JP7425925B2 - 二官能性化合物及び使用方法 - Google Patents
二官能性化合物及び使用方法 Download PDFInfo
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- JJWKQXNHYDJXKF-UHFFFAOYSA-N n-cyclopropyl-1-[3-[2-(1-oxidopyridin-1-ium-3-yl)ethynyl]phenyl]-4-oxo-1,8-naphthyridine-3-carboxamide Chemical compound [O-][N+]1=CC=CC(C#CC=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)=C1 JJWKQXNHYDJXKF-UHFFFAOYSA-N 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
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- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 description 1
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- 229950010037 revamilast Drugs 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
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- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
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- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 229960002485 trolnitrate Drugs 0.000 description 1
- HWKQNAWCHQMZHK-UHFFFAOYSA-N trolnitrate Chemical compound [O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O HWKQNAWCHQMZHK-UHFFFAOYSA-N 0.000 description 1
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- 229940094720 viagra Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/04—Ortho-condensed systems
Description
本出願は、2020年7月30日に出願された米国仮出願第63/058,512号に対する優先権を主張し、その内容全体を参照により本明細書に組み込む。
L1-X-L2 (I)
実施例1 (S)-2-((2-(1-(3-エトキシ-4-メトキシフェニル)-2-(メチルスルホニル)エチル)-1,3-ジオキソイソインドリン-4-イル)アミノ)-2-オキソエチル2,2-ジメチル-3-(ニトロオキシ)プロパノア-ト(化合物-1とも呼ばれる)の調製
化合物-1を以下のステップで調製した。図5は、本開示の幾つかの実施形態による化合物-1を調製する例示的なプロセスを示す図である。
化合物-2を以下のステップで調製した。図6は、本開示の幾つかの実施形態による化合物-2を調製する例示的なプロセスを示す図である。
化合物-3を以下のステップで調製した。図7は、本開示の幾つかの実施形態による化合物-3を調製する例示的なプロセスを示す図である。
化合物-4を以下のステップで調製した。図8は、本開示の幾つかの実施形態による化合物-4を調製する例示的なプロセスを示す図である。
化合物-5を以下のステップで調製した。図9は、本開示の幾つかの実施形態による化合物-5を調製する例示的なプロセスを示す図である。
化合物(例えば、化合物-1、化合物-2、化合物-3、化合物-4、化合物-5、及び化合物-6)によるPDE4(例えば、PDE4A、PDE4C)活性の阻害は、提供された手順に従って、BPS Bioscience(San Diego、USA)からのPDE蛍光偏光アッセイキットを使用してモニタ-した。このアッセイは、FAM-cAMPからのPDEによって生成された蛍光色素FAM標識AMPの結合ビ-ズへの選択的結合に基づいている。
末梢血単核球又は血液における、本開示によって提供される化合物による腫瘍壊死因子α(TNF-α)及びインタ-フェロンγ(IFN-γ)産生の阻害は、Claveauらのプロトコル(JPET、310、752-760、2004)に従うことによってモニタ-した。化合物は、TNF-α及びIFN-γの発現を阻害することができる。
マウス(固形飼料でのC57Bl6)に、10mL/kgの投与量でビヒクルとして1%メチルセルロ-スを使用して、化合物を経口投与した。30分後、LPS(30ug/kg)を鼻から注入して、炎症と急性気道損傷を誘発した。血漿中のTNFaレベル、及びBALF中の細胞浸潤は、24時間のLPSチャレンジ後にモニタ-した。化合物は、マウスの急性長期損傷を緩和することができる。
図10は、マウスに化合物-1を投与した後に産生された化合物-6血中レベルを示す。例示化合物-1(0.5%カルボキシメチルセルロ-ス(CMC)/0.25%Tween-80懸濁液として水中で0.5mg/mLで調剤された)を5mg/kgで4匹のマウスに経口投与した。化合物-1は、経口投与後にマウスで急速に生物活性化され、すべてのマウスで一貫してPDE4阻害代謝物化合物-6を形成した。15分で血液中に約200ng/mLの化合物-6が検出された。化合物-6の血中レベルは、1~2時間の間に約250ng/mLでピ-クに達し、6時間で約25ng/mLまでほぼ消失した。図10から分かるように、血液中の化合物-6のレベルの変動傾向は比較的安定している。化合物-6の血中レベルのこの動的プロファイルは、化合物-6の直接投与による予想される高いCmaxに起因する副作用の軽減など、化合物-6の直接投与を超えて、化合物-6治療に反応する疾患を治療する機会を提供する。
