JP7478133B2 - 腎障害の処置で使用するための化合物 - Google Patents
腎障害の処置で使用するための化合物 Download PDFInfo
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- JP7478133B2 JP7478133B2 JP2021504186A JP2021504186A JP7478133B2 JP 7478133 B2 JP7478133 B2 JP 7478133B2 JP 2021504186 A JP2021504186 A JP 2021504186A JP 2021504186 A JP2021504186 A JP 2021504186A JP 7478133 B2 JP7478133 B2 JP 7478133B2
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- 239000000454 talc Substances 0.000 description 1
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
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Images
Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
特定の実施形態においては、このようなABCA1誘導因子化合物は、以下の式I
A1及びA2の一方はNであり、A1及びA2の他方はCHであり、
R1は、C1~7アルキル、C3~7シクロアルキル、C3~7シクロアルキル-C1~7アルキル、C1~7アルコキシ-C1~7アルキル、ハロゲン-C1~7アルキル、ヘテロシクリル-C1~7アルキル(ここで、ヘテロシクリル基は非置換であるか、又はオキソにより置換されている)、及びヘテロアリール-C1~7アルキル(ここで、ヘテロアリール基は非置換であるか、又は低級アルキルによりモノ又はジ置換されている)からなる群から選択され、
R2及びR6は互いに独立して水素又はハロゲンであり、
R3及びR5は互いに独立して水素、C1~7アルキル、C1~7アルコキシ、ハロゲン、ハロゲン-C1~7アルキル、ハロゲン-C1~7アルコキシ、及びシアノからなる群から選択され、
R4は水素、C1~7アルキル、C1~7アルコキシ、ハロゲン、ハロゲン-C1~7アルキル、ハロゲン-C1~7アルコキシ、アミノ、及びシアノからなる群から選択され、
R7はC1~7アルキル、C3~7シクロアルキル(当該シクロアルキルは非置換であるか又はヒドロキシにより置換されている)、ヘテロシクリル(当該ヘテロシクリルは、N、O及びSから選択される1、2、又は3つのヘテロ原子を含み、非置換であるか、ヒドロキシ又はオキソにより置換されている、3~7個の環原子を有する)、フェニル(ここで、フェニルは非置換であるか、又はC1~7アルキル、ヒドロキシ、C1~7アルコキシ、シアノ、ハロゲン、及びハロゲン-C1~7アルキルからなる群から選択される1つ又は2つの基により置換されている)、及びヘテロアリール(ここで、ヘテロアリールは非置換であるか、又はC1~7アルキル、ヒドロキシ、C1~7アルコキシ、シアノ、ハロゲン、及びハロゲン-C1~7アルキルからなる群から選択される1つ又は2つの基により置換されている)からなる群から選択され、
Gは-(CH2)m-(式中、mは0又は1から選択される)、及び-NR8(式中、R8は水素又はC1~7アルキルである)からなる群から選択される。]
並びに薬学的に許容可能なそれらの塩により表される。
