JP7013464B2 - 巣状分節性糸球体硬化症を治療する方法 - Google Patents
巣状分節性糸球体硬化症を治療する方法 Download PDFInfo
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- JP7013464B2 JP7013464B2 JP2019527910A JP2019527910A JP7013464B2 JP 7013464 B2 JP7013464 B2 JP 7013464B2 JP 2019527910 A JP2019527910 A JP 2019527910A JP 2019527910 A JP2019527910 A JP 2019527910A JP 7013464 B2 JP7013464 B2 JP 7013464B2
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- 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
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- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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Description
R1は、ハロゲンまたはC1~6アルキルであり、
R2は、水素、ハロゲン、C1~6アルキル、C1~6アルコキシ、C1~6ハロアルキル、C1~6ハロアルコキシ、または-CNであり、
R3は、水素、ハロゲン、またはC1~6アルキルであり、
R4は、水素、ハロゲン、またはC1~6アルキルであり、
各R5は、独立して、C1~6アルキル、-OH、または-NH2であり、
nは、0、1、2、または3であり、
A1、A2、およびA3の各々は、-CH-または-N-であり、ここで、A1、A2、またはA3の少なくとも1つは-N-である)の化合物またはその薬学的に許容される塩を投与することを含む方法に関する。
[0019]本開示の化合物、組成物、方法およびプロセスを説明するとき、以下の用語は、別段の指示がない限り以下の意味を有する。
[0022]「アルケニル」は、直鎖状、環状、もしくは分枝状、またはこれらの組合せであり得る不飽和炭化水素基を指す。2~8個の炭素原子を有するアルケニル基が好ましいが、アルケニルは、8個より多い炭素原子を有することができる。アルケニル基は、1、2または3つの炭素-炭素二重結合を含有することができる。アルケニル基の例には、エテニル、n-プロペニル、イソプロペニル、n-ブタ-2-エニル、n-ヘキサ-3-エニル、シクロヘキセニル、シクロペンテニルなどが含まれる。アルケニル基は、別段の指示がない限り非置換である。
[0026]「ハロアルキル」は、置換アルキル基として、最も典型的には1~3個のハロゲン原子で置換されているモノハロアルキルまたはポリハロアルキル基を指す。例には、1-クロロエチル、3-ブロモプロピル、トリフルオロメチルなどが含まれる。
-NR’’’C(O)NR’R”、-NR’R”、-NR’CO2R”、-NR’S(O)R”、-NR’S(O)2R’’’、
-NR’’’S(O)NR’R”、-NR’’’S(O)2NR’R”、-SR’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、
-NR’-C(NHR”)=NR’’’、-SiR’R”R’’’、-N3、置換または非置換C6~10アリール、置換または非置換5~10員ヘテロアリール、および置換または非置換3~10員ヘテロシクリルが含まれる。可能な置換基の数は0~(2m’+1)の範囲であり、ここで、m’はそのような基の炭素原子の全数である。
-NR’’’C(O)NR’R”、-NR’R”、-NR’CO2R”、-NR’S(O)R”、-NR’S(O)2R”、
-NR’’’S(O)NR’R”、-NR’’’S(O)2NR’R”、-SR’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、
-NR’-C(NHR”)=NR’’’、-SiR’R”R’’’、-N3、置換または非置換C1~8アルキル、置換または非置換C2~8アルケニル、置換または非置換C2~8アルキニル、置換または非置換C6~10アリール、置換または非置換5~10員ヘテロアリール、および置換または非置換3~10員ヘテロシクリルが含まれる。可能な置換基の数は、0~芳香族環系の空いている原子価の全数の範囲である。
[0035]「天然の同位体存在度を超える」は、自然に測定された化学元素の同位体の存在度を指す。
[0037]「薬学的に許容される塩」は、哺乳動物などの患者への投与に許容される塩(例えば、所定の投与量レジメンにおいて哺乳動物に許容される安全性を有する塩)を指す。そのような塩は、本明細書に記載されている化合物に見出される特定の置換基に応じて、薬学的に許容される無機または有機塩基から、および薬学的に許容される無機または有機酸から誘導され得る。本開示の化合物が比較的酸性の官能基を含有する場合、塩基付加塩は、そのような化合物の中性形態を十分な量の所望の塩基と、未希釈で(neat)、または適切な不活性溶媒中において接触させることによって得ることができる。薬学的に許容される無機塩基から誘導される塩には、アルミニウム、アンモニウム、カルシウム、銅、第二鉄、第一鉄、リチウム、マグネシウム、マンガン、第一マンガン、カリウム、ナトリウム、亜鉛などの塩が含まれる。薬学的に許容される有機塩基から誘導される塩には、アルギニン、ベタイン、カフェイン、コリン、N,N’-ジベンジルエチレンジアミン、ジエチルアミン、2-ジエチルアミノエタノール、2-ジメチルアミノエタノール、エタノールアミン、エチレンジアミン、N-エチルモルホリン、N-エチルピペリジン、グルカミン、グルコサミン、ヒスチジン、ヒドラバミン、イソプロピルアミン、リシン、メチルグルカミン、モルホリン、ピペラジン、ピペリジン、ポリアミン樹脂、プロカイン、プリン、テオブロミン、トリエチルアミン、トリメチルアミン、トリプロピルアミン、トロメタミンなど、置換アミン、環状アミン、天然に生じるアミンなどを含む第一級、第二級、第三級、および第四級アミンの塩が含まれる。本開示の化合物が比較的塩基性の官能基を含有する場合、酸付加塩は、そのような化合物の中性形態を十分な量の所望の酸と、未希釈で、または適切な不活性溶媒中において接触させることによって得ることができる。薬学的に許容される酸から誘導される塩には、酢酸、アスコルビン酸、ベンゼンスルホン酸、安息香酸、カンホスルホン酸、クエン酸、エタンスルホン酸、フマル酸、グルコン酸、グルコロン酸、グルタミン酸、馬尿酸、臭化水素酸、塩酸、イセチオン酸、乳酸、ラクトビオン酸、マレイン酸、リンゴ酸、マンデル酸、メタンスルホン酸、粘液酸、ナフタレンスルホン酸、ニコチン酸、硝酸、パモ酸、パントテン酸、リン酸、コハク酸、硫酸、酒石酸、p-トルエンスルホン酸の塩などが含まれる。
