基である。こうした基のうち、式(IB)が現在のところ好ましい。基(IA)または(IB)において:
R4bは、イソプロピル基などのC1〜C6アルキルであってもよく;
R4bは、シクロペンチルなどのC3〜C6シクロアルキルであってもよく;
R4bは、フェニルであってもよく;さらに特定すると、該フェニル基は、C1〜C6アルキル、ハロゲン(例えばクロロ)またはヒドロキシから選択される1種または2種の基によって置換されており;例えば、該フェニル基は、2位および/または6位で置換されていてもよく;具体的には、R4bは、2,6−ジクロロフェニル、2−クロロフェニル、または2−ヒドロキシフェニルであってもよく;
R4bは、式(IIa)の基または式(IIb)の基であってもよい。
R3bは、C1〜C3アルキルなどのC1〜C6アルキルであってもよく、例には、メチル、エチル、n−またはイソ−プロピルがある。R3bは、置換C1〜C3アルキルなどの置換C1〜C6アルキルであってもよく、前記置換基は上で定義されている。かかる置換基の例には、C1〜C6アルコキシ、C1〜C6アルキルスルホニルが含まれ、好ましい基R3bは、メトキシメチルである。
リンカーY
Yは、−O−または−S(O)p−である。例えば、Yは−O−または−S−であってもよい。現在のところ、Yは−O−であることが好ましい。
基A
Aは、例えば、配向を問わず式(Va)の二価の基であってもよく、
基R2
基R2は、上で定義した通りの式(IIIa〜e)の基である。好都合には、R2は基(IIIb)または(IIIc)であり、式中、R7およびR8は、エチルまたはメチルである。
上で述べたように、本発明の化合物はp38MAPK阻害剤であり、よってp38酵素の阻害から利益を得る疾患または状態の治療に有用であり得る。かかる疾患および状態は、文献から既知であり、幾つかは上で述べてきた。しかし、該化合物は、一般に抗炎症剤としての使用に、特に呼吸器疾患の治療における使用のために有用である。特に、該化合物は、慢性閉塞性肺疾患(COPD)、慢性気管支炎、肺線維症、肺炎、急性呼吸促迫症候群(ARDS)、肺気腫、または喫煙によって誘発される気腫、内因性(非アレルギー性喘息および外因性(アレルギー性)喘息、軽度の喘息、中等度の喘息、重度の喘息、ステロイド抵抗性喘息、好中球性喘息、気管支炎性喘息、運動誘発性喘息、職業性喘息および細菌感染症後に誘発される喘息、嚢胞性線維症、肺線維症ならびに気管支拡張症の治療に使用することができる。
上で述べたように、本発明が関係する化合物は、p38キナーゼ阻害剤であり、幾つかの疾患、例えば呼吸器の炎症性疾患の治療に有用である。かかる疾患の例は上で言及されており、それには、喘息、鼻炎、アレルギー性気道症候群、気管支炎および慢性閉塞性肺疾患が含まれる。
本発明の化合物 24mg/キャニスター
レシチン、NF液体濃縮物 1.2mg/キャニスター
トリクロロフルオロメタン、NF 4.025g/キャニスター
ジクロロジフルオロメタン、NF 12.15g/キャニスター。
炎症性疾患、特に呼吸器疾患の予防および治療のために、本発明が関係する化合物とともに他の化合物を併用してもよい。よって、本発明は、治療有効量の本発明の化合物と1種または複数の他の治療剤とを含む医薬組成物にも関係する。本発明の化合物との併用療法に適切な治療剤には、それだけには限らないが、以下が含まれる。(1)副腎皮質ステロイド、例えば、プロピオン酸フルチカゾン、フロ酸フルチカゾン、フロ酸モメタゾン、ジプロピオン酸ベクロメタゾン、シクレソニド、ブデソニド、GSK 685698、GSK 870086、QAE 397、QMF 149、TPI−1020など;(2)β2−アドレナリン受容体アゴニスト、例えば、サルブタモール、アルブテロール、テルブタリン、フェノテロールなど、および長時間作用性β2−アドレナリン受容体アゴニスト、例えばサルメテロール、インダカテロール、ホルモテロール(フマル酸ホルモテロールが含まれる)、アルホルモテロール、カルモテロール、GSK 642444、GSK 159797、GSK 159802、GSK 597501、GSK 678007、AZD3199など;(3)副腎皮質ステロイド/長時間作用性β2アゴニスト併用製品、例えば、サルメテロール/プロピオン酸フルチカゾン(Advair/Seretide)、ホルモテロール/ブデソニド(Symbicort)、ホルモテロール/プロピオン酸フルチカゾン(Flutiform)、ホルモテロール/シクレソニド、ホルモテロール/フロ酸モメタゾン、インダカテロール/フロ酸モメタゾン、インダカテロール/QAE 397、GSK 159797/GSK 685698、GSK 