JP2022537350A - ビアリールジアルキルホスフィンオキシドfpr2アゴニスト - Google Patents
ビアリールジアルキルホスフィンオキシドfpr2アゴニスト Download PDFInfo
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- JP2022537350A JP2022537350A JP2021575327A JP2021575327A JP2022537350A JP 2022537350 A JP2022537350 A JP 2022537350A JP 2021575327 A JP2021575327 A JP 2021575327A JP 2021575327 A JP2021575327 A JP 2021575327A JP 2022537350 A JP2022537350 A JP 2022537350A
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- 108010033693 saxagliptin Proteins 0.000 description 1
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- 229960002855 simvastatin Drugs 0.000 description 1
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- RHOYTGAOSPPBRP-GFCCVEGCSA-N tert-butyl N-[(2R)-1-(4-bromo-2,6-difluoroanilino)-5-hydroxy-1-oxopentan-2-yl]carbamate Chemical compound BrC1=CC(=C(C(=C1)F)NC([C@@H](CCCO)NC(OC(C)(C)C)=O)=O)F RHOYTGAOSPPBRP-GFCCVEGCSA-N 0.000 description 1
- NBVNMTABPULZBM-GFCCVEGCSA-N tert-butyl N-[(3R)-1-(4-bromo-2,6-difluorophenyl)-2-oxopiperidin-3-yl]carbamate Chemical compound BrC1=CC(=C(C(=C1)F)N1C([C@@H](CCC1)NC(OC(C)(C)C)=O)=O)F NBVNMTABPULZBM-GFCCVEGCSA-N 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
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- 229960002277 tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
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- 125000005490 tosylate group Chemical group 0.000 description 1
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- 238000011269 treatment regimen Methods 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 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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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本出願は、2019年6月18日出願の米国仮出願番号第62/862,897号に対する優先権を米国特許法第119条(e)の下に主張するものであって、その全てが参照により本明細書に組み込まれる。
Ar1は、1~2個のR1aおよび1~2個のR1bで置換されたフェニル、または1~2個のR1aおよび1~2個のR1bで置換された、1~3個の窒素原子を含む6員環ヘテロアリールであり;
Ar2は、1~4個のR2で置換されたフェニル、または1~4個のR2で置換された、1~3個の窒素原子を含む6員環ヘテロアリールであり;
Ar3は、0~4個のR3で置換されたフェニル、または0~4個のR3で置換されたピリジニルであり;
R1aは、水素またはハロゲンであり;
R1bは、ハロゲン、ハロアルキル、アルコキシ、またはハロアルコキシであり;
R2は、水素、シアノ、ハロゲン、アルキル、ヒドロキシアルキル、ハロアルキル、シクロアルキル、アルコキシ、またはハロアルコキシであり;
R3は、シアノ、ハロゲン、アルキル、アルコキシ、ヒドロキシアルキル、アルコキシアルキル、またはハロアルキルであり;および