本明細書で使用する場合、用語「ABCA1誘導因子化合物」とは、ATP結合カセットトランスポータータンパク質(ABCA1)の発現量又は活性を直接又は間接的に誘導可能な化合物を意味する。トランスポーターABCA1は、細胞コレステロール及びリン脂質ホメオスタシスの主たる制御因子として知られている。具体的には、ABCA1は、コレステロール及びリン脂質の、脂質が不十分なApoリポタンパク質(ApoA1及びApoE)への流出を媒介し、その後初期の高密度リポタンパク質(HDL)を形成する。細胞でABCA1タンパク質の上方制御を測定するためのインビトロアッセイは、例えば国際公開第2012/031817号に記載されている。これらのインビトロアッセイとしては、国際公開第2012/031817号に記載されているコレステロール流出アッセイ又は蛍光性ApoA1結合アッセイが挙げられるが、これらに限定されない。
[式中、A1及びA2の一方はNであり、A1及びA2の他方はNであり、
R1は、C1~7アルキル、C3~7シクロアルキル、C3~7シクロアルキル-C1~7アルキル、C1~7アルコキシ-C1~7アルキル、ハロゲン-C1~7アルキル、ヘテロシクリル-C1~7アルキル(ここで、ヘテロシクリル基は非置換であるか、又はオキソにより置換されている)、及びヘテロアリール-C1~7アルキル(ここで、ヘテロアリール基は非置換であるか、又は低級アルキルによりモノ又はジ置換されている)からなる群から選択され、
R2及びR6は互いに独立して水素又はハロゲンであり、
R3及びR5は互いに独立して水素、C1~7アルキル、C1~7アルコキシ、ハロゲン、ハロゲン-C1~7アルキル、ハロゲン-C1~7アルコキシ、及びシアノからなる群から選択され、
R4は水素、C1~7アルキル、C1~7アルコキシ、ハロゲン、ハロゲン-C1~7アルキル、ハロゲン-C1~7アルコキシ、アミノ、及びシアノからなる群から選択され、
R7はC1~7アルキル、C3~7シクロアルキル(当該シクロアルキルは非置換であるか又はヒドロキシにより置換されている)、ヘテロシクリル(当該ヘテロシクリルは、N、O及びSから選択される1、2、又は3つのヘテロ原子を含み、非置換であるか、ヒドロキシ又はオキソにより置換されている、3~7個の環原子を有する)、フェニル(ここで、フェニルは非置換であるか、又はC1~7アルキル、ヒドロキシ、C1~7アルコキシ、シアノ、ハロゲン、及びハロゲン-C1~7アルキルからなる群から選択される1つ又は2つの基により置換されている)、及びヘテロアリール(ここで、ヘテロアリールは非置換であるか、又はC1~7アルキル、ヒドロキシ、C1~7アルコキシ、シアノ、ハロゲン、及びハロゲン-C1~7アルキルからなる群から選択される1つ又は2つの基により置換されている)からなる群から選択され、
Gは-(CH2)m-(式中、mは0又は1から選択される)、及び-NR8(式中、R8は水素又はC1~7アルキルである)からなる群から選択される。]、
薬学的に許容可能なそれらの塩類の使用に関する。
式Iの化合物、典型的には、実施例にて記載する化合物A及びG、又は薬学的に許容される塩は、腎疾患の処置において有用であることが示されている。
(i)上で定義した式Iの化合物、典型的には、実施例に記載する化合物A又はGを含む医薬であって、以下
(ii)アンギオテンシン変換酵素(ACE)阻害剤薬物、RAS遮断剤;アンギオテンシン受容体遮断薬(ARB);プロテインキナーゼC(PKC)阻害剤;AGE依存性経路の阻害剤;抗炎症剤、GAG;ピリドキサミン(米国特許第7,030,146号);エンドセリン拮抗薬、COX-2阻害剤、PPAR-γアゴニスト、及び、アミホスチン(シスプラチン腎症に使用)、カプトプリル(糖尿病性腎症に使用)、シクロホスファミド(特発性膜性腎症に使用)、チオ硫酸ナトリウム(シスプラチン腎症に使用)、又はトラニラスト;シクロデキストリンなどのその他の化合物並びにこれらの誘導体類(例えばヒドロキシプロピル-β-シクロデキストリン)からなる群から選択される化合物、並びに
(iii)薬学的に許容される担体、及び/又はアジュバント
と組み合わせた、又は会合した、医薬にも関する。
国際公開第2011/029827号の実施例3に記載されている手順に従い、化合物を5-ブロモ-6-クロロ-3-ピリジンカルボン酸、2,2,2-トリフルオロエタノール、(1R,2R)-2-アミノ-シクロヘキサノール、及び3,4-ジクロロフェニルボロン酸から調製した。MS 463.079,465.077(M+H)+.