[0042]本明細書において使用されるとき「治療すること」または「治療」は、哺乳動物などの患者(特に、ヒトまたは愛玩動物)において疾患または医学的状態を治療することまたはその治療であって、患者において疾患または医学的状態を改善すること、すなわち疾患または医学的状態をなくすまたはその退行を引き起こすこと;患者において疾患または医学的状態を抑制すること、例えば疾患または医学的状態の発生を遅らせるまたは停止すること;あるいは患者において疾患または医学的状態の症状を軽減すること;あるいは疾患が発生するのを予防することを含む、治療することまたは治療を指す。
[0044]「UAER」は、尿中アルブミン排出速度を指す。
[0045]本発明のある特定の化合物は、水和形態を含む溶媒和形態と同様に、非溶媒和形態として存在していてよい。一般に、溶媒和形態と非溶媒和形態は、両方とも、本開示の範囲内に包含されることが意図される。
FSGSを治療する方法
[0048]本開示は、患者においてFSGSを治療する方法であって、それを必要とする患者に有効量の式(Ia):
[0050]Ar1は、置換または非置換C6~10アリールおよび置換または非置換5~10員ヘテロアリールからなる群から選択され、
[0051]R1aは、水素、置換または非置換C1~8アルキル、置換または非置換C2~6アルケニル、置換または非置換C2~6アルキニル、および置換または非置換3~10員ヘテロシクリルからなる群から選択され、
[0052]Y1は、-CR2a-、-N-、および-N+(O)--からなる群から選択され、
[0053]Y2は、-CR2b-、-N-、および-N+(O)--からなる群から選択され、
[0054]Y3は、-CR2c-、-N-、および-N+(O)--からなる群から選択され、
[0055]R2a、R2b、およびR2cはそれぞれ独立して、水素、ハロゲン、-CN、-C(O)R3a、-CO2R3a、-C(O)NR3aR4a、
-OR3a、-OC(O)R3a、-OC(O)NR3aR4a、-SR3a、-S(O)R3a、-S(O)2R3a、
-S(O)2NR3aR4a、-NO2、-NR3aR4a、-NR3aC(O)R4a、-NR3aC(O)OR4a、
-NR3aS(O)2R4a、-NR3aC(O)NR4aR5a、置換または非置換C1~8アルキル、置換または非置換C2~8アルケニル、置換または非置換C2~8アルキニル、置換または非置換3~10員ヘテロシクリル、置換または非置換C6~10アリール、および置換または非置換5~10員ヘテロアリールからなる群から選択され、
[0056]R3a、R4a、およびR5aはそれぞれ独立して、水素、置換または非置換C1~8アルキル、置換または非置換C2~8アルケニル、置換または非置換C2~8アルキニル、置換または非置換C6~10アリール、置換または非置換5~10員ヘテロアリール、および置換または非置換3~10員ヘテロシクリルからなる群から選択され、
[0057]R3aおよびR4a、R4aおよびR5a、またはR3aおよびR5aは、それらが結合している原子と一緒になって、置換または非置換5、6、または7員環を形成することができ、
[0058]Lは、結合、-O-、-S-、-S(O)-、-S(O)2-、-CR6R7-、-NR8-、-C(O)-および-NR8C(O)-からなる群から選択され、
[0059]R6およびR7はそれぞれ独立して、水素、ハロゲン、置換または非置換C1~8アルキル、置換または非置換3~10員ヘテロシクリル、置換または非置換C2~6アルケニル、置換または非置換C2~6アルキニル、-CN、-OR9、-NR10R11、-S(O)R9、および-S(O)2R9からなる群から選択され、
[0060]R6およびR7は、それらが結合している炭素原子と一緒になって、置換もしくは非置換C3~8シクロアルキルまたは置換もしくは非置換3~10員ヘテロ環状環を形成することができ、
[0061]R9は、水素、置換または非置換C1~8アルキル、置換または非置換C2~8アルケニル、置換または非置換C2~8アルキニル、置換または非置換C6~10アリール、置換または非置換5~10員ヘテロアリール、および置換または非置換3~10員ヘテロシクリルからなる群から選択され、
[0062]R10およびR11はそれぞれ独立して、置換または非置換C1~8アルキル、置換または非置換3~10員ヘテロシクリル、置換または非置換C6~10アリール、置換または非置換5~10員ヘテロアリール、置換または非置換C2~8アルケニル、および置換または非置換C2~8アルキニルからなる群から選択され、
[0063]-NR10R11のR10およびR11は、窒素と一緒になって、置換もしくは非置換C3~8シクロアルキルまたは置換もしくは非置換3~10員ヘテロシクリルを形成することができ、
[0064]R8は、水素、C(O)R12、S(O)2R12、CO2R12、置換または非置換C1~8アルキル、置換または非置換3~10員ヘテロシクリル、置換または非置換C2~6アルケニル、および置換または非置換C2~6アルキニルからなる群から選択され、
[0065]R12は、置換または非置換C1~8アルキル、置換または非置換C2~6アルケニル、置換または非置換C2~6アルキニル、置換または非置換3~10員ヘテロシクリル、置換または非置換C6~10アリール、および置換または非置換5~10員ヘテロアリールからなる群から選択され、
[0066]Z1は、置換または非置換C6~10アリール、置換または非置換5~10員ヘテロアリール、置換または非置換3~10員ヘテロシクリル、および-NR13R14からなる群から選択され、
[0067]R13およびR14はそれぞれ独立して、水素、置換または非置換C1~8アルキル、置換または非置換C2~8アルケニル、置換または非置換C2~8アルキニル、置換または非置換3~10員ヘテロシクリル、置換または非置換C6~10アリール、置換または非置換5~10員ヘテロアリール、置換または非置換(C1~4アルキル)-(C6~10アリール)、および置換または非置換(C1~4アルキル)-(5~10員ヘテロアリール)からなる群から選択され、
[0068]R13およびR14は、窒素と一緒になって、置換または非置換4、5、6、または7員ヘテロシクリルを形成することができ、