159802/GSK 685698、GSK 642444/GSK 685698、GSK 159797/GSK 870086、GSK 159802/GSK 870086、GSK 642444/GSK 870086、アルホルモテロール/シクレソニドなど;(4)抗コリン剤、例えばムスカリン−3(M3)受容体アンタゴニスト、例えば、臭化イプラトロピウム、臭化チオトロピウム、アクリジニウム(LAS−34273)、NVA−237、GSK 233705、ダロトロピウム、GSK 573719、GSK 961081、QAT 370、QAX 028など;(5)二重薬理M3−抗コリン性/β2−アドレナリン受容体アゴニスト、例えばGSK961081など;(6)ロイコトリエンモジュレーター、例えば、ロイコトリエンアンタゴニスト、例えば、モンテルカスト、ザフィルラスト(zafirulast)もしくはプランルカストなど、または、ロイコトリエン生合成阻害剤、例えばジロートンもしくはBAY−1005など、またはLTB4アンタゴニスト、例えばアメルバントなど、またはFLAP阻害剤、例えば、GSK 2190914、AM−103など;(7)ホスホジエステラーゼ−IV(PDE−IV)阻害剤(経口または吸入)、例えばロフルミラスト、シロミラスト、オグレミラスト、ONO−6126、テトミラスト、トフィミラスト、UK 500,001、GSK 256066など;(8)抗ヒスタミン剤、例えば、選択的ヒスタミン−1(H1)受容体アンタゴニスト、例えば、フェキソフェナジン、シチリジン(citirizine)、ロラチジンもしくはアステミゾールなど、または二重H1/H3受容体アンタゴニスト、例えば、GSK 835726、GSK 1004723など;(9)鎮咳剤、例えば、コデインまたはデキストラモルファン(dextramorphan)など;(10)粘液溶解薬、例えば、N−アセチルシステインまたはフドステイン;(11)去痰薬/粘液動態(mucokinetic)モジュレーター、例えば、アンブロキソール、高張液(例えば、生理食塩水またはマンニトール)または界面活性剤;(12)ペプチド粘液溶解薬、例えば、組換えヒトデオキシリボノクレアーゼI(deoxyribonoclease I)(ドルナーゼ−アルファおよびrhDNアーゼ)またはヘリチジン(helicidin);(13)抗生物質、例えば、アジスロマイシン、トブラマイシンおよびアズトレオナム;(14)非選択的COX−1/COX−2阻害剤、例えば、イブプロフェンまたはケトプロフェンなど;(15)COX−2阻害剤、例えば、セレコキシブおよびロフェコキシブなど;(16)VLA−4アンタゴニスト、例えば、WO97/03094およびWO97/02289に記載のものなど;(17)TACE阻害剤およびTNF−α阻害剤、例えば抗TNFモノクローナル抗体、例えばRemicadeおよびCDP−870など、ならびにTNF受容体免疫グロブリン分子、例えばEnbrelなど;(18)マトリクスメタロプロテアーゼの阻害剤、例えばMMP−12;(19)ヒト好中球エラスターゼ阻害剤、例えば、ONO−6818、またはWO2005/026124、WO2003/053930およびWO06/082412に記載のものなど;(20)A2bアンタゴニスト、例えばWO2002/42298に記載のものなど;(21)ケモカイン受容体機能のモジュレーター、例えば、CCR3およびCCR8のアンタゴニスト;(22)他のプロスタノイド受容体の作用を調節する化合物、例えばトロンボキサンA2アンタゴニスト;DP1アンタゴニスト、例えばMK−0524など、CRTH2アンタゴニスト、例えばODC9101およびAZD1981など、ならびに混合DP1/CRTH2アンタゴニスト、例えばAMG 009など;(23)PPARアゴニスト、それにはPPARαアゴニスト(例えばフェノフィブラートなど)、PPARδアゴニスト、PPARγアゴニスト、例えば、ピオグリタゾン、ロシグリタゾンおよびバラグリタゾンなどが含まれる;(24)メチルキサンチン、例えば、テオフィリンまたはアミノフィリンなど、ならびにメチルキサンチン/副腎皮質ステロイド併用、例えば、テオフィリン/ブデソニド、テオフィリン/プロピオン酸フルチカゾン、テオフィリン/シクレソニド、テオフィリン/フロ酸モメタゾンおよびテオフィリン/ジプロピオン酸ベクロメタゾンなど;(25)A2aアゴニスト、例えばEP1052264およびEP1241176に記載のものなど;(26)CXCR2またはIL−8アンタゴニスト、例えば、SCH 527123またはGSK 656933など;(27)IL−Rシグナル伝達モジュレーター、例えばkineretおよびACZ 885など;(28)MCP−1アンタゴニスト、例えばABN−912など。