化合物Aを、以下の工程で、国際公開第2014/180741号に記載されている手順に従い調製した:
100mLの4ツ口フラスコ内で、2,6-ジクロロ-3-フルオロピリジン(765mg、4.61mmol、当量:1.00、CAS登録番号52208-50-1)、及び(3,4-ジクロロフェニル)トリフルオロホウ酸カリウム(1.21g、4.61mmol、当量:1.00、CAN 850623-68-6)を、ジオキサン(23mL)及び水(13mL)と組み合わせた。2M Na2CO3(6.91mL、13.8mmol、当量:3)、続いて、PdCl2(DPPF)-CH2Cl2付加化合物(169mg、230μmol、当量:0.05、CAS登録番号95464-05-4)を添加した。反応混合物を3回脱気させ、アルゴンでパージした後、撹拌しながら一晩60℃まで加熱した。反応混合物を周囲温度まで冷却し、50mLのH2Oを注いで、tert-ブチルメチルエーテルで抽出した(2×100mL)。有機層をH2O/ブラインで洗浄して合わせ、Na2SO4で乾燥させて真空中で濃縮した。粗物質をフラッシュクロマトグラフィー(シリカゲル、70g、5%~20% ヘプタン中のジクロロメタン)により2回精製し、540mgの表題化合物を白色半固体として得た。
25mLの梨型フラスコ中で、上で調製した6-クロロ-2-(3,4-ジクロロフェニル)-3-フルオロピリジン(530mg、1.44mmol、当量:1.00)をDMSO(8mL)と合わせた。KOH(118mg、2.1mmol、当量:1.46)と2,2,2-トリフルオロエタノール(211mg、153μL、2.11mmol、当量:1.47)を添加し、反応を2時間周囲温度にて続けた。混合物を30mLのH2Oに注ぎ、tert-ブチルメチルエーテルで抽出した(2×40mL)。有機層をH2O/ブラインで洗浄して合わせ、Na2SO4で乾燥させて真空中で濃縮した。粗生成物をフラッシュクロマトグラフィー(シリカゲル、70g、5%~20%ヘプタン中のEtOAc)により精製し、444mgの表題化合物を無色液体として得た;MS(ESI)356.3,358.3,360.3(M+H)+。
35mLのオートクレーブ中で、上で調製した6-クロロ-2-(3,4-ジクロロフェニル)-3-(2,2,2-トリフルオロエトキシ)ピリジン(437mg、1.22mmol、当量:1.00)を5mLのMeOHに溶解させた。アルゴンにより酸素及び湿気から保護し、PdCl2(DPPF)-CH2Cl2付加化合物(75.2mg、92μmol、当量:0.083、CAS登録番号95464-05-4)、続いてトリエチルアミン(233mg、321mL、2.31mmol、当量:2.31)を添加した。次に、反応容器にCOを3回流し、70barまで圧力をかけた後、カルボニル化を20時間110℃で進めた。冷却して圧力を放出した後、粗反応混合物を真空中で濃縮した。次に残留物をAcOEt/H2Oに溶解させ、分液漏斗に移した。水層をEtOAcで逆抽出し、有機層をH2Oとブラインで洗浄して合わせ、Na2SO4で乾燥させて真空中で濃縮した。フラッシュクロマトグラフィー(シリカゲル、70g、10%~40% ヘプタン中のEtOAc)を行って、最終的に327mgの表題生成物を白色固体として得た;MS(ESI)380.4,382.4(M+H)+。
25mLの梨型フラスコ中で、上で調製した6-(3,4-ジクロロフェニル)-5-(2,2,2-トリフルオロエトキシ)ピコリネート(326mg、858μmol、当量:1.00)をテトラヒドロフラン(5mL)と合わせ、無色溶液を得た。水(2.5mL)、続いてLiOH(41.1mg、1.72mmol、当量:2)を添加し、反応混合物を2時間、40℃で撹拌した。反応混合物を5mLの飽和NH4Cl溶液及び3mLの1N KHSO4溶液に注ぎ、EtOAcで抽出した(2×30mL)。有機層を合わせ、Na2SO4で乾燥させて真空中で濃縮すると、表題の酸が322mg、白色泡状物として残った;MS(ESI)366.4,368.4(M+H)+。
25mLの梨型フラスコ中で、上で合成した6-(3,4-ジクロロフェニル)-5-(2,2,2-トリフルオロエトキシ)-ピコリン酸(322mg、879μmol、当量:1.00)をDMF(12mL)に溶解させた。TBTU(O-(ベンゾチアゾール)-1-イル)-N,N,N’,N’-テトラメチルウロニウムテトラフルオロボレート、424mg、1.32mmol、当量:1.5、CAS 登録番号125700-67-6)、及びN,N-ジイソプロピルエチルアミン(568mg、768μL、4.4mmol、当量:5)を添加し、反応混合物を10分間周囲温度にて撹拌した後、(1R,2R)-2-アミノシクロヘキサノールヒドロクロリド(160mg、1.06mmol、当量:1.2、CAS登録番号13374-31-7)を追加の溶媒なしで添加した。次に、反応を3時間室温で進めた。粗製混合物をH2Oで希釈してCH2Cl2で抽出した。有機層を合わせ、Na2SO4で乾燥させて真空中で濃縮した。フラッシュクロマトグラフィー(塩基性アルミナ、50g、10%~80% ヘプタン中のEtOAc)により精製し、EtOAc及びヘプタンからの、粗生成物の沈殿により、表題アミドが白色固体として得られた;高解像度MS(ESI)463.0798,465.0769(M+H)+;予想:463.0798,465.0768。
