JP2022513409A - 血液疾患の治療のための併用療法 - Google Patents
血液疾患の治療のための併用療法 Download PDFInfo
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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- GKTQKQTXHNUFSP-UHFFFAOYSA-N thieno[3,4-c]pyrrole-4,6-dione Chemical compound S1C=C2C(=O)NC(=O)C2=C1 GKTQKQTXHNUFSP-UHFFFAOYSA-N 0.000 description 1
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- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
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- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
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Abstract
Description
本出願は、2018年10月31日に出願された米国仮出願第62/753,409号の利益を主張する。当該仮出願の開示は、参照することにより全体として本明細書に組み込まれる。
本明細書に記載の方法は、選択的JAK1阻害薬を使用する。選択的JAK1阻害薬は、他のヤヌスキナーゼより優先的にJAK1活性を阻害する化合物である。JAK1は、いくつかのサイトカイン及び成長因子シグナル伝達経路において中心的役割を果たし、調節異常の場合、病態をもたらす場合もあれば、病態の一因となる場合もある。例えば、IL-6のレベルは、関節リウマチ、すなわち、それが有害作用を有することが示唆される疾患では上昇している(Fonesca,et al.,Autoimmunity Reviews,8:538-42, 2009)。IL-6は、少なくとも一部は、JAK1を介してシグナル伝達するため、IL-6は、間接的に、JAK1阻害を介して潜在的な臨床的利益をもたらす可能性がある(Guschin,et al.Embo J 14:1421, 1995、Smolen,et al.Lancet 371:987, 2008)。さらに、一部のがんでは、JAK1は、構成的な望ましくない腫瘍細胞の増殖及び生存をもたらすように変異している(Mullighan,Proc Natl Acad Sci USA.106:9414-8, 2009、Flex,J Exp Med.205:751-8, 2008)。他の自己免疫疾患及びがんでは、JAK1を活性化する炎症性サイトカインの全身レベルの上昇もまた、該疾患及び/または随伴症状の一因となり得る。従って、かかる疾患を有する患者は、JAK1を阻害することで利益を得る可能性がある。JAK1の選択的阻害薬は、有効であると同時に、他のJAKキナーゼの不必要かつ潜在的に望ましくない阻害の影響を回避する。
++は、≦100nMを意味する(アッセイ条件については実施例A参照)
+++は、≦300nMを意味する(アッセイ条件については実施例A参照)
aエナンチオマー1に関するデータ
bエナンチオマー2に関するデータ
Xは、NまたはCHであり、
Lは、C(=O)またはC(=O)NHであり、
Aは、フェニル、ピリジニル、またはピリミジニルであり、その各々は、任意に、1個または2個の独立して選択されるR1基で置換され、
各R1は、独立して、フルオロ、またはトリフルオロメチルである。
R2は、C1-6アルキル、C1-6ハロアルキル、C3-6シクロアルキル、またはC3-6シクロアルキル-C1-3アルキルであり、ここで、該C1-6アルキル、C3-6シクロアルキル、及びC3-6シクロアルキル-C1-3アルキルは、各々任意に、フルオロ、-CF3、及びメチルから独立して選択される1、2、または3個の置換基で置換され、
R3は、Hまたはメチルであり、
R4は、H、F、またはClであり、
R5は、HまたはFであり、
R6は、HまたはFであり、
R7は、HまたはFであり、
R8は、Hまたはメチルであり、
R9は、Hまたはメチルであり、
R10は、Hまたはメチルであり、
R11は、Hまたはメチルである。
Cy4は、テトラヒドロ-2H-ピラン環であり、これは、任意に、CN、OH、F、Cl、C1-3アルキル、C1-3ハロアルキル、シアノ-C1-3アルキル、HO-C1-3アルキル、アミノ、C1-3アルキルアミノ、及びジ(C1-3アルキル)アミノから独立して選択される1個または2個の基で置換され、ここで、該C1-3アルキル及びジ(C1-3アルキル)アミノは、任意に、F、Cl、C1-3アルキルアミノスルホニル、及びC1-3アルキルスルホニルから独立して選択される1、2、または3個の置換基で置換され、
R12は、-CH2-OH、-CH(CH3)-OH、または-CH2-NHSO2CH3である。
本明細書に提供する方法は、さらに、治療有効量の免疫調節薬を投与することを含む。
本明細書に提供する方法は、さらに、治療有効量のステロイドを投与することを含む。
細胞の増殖及び生存は、複数のシグナル伝達経路によって影響され得る。従って、かかる状態を治療するために、活性を調節するキナーゼに対して異なる選好を示す異なるキナーゼ阻害剤を組み合わせることが有用である。複数のシグナル伝達経路(または所与のシグナル伝達経路に関与する複数の生体分子)を標的とすることで、細胞集団で生じる薬物耐性の可能性を低減する場合、及び/または治療の毒性を低減する場合がある。
