JP6148400B2 - フェノキシエチルジヒドロ−1h−イソキノリン化合物 - Google Patents
フェノキシエチルジヒドロ−1h−イソキノリン化合物 Download PDFInfo
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- JP6148400B2 JP6148400B2 JP2016513099A JP2016513099A JP6148400B2 JP 6148400 B2 JP6148400 B2 JP 6148400B2 JP 2016513099 A JP2016513099 A JP 2016513099A JP 2016513099 A JP2016513099 A JP 2016513099A JP 6148400 B2 JP6148400 B2 JP 6148400B2
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- pharmaceutically acceptable
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- -1 Phenoxyethyldihydro-1H-isoquinoline compound Chemical class 0.000 title description 13
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- YPWZAMDZNBPGFN-UQBPGWFLSA-N 4-[(1s)-1-[[(3r)-2-(2-phenoxyethyl)-3,4-dihydro-1h-isoquinoline-3-carbonyl]amino]ethyl]benzoic acid Chemical compound C([C@@H]1C(=O)N[C@@H](C)C=2C=CC(=CC=2)C(O)=O)C2=CC=CC=C2CN1CCOC1=CC=CC=C1 YPWZAMDZNBPGFN-UQBPGWFLSA-N 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- QEGVLHIPOFXEGZ-AVRWGWEMSA-N 4-[(1s)-1-[[(3r)-2-[2-(4-fluorophenoxy)ethyl]-3,4-dihydro-1h-isoquinoline-3-carbonyl]amino]ethyl]benzoic acid Chemical compound C([C@@H]1C(=O)N[C@@H](C)C=2C=CC(=CC=2)C(O)=O)C2=CC=CC=C2CN1CCOC1=CC=C(F)C=C1 QEGVLHIPOFXEGZ-AVRWGWEMSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
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- YZDXFUGIDTUCDA-UHFFFAOYSA-N isoquinoline-1-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=NC=CC2=C1 YZDXFUGIDTUCDA-UHFFFAOYSA-N 0.000 description 32
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- ZGSCZTCQNXFWPS-UHFFFAOYSA-N 1-(2-phenoxyethyl)isoquinoline Chemical compound C(Cc1nccc2ccccc12)Oc1ccccc1 ZGSCZTCQNXFWPS-UHFFFAOYSA-N 0.000 description 12
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
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- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 3
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- ZIIQWTRFDRIPFB-SCLBCKFNSA-N methyl 4-[(1S)-1-[[(3R)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]amino]ethyl]benzoate Chemical compound C1N[C@H](CC2=CC=CC=C12)C(=O)N[C@@H](C)C1=CC=C(C(=O)OC)C=C1 ZIIQWTRFDRIPFB-SCLBCKFNSA-N 0.000 description 1
- DUSXEGVIXFYWBJ-RXFWQSSRSA-N methyl 4-[(1S)-1-[[(3R)-2-(2-phenoxyethyl)-3,4-dihydro-1H-isoquinoline-3-carbonyl]amino]ethyl]benzoate Chemical compound O(C1=CC=CC=C1)CCN1CC2=CC=CC=C2C[C@@H]1C(=O)N[C@@H](C)C1=CC=C(C(=O)OC)C=C1 DUSXEGVIXFYWBJ-RXFWQSSRSA-N 0.000 description 1
- XSYGLHLLQZGWPT-ZETCQYMHSA-N methyl 4-[(1s)-1-aminoethyl]benzoate Chemical compound COC(=O)C1=CC=C([C@H](C)N)C=C1 XSYGLHLLQZGWPT-ZETCQYMHSA-N 0.000 description 1