化合物Hを、以下の工程で、国際公開第2014/180741号に記載されている手順に従い調製した:
50mLの4ツ口フラスコ中で、メチル5-ブロモ-6-(2,2,2-トリフルオロエトキシ)ニコチネート(1g、3.18mmol、当量:1.00、CAS登録番号1211589-51-3)及び炭酸セシウム(3.11g、9.55mmol、当量:3)を、トルエン(25mL)及び水(2.8mL)と組み合わせ、無色溶液を得た。反応混合物を3回脱気させ、アルゴンでパージした後、酢酸パラジウム(II)(14.3mg、63.7μmol、当量:0.02)、(4-シアノフェニル)トリフルオロホウ酸カリウム(732mg、3.5mmol、当量:1.1、CAS登録番号850623-36-8)、及びブチルジ-1-アダマンチルホスフィン(68.5mg、191μmol、当量:0.06、CAS登録番号321921-71-5)を連続して添加した。脱気-パージサイクルを、各添加の後に繰り返した。次に、反応混合物を120℃まで5時間加熱した。冷却後、反応混合物を50mLのH2Oに注ぎ、AcOEtで抽出した(2×50mL)。有機層をH2O/ブラインで洗浄して合わせ、Na2SO4で乾燥させて真空中で濃縮した。フラッシュクロマトグラフィー(シリカゲル、50g、50%~100% ヘプタン中のCH2Cl2)による精製によって、最終的に表題化合物を898mg、白色泡状物として得た;MS(ESI)337.2(M+H)+。
25mLの丸底フラスコ中で、上で調製した5-(4-シアノ-フェニル)-6-(2,2,2-トリフルオロ-エトキシ)-ニコチン酸メチルエステル(0.891g、2.65mmol、当量:1.00)を、THF(7mL)及び水(3.5mL)と合わせて淡黄色の二相系を得た。TLCが反応の完了を示したとき、水酸化リチウム(127mg、5.3mmol、当量:2)を添加し、反応混合物を40℃で3時間撹拌した。事前作業:10mLのH2O及び7mLのHCl 1Nを添加し、混合物をAcOEtで抽出して(2×50mL)、有機層を合わせてブラインで洗浄し、Na2SO4で乾燥させて真空中で濃縮した。ヘプタン/EtOAc(9:1)での粉砕により、最終的に、所望の表題生成物を794mg、白色固体として得た;MS(ESI)321.2(M-H)-。
5mLの丸底フラスコ中で、上で調製した5-(4-シアノ-フェニル)-6-(2,2,2-トリフルオロ-エトキシ)-ニコチン酸(0.050g、155μmol、当量:1.00)をTHF(2mL)と合わせ、無色溶液を得た。TBTU(O-(ベンゾチアゾール)-1-イル)-N,N,N’,N’-テトラメチルウロニウムテトラフルオロボレート、74.7mg、233μmol、当量:1.5、CAS登録番号125700-67-6)とN,N-ジイソプロピルエチルアミン(100mg、135μL、776μmol、当量:5を添加した。反応混合物を10分間室温で撹拌した後、3-クロロ-6-(1-メチルヒドラジニル)-ピリダジン(29.5mg、186μmol、当量:1.2、CAN76953-33-8)を添加し、反応混合物を室温で一晩維持した。25mLの1M HClに注ぎ、EtOAcで抽出し(2×50mL)、1M NaOHで洗浄してNa2SO4で乾燥させ、全ての溶媒を真空中で蒸発させた後、フラッシュクロマトグラフィー(シリカゲル、10グラム、2%~10% CH2Cl2中のMeOH)にかけて、ヘプタン/AcOEtからの再結晶を行うことにより、最終的に表題化合物を28mg、白色固体として得た;MS(ESI)463.1,465.3(M+H)+。
化合物Jを、以下の工程で、国際公開第2014/180741号に記載されている手順に従い調製した:
6-(4-クロロ-フェニル)-5-(2,2,2-トリフルオロ-エトキシ)-ピリジン-2-カルボン酸(国際公開第2012/032018号、実施例AEに記載のとおりに調製)をDMF(30mL)と室温で合わせ、無色溶液を得た。ピリミジン-5-アミン、TBTU、及びN-エチルジイソプロピルアミンを添加した。反応混合物を室温で15時間撹拌した。反応混合物を150mLのH2Oに注ぎ、EtOAcで抽出した(2×150mL)。合わせた有機層をブラインで洗浄し、MgSO4で乾燥させて蒸発させた。粗物質をフラッシュクロマトグラフィー(シリカゲル、20g、0%~50%、ヘキサン中のEtOAc)により精製した。LC-MS(ESI)409.068(M+H)+。