本発明の化合物は、本明細書の例に記述する方法の処理手順を適合させることによって調製することができる。
一般式(a)の化合物は、一般式(d):
RaCHO (l)
のアルデヒドと、エタノールまたはテトラヒドロフランなどの適切な溶媒中で、様々な温度、好ましくは室温と80℃の間で反応させることによって調製することができる。
一般式(o):
RaCO2H (o)
の化合物と、トリフェニルホスフィン/トリクロロアセトニトリルなどの適切なアシル化剤/脱水剤を使用して、ジイソプロピルエチルアミンなどの塩基の存在下で、ジクロロメタンまたはアセトニトリルなどの適切な溶媒中で、様々な温度、好ましくは室温と150℃の間で反応させることによって調製することができる。
実験項で使用する略語:aq.=水性;DCM=ジクロロメタン;DIPEA=ジイソプロピルエチルアミン;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=1−エチル−3−(3’−ジメチルアミノプロピル)カルボジイミド;EtOAc=酢酸エチル;EtOH=エタノール;Et2O=ジエチルエーテル;FCC=フラッシュカラムクロマトグラフィー;h=時間;HATU=2−(7−アザ−1H−ベンゾトリアゾル−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスファート;HOBt=1−ヒドロキシ−ベンゾトリアゾール;HPLC=高速液体クロマトグラフィー;LCMS=液体クロマトグラフィー質量分析;MeCN=アセトニトリル;MeOH=メタノール;min=分;NMR=核磁気共鳴;RT=室温;Rt=保持時間;sat.=飽和;SCX−2=強陽イオン交換クロマトグラフィー;TFA=トリフルオロ酢酸;THF=テトラヒドロフラン;H2O=水;IMS=工業用変性アルコール;Et3N=トリエチルアミン;EtNiPr2=ジイソプロピルエチルアミン
構造の名称を、MDL Inc製のAutonom 2000 Nameソフトウェアを使用して割り当てた。化合物の立体化学的割り当ては、重要な中間体についてWO2008/043019に報告されるデータと比較することに基づいている。特に指定のない限り、すべての反応を窒素雰囲気下で行った。
C18逆相カラム(30×4.6mm Phenomenex Luna 粒径3μm)を備えたWaters Platform LC四重極質量分析計、A:水+0.1%ギ酸;B:メタノール+0.1%ギ酸で溶出。勾配:
C18逆相カラム(30×4.6mm Phenomenex Luna 粒径3μm)を備えたWaters ZMD四重極質量分析計、A:水+0.1%ギ酸;B:メタノール+0.1%ギ酸で溶出。勾配:
C18逆相カラム(30×4.6mm Phenomenex Luna 粒径3μm)を備えたWaters ZMD四重極質量分析計、A:水+0.1%ギ酸;B:アセトニトリル+0.1%ギ酸で溶出。勾配:
Higgins Clipeus 5ミクロン C18 100×3.0mmを備え、40℃で維持される、Waters ZMD四重極質量分析計。A:水+0.1%ギ酸;B:MeOH+0.1%ギ酸で溶出。勾配:
Acquity BEH C18 1.7um 100×2.1mm、Acquity BEH Shield RP18 1.7um 100×2.1mmまたはAcquity HSST3 1.8um 100×2.1mmを備え、40℃で維持される、Waters ZMD四重極質量分析計。A:水+0.1%ギ酸;B:CH3CN+0.1%ギ酸で溶出。勾配:
Phenomenex Gemini C18逆相カラム(250×21.20mm 粒径5μm)、A:水+0.1%ギ酸;B:CH3CN+0.1%ギ酸で溶出。勾配−10%A/90%Bから98%A/2%B、20分間−流速18mL/分。検出−波長254nMに設定したインラインUV検出器。
(+/−) 1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[−4−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−cis−1,2,3,4−テトラヒドロ−ナフタレン−1−イル]−尿素