[0069]Y4は、-N-および-N+(O)--からなる群から選択される)の化合物またはその薬学的に許容される塩を投与することを含む方法を提供する。
[0072]R65は、水素、置換または非置換C1~4アルキル、および置換または非置換-SO2(フェニル)からなる群から選択され、
[0073]R60は、-NR61CH2CH2OR62、-NR61CH2CH2NR63R64、-NR61CH2CH2SR62、
[0074]ここで、R61は、水素および置換または非置換フェニルからなる群から選択され、
[0075]R62は、置換または非置換フェニル、および置換または非置換C1~4アルキルからなる群から選択され、
[0076]R63およびR64はそれぞれ独立して、水素、置換または非置換C1~8アルキル、置換または非置換フェニル、置換または非置換-SO2(フェニル)、-C(O)CH3、-C(O)C(O)OH、および-C(O)2C(CH3)3からなる群から選択される)の化合物は、式(Ia)から除外される。
[0078]一部の実施形態において、Lは-C(O)-である。
[0081]一部の実施形態において、Ar1は、置換または非置換C6~10アリールである。一部の実施形態において、Ar1は、ハロゲン、C1~6アルキルおよびC1~6ハロアルキルから選択される1~3つの置換基で置換されているC6~10アリールである。一部の実施形態において、Ar1は、ハロゲン、C1~3アルキルおよびC1~3ハロアルキルから選択される1~3つの置換基で置換されているフェニルである。
[0083]一部の実施形態において、Z1は、置換または非置換5~10員ヘテロアリールであり、Lは-C(O)-であり、Y1は-CR2a-であり、Y2は-CR2b-であり、Y3は-CR2c-であり、R2a、R2b、およびR2cはそれぞれ独立して、水素、ハロゲン、置換または非置換C1~8アルキルからなる群から選択され、R1aは、水素または置換または非置換C1~8アルキルからなる群から選択され、Ar1は、置換または非置換C6~10アリールであり、Y4は-N-である。
[0087]R1は、ハロゲンまたはC1~6アルキルであり、
[0088]R2は、水素、ハロゲン、C1~6アルキル、C1~6アルコキシ、C1~6ハロアルキル、C1~6ハロアルコキシ、または-CNであり、
[0089]R3は、水素、ハロゲン、またはC1~6アルキルであり、
[0090]R4は、水素、ハロゲン、またはC1~6アルキルであり、
[0091]各R5は、独立して、C1~6アルキル、-OH、または-NH2であり、
[0092]nは、0、1、2、または3であり、
[0093]A1、A2、およびA3の各々は、-CH-または-N-であり、ここで、A1、A2、またはA3の少なくとも1つは-N-である)の化合物またはその薬学的に許容される塩を投与することを含む方法も提供する。
R2は、ハロゲンまたはC1~3ハロアルキルであり、
R3は、ハロゲンまたはC1~3アルキルであり、
R4は水素であり、
nは、0であり、
A2は、-CH-であり、
A3は、-N-である。
[0096]一部の実施形態において、化合物は、下記:
[0097]一部の実施形態において、化合物は、下記:
[0098]一部の実施形態において、FSGSを治療する方法は、FSGSの症状または合併症を予防する、低減するまたはなくすことを含む。
[0100]一部の実施形態において、FSGSは、一次性FSGSである。
[0104]一部の実施形態において、化合物またはその薬学的に許容される塩は、1日2回投与される。
[0106]一部の実施形態において、化合物またはその薬学的に許容される塩は、いずれか他の治療用化合物と一緒に投与されない。一部の実施形態において、化合物またはその薬学的に許容される塩は、いずれか他の治療用化合物と同時にまたは連続的に投与されない。一部の実施形態において、化合物またはその薬学的に許容される塩は、単独で投与される。一部の実施形態において、化合物またはその薬学的に許容される塩は、アンギオテンシン受容体II遮断剤(ARB)と投与されない。一部の実施形態において、化合物またはその薬学的に許容される塩は、アンギオテンシン受容体II遮断剤(ARB)と同時にまたは連続的に投与されない。
[0110]一部の実施形態において、化合物またはその薬学的に許容される塩は、アンギオテンシン受容体II遮断剤(ARB)と同時にまたは連続的に投与される。
[0117]一部の実施形態において、1種または複数の追加の治療用化合物は、同時にまたは連続的に投与される。
CCR2活性を調節する化合物
[0119]本開示は、CCR2活性を調節する化合物を提供する。ケモカイン受容体は、ケモカインなどの細胞外リガンドと相互作用する膜内在性タンパク質であり、リガンドに対する細胞応答、例えば、走化性、細胞内カルシウムイオン濃度の増加などを媒介する。したがって、ケモカイン受容体機能の調節、例えば、ケモカイン受容体リガンド相互作用の干渉は、ケモカイン受容体媒介応答を調節し、ケモカイン受容体媒介状態または疾患を治療または予防する。ケモカイン受容体機能の調節には、機能の誘導と阻害の両方が含まれる。達成される調節の種類は、化合物の特性、すなわち、アンタゴニスト、または完全、部分的、もしくは逆アゴニストに応じて決まる。
組成物
[0123]本開示は、それを必要とする患者において、巣状分節性糸球体硬化症(FSGS)を治療するための式I、式(Ia)の化合物、化合物1、化合物2または化合物3を含む薬学的に許容される組成物の投与を企図する。薬学的に許容される組成物は、1種または複数の追加の治療用化合物を含んでもよい。1種または複数の追加の治療用化合物は、FSGSまたは腎疾患を治療する際に有効性を有する化合物から選択され得る。
CCR2モジュレーター
[0142]以下の例は、本開示を例示するものであって、限定するものではない。
追加の組合せ
[0146]本開示の化合物は、単独で、あるいはFSGSを治療するための1種または複数の他の薬物と共に供給され得る。
キットおよびパッケージ
[0150]用語「キット」および「医薬キット」は、1つまたは複数の適当な容器に、1種または複数の医薬組成物およびそれらの使用説明書を含む市販のキットまたはパッケージを指す。一実施形態において、式(I)もしくは(Ia)の化合物、または化合物1、2もしくは3、あるいはそれらの薬学的に許容される塩、およびその投与説明書を含むキットが提供される。一実施形態において、式(I)もしくは(Ia)の化合物、または化合物1、2もしくは3、あるいはそれらの薬学的に許容される塩を、1種または複数(例えば、1、2、3種、1または2種、または1~3種)の追加の治療剤と組み合わせて、それらの投与説明書と含むキットが提供される。