インビトロ実験のために、凍結乾燥した化合物をDMSO(Sigma)中で再構成し、同じ溶媒中で希釈して、20mM、10mM、5mM、1mM、及び0mMのストックを生成し、これらを-20℃で保管した。
ラットコラーゲンI型、RPMI及びITSをCorningから購入した。FBSをGIBCOから、脂肪非含有BSAをSigma-Aldrichから購入した。コレステロール流出アッセイのために、ヒトApoA1及び3H-コレステロールをそれぞれ、Calbiochem及びAmerican Radiolabeled Chemicalsから購入した。
糸球体上皮細胞を96ウェルプレート(Greiner)に播種し、14日間分化させた。次に、細胞をPBSで洗浄し、ビヒクル及び化合物含有又は非含有の培地(RPMI-0.2% BSA)で、18時間37℃、5% CO2でインキュベートした。試験した化合物の濃度は、1μM、5μM、10μM、及び20μMであった。ビヒクル(DMSO)の終濃度は0.1%であった。全ての処理を2通りに行った。メーカーの指示に従い、ApoTox-Glo Triplex Assay(Promega)を使用して細胞傷害性をアッセイした。簡単に言うと、細胞透過性(GF-AFC)及び細胞不透過性(ビス-AAF-R110)ペプチド基質を希釈して、全てのウェルに添加し、細胞を37℃、5% CO2で1時間インキュベートした。細胞の集合を、細胞傷害性の陽性対照としてサポニン(2mg/mL)で処理した。細胞生存能及び細胞傷害性蛍光シグナルを、蛍光マイクロプレートリーダー(SpectraMax i3)を使用してそれぞれ、400nm/505nm、及び485nm/520nmの励起/発光で測定した。細胞傷害性基質で得たRFUシグナルを、同じウェル内で生存可能な基質により得たシグナルに対して正規化して、ウェルあたりの異なる細胞数の効果を除外した。
13日間分化したヒト糸球体上皮細胞を、2% FBSを含有するRPMI培地中で、1μCi/mLの[3H]-コレステロールを用いて24時間標識した。次に、細胞をPBSで洗浄し、ビヒクル、又は化合物Cpd C(1μM)、Cpd A(1μM、5μM)、及びCpd G(1μM、5μM、10μM)を補充した平衡培地(RPMI-0.2%脂肪非含有BSA)で18時間インキュベートした。次に、細胞をPBSで洗浄し、20μg/mLのヒトApoA1を含有する、又は非含有の平衡培地で、18時間37℃、5% CO2でインキュベートした。培地を収集し、12,000xgで5分間スピンし、200μLのアリコートの放射能を、液体シンチレーションにより計測した。細胞をPBSで洗浄し、250μLの0.1% SDS、0.1M NaOHで溶解し、100μLのアリコートの放射能を、液体シンチレーションにより測定した。コレステロール流出を、以下の式により、培地に対する、細胞から取り除いた標識コレステロールの割合として計算した:
流出(%)=100×{(培地のcpm)/[(培地のcpm)+(溶解物のcpm)]}
14日間分化させた糸球体上皮細胞を、RPMI-0.2% FBS中で18時間飢餓状態にし、その後、完全培地中で18時間、37℃及び5% CO2で、新たに調製した化合物の希釈液にて処理した。1μM、5μM、及び10μMの化合物濃度を評価した。次に、細胞をPBSで洗浄し、プロテアーゼ及びホスファターゼ阻害剤カクテル(Roche)を補充した、1X細胞溶解緩衝液(Cell Signaling)で溶解した。総タンパク質含有量をBCA法(Pierce,Thermoscientific)により測定した。ABCA1の発現をウェスタンブロットにより分析した。
14日間分化させた糸球体上皮細胞を、化合物Cpd C(1μM)、Cpd A(5μM)、及びCpd G(10μM)で18時間処理した後洗浄して、氷冷PBSで掻き取った。細胞を1,000xgで5分間遠心分離にかけ、上清を注意深く吸引して、ペレットを、Rocheのプロテアーゼ阻害剤カクテルを補充した低張性緩衝液(15mM KCl、1.5mM MgCl2、10mM HEPES、及び1mM DTT)中で懸濁した。ガラスダウンサー中で、2回の凍結及び解凍サイクルにて起泡させることで、細胞を更に確実に破壊した。スクロースを添加し、227mMの終濃度にして、細胞を1,000xgにて30分間、4℃で遠心分離にかけた。次に、上清を新しい管に移し、10,000xgにて15分間、4℃で遠心分離にかけた。ミクロソーム分画を含有するペレットを収集し、上清を新しい管に移して、100,000xgにて1時間、4℃で遠心分離にかけた。ペレット処理した原形質膜画分を収集し、非膜性サイトゾル分画を含有する上清を、Vivaspin 500フィルターカラム内で濃縮した。各画分内での、ABCA1、並びに、原形質膜に存在することが知られているタンパク質(Na+/K+ナトリウムポンプ)及び細胞質基質(MEK)の存在を、ウェスタンブロットにより確認した。