例1e(87mg、0.27mmol)のジオキサン(2mL)溶液を、EtNiPr2(49uL、0.3mmol)および2,2,2−トリクロロエチル3−tert−ブチル−1−p−トリル−1H−ピラゾル−5−イルカルバメート(109mg、0.27mmol)とともに、70℃で20時間加熱した。反応物を放冷し、H2O−EtOAcの間で分配し、有機相を乾燥し(Na2SO4)、真空中で濃縮した。残留物をFCC(0〜6% 9:1 MeOH/0.88NH3−CH2Cl2)により精製して、MeOH中にスラリー化し、標記化合物を無色固体として得た(57mg)。LCMS(方法4):Rt 12.03分、m/z 578 [MH+]。
(+/−) 1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[4−(3−イソプロピル[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−trans−1,2,3,4−テトラヒドロ−ナフタレン−1−イル]−尿素
(+/−) 1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−{4−[3−(2−ヒドロキシ−フェニル)[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ]−cis−1,2,3,4−テトラヒドロ−ナフタレン−1−イル}−尿素
1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[(1R,4R)−4−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−1,2,3,4−テトラヒドロ−ナフタレン−1−イル]−尿素
1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[(1R,4S)−4−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−1,2,3,4−テトラヒドロ−ナフタレン−1−イル]−尿素
標記化合物を、(1S,4R)−4−アミノ−1,2,3,4−テトラヒドロ−ナフタレン−1−オール(例9、ステップb)を使用して、例1、ステップeおよびfと同様の方法で調製した。LCMS(方法5):Rt 4.84分、m/z 578[MH+]。
1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[(1S,4R)−4−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−1,2,3,4−テトラヒドロ−ナフタレン−1−イル]−尿素
1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[(1S,4S)−4−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−1,2,3,4−テトラヒドロ−ナフタレン−1−イル]−尿素
1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[(1R,3R)−3−(3−イソプロピル[1,2,4]トリアゾロ[4,3a]ピリジン−6−イルオキシ)−インダン−1−イル]−尿素
1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[(1S,3S)−3−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−インダン−1−イル]−尿素
1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[(1R,3S)−3−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−インダン−1−イル]−尿素
1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[(1S,3R)−3−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−インダン−1−イル]−尿素
1−(5−tert−ブチル−イソキサゾル−3−イル)−3−[(1S,4S)−4−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−1,2,3,4−テトラヒドロ−ナフタレン−1−イル]−尿素
N−(5−tert−ブチル−3−{3−[(1S,4S)−4−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−1,2,3,4−テトラヒドロ−ナフタレン−1−イル]−ウレイド}−2−メトキシ−フェニル)−メタンスルホンアミド
