JP2023504690A - フェニルイソキサゾリルメチレン-ナフタレン-エーテル誘導体の使用、及び医薬組成物 - Google Patents
フェニルイソキサゾリルメチレン-ナフタレン-エーテル誘導体の使用、及び医薬組成物 Download PDFInfo
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- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Description
本明細書の目的を解釈するために以下のように定義され、かつ適切な場合、単数形の用語は複数形も含み、逆もまた同様である。
R1、R2及びR3は、それぞれ独立に、H、ハロゲン、及び非置換又はハロゲン置換C1~6アルキル、及び非置換又はハロゲン置換C1~6アルコキシから選択され、条件としては、R1、R2及びR3のうちの少なくとも1つは水素ではなく、R0は非置換又はハロゲン置換C1~6アルキル、C3~6シクロアルキル、及びC4~7アルキルシクロアルキルから選択され、
X1及びX2は、独立に、H及びハロゲンから選択され、
-O-Z(酸素原子を介してナフタレン環に連結された残基Z)基はナフタレン環に連結され、ここで、Zは残基であり、5~10員アリール又はN、O及びSから選択される1つ又は複数のヘテロ原子を含有する5~10員ヘテロアリールから選択され、前記5~10員アリール又は5~10員ヘテロアリールはR4によって置換されておりかつ任意にさらにR5によって置換され、
R4は-COOH、-CH2COOH、-NHSO2CF3、-SO2NH-C1~6アルキル、-SO3H、-CONHSO2-C1~6アルキル、-CONHSO2-C3~6シクロアルキル、-CONHSO2-5~10員アリール、及びアリールをC1~6アルキルで置換した-CONHSO2-5~10員アリールから選択され、かつR5はH、C1~6アルキル、ハロゲン、C1~6ハロアルキル、-O-(C1~6アルキル)、及び-NH-(C1~6アルキル)から選択される。)
本発明の好ましい実施形態では、R1、R2及びR3は、それぞれ独立に、H、ハロゲン、及びC1~3ペルフルオロアルコキシから選択され、例えばH、Cl、F及び-O-CF3である。本発明の1つの実施形態では、R1及びR2は全てClであり、かつR3はHである。本発明の別の実施形態では、R1及びR2は全てClであり、かつR3はFである。本発明のさらなる実施形態では、R1及びR2は全てClであり、かつR3は-O-CH3である。本発明のまた別の実施形態では、R1は-O-CF3であり、かつR2及びR3は全てHである。本発明のまた別の実施形態では、R0はイソプロピル又はシクロプロピルである。
(a)式(A1)のハロゲン化合物とジナフトールを反応させ、式(A2)のエーテルを得る。反応は、極性溶媒にてアルカリと反応し、好ましくはDMF又はアセトニトリル等にて炭酸セシウム又は炭酸カリウム又は類似のアルカリと反応し、
ここで、
Xはハロゲンであり、
R1、R2及びR3は、独立に、H、ハロゲン、非置換又はハロゲン置換C1~6アルキル、及び非置換又はハロゲン置換C1~6アルコキシから選択され、条件としては、R1、R2及びR3のうちの少なくとも1つは水素ではなく、R0は非置換又はハロゲン置換C1~6アルキル、C3~6シクロアルキル、C4~7アルキルシクロアルキルから選択される。
R4は-COOH、-CH2COOH、-NHSO2CF3、-SO2NH-C1~6アルキル、-SO3H、-CONHSO2-C1~6アルキル、-CONHSO2-C3~6シクロアルキル、-CONHSO2-5~10員アリール、及びアリールをC1~6アルキルで置換した-CONHSO2-5~10員アリールから選択され、かつR5はH、C1~6アルキル、ハロゲン、及びC1~6ハロアルキルから選択され、任意により、
(c)-COOH置換基を含有する式(I)化合物をアミド化合物と反応させ、式(I)化合物のアミド化合物を得る。及び、任意により
(d)Zが-COOH及び-CH2COOHから選択されるR4によって置換された場合、当業者に公知の条件下で加水分解によりエステル前駆体を遊離酸に転化する。
(a)式(A1)ハロゲン化合物を置換ナフトール(B1)と反応させ、式(B2)のエーテルを得る。反応は極性溶媒にてアルカリと反応し、好ましくはDMF又はアセトニトリル等にて炭酸セシウム又は炭酸カリウム又は類似のアルカリと反応する。
ここで、X3はハロゲン、好ましくは臭素又はヨウ素、より好ましくは臭素である。
(a)置換ナフトール(C1)をハロゲン化合物X-Zと反応させ、式(C2)のエーテルを得て、ここで、反応は極性溶媒にてアルカリと反応し、好ましくはDMF又はアセトニトリル等にて炭酸セシウム又は炭酸カリウム又は類似のアルカリと反応する。
ここで、X4はハロゲン、好ましくは臭素又はヨウ素、より好ましくは臭素である。
(a)スキームCにおける記載と類似の条件下で、ジナフトールをハロゲン化合物X-Zと反応させ、式(C4)のエーテルを得る。
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ニコチン酸(化合物1)の製造
5-クロロ-6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ニコチン酸(化合物3)の製造
2-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)チアゾール-5-カルボン酸(化合物4)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)-5-メチルニコチン酸(化合物5)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)-N-(シクロプロピルスルホニル)ニコチンアミド(化合物6)の製造