溶解物、又は細胞画分を、緩衝液サンプルにより55℃で10分間、減圧条件にてインキュベートした。合計で30gの、溶解物中のタンパク質、及び、細胞画分調製物中で収集した体積の3分の1を、4~20%ゲル中のSDSPAGE(Biorad)で分離した後、タンパク質をPVDF膜に移した。膜を5%乳で遮断し、タンパク質特異的抗体で18時間4℃にてブロットした。以下の抗体を使用した:マウス抗ABCA1(Abcam;1:1,000)、ウサギ抗GAPDH抗体(Millipore;1:10,000)、ウサギ抗MEK及び抗Na+/K+ATPase(Cell Signaling;1:1,000)。PBS-Tで洗浄した後、5%乳中で、HRP(Promega)に1:10,000で抱合体化した、抗マウス及び抗ウサギ特異的抗体を用いて、膜をインキュベートした。膜を洗浄して、Western bright ECL基質(Advansta)を使用してシグナルを展開した。
研究認可
マウスにおける化合物を試験するための研究手順は、University of Miami’s IACUCにより認可された。University of Miami(UM)は、Office of Laboratory Animal Welfare、NIHと共に、Animal Welfare Assuranceのファイルを有している(A-3224-01、2014年11月24日に有効化)。更に、UMは、US Department of Agriculture Animal and Plant Health Inspection Serviceにより登録されている(2014年12月、登録58-R-007)。2013年10月22日時点で、Council on Accreditation of the Association for Assessment and Accreditation of Laboratory Animal Care(AAALAC International)は、UMの完全な認定を続けている。
購入したメスBalb/cマウスは、6週齢の時点でJackson Labsから購入し、実験の開始前に2週間、我々の設備にて保管した。
129 Col4a3tm1/Dec/JマウスをJackson Labsから購入し、交配してCol4a3 KOマウスを生成した。マウスをジェノタイピングして、プライマー:F(TGCTCTCTCAAATGCACCAG)、R(CCAGGCTTAAAGGGAAATCC)、及びRm(GCTATCAGGACATAGCGTTGG)を使用して、PCR反応(94Cで5分間、続けて、95Cで30秒・60Cで15秒・及び72Cで30秒を30サイクル、並びに72Cで1分)で、選択した。129匹のCol4A3-KOマウスを、それぞれ5匹のマウス(オス及びメス)がいる2つの群に分けた。4週齢の時点で、マウスは、ビヒクル又はCpd G(100mg/Kg)のいずれかを経口摂食で、4週間毎日受けることを開始した。体重測定及び随時尿採集を、1週間に1回実施した。動物を、8週齢の時点で、処置の終わりに犠牲にした。後続の研究もまた実施して、病気が確立した時点での、Col4A3-KOマウスの処置がマウスの生残を延ばすか否かを評価した。本研究では、マウスを、6週齢の時点で開始する、Cpd G(100mg/Kg/日)を毎日経口摂食することにより処理し、生残を評価した。
Jackson laboratoryから、B6.BKSdb/db、及びB6.BKSdb/+マウスを購入した。14週齢の時点で、マウスは、ビヒクル又はABCA1誘導因子であるCpd A(30mg/Kg)を、経口摂食により1日1回4週間、受けることを開始した。体重測定及び尿採集を毎週行った。マウスを18週齢で犠牲にし、採血して組織を処理し、以下のとおりに分析した。
随時尿サンプルを全てのマウスから、ベースライン及び犠牲時に採集した。アルブミンELISAキット(Bethyl laboratories)、及びクレアチニン測定のための比色分析アッセイ(Stanbio)を使用して、泌尿器のアルブミン及びクレアチニンを測定した。アルブミン尿を計算し、クレアチニン(mg)で除したアルブミン(μg)として表した。糖尿病マウスモデルに関して、体重及び血糖を2週間に1回ベースで測定した。