化合物-1及び化合物-2を5mg/mlで、化合物-4を1mg/mlで、水中1%CMC/0.5%Tween-80にビヒクルとして調剤した。血漿中の総硝酸エステル及び総ニトラ-トレベルは、提供されたプロトコルに従って、一酸化窒素アッセイキット(ab65327、AbCam)を使用して定量化した。デ-タは平均値(±SEM、3匹のマウス/グル-プ)であった。
Claims (7)
- 式(II)で表される化合物であって、
-X-は、エステル結合、アミド結合、又は存在せず、
L1は、-C(CH 3 ) 2 -CH 2 -ONO 2 、-C(CH 3 )-(CH 2 -ONO 2 ) 2 、-(CH 2 ) 2 -ONO 2 、-CH-(CH 2 -ONO 2 ) 2 、-(CH 2 ) 2 -CH-(CH 2 -ONO 2 ) 2 、-(CH 2 ) 2 -CH(ONO 2 )-CH 2 -ONO 2 、又は
であるが、但し、-X-が存在しない場合には、L 1 は、
であることを特徴とする化合物。 - 前記化合物は、
である、ことを特徴とする請求項1に記載の化合物。 - 前記化合物は、
である、ことを特徴とする請求項1に記載の化合物。 - 前記化合物は、
である、ことを特徴とする請求項1に記載の化合物。 - 請求項1~4のいずれか一項に記載の化合物及び薬学的に許容可能な担体を含む組成物。
- 対象におけるホスホジエステラーゼ(PDE)関連疾患を治療又は予防するための請求項5に記載の組成物。
- 急性肺損傷(ALI)又は急性呼吸窮迫症候群(ARDS)を治療又は予防するための請求項5に記載の組成物。
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Citations (4)
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JP2001504457A (ja) | 1996-11-01 | 2001-04-03 | ニトロメド インコーポレーテッド | ニトロソ化およびニトロシル化ホスホジエステラーゼ阻害剤化合物、組成物及びその使用法 |
WO2012083153A1 (en) | 2010-12-16 | 2012-06-21 | Nektar Therapeutics | Oligomer-containing apremilast moiety compounds |
JP2018535259A (ja) | 2015-11-16 | 2018-11-29 | トパドゥール ファーマ アーゲー | ホスホジエステラーゼ阻害剤としての2−フェニル−3,4−ジヒドロピロロ[2,1−f][1,2,4]トリアジノン誘導体およびその使用 |
JP2021533152A (ja) | 2018-08-06 | 2021-12-02 | ニコックス エス.エー. | 一酸化窒素放出性ホスホジエステラーゼ5型阻害薬 |
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US6331543B1 (en) * | 1996-11-01 | 2001-12-18 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use |
EP3539539A1 (en) * | 2013-06-17 | 2019-09-18 | Celgene Corporation | Tablet formulations of (+)-2-[1 -(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione |
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JP2001504457A (ja) | 1996-11-01 | 2001-04-03 | ニトロメド インコーポレーテッド | ニトロソ化およびニトロシル化ホスホジエステラーゼ阻害剤化合物、組成物及びその使用法 |
WO2012083153A1 (en) | 2010-12-16 | 2012-06-21 | Nektar Therapeutics | Oligomer-containing apremilast moiety compounds |
JP2018535259A (ja) | 2015-11-16 | 2018-11-29 | トパドゥール ファーマ アーゲー | ホスホジエステラーゼ阻害剤としての2−フェニル−3,4−ジヒドロピロロ[2,1−f][1,2,4]トリアジノン誘導体およびその使用 |
JP2021533152A (ja) | 2018-08-06 | 2021-12-02 | ニコックス エス.エー. | 一酸化窒素放出性ホスホジエステラーゼ5型阻害薬 |
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TWI810622B (zh) | 2023-08-01 |
CN113767104B (zh) | 2023-08-22 |
CA3187693A1 (en) | 2022-02-03 |
EP4175943A4 (en) | 2023-11-15 |
CN113767104A (zh) | 2021-12-07 |
EP4175943A1 (en) | 2023-05-10 |
TW202214564A (zh) | 2022-04-16 |
JP2023532145A (ja) | 2023-07-26 |
US20230174482A1 (en) | 2023-06-08 |
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