R4は、アルキルまたはアルコキシである]
の化合物またはその立体異性体、互変異性体、または医薬的に許容される塩である。
Ar1は、1個のR1aおよび1~2個のR1bで置換されたフェニル、または1個のR1aおよび1~2個のR1bで置換された、1~2個の窒素原子を含む6員環ヘテロアリールであり;
Ar2は、1~3個のR2で置換されたフェニルまたは1~4個のR2で置換されたピリジニルであり;
R1aは、水素またはハロゲンであり;
R1bは、ハロゲン、C1-4ハロアルキル、C1-4アルコキシ、またはC1-4ハロアルコキシであり;
R2は、水素、ハロゲン、C1-4アルキル、C1-4ヒドロキシアルキル、C1-4ハロアルキル、C3-6シクロアルキル、C1-4アルコキシ、またはC1-4ハロアルコキシであり;および
R4は、C1-3アルキルである]
の化合物またはその立体異性体、互変異性体、または医薬的に許容される塩である。
Ar1は、1個のR1aおよび1~2個のR1bで置換されたフェニル、1個のR1aおよび1~2個のR1bで置換されたピリジニル、または1個のR1aおよび1~2個のR1bで置換されたピラジニルであり;
R1aは、水素またはハロゲンであり;
R1bは、ハロゲン、C1-4ハロアルキル、C1-4アルコキシ、またはC1-4ハロアルコキシであり;
R2は、水素、ハロゲン、C1-4アルキル、C1-4ヒドロキシアルキル、C1-4ハロアルキル、C3-6シクロアルキル、C1-4アルコキシ、またはC1-4ハロアルコキシであり;および
R4は、C1-2アルキルである]
の化合物またはその立体異性体、互変異性体、または医薬的に許容される塩である。
R1aは、水素またはFであり;
R1bは、ハロゲン、C1-2ハロアルキル、またはC1-2アルコキシであり;
R2は、水素、ハロゲン、C1-3アルキル、C1-3ハロアルキル、またはC3-6シクロアルキルであり;および
R4は、メチルまたはエチルである]
の化合物またはその立体異性体、互変異性体、または医薬的に許容される塩である。
R1aが、水素またはFであり;
R1bが、F、Cl、またはCF3であり;および
R2が、水素、F、Cl、またはシクロプロピルであり;および
R4が、メチルである、
式(IV)または(VI)の化合物、またはその立体異性体、互変異性体、または医薬的に許容される塩である。
R1aは、水素またはFであり;
R1bは、ハロゲン、C1-2ハロアルキル、またはC1-2アルコキシであり;
R2は、ハロゲンであり;および
R4は、メチルまたはエチルである]
の化合物またはその立体異性体、互変異性体、または医薬的に許容される塩である。
R1aは、水素またはFであり;
R1bは、ハロゲン、C1-2ハロアルキル、またはC1-2アルコキシであり;
R2は、ハロゲン、C1-3アルキル、C1-3ハロアルキル、またはC3-6シクロアルキルであり;および
R4は、メチルまたはエチルである]
の化合物またはその立体異性体、互変異性体、または医薬的に許容される塩である。
R1aは、水素またはハロゲンであり;
R1bは、ハロゲン、C1-2ハロアルキル、またはC1-2アルコキシであり;
R2は、水素、ハロゲン、C1-3アルキル、またはC3-6シクロアルキルであり;および
R4は、C1-2アルキルである]
の化合物またはその立体異性体、互変異性体、または医薬的に許容される塩である。
R1bは、ハロゲン、C1-2ハロアルキル、またはC1-2アルコキシであり;
R2は、水素、ハロゲン、C1-3アルキル、またはC3-6シクロアルキルであり;および
R4は、C1-2アルキルである]
の化合物またはその立体異性体、互変異性体、または医薬的に許容される塩である。
Ar1は、1個のR1aおよび1~2個のR1bで置換されたフェニル、1個のR1aおよび1~2個のR1bで置換されたピリジニル、または1個のR1aおよび1~2個のR1bで置換されたピラジニルであり;
R1aは、水素またはハロゲンであり;
R1bは、ハロゲン、C1-4ハロアルキル、C1-4アルコキシ、またはC1-4ハロアルコキシであり;および
R4は、C1-2アルキルである]
の化合物またはその立体異性体、互変異性体、または医薬的に許容される塩である。
N-ホルミルペプチド受容体(FPR)は、炎症中に白血球応答を促進させる化学誘引物質受容体のファミリーである。FPRは、7回膜貫通型G蛋白質共役受容体スーパーファミリーに属し、抑制性Gタンパク質(Gi)に結合する。ヒトでは3種のファミリーメンバー(FPR1、FPR2およびFPR3)が同定されており、主に幅広い骨髄系細胞に見られ、複数の臓器および組織でも報告されている。FPRは、アゴニストが結合後、多数の生理学的経路(例えば細胞内シグナル伝達変換、Ca2+の遊離および転写)を活性化させる。該ファミリーは、炎症誘発性下流応答および炎症収束性下流応答の両方を活性化するタンパク質、ポリペプチドおよび脂肪酸代謝物などの多様なリガンドと相互作用する。FPR2およびFPR1環状アデノシン一リン酸(cAMP)アッセイは、本特許中の化合物の活性を測るために用いられた。