腎皮質の細断物を、免疫蛍光浅色及び脂肪滴の更なる分析のために、OCTに埋め込んだ。具体的には、切断して、WT1抗体(1:200,Santa Cruz)及びProLong GOLD DAPI固定培地で染色した4μm厚の組織断片を使用して、糸球体性断面当たりの糸球体上皮細胞の数を測定した。40倍の湿った対物レンズを備えるLeica SP5倒立顕微鏡を使用する共焦点顕微鏡法により、画像を入手した。マウス当たり20個の糸球体を定量化した。
統計。全ての値を、平均+標準偏差として表す。Prism GraphPad 7ソフトウェアを使用して統計分析を実施した。2つ以上の化合物用量を使用して、群が通常のデータ分布を示す場合、一元ANOVAを使用して結果を分析した。差が観察される場合、対照(ビヒクル)の平均を、ダネット検定を使用して各群の平均と比較した。テューキー検定を、複数の比較のために実施した。
化合物の細胞傷害性
細胞傷害性アッセイを実施して、培養したヒト糸球体上皮細胞で安全に使用可能な化合物の濃度範囲を測定した。
インビトロ実験を行い、動物研究で更に使用するための、糸球体上皮細胞内でのABCA1の機能的発現をよりよく誘発する化合物を選択した。したがって、化合物のABCA1タンパク質発現、血漿膜におけるABCA1局在化、及びApoA1が媒介するコレステロール流出における効果を研究した。
腎損傷のADRモデルは、薬剤が誘発したタンパク尿腎疾患のモデルであり、巣状分節性糸球体硬化症(FSGS)の、最も幅広く用いられた実験モデルを保持する。用量範囲を見いだす実験を、インビトロ実験で選択した化合物を用いて実施した。
未処理のCoL4a3 KOマウスは、深刻なアルブミン尿を進行させ、4週齢と8週齢の間で、高いBUN及び血清クレアチニン濃度を進行させた。これらのマウスは8週齢までにESRDに達し、その時点を超えて生残しない。
ABCA1の増加は、糸球体上皮細胞の損傷及びDKDを回復する
ABCA1を、肥満糖尿病db/dbマウスモデルにおけるDKD用の処置標的として確認することを目標とした。ABCA1の薬理学的誘導因子で処理したdb/dbマウスは、db/dbビヒクル処理したマウスと比較して、処理の2週間後(16週間)にアルブミン尿の減少を経験し、及び更に、処理の4週間後(18週間)(図12A)にも経験した。血中尿素窒素(BUN)は有意に改善されたことが判明し(図12B)、これは、db/dbマウスと比較して、ABCA1誘導因子(化合物A)処理群における、コレステロールエステルの有意な減少(図12C~D)と相関していた。腎皮質の断片を、db/dbマウス経験におけるABCA1誘導因子の処置が、WT1溶性細胞を定量化することにより測定される糸球体上皮細胞の数(図12E~F)、PAS染色断片を使用して測定したメサンギウム拡大(図12G~H)、及び、TEM画像を使用して測定した糸球体上皮細胞足突起の消滅(図12I~J)を改善したことを示した、様々な組織学的評価に使用した。
Claims (18)
- ABCA1誘導因子化合物、並びに薬学的に許容される担体及び/又はアジュバントを含む、腎疾患の処置で使用するための医薬組成物であって、
前記ABCA1誘導因子化合物が
6-(3,4-ジクロロフェニル)-N-[(1R,2R)-2-ヒドロキシシクロヘキシル]-5-(2,2,2-トリフルオロエトキシ)ピリジン-2-カルボキサミド、
5-(3,4-ジクロロ-フェニル)-N-((1R,2R)-2-ヒドロキシ-シクロヘキシル)-6-(2,2,2-トリフルオロ-エトキシ)-ニコチンアミド、
又は薬学的に許容されるその塩
である、医薬組成物。 - 前記腎疾患が慢性腎疾患、一次若しくは二次糸球体性疾患、又はタンパク尿腎疾患から選択される、請求項1に記載の医薬組成物。
- 前記糸球体性疾患がアルポート症候群又は巣状分節性糸球体硬化症である、請求項2に記載の医薬組成物。
- 前記腎疾患が糖尿病性腎疾患である、請求項1に記載の医薬組成物。
- 経口投与用に製剤化されている、請求項1~4のいずれか一項に記載の医薬組成物。
- 局所、経鼻、眼内、静脈内、筋肉内、皮下、硝子体内、髄腔内、又は経皮での投与用に製剤化されている、請求項1~5のいずれか一項に記載の医薬組成物。
- 前記ABCA1誘導因子化合物の1日の用量が20~800mg/日であるように投与される、請求項1~6のいずれか一項に記載の医薬組成物。
- 前記ABCA1誘導因子化合物の1日の用量が200mg/日である、請求項7の一項に記載の医薬組成物。
- 投与レジメンが1日1回、1日2回、1日3回、3日に1回、1週間に1回、2週間に1回、又はひと月に1回である、請求項1~8のいずれか一項に記載の医薬組成物。
- 負荷用量レジメンが、最初の7日間、14日間、又は30日間に用量を2倍にする、請求項1~9のいずれか一項に記載の医薬組成物。