- MZDGXTXYHXDWIM-UHFFFAOYSA-N methyl benzoate;hydrochloride Chemical compound Cl.COC(=O)C1=CC=CC=C1 MZDGXTXYHXDWIM-UHFFFAOYSA-N 0.000 description 1
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- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epidemiology (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Description
以下の調製および実施例は、本発明をさらに例示する。それとは反対の注記がない限り、本明細書に例示される化合物は、Accelrys Draw(IUPAC名)を用いて命名および番号付けされる。
調製2
hEP1およびhEP4膜を、ヒトEP1(Genbank受入番号AY275470)またはEP4(Genbank受入番号AY429109)受容体を安定発現する組み換えHEK293細胞から調製する。hEP2およびhEP3膜を、EP2(Genbank受入番号AY275471)またはEP3(isoform VI:Genbank受入番号AY429108)受容体プラスミドで一過的にトランスフェクトしたHEK293細胞から調製する。凍結細胞ペレットを、テフロン(登録商標)/ガラスホモジナイザーを用いて均質化緩衝液中で均質化する。膜タンパク質を分取してドライアイス上で急速凍結し、その後−80℃で貯蔵する。均質化緩衝液(例えば、Mauback,K.A.、British Journal of Pharmacology、156:316〜327(2009年)を参照)は、10mMトリス−HCl、pH7.4、250mMスクロース、1mM EDTA、0.3mMインドメタシンに加えてRoche Molecular Biochemicals(カタログ番号1 697 498)から得られるComplete(商標)を、EDTAと共に含有した。
アッセイを、ヒトEP4受容体を安定発現する組み換えHEK293細胞において行った。細胞株を、高グルコースならびに10%ウシ胎児血清(FBS)、1mMピルビン酸ナトリウム、10mM HEPES、500μg/mLのジェネテシンおよび2mM L−グルタミンを補ったピリドキシン塩酸塩(Invitrogen)を含むDMEM中で培養することにより維持する。コンフルエント培養を、37℃で5%CO2を含有する雰囲気中で成長させる。細胞を、0.25%トリプシン−EDTAを用いて採取し、凍結培地(6%DMSOを含むFBS)中に107細胞/mLで懸濁させ、アリコートを液体窒素中に貯蔵する。アッセイの直前に、細胞をDMEM中で融解し、遠心分離し、cAMP緩衝液中に再懸濁させる。
ラットEP4 cDNA(Genebank受入#NM_03276)を、pcDNA 3.1ベクター内にクローン化し、続いて受容体発現のためにHEK293細胞においてトランスフェクトした。ラットEP4の安定クローンを拡大し次いで今後の化合物スクリーニングのための細胞バンクとして凍結する。rEP4細胞においてEP4アンタゴニスト化合物を試験するために、凍結細胞を融解し次いで細胞をcAMPアッセイ緩衝液中に再懸濁させる。cAMP緩衝液は、20mM HEPES(Hyclone、SH30237)、0.1%BSA(Gibco、15260)および125μM IBMX(Sigma、I5879)を補ったフェノールレッド(Hyclone、SH30268)を含まないHBSSから作られる(例えば、Murase,A.ら、Life Sciences、82:226〜232(2008年)を参照されたい)。細胞を、96−ウェルハーフエリア平底ポリスチレン黒色プレート(Costar 3694)内に平板化する。化合物を、DMSOで段階希釈して10点濃度反応曲線を与える。次いで希釈した化合物を、PGE2(Cayman 14010、EC80を生成するために予め定められた濃度)を含有するcAMPアッセイ緩衝液にDMSO/緩衝液の比率1/100で加える。細胞を、化合物でPGE2(EC80濃度)の存在下で室温で30分間処理する。細胞から発生したcAMPレベルを、cAMP HTRFアッセイキット(Cisbio 62AM4PEC)によって定量化する。プレートを、HTRF最適化プロトコール(PerkinElmer)を用いてEnVisionプレートリーダー上で読み取る。IC50を、Graphpad Prism(v.4)非線形回帰、シグモイド用量反応曲線適合を用いて計算する。
マクロファージ/単球からのLPS−誘導性TNFα産生へのPGE2の阻害効果は、EP4受容体によって仲介されると考えられている(Murase,A.ら、Life Sciences、82:226〜232(2008年)参照)。ヒト全血におけるLPS−誘導性TNFα産生へのPGE2の阻害効果を逆転させる実施例1の化合物の能力は、機能的活性の証拠である。
Claims (11)
- 治療において使用するための、請求項1〜6のいずれか一項に記載の化合物またはその薬学的に許容可能な塩を含む医薬組成物。
- 治療において使用するための、1種または複数の薬学的に許容可能な担体、希釈剤、または賦形剤と共に請求項1〜6のいずれか一項に記載の化合物またはその薬学的に許容可能な塩を含む医薬組成物。
- 患者における変形性関節炎を治療するための、請求項1〜6のいずれか一項に記載の化合物またはその薬学的に許容可能な塩を含む医薬組成物。