該化合物は、医薬組成物の形態で投与することができる。これらの組成物は、医薬分野で周知の方法で調製することができ、局所治療が適応されるか全身的治療が適応されるかに応じて、及び治療される領域に応じて、様々な経路で投与することができる。投与は、局所(経皮、表皮、点眼、ならびに鼻腔内、膣内及び直腸送達を含めた粘膜に対するもの等)、経肺(例えば、ネブライザーによるものを含めた散剤もしくはエアゾール剤の吸入もしくは吹送によるもの、気管内または鼻腔内)、経口あるいは非経口でよい。非経口投与としては、静脈内、動脈内、皮下、腹腔内、筋内または注射もしくは注入、あるいは頭蓋内、例えば、髄腔内または脳室内投与が挙げられる。非経口投与は、単回ボーラス投与の形態であってもよいし、例えば、連続潅流ポンプによる投与でもよい。局所投与用の医薬組成物及び製剤としては、経皮パッチ、軟膏剤、ローション剤、クリーム、ゲル剤、滴剤、座剤、噴霧剤、液剤及び散剤が挙げられ得る。従来の医薬担体、水性、粉末または油性基剤、増粘剤等が必要または望ましい場合がある。
本出願はまた、有用な医薬品キットも含み、これには、治療有効量の該化合物、またはその実施形態のいずれかを含む医薬組成物を含む1つ以上の容器が含まれる。当業者には容易に分かるように、かかるキットはさらに、様々な従来の医薬品キットの成分の1つ以上、例えば、1つ以上の医薬的に許容される担体を含む容器、追加の容器等を含むことができる。成分の投与量、投与のためのガイドライン、及び/または成分を混合するためのガイドラインを示す使用説明書を、挿入物またはラベルとして、該キットに含めることもできる。
血液疾患または障害を治療するために免疫調節薬及びステロイドと組み合わせて使用することができる選択的JAK1阻害薬を、Park et al.,Analytical Biochemistry 1999, 269, 94-104に記載の以下のインビトロアッセイに従い、JAK標的の阻害活性について調べた。N末端にHisタグを有するヒトJAK1(a.a.837-1142)、JAK2(a.a.828-1132)及びJAK3(a.a.781-1124)の触媒ドメインを、昆虫細胞中でバキュロウイルスを使用して発現させ、精製する。JAK1、JAK2、またはJAK3の触媒活性を、ビオチン化ペプチドのリン酸化を測定することでアッセイした。このリン酸化ペプチドは、均一系時間分解蛍光(HTRF)によって検出した。化合物のIC50は、各キナーゼについて、酵素、ATP及び500nMのペプチドを、100mMのNaCl、5mMのDTT、及び0.1mg/mL(0.01%)のBSAとともに含む50mMのTris(pH7.8)緩衝液を含む40μLの反応物中で測定した。1mMのIC50測定の場合、反応物中のATP濃度は1mMである。反応は、室温で1時間行い、その後、45mMのEDTA、300nMのSA-APC、6nMのEu-Py20を含むアッセイ緩衝液(Perkin Elmer,Boston,MA)20μLで停止させた。ユーロピウム標識抗体への結合を40分行い、HTRFシグナルをFusionプレートリーダー(Perkin Elmer,Boston,MA)で測定した。表1の化合物をこのアッセイで調べたところ、表1のIC50値を有することが分かった。
I.デザイン:
・シングルアーム
・第2相
・3剤併用:イタシチニブ(化合物1、表1)、ステロイド(メチルプレドニゾロンまたはデキサメタゾン)、及びレナリドミド
II.主要目的:
・ORR(CR+VGPR+PR)。ORR(奏効率)は、部分奏効(PR)、最良部分奏効(VGPR)、または完全奏効(CR)を有する治験参加者のパーセンテージとして定義され、国際骨髄腫作業部会(IMWG)の基準を用い、各4週間または28日間の治療周期後に特定する。
III.主要エンドポイント
・IMWG基準尺度
IV.副次的エンドポイント:
・全生存期間(OS)
・無増悪生存期間(PFR)
・奏効までの期間(TTR):治療の開始からPR、VGPRまたはCRの最初のエビデンスまでの期間として定義される
・奏効持続期間(DOR):奏効例に関して、奏効の開始から奏効の喪失までが測定される
・イタシチニブ+レナリドミド+ステロイドの組み合わせの安全性及び忍容性
・ベースラインから、変数が測定される各来院までの血清及び尿中のMタンパク質レベルの変化及び変化率
・生活の質(QOL)/症状の尺度
V.探索的エンドポイント
・臨床的有用性(CR+VGPR+PR+MR)、ここで、MRは最小奏効であり:PRの基準のすべてではなく一部を満たす患者
VI.選択基準:
・iMID及びプロテアソームを含めた治療の3ライン以上からの(4番目のライン)再発性/難治性多発性骨髄腫(RRMM)。患者は、最後の治療投与から8週間を超えて進行した場合に再発したと見なされる。患者は、治療を受けている最中に、または最後の治療投与から8週間以内に進行した場合は難治性である
・測定可能病変が認められるMMを現在有する。具体的には、患者は、血清電気泳動で、少なくとも0.5g/dLのモノクローナル免疫グロブリンスパイク、及び/または少なくとも200mg/24時間の尿中のモノクローナルタンパク質レベルを示す。測定可能な血清及び尿中Mタンパク質レベルを示さない患者については、無血清軽鎖アッセイ(SFLC)>100mgLを含めるか、または異常なSFLC比を使用することができる。
VII.除外基準:
・プレドニゾンまたは同等のもの20mg/日を超えるコルチコステロイドを治験薬から3週間以内に受けている。治療の開始時のステロイド投与の強度が、治験前のステロイドの投与によって変化しないようにするため。
VIII.治験治療:
・イタシチニブ(各周期1~28日目に100mg~600mgBID)、レナリドミド(各周期1~21日目に10mgQD)、ステロイド(例えば、メチルプレドニゾロン(MP)[各周期1~28日目の間に40mgQOD(1日おき)もしくはQD]またはデキサメタゾン[各周期1~28日目に2mg~20mgQODもしくはQD])。
・イタシチニブ(各周期1~28日目に100mg~600mgQD)、レナリドミド(各周期1~21日目に10mgQD)、ステロイド(例えば、メチルプレドニゾロン(MP)[各周期1~28日目の間に40mgQOD(1日おき)もしくはQD]またはデキサメタゾン[各周期1~28日目に2mg~20mgQODもしくはQD])。
・QODは1日おきであり、QDは1日1回であり、及びBIDは1日2回である
IX.症例数
・N=およそ87
・ORRが15%を超えるという仮説は、正確な二項分布を使用し、片側第一種過誤≦0.025を用いて検定する。87名の治験参加者では、この検定は、30%のORRに対する帰無仮説を棄却するために、正確な第一種過誤0.0167で90.7%の検定力を有する。
X.治療期間
・6ヶ月、28日周期、生存に関する追跡を行う。
ヒト多発性骨髄腫細胞株KMS12BM、OPM2(DSMZ)、MM1.R、MM1.S(ATCC)及びKMS11(JCRB)を、白色96ウェルプレート(Greiner Bio One)で、104細胞にて100μLの培地に播種した。デキサメタゾン(Sigma)、レナリドミド(Chemscene)、イタシチニブの組み合わせ、またはDMSO対照を次いで加えた。用量は、これらの薬剤に対する各細胞株の感受性を検出するように設計したパイロット試験に基づいて選択した。各用量の組み合わせを三連で行った。72時間後、Cell Titer Glo(Promega)アッセイを製造業者のプロトコルの通りに行い、細胞の生存を評価した。
Claims (28)
- 治療を必要とする患者における白血病、リンパ腫、及び多発性骨髄腫から選択される血液疾患の治療方法であって、前記患者に対して、(a)治療有効量の選択的JAK1阻害薬、(b)治療有効量の免疫調節薬、及び(c)治療有効量のステロイドを投与することを含む前記方法であり、
(a)前記JAK1阻害薬は、
{1-{1-[3-フルオロ-2-(トリフルオロメチル)イソニコチノイル]ピペリジン-4-イル}-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリル、
4-{3-(シアノメチル)-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-1-イル}-N-[4-フルオロ-2-(トリフルオロメチル)フェニル]ピペリジン-1-カルボキサミド、
[3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]-1-(1-{[2-(トリフルオロメチル)ピリミジン-4-イル]カルボニル}ピペリジン-4-イル)アゼチジン-3-イル]アセトニトリル、
4-[3-(シアノメチル)-3-(3’,5’-ジメチル-1H,1’H-4,4’-ビピラゾール-1-イル)アゼチジン-1-イル]-2,5-ジフルオロ-N-[(1S)-2,2,2-トリフルオロ-1-メチルエチル]ベンズアミド、
((2R,5S)-5-{2-[(1R)-1-ヒドロキシエチル]-1H-イミダゾ[4,5-d]チエノ[3,2-b]ピリジン-1-イル}テトラヒドロ-2H-ピラン-2-イル)アセトニトリル、
3-[1-(6-クロロピリジン-2-イル)ピロリジン-3-イル]-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]プロパンニトリル、
3-(1-[1,3]オキサゾロ[5,4-b]ピリジン-2-イルピロリジン-3-イル)-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]プロパンニトリル、
4-[(4-{3-シアノ-2-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]プロピル}ピペラジン-1-イル)カルボニル]-3-フルオロベンゾニトリル、
4-[(4-{3-シアノ-2-[3-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピロール-1-イル]プロピル}ピペラジン-1-イル)カルボニル]-3-フルオロベンゾニトリル、
[trans-1-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]-3-(4-{[2-(トリフルオロメチル)ピリミジン-4-イル]カルボニル}ピペラジン-1-イル)シクロブチル]アセトニトリル、
{trans-3-(4-{[4-[(3-ヒドロキシアゼチジン-1-イル)メチル]-6-(トリフルオロメチル)ピリジン-2-イル]オキシ}ピペリジン-1-イル)-1-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]シクロブチル}アセトニトリル、
{trans-3-(4-{[4-{[(2S)-2-(ヒドロキシメチル)ピロリジン-1-イル]メチル}-6-(トリフルオロメチル)ピリジン-2-イル]オキシ}ピペリジン-1-イル)-1-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]シクロブチル}アセトニトリル、
{trans-3-(4-{[4-{[(2R)-2-(ヒドロキシメチル)ピロリジン-1-イル]メチル}-6-(トリフルオロメチル)ピリジン-2-イル]オキシ}ピペリジン-1-イル)-1-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]シクロブチル}アセトニトリル、