終濃度の範囲が0.020nM~100μMの試験化合物/DMSO(最終濃度1%)を予め加えたProxiplates 384ウェル(Perkin-Elmer)に、フォルスコリン(FPR2に対して最終濃度5μMまたはFPR1に対して最終濃度10μM)およびIBMX(最終濃度200μM)の混合物を加えた。ヒトFPR1またはヒトFPR2受容体を過剰発現させたチャイニーズハムスター卵巣細胞(CHO)を適格な10%FBS、Zeocin(250μg/mL)およびハイグロマイシン(300μg/mL、Life Technologies)を補充したF-12(Ham's)培地で培養した。0.1%BSA(Perkin-Elmer)を補充したDulbecco's PBS(カルシウムおよびマグネシウム入り)(Life Technologies)に溶解した2,000個のヒトFPR2細胞または4,000個のヒトFPR1細胞を1ウェルずつ加え、反応を開始した。得られた反応混合物を30分間室温でインキュベートした。HTRF HiRange cAMPアッセイ試薬キット(Cisbio)を用いて取扱説明書に従って細胞内cAMPの濃度を決定した。クリプタート結合抗cAMPおよびd2-フルオロフォア標識cAMPの溶液を付属溶解緩衝液でそれぞれ作製した。反応完了後、細胞を等体積のd2-cAMP溶液および抗cAMP溶液で溶解した。1時間室温でインキュベーション後、Envision(Perkin-Elmer)を用いて400nmで励起させ、590nmおよび665nmで二重に発光させ、時間分解蛍光強度を測定した。検量線を別でcAMP標準を用いて作成し、1μM~0.1pMの範囲の濃度のcAMPに対する665nmの蛍光強度から590nmの蛍光強度をプロットすることで得た。次いでcAMP生成を阻害する化合物の有効性および活性を、cAMP濃度対化合物濃度のプロットから4変数ロジスティック方程式にフィッティングすることで決定した。
本発明の化合物は、FPR2受容体に関連する様々な症状および障害(例えばベーチェット病、スウィート病、全身性エリテマトーデス(SLE)、ウェゲナー肉芽腫症、ウイルス感染症、糖尿病、肢切断、がん、細菌感染症、物理的外傷、放射線照射などの身体障害、血管収縮、アナフィラキシー反応、アレルギー反応、鼻炎、ショック(内毒素性、出血性、外傷性、内臓虚血性、および循環性ショック)、リウマチ性関節炎、痛風、乾癬、良性前立腺肥大症、心筋虚血、心筋梗塞、心不全、脳損傷、肺疾患、COPD、COAD、COLD、急性肺損傷、急性呼吸窮迫症候群、慢性気管支炎、肺気腫、喘息(アレルギー喘息および非アレルギー喘息)、嚢胞性線維症、腎線維症、腎症、腎臓糸球体疾患、潰瘍性大腸炎、IBD、クローン病、歯周炎、疼痛、アルツハイマー病、AIDS、ぶどう膜炎緑内障、結膜炎、シェーグレン症候群、鼻炎、アテローム性動脈硬化症、多発性硬化症などの神経炎症性疾患、脳卒中、敗血症)の治療のために哺乳動物、好ましくはヒトに投与され得る。
典型的な注射製剤は、少なくとも1つの本発明の化合物(250mg)を無菌状態でバイアルに加え、無菌状態で凍結乾燥および密封することで製造される。使用の際は、バイアルの内容物を生理食塩水(2mL)と混合し、注射製剤を調製する。
本明細書で用いる略語は、以下の通り定義される。「1x」は1回、「2x」は2回、「3x」は3回、「℃」は摂氏温度、「aq」は水溶液、「Col」はカラム、「eq」は当量、「g」はグラム、「mg」はミリグラム、「L」はリットル、「mL」はミリリットル、「μL」マイクロリットル、「n」はノルマル、「M」はモーラー、「nM」はナノモーラー、「mol」はモル、「mmol」はミリモル、「min」は分、「h」は時間、「rt」は室温、「RT」は保持時間、「ON」は終夜、「atm」は大気圧、「psi」は重量ポンド平方インチ、「conc」は濃縮、「aq」は水溶液、「sat」または「sat'd」は飽和、「MW」は分子量、「mw」または「μwave」はマイクロ波、「mp」は融点、「Wt」は重量、「MS」または「Mass Spec」はマススペクトロメトリー、「ESI」はエレクトロスプレーイオン化質量分析、「HR」は高分解能、「HRMS」は高分解能マススペクトロメトリー、「LCMS」は液体クロマトグラフィーマススペクトロメトリー、「HPLC」は高速液体クロマトグラフィー、「RP HPLC」は逆相 HPLC、「TLC」または「tlc」は薄層クロマトグラフィー、「NMR」は核磁気共鳴分光法、「NOE」は核オーバーハウザー効果分光法、「1H」はプロトン、「δ」はデルタ、「s」はシングレット、「d」はダブレット、「t」はトリプレット、「q」はカルテット、「m」はマルチプレット、「br」はブロード、「Hz」はヘルツ、および「α」、「β」、「R」、「S」、「E」、および「Z」は当業者に知られている立体化学的記号である。
UV検出: 220nm
カラム: Waters BEH C18 2.1 x 50mm