他の疾患
[0152]単独でまたは組み合わせて使用される、式(I)、(Ia)の化合物、化合物1、化合物2もしくは化合物3、またはそれらの薬学的に許容される塩および/もしくはプロドラッグ、あるいはそれらの組成物は、他の疾患を治療するのに有用であり得る。これらの疾患には、慢性腎疾患、糖尿病性腎症、末期腎疾患、糸球体疾患、グッドパスチャー症候群、糸球体腎炎、糸球体硬化症、IgA腎症、膜性増殖性糸球体腎炎、膜性糸球体腎炎、ウェゲナー肉芽腫症、血管炎、Anca血管炎、腎不全、腎線維症、バーター病、腎石灰沈着症、水腎症、膿腎症、肝腎症候群、溶血性尿毒症症候群、腎炎、尿崩症、腎性尿崩症、腎不全、神経原性尿崩症、ウルフラム症候群、ネフローゼ症候群、微小変化型疾患、腎周囲炎、デント病、ギテルマン症候群、腎硬化症、腎尿細管疾患(Renal tubule disease)、肝腎症候群、高窒素血症、尿毒症、アルポート症候群、糸球体腎炎、ループス腎炎、腎盂炎、腎盂腎炎、腎盂膀胱炎、糸球体傷害、多発性嚢胞腎、後天性多発性嚢胞腎、常染色体性優性多発性嚢胞腎、常染色体性劣性多発性嚢胞腎、アブデルハルデン・カウフマン・リグナック症候群(腎性シスチン症)、腹部コンパートメント症候群、アセトアミノフェン起因性腎毒性(acetaminophen-induced Nephrotoxicity)、急性腎不全、急性腎傷害、急性大葉性腎炎(acute Lobar Nephronia)、急性リン酸腎症、急性尿細管壊死、アデニンホスホリボシル転移酵素欠損症、アデノウイルス腎炎、アルポート症候群、アミロイドーシス、血管筋脂肪腫、鎮痛薬腎症、抗リン脂質抗体症候群、抗TNF-α療法関連糸球体腎炎、APOL1変異、見かけの鉱質コルチコイド過剰症候群、アリストロキア酸腎症、漢方薬腎症、バルカン風土性腎症、ビート尿、β-サラセミア腎疾患、胆汁円柱腎症、自然腎におけるBKポリオーマウイルス腎症、膀胱括約筋協調不全、膀胱タンポナーデ、越境者腎症(border-Crossers’ Nephropathy)、バーボンウイルスおよび急性腎傷害、急性腎機能障害、バイエッタ、C1q腎症、カンナビノイド悪阻急性腎不全(cannabinoid Hyperemesis Acute Renal Failure)、心腎症候群、カルフィルゾミブ起因性腎傷害(carfilzomib-Indiced Renal Injury)、CFHR5腎症、糸球体症を伴うシャルコー・マリー・トゥース病、コレステロール塞栓症(cholesterol Emboli)、チャーグ・ストラウス症候群、乳び尿、コリスチン腎毒性、膠原線維糸球体症、虚脱性糸球体症、CMVに関連する虚脱性糸球体症、先天性ネフローゼ症候群、腎錐体症候群(マインツァー・サルディノ症候群またはサルディノ・マインツァー病)、造影剤腎症、硫酸銅中毒(copper Sulpfate Intoxication)、腎皮質壊死、クリゾチニブ関連急性腎傷害、クリオグロブリン血症(cryoglobuinemia)、結晶グロブリン起因性腎症(crystalglobulin-Induced Nephropathy)、嚢胞性腎疾患、後天性シスチン尿症、デンスデポジット病、透析不均衡症候群、糖尿病性腎疾患、びまん性メサンギウム硬化症、重複尿管、EAST症候群、エルトハイム・チェスター病、ファブリー病、家族性低カルシウム尿性高カルシウム血症、ファンコニー症候群、フレイザー症候群、フィブロネクチン糸球体症、細線維性糸球体腎炎およびイムノタクトイド糸球体症、フレーリー症候群、巣状硬化症、巣状糸球体硬化症、ギャロウェイ・モワト症候群、腎関与を伴う巨細胞性(側頭)動脈炎、糸球体尿細管逆流症、糖尿症、ハンタウイルス感染ポドサイト障害(hantavirus Infection Podocytopathy)、熱ストレス腎症、血尿、非典型溶血性尿毒症症候群(aHUS)、血球貪食症候群、出血性膀胱炎、流行性腎症(nephropathis Epidemica)、ヘモジデリン尿症、ヘモジデリン沈着症、糸球体症、肝性糸球体症(hepathic glomerulopathy)、肝静脈閉塞性疾患、類洞閉塞症候群、C型肝炎関連腎疾患、肝腎症候群、HIV関連腎症(HIVAN)、HNF1B関連常染色体性優性尿細管間質性腎疾患、馬蹄腎(腎融合)、ハナー潰瘍、高アルドステロン症、高カルシウム血症、高カリウム血症、高マグネシウム血症、高ナトリウム血症、高シュウ酸尿症、高リン血症、低カルシウム血症、低補体血症性蕁麻疹様血管炎症候群、低カリウム血症、低カリウム血症起因性腎機能障害、低カリウム血性周期性四肢麻痺、低マグネシウム血症、低ナトリウム血症、低リン血症、IgA腎症、IgG4腎症、免疫チェックポイント療法関連間質性腎炎、間質性膀胱炎、有痛性膀胱症候群、間質性腎炎、アイブマーク症候群、ケタミン関連膀胱機能不全、腎結石、腎石症、コンブチャ茶毒性、鉛腎症および鉛関連腎毒性、レプトスピラ症腎疾患、軽鎖沈着疾患、単クローン性免疫グロブリン沈着疾患、リドル症候群、ライトウッド・アルブライト症候群、リポタンパク質糸球体症、リチウム腎毒性、LMX1B変異により発症する遺伝性FSGS(LMX1B Mutations Cause Hereditary FSGS)、腰腹痛血尿、ループス、全身性エリテマトーデス、ループス腎疾患、ループス腎炎、抗好中球細胞質抗体血清陽性を示すループス腎炎、ループスポドサイト障害、ライム病関連糸球体腎炎、リゾチーム腎症、マラリア腎症、悪性腫瘍関連腎疾患、悪性高血圧症、マラコプラキア、外尿道口狭窄、髄質性嚢胞腎疾患、ウロモジュリン関連腎症、若年性高尿酸血症性腎症1型、海綿腎、巨大尿管、メラミン毒性および腎臓、膜性増殖性糸球体腎炎、膜性腎症、マスクされたIgGκ沈着物を伴う膜様性糸球体症(Membranous-like Glomerulopathy with Masked igG kappa Deposits)、中央アメリカ腎症、代謝性アシドーシス、代謝性アルカローシス、メトトレキサート関連腎不全、顕微鏡的多発性血管炎、ミルク・アルカリ症候群(Milk-alkalai syndrome)、微小変化型疾患、MDMA(Molly;Ecstacy;3,4-メチレンジオキシメタンフェタミン)および腎不全、MUC1腎症、多嚢胞性異形成腎、多発性骨髄腫、骨髄増殖性腫瘍および糸球体症、爪膝蓋骨症候群、腎石灰沈着症、腎性全身性線維症、腎下垂症(遊走腎、腎下垂)、ネフローゼ症候群、過敏膀胱、結節性糸球体硬化症、非淋菌性尿道炎、ナットクラッカー症候群、寡巨大糸球体症、口顔面指症候群、オロト酸尿症、起立性低血圧、起立性タンパク尿、浸透圧利尿、浸透圧ネフローゼ、卵巣過剰刺激症候群、シュウ酸腎症、ページ腎、乳頭壊死、乳頭腎症候群(腎コロボーマ症候群、孤立性腎低形成)、腹膜腎症候群(peritoneal-Renal