4-(4-{3-[(ジメチルアミノ)メチル]-5-フルオロフェノキシ}ピペリジン-1-イル)-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]ブタンニトリル、
5-{3-(シアノメチル)-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-1-イル}-N-イソプロピルピラジン-2-カルボキサミド、
4-{3-(シアノメチル)-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-1-イル}-2,5-ジフルオロ-N-[(1S)-2,2,2-トリフルオロ-1-メチルエチル]ベンズアミド
5-{3-(シアノメチル)-3-[4-(1H-ピロロ[2,3-b]ピリジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-1-イル}-N-イソプロピルピラジン-2-カルボキサミド、
{1-(cis-4-{[6-(2-ヒドロキシエチル)-2-(トリフルオロメチル)ピリミジン-4-イル]オキシ}シクロヘキシル)-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリル、
{1-(cis-4-{[4-[(エチルアミノ)メチル]-6-(トリフルオロメチル)ピリジン-2-イル]オキシ}シクロヘキシル)-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリル、
{1-(cis-4-{[4-(1-ヒドロキシ-1-メチルエチル)-6-(トリフルオロメチル)ピリジン-2-イル]オキシ}シクロヘキシル)-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリル、
{1-(cis-4-{[4-{[(3R)-3-ヒドロキシピロリジン-1-イル]メチル}-6-(トリフルオロメチル)ピリジン-2-イル]オキシ}シクロヘキシル)-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリル、
{1-(cis-4-{[4-{[(3S)-3-ヒドロキシピロリジン-1-イル]メチル}-6-(トリフルオロメチル)ピリジン-2-イル]オキシ}シクロヘキシル)-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリル、
{trans-3-(4-{[4-({[(1S)-2-ヒドロキシ-1-メチルエチル]アミノ}メチル)-6-(トリフルオロメチル)ピリジン-2-イル]オキシ}ピペリジン-1-イル)-1-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]シクロブチル}アセトニトリル、
{trans-3-(4-{[4-({[(2R)-2-ヒドロキシプロピル]アミノ}メチル)-6-(トリフルオロメチル)ピリジン-2-イル]オキシ}ピペリジン-1-イル)-1-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]シクロブチル}アセトニトリル、
{trans-3-(4-{[4-({[(2S)-2-ヒドロキシプロピル]アミノ}メチル)-6-(トリフルオロメチル)ピリジン-2-イル]オキシ}ピペリジン-1-イル)-1-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]シクロブチル}アセトニトリル、及び
{trans-3-(4-{[4-(2-ヒドロキシエチル)-6-(トリフルオロメチル)ピリジン-2-イル]オキシ}ピペリジン-1-イル)-1-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]シクロブチル}アセトニトリル
から選択されるか、または上述のもののいずれかの医薬的に許容される塩であり、
(b)前記免疫調節薬は、サリドマイド、レナリドミド、アプレミラスト、リノミド、及びポマリドミドから選択されるか、または上述のもののいずれかの医薬的に許容される塩であり、
(c)前記ステロイドは、プレドニゾン、メチルプレドニゾロン、デキサメタゾン、ヒドロキシコルチゾン、コルチゾン、デスオキシコルチコステロン、フルドロコルチゾン、ベタメタゾン、プレドニゾロン、メチルプレドニゾン、パラメタゾン、トリアムシノロン、フルメタゾン、フルオシノロン、フルオシノニド、フルプレドニゾロン、ハルシノニド、フルランドレノリド、メプレドニゾン、及びメドリゾンから選択されるか、または上述のもののいずれかの医薬的に許容される塩である、前記方法。 - 前記選択的JAK1阻害薬が、{1-{1-[3-フルオロ-2-(トリフルオロメチル)イソニコチノイル]ピペリジン-4-イル}-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリル、またはその医薬的に許容される塩である、請求項1に記載の方法。
- 前記選択的JAK1阻害薬が、{1-{1-[3-フルオロ-2-(トリフルオロメチル)イソニコチノイル]ピペリジン-4-イル}-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリルのアジピン酸塩である、請求項1に記載の方法。
- 前記免疫調節薬が、サリドマイド、またはその医薬的に許容される塩である、請求項1~3のいずれか1項に記載の方法。
- 前記免疫調節薬が、レナリドミド、またはその医薬的に許容される塩である、請求項1~3のいずれか1項に記載の方法。
- 前記免疫調節薬が、ポマリドミド、またはその医薬的に許容される塩である、請求項1~3のいずれか1項に記載の方法。