5-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ピラジン-2-カルボン酸(化合物7)の製造
2-クロロ-6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ニコチン酸(化合物8)の製造
5-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ピコリン酸(化合物9)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)-2-メチルニコチン酸(化合物10)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ピコリン酸(化合物11)の製造
2-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)イソニコチン酸(化合物12)の製造
3-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ピコリン酸(化合物13)の製造
2-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)安息香酸(化合物14)の製造
2-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ニコチン酸(化合物15)の製造
3-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)イソニコチン酸(化合物16)の製造
6-((6-((5-シクロプロピル-3-(2-(トリフルオロメトキシ)フェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ニコチン酸(化合物17)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロ-4-フルオロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ニコチン酸(化合物18)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロ-4-メトキシフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ニコチン酸(化合物19)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)-1-フルオロナフタレン-2-イル)オキシ)ニコチン酸(化合物20)の製造
6-((1-クロロ-6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ニコチン酸(化合物21)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-1-イル)オキシ)ニコチン酸(化合物22)の製造
2-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-1-イル)オキシ)イソニコチン酸(化合物24)の製造
3-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-1-イル)オキシ)ピコリン酸(化合物25)の製造
2-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-1-イル)オキシ)-4-フルオロ安息香酸(化合物26)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-1-イル)オキシ)-2-メチルニコチン酸(化合物27)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-1-イル)オキシ)-5-メチルニコチン酸(化合物28)の製造
6-((5-クロロ-6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)-イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ニコチン酸(化合物29)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)-2-フルオロナフタレン-1-イル)オキシ)ニコチン酸(化合物30)の製造
6-((7-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ニコチン酸(化合物31)の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)-5-フルオロナフタレン-2-イル)オキシ)ニコチン酸(化合物32)の製造
6-((5-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)ニコチン酸の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)-5-フルオロナフタレン-2-イル)オキシ)-2-メチルニコチン酸の製造
6-(((7-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)-8-フルオロナフタレン-2-イル)オキシ)ニコチン酸の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)-5-フルオロナフタレン-1-イル)オキシ)-2-メチルニコチン酸の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-1-イル)オキシ)-5-メチルピコリン酸の製造
6-((2,4-ジクロロ-6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-1-イル)オキシ)ニコチン酸の製造