Syndrome)、後部尿道弁、感染後糸球体腎炎、連鎖球菌感染後糸球体腎炎、結節性多発動脈炎、多発性嚢胞腎、後部尿道弁、子癇前症、プロポフォール注入症候群、単クローン性IgG沈着物を伴う増殖性糸球体腎炎(Nasr病)、プロポリス関連腎不全、タンパク尿、偽性高アルドステロン症、偽性低重炭酸血症(pseudohypobicarbonatemia)、偽性副甲状腺機能低下症、肺腎症候群、腎盂腎炎、膿腎症、放射線性腎症、リフィーディング症候群、逆流性腎症、急速進行性糸球体腎炎、腎膿瘍、腎周囲膿瘍(Peripnephric Abscess)、腎無発生、腎弓状静脈微小血栓関連急性腎傷害、腎動脈瘤、腎動脈狭窄、腎細胞がん、腎嚢胞、運動誘発性急性腎不全を伴う腎性低尿酸血症、腎梗塞、腎性骨異栄養症、腎尿細管性アシドーシス、レニン変異および常染色体性優性尿細管間質性腎疾患、レニン分泌腫瘍(傍糸球体細胞腫)、リセットオスモスタット、大静脈後尿管、後腹膜線維症、横紋筋融解症、肥満外科手術(Bariatric Sugery)に関連した横紋筋融解症、関節リウマチ関連腎疾患、サルコイドーシス腎疾患、塩喪失、住血吸虫症および糸球体疾患、シムケ型免疫不全性骨異形成症、強皮症腎クリーゼ、蛇紋石腓骨多発性嚢胞腎症候群、エクスナー症候群、鎌状赤血球腎症、シェーグレン症候群、合成カンナビノイド使用および急性腎傷害、造血細胞移植後の腎疾患、幹細胞移植に関連した腎疾患、菲薄基底膜病、良性家族性血尿、膀胱三角部炎、結核、結節性硬化症、尿細管形成不全、近位尿細管刷子縁に対する自己抗体に帰因する免疫複合体性尿細管間質性腎炎、腫瘍崩壊症候群、尿毒症、尿毒症性視神経症、嚢胞性尿管炎、尿管瘤、尿道カルンクル、尿道狭窄、尿失禁、尿路感染症、尿路閉塞、ウロモジュリン関連腎疾患、血管運動性腎症、膀胱腸瘻、膀胱尿管逆流、フォンヒッペル・リンダウ病、ワルデンシュトレームマクログロブリン血症糸球体腎炎、ワルファリン関連腎症、ヴェーゲナー肉芽腫症、多発性血管炎を伴う肉芽腫症、ウエストナイルウイルス、ヴンダーリッヒ症候群、ツェルウェガー症候群、脳肝腎症候群、黒色腫、膠芽腫、食道腫瘍、上咽頭癌、ブドウ膜黒色腫、リンパ腫、リンパ球性リンパ腫、原発性CNSリンパ腫、T細胞リンパ腫、びまん性大細胞型B細胞性リンパ腫、縦隔原発大細胞型B細胞性リンパ腫、前立腺がん、去勢抵抗性前立腺がん、慢性骨髄球性白血病、カポジ肉腫、線維肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫、血管肉腫、リンパ管肉腫、滑膜腫、髄膜腫、平滑筋肉腫、横紋筋肉腫、軟部組織の肉腫、肉腫、敗血症、胆管腫瘍、基底細胞癌、胸腺新生物、甲状腺のがん、副甲状腺のがん、子宮がん、副腎のがん、肝臓感染症、メルケル細胞癌、神経腫瘍、濾胞中心リンパ腫、結腸がん、ホジキン病、非ホジキンリンパ腫、白血病、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ芽球性白血病、慢性リンパ性白血病を含む、慢性または急性白血病、多発性骨髄腫、卵巣腫瘍、骨髄異形成症候群、皮膚または眼内悪性黒色腫、腎細胞癌、小細胞肺がん、肺がん、中皮腫、乳がん、扁平上皮非小細胞肺がん(SCLC)、非扁平上皮NSCLC、結腸直腸がん、卵巣がん、胃がん、肝細胞癌、膵癌、膵がん、膵管腺癌、頭頸部の扁平上皮癌、頭部または頚部のがん、消化管のがん、胃がん、骨がん、皮膚がん、直腸がん、肛門部のがん、精巣がん、ファロピウス管の癌腫、子宮内膜の癌腫、頸部の癌腫、腟の癌腫、外陰部の癌腫、食道がん、小腸がん、内分泌系のがん、尿道のがん、陰茎のがん、膀胱のがん、腎臓のがん、尿管のがん、腎盂の癌腫、中枢神経系(CNS)の新生物、腫瘍血管新生、脊髄軸腫瘍、脳幹グリオーマ、下垂体腺腫、類表皮がん、石綿肺(abestosis)、癌腫、腺癌、乳頭癌、嚢胞腺癌、気管支癌、腎細胞癌、移行上皮癌、絨毛癌、セミノーマ、胎児性癌、ウィルムス腫瘍、多形性腺腫、肝細胞乳頭腫、腎管状腺腫、嚢腺腫、乳頭腫、腺腫、平滑筋腫、横紋筋腫、血管腫、リンパ管腫、骨腫、軟骨腫、脂肪腫および線維腫が含まれるが、これらに限定されない。これらの疾患のいずれに対しても、本開示の化合物は、本開示で開示された治療剤を含む、他の治療剤と組み合わされ得る。
5/6残存腎モデル
[0154]5/6残存腎129X1/SvJマウスは、Jackson Laboratoriesから得た。マウスには、標準固形飼料を常用させ、自由に水を摂取させた。2段階で、マウス手術を行った。イソフルラン麻酔下、左腎塊の2/3を解剖した。7~10日後、右片側腎摘出を行った。5/6腎摘出6週間後に、マウスを研究のためにランダム化した。化合物3およびそのビヒクルを1%HPMCで製剤化して、100mg/kgで1日1回皮下投与した。各群について6匹の動物を使用した。
[0157]図2は、化合物3が、5/6残存腎モデルにおいて腎間質マクロファージの数を低減することを示す。
[0159]図4は、化合物3が、5/6残存腎モデルにおいてタコ足細胞数を増加させたことを示す。
[0161]図6は、化合物3が、5/6残存腎モデルにおいてメサンギウム融解を有する糸球体の百分率に有用性のある効果を与えることを示す。
実施例2
アドリアマイシン腎症モデル
[0163]実験を雌Balb/cマウス(Jackson Laboratories)において行った。マウスには、標準固形飼料を常用させ、自由に水を摂取させた。7.5mg/kgのアドリアマイシン(Selleck Chemicals)または生理食塩水(対照)を、0日目に、イソフルラン麻酔をかけた動物に尾静脈注射した。化合物1およびそのビヒクル(1%HPMC)を1%HPMCで製剤化して、90mg/kgで1日1回皮下投与した。カンデサルタンおよびそのビヒクル(H2O)を1日1回経口投与した。各群について12匹の動物を使用した。
[0166]図9は、化合物1がカンデサルタン(CST)と組み合わされて、UAERレベルの低減を引き起こすことを示す。
組合せ治療を用いた5/6残存腎モデル
[0167]5/6残存腎129X1/SvJマウスは、Jackson Laboratoriesから得た。マウスには、標準固形飼料を常用させ、自由に水を摂取させた。マウス手術を2段階で行った。イソフルラン麻酔をかけて、左腎塊の2/3を解剖した。7~10日後、右片側腎摘出を行った。5/6腎摘出3~6週間後に、マウスを研究のためにランダム化した(1群当たりn=12匹)。化合物3およびそのビヒクルを1%HPMCで製剤化して、100mg/kgで1日1回皮下投与した。カンデサルタン(AK Scientific)およびそのビヒクル(H2O)を、5mg/kgで1日1回経口投与した。1群当たり2匹の動物を1、2、および3週目に安楽死させて、組織学的検査およびIHCを行った。