流速: 1.0mL/分
溶媒A: 0.1%TFA、95%水、5%ACN
溶媒B: 0.1%TFA、5%水、95%ACN
方法B: 0~100%Bで3分かけて溶出後、100%Bで0.75分間溶出する、直線グラジエント;
UV検出: 220nm
カラム: Waters BEH C18 2.1 x 50mm
流速: 1.0mL/分
溶媒A: 95%水、5%ACN(10mM酢酸アンモニウム含有)
溶媒B: 5%水、95%ACN(10mM酢酸アンモニウム含有)
方法C: Ascentis Express C18、2.1 x 50mm、粒子径: 2.7μm; 溶媒A: 95%水、5%ACN、0.05%TFA; 溶媒B: 95%ACN、5%水(0.1%TFA含有); 温度: 50℃; グラジエント: 0~100%Bで3分かけて溶出後、次いで0~100%Bで1分間溶出; 流速: 1.1mL/分
方法D: Ascentis Express C18、2.1 x 50mm、粒子径: 2.7μm; 溶媒A: 95%水、5%ACN(10mM酢酸アンモニウム含有); 溶媒B: 95%ACN、5%水(10mM酢酸アンモニウム含有); 温度: 50℃; グラジエント: 0~100%Bで3分かけて溶出後、次いで0~100%Bで1分間溶出; 流速: 1.1mL/分
方法I: Chiralpak AD-H、250 x 4.6mm、粒子径: 5.0μm; %CO2: 60%、%共溶媒: 40% {0.2%DEA/IPA:ACN(1:1)}、総合流速: 4.0g/分、背圧: 100bars、温度 : 25℃、UV: 218nm
方法II: Chiralpak OD-H、250 x 4.6mm、粒子径: 5.0μm; %CO2: 60%、%共溶媒: 40% {0.2%DEA/IPA:ACN(1:1)}、総合流速: 4.0g/分、背圧: 104bars、温度 : 24.9℃、UV: 287nm
方法III: Chiralpak OJ-H、250 x 4.6mm、粒子径: 5.0μm; %CO2: 60%、%共溶媒: 30%(0.3%DEA/メタノール)、総合流速: 4.0g/分、背圧: 101bars、温度 : 23.6℃、UV: 272nm
方法IV: Chiralpak AS-H、250 x 4.6mm、粒子径: 5.0μm; %CO2: 60%、%共溶媒: 40%(0.3%DEA/メタノール)、総合流速: 4.0g/分、背圧: 102bars、温度 : 25.4℃、UV: 272nm
方法V: Chiralcel OJ-H、250 x 4.6mm、粒子径: 5.0μm; %CO2: 60%、%共溶媒: 40%(0.2%DEA/メタノール)、総合流速: 4.0g/分、背圧: 102bars、温度: 24.6℃、UV: 272nm
方法VI: Luxcellulose-2、250 x 4.6mm、粒子径: 5.0μm; %CO2: 60%、%共溶媒: 35%(0.2%DEA/メタノール)、総合流速: 3.0g/分、背圧: 101bars、温度: 23.6℃、UV: 260nm
方法VII: Chiralcel AS-H、250 x 4.6mm、粒子径: 5.0μm; %CO2: 60%、%共溶媒: 40%(0.2%DEA/メタノール)、総合流速: 4.0g/分、背圧: 101bars、温度: 24.4℃、UV: 270nm
方法VIII: Chiralpak IC、250 x 4.6mm、粒子径: 5.0μm; %CO2: 60%、%共溶媒: 40%(0.2%DEA/メタノール)、総合流速: 4.0g/分、背圧: 101bars、温度: 24.4℃、UV: 270nm
方法IX: カラム: Chiralpak IF(250 X 4.6mm)、5μ、移動相: 0.2%DEA/エタノール、流速: 1.0mL/分
方法X: カラム: LUX AMYLOSE 2(250 X 4.6mm)、5μ、移動相: 0.2%DEA/n-ヘキサン:エタノール: 5:95、流速: 1.0mL/分
方法XI: カラム: Chiralcel OD-H(250 X 4.6mm)、5μ、移動相: 0.2%DEA/n-ヘキサン:エタノール: 70:30、流速: 1.0mL/分
方法XII: カラム: Chiralpak ID(250 X 4.6mm)、5μ、移動相: 0.1%DEA/メタノール、流速: 1.0mL/分
MS(ESI)m/z: 405.2(M+H)+; 1H NMR(400MHz、CDCl3) δ 7.36 (m, 1H), 6.96 (m, 1H), 5.44 (s, 1H), 4.37-4.22 (m, 1H), 3.71-3.58 (m, 2H), 2.69-2.55 (m, 1H), 2.16-2.02 (m, 2H), 1.77 (m, 1H), 1.47 (m, 9H)