- 前記免疫調節薬が、アプレミラスト、またはその医薬的に許容される塩である、請求項1~3のいずれか1項に記載の方法。
- 前記ステロイドが、メチルプレドニゾロン、またはその医薬的に許容される塩である、請求項1~7のいずれか1項に記載の方法。
- 前記ステロイドが、デキサメタゾン、またはその医薬的に許容される塩である、請求項1~7のいずれか1項に記載の方法。
- 前記ステロイドが、プレドニゾン、またはその医薬的に許容される塩である、請求項1~7のいずれか1項に記載の方法。
- 前記血液疾患が、慢性リンパ性白血病である、請求項1~10のいずれか1項に記載の方法。
- 前記血液疾患が、非ホジキンリンパ腫である、請求項1~10のいずれか1項に記載の方法。
- 前記非ホジキンリンパ腫が、B細胞関連である、請求項12に記載の方法。
- 前記血液疾患が、多発性骨髄腫である、請求項1~10のいずれか1項に記載の方法。
- 前記多発性骨髄腫が、再発性、難治性、または再発性難治性多発性骨髄腫である、請求項14に記載の方法。
- 前記血液疾患が、多発性骨髄腫であり、前記選択的JAK1阻害薬が、{1-{1-[3-フルオロ-2-(トリフルオロメチル)イソニコチノイル]ピペリジン-4-イル}-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリル、またはその医薬的に許容される塩であり、前記免疫調節薬が、レナリドミド、またはその医薬的に許容される塩であり、前記ステロイドが、メチルプレドニゾロンもしくはデキサメタゾン、またはその医薬的に許容される塩である、請求項1に記載の方法。
- 前記血液疾患が、多発性骨髄腫であり、前記選択的JAK1阻害薬が、{1-{1-[3-フルオロ-2-(トリフルオロメチル)イソニコチノイル]ピペリジン-4-イル}-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリル、またはその医薬的に許容される塩であり、前記免疫調節薬が、レナリドミド、またはその医薬的に許容される塩であり、前記ステロイドが、デキサメタゾン、またはその医薬的に許容される塩である、請求項1に記載の方法。
- 前記多発性骨髄腫が、再発性、難治性、または再発性難治性多発性骨髄腫である、請求項16または17に記載の方法。
- 前記選択的JAK1阻害薬が、遊離塩基基準で約200mg~約1200mgの1日量で投与される、請求項1~18のいずれか1項に記載の方法。
- 前記免疫調節薬が、遊離塩基基準で約2.5mg~約25mgの1日量で投与される、請求項1~19のいずれか1項に記載の方法。
- 前記ステロイドが、遊離塩基基準で約20mg~約60mgの1日量で投与される、請求項1~20のいずれか1項に記載の方法。
- 前記選択的JAK1阻害薬、前記免疫調節薬、及び前記ステロイド、またはその医薬的に許容される塩の周期的投与を含む、請求項1~21のいずれか1項に記載の方法。
- 前記選択的JAK1阻害薬が、28日の治療周期において、1~28日目に、遊離塩基基準で約200mg~約1200mgの1日量で投与される、請求項1~22のいずれか1項に記載の方法。
- 前記選択的JAK1阻害薬が、1つ以上の持続放出剤形として投与される、請求項1~23のいずれか1項に記載の方法。
- 前記免疫調節薬が、28日の治療周期において、1~21日目に、遊離塩基基準で約2.5mg~約25mgの1日量で投与される、請求項1~24のいずれか1項に記載の方法。
- 前記ステロイドが、28日の治療周期において、1~28日目の間1日おきに、遊離塩基基準で約20mg~約60mgの量で投与される、請求項1~25のいずれか1項に記載の方法。
- 治療を必要とする患者における多発性骨髄腫の治療方法であって、前記患者に対して、(a){1-{1-[3-フルオロ-2-(トリフルオロメチル)イソニコチノイル]ピペリジン-4-イル}-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリル、またはその医薬的に許容される塩を、28日の治療周期において、1~28日目に、遊離塩基基準で1日量約200~約1200mg、(b)レナリドミド、またはその医薬的に許容される塩を、28日の治療周期において、1~21日目に、遊離塩基基準で1日量約10mg、及び(c)メチルプレドニゾロン、またはその医薬的に許容される塩を、28日の治療周期において、1~28日目の間1日おきに、遊離塩基基準で1日量約40mg投与することを含む、前記方法。
- 治療を必要とする患者における多発性骨髄腫の治療方法であって、前記患者に対して、(a){1-{1-[3-フルオロ-2-(トリフルオロメチル)イソニコチノイル]ピペリジン-4-イル}-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリル、またはその医薬的に許容される塩を、28日の治療周期において、1~28日目に、遊離塩基基準で1日量約200~約1200mg、(b)レナリドミド、またはその医薬的に許容される塩を、28日の治療周期において、1~21日目に、遊離塩基基準で1日量約10mg、及び(c)デキサメタゾン、またはその医薬的に許容される塩を、28日の治療周期において、1~28日目に、遊離塩基基準で1日量約2mg~約20mg投与することを含む、前記方法。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG10201703533VA (en) | 2012-11-01 | 2017-06-29 | Incyte Corp | Tricyclic fused thiophene derivatives as jak inhibitors |