(+/−) 1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[9−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−cis−6,7,8,9−テトラヒドロ−5H−ベンゾシクロヘプテン−5−イル]−尿素
標記化合物を、例1ステップeおよびfと同様の方法で、例18ステップaの生成物から出発して調製した。LCMS(方法5):Rt 4.84分、m/z 592[MH+]。
(+/−) 1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[9−(3−イソプロピル−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ)−trans−6,7,8,9−テトラヒドロ−5H−ベンゾシクロヘプテン−5−イル]−尿素
標記化合物を、例1ステップeおよびfと同様の方法で、例19ステップaから出発して調製した。LCMS(方法5):Rt 4.87分、m/z 592[MH+]。
1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−((1S,4S)−4−{3−[2−(2−ヒドロキシ−エチルスルファニル)−フェニル]−[1,2,4]トリアゾロ[4,3−a]ピリジン−6−イルオキシ}−1,2,3,4−テトラヒドロ−ナフタレン−1−イル)−尿素
例20ステップc(38mg、0.05mmol)および4−メチルベンゼンスルホン酸(9mg、0.05mmol)のMeOH(2mL)溶液を、室温で3時間、次いで60℃で5時間撹拌した。混合物を室温まで冷却し、真空中で濃縮した。残留物を、MeOHを含むDCM(0から10%)を使用するFCCにより精製して、標記化合物を黄色固体として得た(15mg、44%)。LCMS(方法5):Rt 4.83分、m/z 688 [MH+]。
1−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−3−[(1S,4S)−4−(3−tert−ブチル[1,2,4]トリアゾロ[4,3a]ピリジン−6−イルオキシ)−1,2,3,4−テトラヒドロ−ナフタレン−1−イル]−尿素
N−(4−{(1S,4S)−4−[3−(5−tert−ブチル−2−p−トリル−2H−ピラゾル−3−イル)−ウレイド]−1,2,3,4−テトラヒドロ−ナフタレン−1−イルオキシメチル}−ピリジン−2−イル)−2−メトキシ−アセトアミド
例21ステップd(40mg、0.076mmol)、DIPEA(28μL、0.167mmol)およびメトキシアセチルクロリド(15.2μL、0.16mmol)のDCM(1mL)溶液を、室温で2時間撹拌した。反応混合物を真空中で濃縮し、残留物をHPLC(30から95%のCH3CNを含むH2O+0.1%ギ酸)により精製して、標記化合物を白色固体として得た(21mg、46%)。LCMS(方法5):Rt 5.05分、m/z 597 [MH+]。
p38キナーゼアッセイ
大腸菌で発現させ、MKK6酵素(Calbiochem #559324)とのインキュベーションにより活性化したヒト組換えp38酵素を酵素活性源として使用する。
アッセイ緩衝液に添加する前に、化合物をDMSOで希釈し、アッセイの最終DMSO濃度を1%とする
IC50は、所与の化合物が、対照の50%阻害を実現する濃度と定義される
結果を以下の表に示す。
細胞のp38の阻害は、TNFαの放出を抑制する。TNFαの放出とは、新鮮に採取されたヒト血液から単離されたLPS活性化THP−1細胞(不死化単球細胞系)または末梢血単核球(PBMC’s)の上清中のTNFαの量を測定することによって定量化される、機能的反応である。
Claims (15)
- 式(I)の化合物、または医薬として許容されるその塩:
R1は、式(IA)または(IB)または(IC)の基であり:
R4bは、C1〜C6アルキル、C3〜C6シクロアルキル、任意選択により置換されたフェニル、任意選択により置換された5員もしくは6員の単環式ヘテロアリール、または式(IIa)もしくは(IIb)の基であり;
R3bは、任意選択により置換されたC1〜C6アルキル;−NH2;モノ−またはジ−(C1〜C6)アルキルアミノ;モノ−またはジ−(C1〜C3)アルキル−X−(C1〜C3)アルキルアミノ(式中、Xは、O、S、またはNH;N−モルホリノ;N−ピペリジニル、N−ピペラジニルもしくはN−(C1〜C3)アルキルピペラジン−1−イル)であり;
Yは、−O−または−S(O)p−(式中、pは0、1または2)であり;