- アンギオテンシン変換酵素(ACE)阻害剤薬物、RAS遮断剤;アンギオテンシン受容体遮断薬(ARB);プロテインキナーゼC(PKC)阻害剤;AGE依存性経路の阻害剤;抗炎症剤;GAG;ピリドキサミン;エンドセリンアンタゴニスト、COX-2阻害剤、PPAR-γアンタゴニスト、並びに、アミホスチン、カプトプリル、シクロホスファミド、チオ硫酸ナトリウム、トラニラスト又はシクロデキストリンなどのその他の化合物及びこれらの誘導体、ビタミンD誘導体、抗高血糖剤並びに抗高コレステロール血症剤からなる群から選択される化合物と同時、逐次的、又は個別に使用するための、請求項1~10のいずれか一項に記載の医薬組成物。
- 腎疾患の治療及び/又は予防用の医薬を調製するための、請求項1で定義されたABCA1誘導因子化合物の使用。
- 局所、経口、経鼻、眼内、静脈内、筋肉内、皮下、硝子体内、髄腔内、又は経皮の経路により投与される、請求項1に記載の医薬組成物。
- 前記投与が1日1回、1日2回、1日3回、3日に1回、1週間に1回、2週に1回、又はひと月に1回である、請求項13に記載の医薬組成物。
- 前記投与が1日1回である、請求項14に記載の医薬組成物。
- 前記ABCA1誘導因子化合物の1日の用量が20~800mg/日であるように投与される、請求項13~15に記載の医薬組成物。
- 処置に有効な量のアンギオテンシン変換酵素阻害剤又はアンギオテンシン受容体遮断剤と組み合わせて、同時に、個別に、又は逐次的に投与される、請求項13~16のいずれか一項に記載の医薬組成物。
- アンギオテンシン変換酵素(ACE)阻害剤薬物;RAS遮断剤;アンギオテンシン受容体遮断薬(ARB);プロテインキナーゼC(PKC)阻害剤;AGE依存性経路の阻害剤;抗炎症剤;GAG;ピリドキサミン;エンドセリンアンタゴニスト、COX-2阻害剤、PPAR-γアンタゴニスト、並びに、アミホスチン、カプトプリル、シクロホスファミド、チオ硫酸ナトリウム、トラニラスト又はシクロデキストリンなどのその他の化合物及びこれらの誘導体、ビタミンD誘導体、抗高血糖剤並びに抗高コレステロール血症剤からなる群から選択される処置有効量の化合物と組み合わせて同時に、個別に、又は逐次的に投与される、請求項13~16のいずれか一項に記載の医薬組成物。
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US7030146B2 (en) | 1996-09-10 | 2006-04-18 | University Of South Carolina | Methods for treating diabetic neuropathy |
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JP2016523943A (ja) | 2013-07-10 | 2016-08-12 | グラクソスミスクライン、インテレクチュアル、プロパティー、ナンバー2、リミテッドGlaxosmithkline Intellectual Property No.2 Limited | 糸球体疾患の治療に使用するためのロスマピモド |
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US20200085810A1 (en) | 2020-03-19 |
JP2021531308A (ja) | 2021-11-18 |
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CN117736141A (zh) | 2024-03-22 |
IL280368B1 (en) | 2023-10-01 |
JP2024096989A (ja) | 2024-07-17 |
CN112469442B (zh) | 2024-04-09 |
US20210275514A1 (en) | 2021-09-09 |
CN112469442A (zh) | 2021-03-09 |
WO2020021097A1 (en) | 2020-01-30 |
IL280368A (en) | 2021-03-25 |
CA3104793A1 (en) | 2020-01-30 |
TW202019486A (zh) | 2020-06-01 |
KR20210038884A (ko) | 2021-04-08 |
IL280368B2 (en) | 2024-02-01 |
EP3826679A1 (en) | 2021-06-02 |
MX2021000976A (es) | 2021-03-31 |
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