JP2021519772A (ja) | 2018-03-30 | 2021-08-12 | インサイト・コーポレイションIncyte Corporation | 炎症性皮膚疾患のバイオマーカー |
US11372003B2 (en) | 2018-04-13 | 2022-06-28 | Incyte Corporation | Biomarkers for graft-versus-host disease |
EP3934651A1 (en) | 2019-03-05 | 2022-01-12 | Incyte Corporation | Jak1 pathway inhibitors for the treatment of chronic lung allograft dysfunction |
US11992490B2 (en) | 2019-10-16 | 2024-05-28 | Incyte Corporation | Use of JAK1 inhibitors for the treatment of cutaneous lupus erythematosus and Lichen planus (LP) |
Family Cites Families (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL202623B1 (pl) | 2000-06-28 | 2009-07-31 | Smithkline Beecham Plc | Sposób wytwarzania drobno zmielonego preparatu substancji leczniczej, drobno zmielona substancja lecznicza wytworzona tym sposobem i zawierająca ją kompozycja farmaceutyczna |
WO2005105814A1 (en) | 2004-04-28 | 2005-11-10 | Incyte Corporation | Tetracyclic inhibitors of janus kinases |
AR054416A1 (es) | 2004-12-22 | 2007-06-27 | Incyte Corp | Pirrolo [2,3-b]piridin-4-il-aminas y pirrolo [2,3-b]pirimidin-4-il-aminas como inhibidores de las quinasas janus. composiciones farmaceuticas. |
CA2621261C (en) | 2005-09-22 | 2014-05-20 | Incyte Corporation | Azepine inhibitors of janus kinases |
CN103214483B (zh) | 2005-12-13 | 2014-12-17 | 因塞特公司 | 作为两面神激酶抑制剂的杂芳基取代的吡咯并[2,3-b]吡啶和吡咯并[2,3-b]嘧啶 |
ES2415863T3 (es) | 2006-12-22 | 2013-07-29 | Incyte Corporation | Heterociclos sustituidos como inhibidores de Janus Quinasas |
EP2740731B1 (en) | 2007-06-13 | 2016-03-23 | Incyte Holdings Corporation | Crystalline salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
CL2008001709A1 (es) | 2007-06-13 | 2008-11-03 | Incyte Corp | Compuestos derivados de pirrolo [2,3-b]pirimidina, moduladores de quinasas jak; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como cancer, psoriasis, artritis reumatoide, entre otras. |
MX2010005300A (es) | 2007-11-16 | 2010-06-25 | Incyte Corp | 4-pirazolil-n-arilpirimidin-2-aminas y 4-pirazolil-n-heteroarilpir imidin-2-aminas como inhibidores de cinasas janus. |
DK2288610T3 (en) | 2008-03-11 | 2016-11-28 | Incyte Holdings Corp | Azetidinesulfonic AND CYCLOBUTANDERIVATER AS JAK INHIBITORS |
CL2009001884A1 (es) | 2008-10-02 | 2010-05-14 | Incyte Holdings Corp | Uso de 3-ciclopentil-3-[4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)propanonitrilo, inhibidor de janus quinasa, y uso de una composición que lo comprende para el tratamiento del ojo seco. |
JOP20190231A1 (ar) | 2009-01-15 | 2017-06-16 | Incyte Corp | طرق لاصلاح مثبطات انزيم jak و المركبات الوسيطة المتعلقة به |