MS(ESI)m/z: 527.1(M+H)+; 1H NMR(300MHz、CDCl3) δ 7.36-7.35 (m, 5H), 7.16 (d, J = 5.4 Hz, 2H), 5.35-5.30 (m, 1H), 5.15-5.11 (m, 2H), 2.72-2.48 (m, 2H), 2.31-2.19 (m, 1H), 2.10-1.99 (m, 1H), 1.54 (s, 9H), 1.53-1.50 (m, 1H), 0.90-0.84 (m, 1H)
MS(ESI)m/z: 423.1(M+H)+ ;1H NMR(400MHz、CDCl3) δ 8.28 (br s, 1H), 7.17-7.12 (m, 2H), 5.36 (br s, 1H), 4.52-4.48 (m, 1H), 3.79 (q, J = 5.5 Hz, 2H), 2.10-1.97 (m, 1H), 1.94-1.68 (m, 3H), 1.52-1.44 (m, 9H)
MS(ESI)m/z: 405.1(M+H)+ ;1H NMR(400MHz、CDCl3) δ 7.20-7.18 (m, 1H), 7.16-7.12 (m, 1H), 5.44 (br s, 1H), 4.36-4.24 (m, 1H), 3.66-3.51 (m, 2H), 2.66-2.56 (m, 1H), 2.12-2.05 (m, 2H), 1.81-1.70 (m, 1H), 1.57-1.45 (s, 9H)
MS(ESI)m/z: 550.2(M+H)+ ;1H NMR(400MHz、DMSO-d6) δ 8.67 (d, J = 2.2 Hz, 1H), 8.17 (t, J = 8.9 Hz, 1H), 8.01-7.88 (m, 1H), 7.74-7.57 (m, 2H), 7.50-7.33 (m, 2H), 7.33-7.21 (m, 2H), 7.21-7.05 (m, 2H), 4.48-4.37 (m, 1H), 3.85-3.62 (m, 2H), 2.31 (dd, J = 12.3, 6.5 Hz, 1H), 2.17-1.93 (m, 2H), 1.86 (d, J = 6.5 Hz, 1H), 1.49 (d, J = 13.5 Hz, 6H); 保持時間=1.539分、99.2%(方法D)
実施例2: 1H NMR(400MHz、DMSO-d6) δ 8.95 (br. s., 1H), 8.42 (t, J = 8.3 Hz, 1H), 7.95 (m, 1H), 7.73-7.56 (m, 3H), 7.50 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 3.7 Hz, 1H), 7.34-7.15 (m, 3H), 4.52-4.39 (m, 1H), 3.76-3.68 (m, 2H), 2.39-2.28 (m, 1H), 2.22-1.96 (m, 2H), 1.91-1.85 (m,1H), 1.49 (d, J = 13.5 Hz, 6H)
実施例3: 1H NMR(400MHz、DMSO-d6) δ 8.64 (s, 1H), 8.17 (t, J = 8.9 Hz, 1H), 7.91 (m, 1H), 7.73-7.44 (m, 2H), 7.44-7.33 (m, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.23-7.09 (m, 2H), 4.50-4.38 (m, 1H), 3.72-3.59 (m, 2H), 2.35-2.29 (m, 1H), 2.1-2.02 (m, 2H), 1.84 (d, J = 5.6 Hz, 1H), 1.75-1.51 (m, 4H), 1.07-0.79 (m, 6H)
実施例4: 1H NMR(400MHz、DMSO-d6) δ 9.38 (br. s., 1H), 8.83 (s, 1H), 8.21-8.09 (m, 1H), 8.02 (m, 1H), 7.94 (m, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.35 (m, 1H), 7.32-7.14 (m, 2H), 7.10 (d, J = 7.1 Hz, 1H), 4.53-4.39 (m, 1H), 3.75-3.56 (m, 2H), 2.42-2.38 (m, 1H), 2.15-1.82 (m, 4H), 1.44-1.14 (m, 6H), 1.04-0.85 (m, 3H), 0.64-0.60 (m, 1H)
実施例5: 1H NMR(400MHz、DMSO-d6) δ 8.69 (s, 1H), 8.17 (m, 1H), 8.01-7.87 (m, 1H), 7.64-7.44 (m, 2H), 7.44-7.31 (m, 2H), 7.28-7.25 (m, 2H), 7.23-6.95 (m, 3H), 4.38 -4.34 (m, 1H), 3.66-3.55 (m, 2H), 2.35-2.30 (m, 1H), 2.09-2.03 (m, 2H), 1.92-1.86 (m, 2H), 1.33-1.27 (m, 6H), 0.87-0.84 (m, 3H), 0.64-0.61 (m, 1H)