[0172]化合物2は、下記:
[0173]化合物3は、下記:
[0174]観察された特異的な薬理学的反応は、選択された特定の活性化合物、または医薬担体が存在するか、否か、ならびに用いられる製剤の種類および投与様式に従って、また応じて変わることがあり、結果におけるそのような予測される変動または差異は、本開示の実施において考慮される。
態様1
それを必要とする患者において巣状分節性糸球体硬化症(FSGS)を治療する方法であって、患者に有効量の式I:
R 1 は、ハロゲンまたはC 1~6 アルキルであり、
R 2 は、水素、ハロゲン、C 1~6 アルキル、C 1~6 アルコキシ、C 1~6 ハロアルキル、C 1~6 ハロアルコキシ、または-CNであり、
R 3 は、水素、ハロゲン、またはC 1~6 アルキルであり、
R 4 は、水素、ハロゲン、またはC 1~6 アルキルであり、
各R 5 は、独立して、C 1~6 アルキル、-OH、または-NH 2 であり、
nは、0、1、2、または3であり、
A 1 、A 2 、およびA 3 の各々は、-CH-または-N-であり、ここで、A 1 、A 2 、またはA 3 の少なくとも1つは-N-である)の化合物またはその薬学的に許容される塩を投与することを含む方法。
態様2
R 1 が、ハロゲンまたはメチルであり、
R 2 が、ハロゲンまたはC 1~3 ハロアルキルであり、
R 3 が、ハロゲンまたはC 1~3 アルキルであり、
R 4 が、水素であり、
nが、0であり、
A 2 が、-CH-であり、
A 3 が、-N-である、
態様1に記載の方法。
態様3
化合物が、下記:
態様4
化合物が、下記:
態様5
化合物が、下記:
態様6
FSGSを治療する方法が、FSGSの症状または合併症を予防する、低減するまたはなくすことを含む、態様1から5のいずれか一項に記載の方法。
態様7
FSGSを治療する方法が、患者において末期腎疾患の発症を予防する、なくすまたは遅延させることを含む、態様1から6のいずれか一項に記載の方法。
態様8
FSGSが、一次性FSGSである、態様1から7のいずれか一項に記載の方法。
態様9
FSGSが、二次性FSGSである、態様1から7のいずれか一項に記載の方法。
態様10
二次性FSGSが、感染もしくはウイルス、疾患、毒素もしくは薬物への曝露、またはネフロン喪失、および過剰濾過に関連している、態様9に記載の方法。
態様11
FSGSが、HIV、鎌状赤血球症、ループス、アナボリックステロイド、ヘロインもしくはパミドロネートへの曝露、慢性腎盂腎炎および逆流、病的肥満、または糖尿病に関連している、態様10に記載の方法。
態様12
タンパク尿を減少させること、タンパク尿の増加を遅らせること、UACRを低減すること、尿中アルブミンクレアチニン比(UACR)の増加を遅らせること、UAERを減少させること、UAERの増加を遅らせること、アルブミン尿を低減すること、アルブミン尿の増加を遅らせること、糸球体タコ足細胞密度を増加させること、糸球体基底膜(GBM)肥厚を予防するまたは遅らせること、糸球体面積を減少させること、腎間質マクロファージの数を低減すること、腎組織の線維化を減少させるまたは遅らせること、腎臓における炎症を止めるまたは減少させること、マクロファージにより誘発される腎臓損傷を止めるまたは減少させること、推定糸球体濾過量(eGFR)を増加させるまたは正常化すること、eGFRの低下を弱めること、糸球体硬化を低減すること、糸球体細胞外マトリックスの拡大を止めるまたは減少させること、ヒアリン塊の沈着を止めるまたは減少させること、糸球体上皮過形成病変(EPHL)を止めるまたは低減すること、およびリンパ球浸潤を止めるまたは減少させることのうちの1つまたは複数を含む、態様1から11のいずれか一項に記載の方法。
態様13
化合物またはその薬学的に許容される塩が、経口投与される、態様1から12のいずれか一項に記載の方法。
態様14
化合物またはその薬学的に許容される塩が、1日2回投与される、態様1から13のいずれか一項に記載の方法。
態様15
化合物またはその薬学的に許容される塩が、1日1回投与される、態様1から14のいずれか一項に記載の方法。
態様16
患者に1種または複数の追加の治療用化合物を投与することをさらに含む、態様1から15のいずれか一項に記載の方法。
態様17
1種または複数の追加の治療用化合物が、抗高血圧薬、スタチン、血管拡張薬、ステロイド、細胞傷害性薬、利尿薬、非ステロイド系抗炎症薬(NSAID)、コレステロールまたはトリグリセリド低減剤、および免疫抑制薬の1種または複数から選択される、態様16に記載の方法。
態様18
1種または複数の追加の治療用化合物が、アンギオテンシン変換酵素(ACE)阻害剤およびアンギオテンシン受容体II遮断剤(ARB)からなる群から選択される、態様16に記載の方法。
態様19
1種または複数の追加の治療用化合物が、ラミプリル、ペリンドプリル、リシノプリル、ペリンドプリルアルギニン、カプトプリル、スピラプリル、キナプリル、エナラプリル、イミダプリル、ホシノプリル、ゾフェノプリル、ベナゼプリル、トランドラプリル、ベラパミル、ベナゼプリル、アムロジピン、トランドラプリル、P-003、シラザプリル、デラプリル、モエキシプリル、キナプリル、ホシノプリル、テモカプリル、ロサルタン、カンデサルタン、イルベサルタン、テルミサルタン、オルメサルタン、バルサルタン、アジルサルタン、テルミサルタン、フィマサルタン、EMA-401、アジルサルタンメドキソミルカリウム、スパルセンタン、カンデサルタンシレキセチル、オルメサルタンメドキソミル、TRV-027、ロサルタンカリウム、YH-22189、アジルサルタントリメチルエタノールアミン、アリサルタンイソプロキシル、およびエプロサルタンからなる群から選択される、態様18に記載の方法。
態様20
1種または複数の追加の治療用化合物が、Bリンパ球抗原CD20阻害剤、ナトリウムグルコース輸送体2阻害剤、T細胞表面糖タンパク質CD28阻害剤;細胞傷害性Tリンパ球タンパク質4刺激剤、38 MAPキナーゼ阻害剤、N-アセチルマンノサミンキナーゼ刺激剤、副腎皮質刺激ホルモンリガンド、インテグリンアルファ-V/ベータ-3アンタゴニスト;結合組織増殖因子リガンド阻害剤、およびTGFベータアンタゴニストからなる群から選択される、態様16に記載の方法。
態様21