DK2432472T3 (da) | 2009-05-22 | 2019-11-18 | Incyte Holdings Corp | 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl]octan- eller heptan-nitril som jak-inhibitorer |
BRPI1012159B1 (pt) | 2009-05-22 | 2022-01-25 | Incyte Holdings Corporation | Compostos derivados de n-(hetero)aril-pirrolidina de pirazol-4-il-pirrolo[2,3-d] pirimidinas e pirrol-3-il-pirrolo[2,3-d] pirimidinas como inibidores de janus cinase, composições farmacêuticas compreendendo os referidos compostos e usos dos mesmos |
TW201113285A (en) | 2009-09-01 | 2011-04-16 | Incyte Corp | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
PT2486041E (pt) | 2009-10-09 | 2013-11-14 | Incyte Corp | Derivados hidroxilo, ceto e glucuronido de 3-(4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)-3-ciclopentil-propanonitrilo |
MX2012009541A (es) | 2010-02-18 | 2012-10-01 | Incyte Corp | Derivados de ciclobutano y metilciclobutano como inhibidores de janus cinasa. |
KR102283091B1 (ko) | 2010-03-10 | 2021-07-30 | 인사이트 홀딩스 코포레이션 | Jak1 저해제로서의 피페리딘4일 아제티딘 유도체 |
EP2574168B9 (en) | 2010-05-21 | 2016-10-05 | Incyte Holdings Corporation | Topical formulation for a jak inhibitor |
AR083933A1 (es) | 2010-11-19 | 2013-04-10 | Incyte Corp | Derivados de pirrolopiridina y pirrolopirimidina sustituidos con ciclobutilo como inhibidores de jak |
JP5917544B2 (ja) | 2010-11-19 | 2016-05-18 | インサイト・ホールディングス・コーポレイションIncyte Holdings Corporation | Jak阻害剤としての複素環置換ピロロピリジンおよびピロロピリミジン |
PT2675451E (pt) | 2011-02-18 | 2015-10-16 | Incyte Corp | Terapia de combinação com inibidores mtor/jak |
CN103797010B (zh) | 2011-06-20 | 2016-02-24 | 因塞特控股公司 | 作为jak抑制剂的氮杂环丁烷基苯基、吡啶基或吡嗪基甲酰胺衍生物 |
CA2844507A1 (en) | 2011-08-10 | 2013-02-14 | Novartis Pharma Ag | Jak pi3k/mtor combination therapy |
TW201313721A (zh) | 2011-08-18 | 2013-04-01 | Incyte Corp | 作為jak抑制劑之環己基氮雜環丁烷衍生物 |
UA111854C2 (uk) | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | Способи і проміжні сполуки для отримання інгібіторів jak |
US9193733B2 (en) | 2012-05-18 | 2015-11-24 | Incyte Holdings Corporation | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
SG10201703533VA (en) | 2012-11-01 | 2017-06-29 | Incyte Corp | Tricyclic fused thiophene derivatives as jak inhibitors |
CR20190073A (es) | 2012-11-15 | 2019-04-25 | Incyte Holdings Corp | FORMAS DE DOSIFICACIÓN DE RUXOLITINIB DE LIBERACIÓN SOTENIDA (Divisional 2015-265) |
RS62867B1 (sr) | 2013-03-06 | 2022-02-28 | Incyte Holdings Corp | Postupci i intermedijeri za dobijanje inhibitora jak |