実施例6: 1H NMR(400MHz、DMSO-d6) δ 8.30 (d, J = 1.5 Hz, 1H), 7.95 (m, 1H), 7.86 (m, 1H), 7.70-7.55 (m, 2H), 7.38 (m, 1H), 7.33-7.19 (m, 2H), 6.90 (d, J = 6.8 Hz, 1H), 6.86 (m, 1H), 6.71 (m, 1H), 4.45-4.33 (m, 1H), 3.82-3.59 (m, 5H), 2.32-2.24 (m, 1H), 2.14-1.97 (m, 2H), 1.88-1.73 (m, 1H), 1.59-1.34 (m, 6H)
実施例7: 1H NMR(400MHz、DMSO-d6) δ 8.63 (d, J = 2.4 Hz, 1H), 8.17 (m, 1H), 7.92 (m, 1H), 7.69-7.52 (m, 2H), 7.49-7.24 (m, 4H), 7.22-7.05 (m, 2H), 4.50-4.40 (m, 1H), 3.77-3.58 (m, 2H), 2.32 (dd, J = 12.0, 5.9 Hz, 1H), 2.17-1.94 (m, 2H), 1.90-1.77 (m, 1H), 1.46 (d, J = 13.5 Hz, 6H)
実施例8: 1H NMR(400MHz、DMSO-d6) δ 8.88 (s, 2H), 8.40 (d, J = 1.2 Hz, 1H), 7.95 (m, 1H), 7.73-7.57 (m, 2H), 7.53 (s, 1H), 7.38 (s, 1H), 7.34-7.17 (m, 2H), 4.47 (m, 1H), 3.79-3.75 (m, 1H), 3.74-3.68 (m, 1H), 2.37-2.33 (m, 1H), 2.18-1.98 (m, 2H), 1.98-1.80 (m, 1H), 1.53-1.46 (m, 6H)
実施例9: 1H NMR(400MHz、DMSO-d6) δ 9.41 (s, 1H), 8.83 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.03 (m, 1H), 7.98-7.90 (m, 1H), 7.72-7.54 (m, 2H), 7.37 (m, 1H), 7.33-7.18 (m, 2H), 4.56-4.47 (m, 1H), 3.79-3.73 (m, 1H), 3.72-3.66 (m, 1H), 2.38 (m, 1H), 2.16-1.98 (m, 2H), 1.96-1.87 (m, 1H), 1.49 (d, J = 13.5 Hz, 6H)
実施例10: 1H NMR(400MHz、DMSO-d6) δ 8.96 (s, 1H), 8.01-7.89 (m, 1H), 7.73-7.56 (m, 2H), 7.56-7.41 (m, 2H), 7.41-7.34 (m, 1H), 7.33-7.14 (m, 4H), 6.62 (d, J = 7.1 Hz, 1H), 4.45-4.35 (m, 1H), 3.80-3.60 (m, 2H), 2.31 (m, 1H), 2.16-1.94 (m, 2H), 1.88 (m, 1H), 1.48 (d, J = 13.5 Hz, 6H)
実施例11: 1H NMR(400MHz、DMSO-d6) δ 8.92 (d, J = 2.9 Hz, 1H), 8.42 (m, 1H), 7.93 (m, 1H), 7.73-7.55 (m, 3H), 7.51 (d, J = 8.6 Hz, 1H), 7.46-7.35 (m, 3H), 7.33 (d, J = 7.3 Hz, 1H), 4.52-4.43 (m, 1H), 3.75-3.59 (m, 2H), 2.37-2.32 (m, 1H), 2.21-1.94 (m, 2H), 1.92-1.80 (m, 1H), 1.46 (d, J = 13.5 Hz, 6H)
実施例12: 1H NMR(400MHz、DMSO-d6) δ 9.81 (s, 1H), 8.63-8.52 (m, 1H), 8.13 (s, 1H), 8.07 (dd, J = 9.0, 2.4 Hz, 1H), 7.99-7.90 (m, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.70-7.56 (m, 2H), 7.43-7.34 (m, 1H), 7.34-7.22 (m, 2H), 4.54-4.45 (m, 1H), 3.83-3.74 (m, 1H), 3.74-3.65 (m, 1H), 2.41-2.30 (m, 1H), 2.17-1.97 (m, 2H), 1.95-1.79 (m, 1H), 1.48 (d, J = 13.5 Hz, 6H)