1種または複数の追加の治療用化合物が、リツキシマブ、ダパグリフロジン、スパルセンタン、アバタセプト、DMX-200、プロパゲルマニウム、イルベサルタン、ロスマピモド、X-M74、Acthar Gel、VAR-200、シレンギチド、パムレブルマブ、DEX-M74、フレソリムマブ、およびSHP-627からなる群から選択される、態様16に記載の方法。
態様22
1種または複数の追加の治療用化合物が、エンドセリンET-Aアンタゴニスト、エンドセリンET-1アンタゴニスト、エンドセリンET-2アンタゴニスト、エンドセリンET-3アンタゴニスト、エンドセリンET-B1アンタゴニスト、エンドセリンET-B2アンタゴニスト、エンドセリンET-Cアンタゴニスト、Bリンパ球刺激剤リガンド阻害剤、Bリンパ球抗原CD20阻害剤、細胞傷害性Tリンパ球タンパク質4刺激剤、T細胞表面糖タンパク質CD28阻害剤、MEKK-5タンパク質キナーゼ阻害剤、結合組織増殖因子リガンド阻害剤、マンナン結合レクチンセリンプロテアーゼ2阻害剤、Sykチロシンキナーゼ阻害剤、ナトリウムグルコース輸送体2阻害剤、エリスロポエチン受容体アゴニスト、イノシン一リン酸デヒドロゲナーゼ阻害剤;C5遺伝子阻害剤、インスリン感受性改善薬、カリウムチャネル阻害剤、ミネラロコルチコイド受容体アンタゴニスト、Jak1チロシンキナーゼ阻害剤、Jakチロシンキナーゼ阻害剤、Jak2チロシンキナーゼ阻害剤、P2Y12プリン受容体アンタゴニスト、補体C5因子阻害剤、カルシニューリン阻害剤、アルドステロンアンタゴニスト、ミネラロコルチコイド受容体アンタゴニスト、レニン阻害剤、ミネラロコルチコイド受容体アンタゴニスト、FGF受容体アンタゴニスト、PDGF受容体アンタゴニスト、TGFベータアンタゴニスト、p38 MAPキナーゼ阻害剤、ミオシン刺激剤、ベータ2アドレナリン受容体アゴニスト、グルココルチコイドアゴニスト、ムスカリン受容体アンタゴニスト、アポリポタンパク質遺伝子刺激剤、シクロオキシゲナーゼ1阻害剤、バソプレシンV1アゴニスト、アンギオテンシン変換酵素2刺激剤、PPARガンマアゴニスト、プロスタノイド受容体アンタゴニスト、CX3CR1ケモカインアンタゴニスト、PDGF受容体ベータモジュレーター、ヘパリンアゴニスト、細胞外マトリックスタンパク質モジュレーター、ミネラロコルチコイド受容体アンタゴニスト、アンギオテンシン変換酵素(ACE)と中性エンドペプチダーゼ(EP)の二重阻害剤、およびジペプチジルペプチダーゼ阻害剤からなる群から選択される、態様16に記載の方法。
態様23
1種または複数の追加の治療用化合物が、INT-767、ベリムマブ、シナカルセト、リツキシマブ、ロサルタン、アバタセプト、カンデサルタン、セロンセルチブ、ミオイノシトール六リン酸、PBI-4050、OMS-721、フォスタマチニブ、イルベサルタン、カナグリフロジン、メトキシポリエチレングリコール-エポエチンベータ、ミコフェノール酸モフェチル、ALN-CC5、オビヌツズマブ、レナメジン、パルボシクリブ、ボセンタン、DM-199、ブデソニド、アミファンプリジン、アミファンプリジンリン酸塩、ダブラフェニブ、ダパグリフロジン、ダパグリフロジンプロパンジオール、コルチコトロピン、TNT-009、デフィブロチド、フィネレノン、バリシチニブ、チカグレロル、アンブリセンタン、エクリズマブ、ペグビソマント、エパルレスタット、カモスタットメシル酸塩、オクトレオチド、オクトレオチド酢酸塩、GKT-831、ウラリチド、バルドキソロン、バルドキソロンメチル、トルバプタン、オルメサルタンメドキソミル、タクロリムス、MT-3995、イルベサルタン+プロパゲルマニウム、アタシセプト、イフェトロバン、イフェトロバンナトリウム、アファチニブ、アトラセンタン、TAK-272、AST-120、フィマサルタン、GR-MD-02、CS-3150、ピルフェニドン、オメカムティブメカビル、オメカムチブ、ベクロメタゾン、ジプロピオン酸ベクロメタゾン、アパベタロン、スパルセンタン、ChronSeal、アゼリラゴン、パムレブルマブ、アテシドルセン、ガバペンチンエナカルビル、ガバペンチン、イミダプリル、センデリチド、BMP-7、GLY-230、組換えエリスロポエチン刺激タンパク質、2MD、テルリプレシン、ピリドキサミン二塩酸塩、ピリドキサミン、DEX-M74、GSK-2586881、SER-150-DN、クラゾセンタン、ブリシビモド、AKB-9778、エプトテルミンアルファ、ベナゼプリル、エムリカサン、エポプロステノール、DW-1029M、ベンダザックリシン、セリシクリブ、BPS-804、アバコパン、ALLO-ASC-DFU、SM-101、プロザリズマブ、ベラプロストナトリウム、ベラプロスト、ロスマピモド、PEG-bHb-CO、組換えヒトアルカリホスファターゼ、CXA-10、SAR-407899、BI-655088、BOT-191、スロデキシド、ボナパニターゼ、ソマトロピン、トピロキソスタット、SB-030、SHP-627、KBP-5074、EA-230、エマプチカプペゴル、フェニル酪酸ナトリウム、BB-3、Hemalb、チリラザド、ASP-8232、VPI-2690B、オクトレオチド酢酸塩、EPO-018B、トラセミド、レイン、PHN-033、エプロサルタン、KP-100IT、NCTX、ERC-124、サプロプテリン、パルナパリンナトリウム、パルナパリン、フェノルドパム、およびビタミンDからなる群から選択される、態様16に記載の方法。
態様24
患者が、体外血液浄化、同種移植、および/または幹細胞治療も施される、態様1から23のいずれか一項に記載の方法。
態様25
1種または複数の追加の治療用化合物が、同時にまたは連続的に投与される、態様16から23のいずれか一項に記載の方法。
態様26
1種または複数の追加の治療用化合物が、式Iの化合物と一緒に単一の医薬組成物として、または個別の医薬組成物として投与される、態様16から23のいずれか一項に記載の方法。
[0175]本開示の特定の実施態様が本明細書において説明され、詳細に記載されているが、本開示はそれらに限定されない。上記の詳細な記載は、本開示を例示するために提供されており、本開示のあらゆる限定を構成すると考慮されるべきではない。変更が当業者には明らかであり、本開示の精神を逸脱しない全ての変更が、添付の特許請求の範囲の範囲に含まれることが意図される。
Claims (20)
- 必要とする患者において巣状分節性糸球体硬化症(FSGS)を治療するための医薬組成物であって、式I:
R1は、ハロゲンまたはC1~6アルキルであり、
R2は、水素、ハロゲン、C1~6アルキル、C1~6アルコキシ、C1~6ハロアルキル、C1~6ハロアルコキシ、または-CNであり、
R3は、水素、ハロゲン、またはC1~6アルキルであり、
R4は、水素、ハロゲン、またはC1~6アルキルであり、