- 患者におけるリウマチ性関節炎を治療するための、請求項1〜6のいずれか一項に記載の化合物またはその薬学的に許容可能な塩を含む医薬組成物。
- 患者における変形性関節炎またはリウマチ性関節炎と関連した痛みを治療するための、請求項1〜6のいずれか一項に記載の化合物またはその薬学的に許容可能な塩を含む医薬組成物。
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CN (1) | CN105209438B (ja) |
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CR20180323A (es) | 2015-11-20 | 2018-08-06 | Idorsia Pharmaceuticals Ltd | Derivados de indol n-sustituídos como moduladores de los receptores de pge2 |
AR111874A1 (es) | 2017-05-18 | 2019-08-28 | Idorsia Pharmaceuticals Ltd | Derivados de pirimidina |
JP7065117B2 (ja) | 2017-05-18 | 2022-05-11 | イドーシア ファーマシューティカルズ リミテッド | N-置換インドール誘導体 |
CA3060394A1 (en) | 2017-05-18 | 2018-11-22 | Idorsia Pharmaceuticals Ltd | Pyrimidine derivatives as pge2 receptor modulators |
AR111807A1 (es) | 2017-05-18 | 2019-08-21 | Idorsia Pharmaceuticals Ltd | Derivados de benzofurano y benzotiofeno como moduladores del receptor pge2 |
UA125123C2 (uk) | 2017-05-18 | 2022-01-12 | Ідорсія Фармасьютікалз Лтд | Фенільні похідні як модулятори pge2 рецепторів |
TW202228674A (zh) | 2020-11-13 | 2022-08-01 | 日商小野藥品工業股份有限公司 | 藉由併用ep4拮抗藥與免疫檢查點抑制物質而進行之癌症治療 |
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IT1270615B (it) | 1994-07-14 | 1997-05-07 | Smithkline Beecham Farma | Uso di derivati di chinolina |
US6649606B1 (en) | 2001-11-09 | 2003-11-18 | Bristol-Myers Squibb Co. | Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity |
EP1450844A4 (en) | 2001-11-09 | 2009-07-29 | Enzon Inc | THIOL-LINKED POLYMER PROMEDICAMENTS USING BENZYL ELIMINATION SYSTEMS |
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AU2014265762A1 (en) | 2015-10-15 |
BR112015026967A2 (pt) | 2017-07-25 |
CA2908400A1 (en) | 2014-11-20 |
PL2997015T3 (pl) | 2017-09-29 |
HUE033574T2 (hu) | 2017-12-28 |
ZA201507566B (en) | 2017-06-28 |
BR112015026967A8 (pt) | 2018-01-30 |
US20160052889A1 (en) | 2016-02-25 |
KR20150140831A (ko) | 2015-12-16 |
ES2626976T3 (es) | 2017-07-26 |
WO2014186218A1 (en) | 2014-11-20 |
PT2997015T (pt) | 2017-04-24 |
SA515370035B1 (ar) | 2018-01-04 |
TW201534588A (zh) | 2015-09-16 |
CA2908400C (en) | 2017-04-11 |
KR101798315B1 (ko) | 2017-11-15 |
MX2015015841A (es) | 2016-03-04 |
EP2997015B1 (en) | 2017-04-05 |
TWI636046B (zh) | 2018-09-21 |
JP2016519140A (ja) | 2016-06-30 |
CN105209438A (zh) | 2015-12-30 |
BR112015026967B1 (pt) | 2023-01-10 |
US9371289B2 (en) | 2016-06-21 |
EA027306B1 (ru) | 2017-07-31 |
EP2997015A1 (en) | 2016-03-23 |
CN105209438B (zh) | 2017-04-12 |
EA201591915A1 (ru) | 2016-04-29 |
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