実施例13: 1H NMR(400MHz、DMSO-d6) δ 8.48 (s, 1H), 7.92 (m, 1H), 7.72-7.53 (m, 2H), 7.46-7.36 (m, 3H), 7.35-7.22 (m, 2H), 6.91-6.75 (m, 2H), 6.47 (d, J = 6.8 Hz, 1H), 4.42 (m, 1H), 3.70 (s, 3H), 3.68-3.58 (m, 2H), 2.35-2.27 (m, 1H), 2.18-1.93 (m, 2H), 1.89-1.78 (m, 1H), 1.46 (d, J = 13.5 Hz, 6H)
実施例14: 1H NMR(400MHz、DMSO-d6) δ 8.93-8.82 (m, 1H), 8.16 (d, J = 2.2 Hz, 1H), 8.02 (m, 1H), 7.95-7.86 (m, 1H), 7.69-7.58 (m, 3H), 7.34 (m, 1H), 7.28 (m, 1H), 7.21-7.14 (m, 1H), 4.55-4.48 (m, 1H), 3.81-3.74 (m, 1H), 3.72-3.65 (m, 1H), 2.42-2.34 (m, 1H), 2.18-1.93 (m, 2H), 1.96-1.84 (m, 1H), 1.81-1.66 (m, 3H), 1.65-1.52 (m, 1H), 1.11-0.68 (m, 6H)
実施例15: 1H NMR(400MHz、DMSO-d6) δ 9.42 (s, 1H), 8.81 (d, J = 5.9 Hz, 1H), 8.18 (s, 1H), 8.10-7.98 (m, 1H), 7.90 (m, 1H), 7.74-7.50 (m, 2H), 7.35 (m, 1H), 7.29 (m, 2H), 4.61-4.48 (m, 1H), 3.68 (m, 2H), 2.43-2.37 (m, 1H), 2.18-1.99 (m, 2H), 1.97-1.84 (m, 1H), 1.78-1.54 (m, 4H), 1.03-0.77 (m, 6H)
実施例16: 1H NMR(400MHz、DMSO-d6) δ 8.74 (d, J = 2.4 Hz, 1H), 8.24 (m, 1H), 7.95 (m, 7.6, 1.3 Hz, 1H), 7.70-7.57 (m, 2H), 7.45-7.22 (m, 4H), 7.20-7.09 (m, 2H), 4.47-4.37 (m, 1H), 3.77-3.61 (m, 2H), 2.35-2.30 (m, 1H), 2.12-1.99 (m, 2H), 1.91-1.80 (m, 1H), 1.58-1.41 (m, 6H)
実施例17: 1H NMR(400MHz、DMSO-d6) δ 9.68 (s, 1H), 8.88 (d, J = 1.5 Hz, 1H), 8.40 (d, J = 1.2 Hz, 1H), 7.92 (m, 1H), 7.72-7.54 (m, 2H), 7.50 (d, J = 6.8 Hz, 1H), 7.45-7.26 (m, 3H), 4.55-4.45 (m, 1H), 3.77-3.55 (m, 2H), 2.42-2.34 (m, 1H), 2.21-1.94 (m, 2H), 1.93-1.80 (m, 1H), 1.46 (d, J = 13.5 Hz, 6H)
実施例18: 1H NMR(400MHz、DMSO-d6) δ 9.52 (s, 1H), 9.26 (s, 1H), 8.47 (s, 1H), 8.20 (m, 1H), 7.95 (m, 1H), 7.75-7.53 (m, 2H), 7.37 (m, 1H), 7.33-7.19 (m, 2H), 4.60-4.52 (m, 1H), 3.80-3.76 (m, 1H), 3.75-3.66 (m, 1H), 2.41 (m, 1H), 2.07 (d, J = 5.1 Hz, 2H), 1.99-1.88 (m, 1H), 1.49 (d, J = 13.5 Hz, 6H)
実施例19: 1H NMR(400MHz、DMSO-d6) δ 8.72 (br. s., 1H), 8.65 (s, 1H), 8.16 (m, 1H), 8.08 (m, 1H), 7.90 (m, 1H), 7.75-7.55 (m, 3H), 7.55-7.46 (m, 1H), 7.40 (d, J = 12.5 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 4.40 (m, 1H), 3.85 (m, 1H), 3.79-3.70 (m, 1H), 2.28 (d, J = 5.9 Hz, 1H), 2.16-1.91 (m, 2H), 1.86 (d, J = 6.4 Hz, 1H), 1.46 (d, J = 13.5 Hz, 6H)