HUE043573T2 (hu) | 2013-05-17 | 2019-08-28 | Incyte Corp | Bipirazol só, amely JAK-gátlóként alkalmazható |
EP3030227B1 (en) | 2013-08-07 | 2020-04-08 | Incyte Corporation | Sustained release dosage forms for a jak1 inhibitor |
US20150065447A1 (en) | 2013-08-20 | 2015-03-05 | Incyte Corporation | Survival benefit in patients with solid tumors with elevated c-reactive protein levels |
HUE041456T2 (hu) | 2014-02-28 | 2019-05-28 | Incyte Corp | JAK1 inhibitorok myelodysplasiás szindrómák kezelésére |
CA2947418A1 (en) | 2014-04-30 | 2015-11-05 | Incyte Corporation | Processes of preparing a jak1 inhibitor and new forms thereto |
WO2015184087A2 (en) * | 2014-05-28 | 2015-12-03 | Institute For Myeloma & Bone Cancer Research | Anti-cancer effects of jak2 inhibitors in combination with thalidomide derivatives and glucocorticoids |
US9498467B2 (en) | 2014-05-30 | 2016-11-22 | Incyte Corporation | Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1 |
CA3039178A1 (en) | 2016-10-03 | 2018-04-12 | TLL Pharmaceutical, LLC | Novel jak1 selective inhibitors and uses thereof |
AR113922A1 (es) | 2017-12-08 | 2020-07-01 | Incyte Corp | Terapia de combinación de dosis baja para el tratamiento de neoplasias mieloproliferativas |
PE20211310A1 (es) | 2018-01-30 | 2021-07-22 | Incyte Corp | Procedimiento para la elaboracion de un recipiente de vidrio de sosa-cal a partir de materiales formadores de vidrio 100% reciclados y un recipiente de vidrio elaborado a partir de dicho procedimiento |
WO2019161098A1 (en) | 2018-02-16 | 2019-08-22 | Incyte Corporation | Jak1 pathway inhibitors for the treatment of cytokine-related disorders |
JP2021519775A (ja) | 2018-03-30 | 2021-08-12 | インサイト・コーポレイションIncyte Corporation | Jak阻害剤を用いる化膿性汗腺炎の治療 |
JP2021519772A (ja) | 2018-03-30 | 2021-08-12 | インサイト・コーポレイションIncyte Corporation | 炎症性皮膚疾患のバイオマーカー |
US11372003B2 (en) | 2018-04-13 | 2022-06-28 | Incyte Corporation | Biomarkers for graft-versus-host disease |
WO2020132210A1 (en) | 2018-12-19 | 2020-06-25 | Incyte Corporation | Jak1 pathway inhibitors for the treatment of gastrointestinal disease |
EP3934651A1 (en) | 2019-03-05 | 2022-01-12 | Incyte Corporation | Jak1 pathway inhibitors for the treatment of chronic lung allograft dysfunction |
WO2021072098A1 (en) | 2019-10-10 | 2021-04-15 | Incyte Corporation | Biomarkers for graft-versus-host disease |
WO2021072232A1 (en) | 2019-10-11 | 2021-04-15 | Incyte Corporation | Bicyclic amines as cdk2 inhibitors |
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