Aは、フェニル環に縮合した、5、6または7個の環原子を有する、任意選択により置換されたシクロアルキレン基であり;
R2は、式(IIIa)、(IIIb)、(IIIc)、(IIId)または(IIIe)の基であり:
qは、0、1、2または3であり;
Tは、−N=または−CH=であり;
R5は、HまたはFであり;
R7は、−CH3;−C2H5;−CH2OH、−CH2SCH3;−SCH3または−SC2H5であり;
R8は、−CH3または−C2H5であり;また
R6の各出現は、独立に、H、C1〜C6アルキル、ヒドロキシもしくはハロであるか;または、R6の単一の出現は、式(IVa)、(IVb)もしくは(IVc)の基であり;
式(IVa)、(IVb)および(IVc)において、nおよびpは上で定義した通りであり;
また、R6において、式中:
R61aおよびR61bは、H、アルキルであるか、または、R61aおよびR61bは、それらが結合した窒素とともに繋がり、NおよびOから選択されるさらなるヘテロ原子を任意選択により含有する4〜7員の複素環式環を形成してもよい)。 - Yが、−O−または−S−である、請求項1に記載の化合物。
- Yが−O−である、請求項4に記載の化合物。
- −NH−A−Y−が、請求項3で定義した通りの式(B)、(C)、(D)、(E)、(I)または(J)を有し、式中、Yが−O−である、請求項4に記載の化合物。
- R4bが、イソプロピル、シクロペンチル、または、C1〜C6アルキル、ハロゲンおよびヒドロキシから選択される1種または2種の基によって任意選択により置換されたフェニルである、請求項1から6のいずれかに記載の化合物。
- R4bが、2,6−ジクロロフェニル、2−クロロフェニル、または2−ヒドロキシフェニルである、請求項1から6のいずれかに記載の化合物。
- R3bがメトキシメチルである、請求項1から6のいずれかに記載の化合物。
- R2が、基(IIIb)または(IIIc)であり、式中、R7およびR8が、独立にエチルまたはメチルである、1から9請求項のいずれかに記載の化合物。
- R2が、基(IIIb1)または(IIIb2)である、請求項1から9のいずれかに記載の化合物。
- 請求項1から11のいずれかに記載の化合物を、医薬として許容可能な1種または複数の担体とともに含む、医薬組成物。
- 肺内投与のための吸入に適合させた、請求項12に記載の組成物。
- p38 MAPキナーゼ活性の阻害から利益を得る疾患または状態の治療に使用するための、請求項1から11のいずれかに記載の化合物。
- 前記疾患が、慢性閉塞性肺疾患、成人呼吸促迫症候群(ARDS)、他の薬物療法の結果である気道過敏症の増悪、または肺高血圧症と関連する気道疾患である、請求項14に記載の通りに使用するための化合物。
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MX2012014371A (es) | 2013-01-29 |
US8916708B2 (en) | 2014-12-23 |
WO2011154738A1 (en) | 2011-12-15 |
UA104677C2 (ru) | 2014-02-25 |
AU2011263492A1 (en) | 2013-01-10 |
JP5791708B2 (ja) | 2015-10-07 |
AU2011263492B2 (en) | 2015-11-12 |
SG186228A1 (en) | 2013-01-30 |
GB201009731D0 (en) | 2010-07-21 |
BR112012031226A2 (pt) | 2018-03-06 |
CN103140489A (zh) | 2013-06-05 |
US20130143914A1 (en) | 2013-06-06 |
IL223463A (en) | 2016-12-29 |
RU2586223C2 (ru) | 2016-06-10 |
EP2580212A1 (en) | 2013-04-17 |
ZA201209289B (en) | 2014-02-26 |
KR20130086944A (ko) | 2013-08-05 |
CN103140489B (zh) | 2016-05-18 |
RU2012153164A (ru) | 2014-06-20 |
CA2802010A1 (en) | 2011-12-15 |
MY159239A (en) | 2016-12-30 |
EP2580212B1 (en) | 2015-01-28 |
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