実施例20: 1H NMR(400MHz、DMSO-d6) δ 9.40-9.15 (br. s., 1H), 8.80 (br. s., 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.02 (m, 1H), 7.96-7.84 (m, 1H), 7.71-7.51 (m, 2H), 7.48-7.27 (m, 3H), 4.60-4.48 (m, 1H), 3.76-3.57 (m, 2H), 2.39 (m, 1H), 2.17-2.00 (m, 2H), 2.00-1.81 (m, 1H), 1.46 (d, J = 13.5 Hz, 6H)
実施例21: 1H NMR(400MHz、DMSO-d6) δ 9.76 (s, 1H), 8.58 (s, 1H), 8.17-8.04 (m, 2H), 7.96-7.89 (m, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.65 (m, 1H), 7.59 (m, 1H), 7.47-7.31 (m, 3H), 4.59-4.49 (m, 1H), 3.68 (m, 2H), 2.37 (m, 1H), 2.20-1.96 (m, 2H), 1.94-1.81 (m, 1H), 1.46 (d, J = 13.5 Hz, 6H)
Claims (16)
- 式(I):
Ar1は、1~2個のR1aおよび1~2個のR1bで置換されたフェニル、または1~2個のR1aおよび1~2個のR1bで置換された、1~3個の窒素原子を含む6員環ヘテロアリールであり;
Ar2は、1~4個のR2で置換されたフェニル、または1~4個のR2で置換された、1~3個の窒素原子を含む6員環ヘテロアリールであり;
Ar3は、0~4個のR3で置換されたフェニル、または0~4個のR3で置換されたピリジニルであり;
R1aは、水素またはハロゲンであり;
R1bは、ハロゲン、ハロアルキル、アルコキシ、またはハロアルコキシであり;
R2は、水素、シアノ、ハロゲン、アルキル、ヒドロキシアルキル、ハロアルキル、シクロアルキル、アルコキシ、またはハロアルコキシであり;
R3は、シアノ、ハロゲン、アルキル、アルコキシ、ヒドロキシアルキル、アルコキシアルキル、またはハロアルキルであり;および
R4は、アルキルまたはアルコキシである]
の化合物またはその医薬的に許容される塩。 - 式(II):
Ar1は、1個のR1aおよび1~2個のR1bで置換されたフェニル、または1個のR1aおよび1~2個のR1bで置換された、1~2個の窒素原子を含む6員環ヘテロアリールであり;
Ar2は、1~3個のR2で置換されたフェニル、または1~3個のR2で置換されたピリジニルであり;
R1aは、水素またはハロゲンであり;
R1bは、ハロゲン、C1-4ハロアルキル、C1-4アルコキシ、またはC1-4ハロアルコキシであり;
R2は、水素、ハロゲン、C1-4アルキル、C1-4ヒドロキシアルキル、C1-4ハロアルキル、C3-6シクロアルキル、C1-4アルコキシ、またはC1-4ハロアルコキシであり;および
R4は、C1-3アルキルである]
の構造を有する請求項1の化合物またはその医薬的に許容される塩。 - 式(III):
Ar1は、1個のR1aおよび1~2個のR1bで置換されたフェニル、1個のR1aおよび1~2個のR1bで置換されたピリジニル、または1個のR1aおよび1~2個のR1bで置換されたピラジニルであり;
R1aは、水素またはハロゲンであり;
R1bは、ハロゲン、C1-4ハロアルキル、C1-4アルコキシ、またはC1-4ハロアルコキシであり;
R2は、水素、ハロゲン、C1-4アルキル、C1-4ヒドロキシアルキル、C1-4ハロアルキル、C3-6シクロアルキル、C1-4アルコキシ、またはC1-4ハロアルコキシであり;および
R4は、C1-2アルキルである]
の構造を有する請求項1または2の化合物またはその医薬的に許容される塩。 - 式中、
R1aは、水素またはFであり;
R1bは、F、Cl、またはCF3であり;
R2は、水素、F、Cl、イソプロピル、CF3、またはシクロプロピルであり;および
R4は、メチルである、
請求項4または5の化合物、またはその医薬的に許容される塩。 - 請求項1~11のいずれか一項に記載の化合物またはその医薬的に許容される塩、および医薬的に許容される担体、希釈剤、または賦形剤を含む、組成物。
- 治療に用いるための、請求項1~11のいずれか一項に記載の化合物、または請求項12に記載の組成物。
- 治療が必要な患者に対し、治療上有効量の請求項1~11のいずれか一項に記載の化合物を投与することを特徴とする、心臓疾患の治療方法。
- 心臓疾患が、狭心症、不安定狭心症、心筋梗塞、心不全、急性冠疾患、および医原性心臓損傷からなる群から選択される、請求項14の方法。
- 心不全が、うっ血性心不全、収縮期心不全、拡張期心不全、駆出率が低下した心不全(HFREF)、駆出率が保たれた心不全(HFPEF)、急性心不全、虚血性および非虚血性の慢性心不全からなる群から選択される、請求項15の方法。
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