各R5は、独立して、C1~6アルキル、-OH、または-NH2であり、
nは、0、1、2、または3であり、
A1、A2、およびA3の各々は、-CH-または-N-であり、ここで、A1、A2、またはA3の少なくとも1つは-N-である)の化合物またはその薬学的に許容される塩を含む医薬組成物。 - R1が、ハロゲンまたはメチルであり、
R2が、ハロゲンまたはC1~3ハロアルキルであり、
R3が、ハロゲンまたはC1~3アルキルであり、
R4が、水素であり、
nが、0であり、
A2が、-CH-であり、
A3が、-N-である、
請求項1に記載の医薬組成物。 - FSGSが、一次性FSGSである、請求項1に記載の医薬組成物。
- FSGSが、二次性FSGSである、請求項1に記載の医薬組成物。
- 二次性FSGSが、HIV、鎌状赤血球症、ループス、アナボリックステロイド、ヘロインもしくはパミドロネートへの曝露、慢性腎盂腎炎および逆流、病的肥満、または糖尿病に関連している、請求項7に記載の医薬組成物。
- FSGSが、HIV、鎌状赤血球症、ループス、アナボリックステロイド、ヘロインもしくはパミドロネートへの曝露、慢性腎盂腎炎および逆流、病的肥満、または糖尿病に関連している、請求項1に記載の医薬組成物。
- 化合物またはその薬学的に許容される塩が、経口投与される、請求項1に記載の医薬組成物。
- 化合物またはその薬学的に許容される塩が、1日2回投与される、請求項1に記載の医薬組成物。
- 化合物またはその薬学的に許容される塩が、1日1回投与される、請求項1に記載の医薬組成物。
- 前記治療が、患者に1種または複数の追加の治療用化合物を投与することをさらに含む、請求項1に記載の医薬組成物。
- 患者が、体外血液浄化、同種移植、および/または幹細胞治療も施される、請求項1に記載の医薬組成物。
- 1種または複数の追加の治療用化合物が、同時にまたは連続的に投与される、請求項13に記載の医薬組成物。
- 必要とする患者において一次性巣状分節性糸球体硬化症(FSGS)を治療するための医薬組成物であって、式I:
R 1 は、ハロゲンまたはC 1~6 アルキルであり、
R 2 は、水素、ハロゲン、C 1~6 アルキル、C 1~6 アルコキシ、C 1~6 ハロアルキル、C 1~6 ハロアルコキシ、または-CNであり、
R 3 は、水素、ハロゲン、またはC 1~6 アルキルであり、
R 4 は、水素、ハロゲン、またはC 1~6 アルキルであり、
各R 5 は、独立して、C 1~6 アルキル、-OH、または-NH 2 であり、
nは、0、1、2、または3であり、
A 1 、A 2 、およびA 3 の各々は、-CH-または-N-であり、ここで、A 1 、A 2 、またはA 3 の少なくとも1つは-N-である)の化合物またはその薬学的に許容される塩を含む医薬組成物。 - R 1 が、ハロゲンまたはメチルであり、
R 2 が、ハロゲンまたはC 1~3 ハロアルキルであり、
R 3 が、ハロゲンまたはC 1~3 アルキルであり、
R 4 が、水素であり、
nが、0であり、
A 2 が、-CH-であり、
A 3 が、-N-である、
請求項16に記載の医薬組成物。
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CA3044621A1 (en) * | 2016-11-23 | 2018-05-31 | Chemocentryx, Inc. | Method of treating focal segmental glomerulosclerosis |
SG11202002975YA (en) | 2017-10-11 | 2020-04-29 | Chemocentryx Inc | Treatment of focal segmental glomerulosclerosis with ccr2 antagonists |
CN112441916A (zh) * | 2019-08-29 | 2021-03-05 | 广东药科大学 | 新型苯乙酸衍生物、其制备方法及其作为药物的用途 |
JP2023506768A (ja) | 2019-12-12 | 2023-02-20 | ティン セラピューティックス エルエルシー | 聴覚損失の予防及び治療のための組成物及び方法 |
CA3161516A1 (en) | 2019-12-17 | 2021-06-24 | Philip Thomas FROHLICH | Methods of treating iga nephropathy with atrasentan |
WO2021207723A2 (en) * | 2020-04-10 | 2021-10-14 | Chinook Therapeutics, Inc. | Methods of treating diabetic kidney disease |
EP4260859A4 (en) * | 2020-12-11 | 2024-05-15 | Jiangsu Hengrui Pharmaceuticals Co Ltd | APPLICATION OF A JAK INHIBITOR IN NEPHTOPATHY |
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CA3044621A1 (en) | 2018-05-31 |
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EP3544602A4 (en) | 2020-07-08 |
CN110177549A (zh) | 2019-08-27 |
EP4134080A1 (en) | 2023-02-15 |
EP3544602A1 (en) | 2019-10-02 |
WO2018098353A1 (en) | 2018-05-31 |
AU2017363299B2 (en) | 2022-12-22 |
JP2019535776A (ja) | 2019-12-12 |
RU2022102328A (ru) | 2022-04-01 |
IL266751B (en) | 2022-07-01 |
IL294410B2 (en) | 2024-02-01 |
IL294410B1 (en) | 2023-10-01 |
RU2019119129A3 (ja) | 2021-03-26 |
IL294410A (en) | 2022-08-01 |
US20200323832A1 (en) | 2020-10-15 |
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