6-((2-クロロ-6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-1-イル)オキシ)ニコチン酸の製造
6-((1-クロロ-6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-2-イル)オキシ)-2-メチルニコチン酸の製造
2-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)-2-フルオロナフタレン-1-イル)オキシ)-4-フルオロ安息香酸の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)-2-フルオロナフタレン-1-イル)オキシ)-2-メチルニコチン酸の製造
6-((2-クロロ-6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)ナフタレン-1-イル)オキシ)-2-メチルニコチン酸の製造
6-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)-2-フルオロナフタレン-1-イル)オキシ)-5-メチルニコチン酸の製造
2-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)-2-フルオロナフタレン-1-イル)オキシ)ニコチン酸の製造
2-((6-((5-シクロプロピル-3-(2,6-ジクロロフェニル)イソオキサゾール-4-イル)メトキシ)-2-フルオロナフタレン-1-イル)オキシ)-4-フルオロ安息香酸の製造
HBV細胞における式(I)化合物の測定
PHH(初代ヒト肝細胞)測定:細胞系及び化合物による治療
PHH細胞を1.32×105細胞/ウェルの密度で48ウェルプレートに接種した。PHH細胞の接種日を0日目とした。1日目に1600GE/細胞のHBV(D型)でPHH細胞を感染させた。2日目、4日目、6日目、及び8日目に化合物を含む培地を交換した。9日目に、細胞をCCK8で処理し、培養上澄み液及び細胞を収集した。
マニュアルに従い、QIAamp96DNA血液キットを用いて培養上澄み液中のDNAを分離し、qPCRによって定量した。80μlの培養上澄み液サンプルを用いてDNAを抽出した。溶出体積を120μlとした。PCR混合物(8μl/ウェル)及びサンプル(2μl/ウェル)又はプラスミド標準品(2μl/ウェル)を384ウェル光学反応プレートに添加し、以下のプログラムを用いた:95℃で10分間、その後、95℃で15秒、60℃で1分間、40サイクル。
HBVDNA阻害百分率=(1-テストサンプルのHBVDNAコピー数/1%DMSO対照の平均HBVDNAコピー数)×100%
HBVRNA阻害百分率=(1-テストサンプルのHBVRNAコピー数/1%DMSO対照の平均HBVRNAコピー数)×100%
HBsAg阻害百分率=(1-サンプルのHBsAg数/1%DMSO対照のHBsAg数)×100%
HBeAg阻害百分率=(1-サンプルのHBeAg数/1%DMSO対照のHBeAg数)×100%
細胞活性%=サンプル値/1%DMSO値×100%。
図1、2、3に示すように、PHH測定では、化合物1、22及び27は細胞外HBVDNAHBsAg及びHBVRNAに対して用量依存的阻害作用を有する。対照としてのETVはHBVDNAを顕著に阻害したが、HBVHBsAg及びHBVRNAに対して顕著な阻害が見られなかった。
AAV/HBVマウスモデル及び化合物による治療
-28日目に尾静脈を介して5週齢雄C57BL/6マウス(上海吉輝実験動物飼育有限公司より購入)にrAAV8-1.3HBV(1×1011v.g.)を投与して感染させた。14日間、21日間後、すなわち-4日目に、顎下静脈から採血してHBVDNA及びHBsAgレベルを決定した。-4日目に、HBVDNA及びHBsAg結果に基づいてマウス40匹を選択して、5群にランダムに分けた。マウスをHBVウイルスで感染させてから28日間後、毎日経口投与により1回治療し、4週間持続した。群1には溶媒(0.5%CMC-Na、10ml/kg)、群2には陽性対照ETV(0.1mg/kg)を投与した。群3、群4及び群5には化合物33をそれぞれ10mg/kg、30mg/kg及び60mg/kg投与した。毎週顎下静脈から採血してHBVDNA、HBVRNA及びHBsAgの濃度を決定した。28日目に、心臓から採血した。
qPCRによってHBVDNAを測定した。QIAamp96DNA血液キットの取扱書に従ってマウス血漿中のDNAを分離し、qPCRによって以下のプログラムに従って定量した:95℃で10分間、その後、95℃で15秒、60℃で1分間、40サイクル。
各群の平均値±標準差を計算し、Student’st-testによって分析した。
図4に示すように、化合物33をマウスに投与してから28日間後、高用量群(60mg/kg)では、HBVDNAは溶媒群のHBVDNAよりも明らかに低い。平均には、高用量群のlog10[DNAコヒー/uL]は溶媒群のlog10[DNAコヒー/uL]よりも0.77~1.12(p<0.05)低い。
Claims (24)
- ヒト又は動物B型肝炎ウイルス感染の治療又は予防方法であって、
式(I)構造を有するフェニルイソキサゾリルメチレン-ナフタレン-エーテル誘導体、及びその薬学的に許容される塩、エステル又は立体異性体を、これを必要とするヒト又は動物に治療有効量で投与することを含む、方法。
R1、R2及びR3は、それぞれ独立に、H、ハロゲン、非置換又はハロゲン置換C1~6アルキル、及び非置換又はハロゲン置換C1~6アルコキシから選択され、条件としては、R1、R2及びR3のうちの少なくとも1つは水素ではなく、R0は非置換又はハロゲン置換C1~6アルキル、C3~6シクロアルキル、及びC4~7アルキルシクロアルキルから選択され、
X1及びX2は、独立に、H及びハロゲンから選択され、
-O-Z基はナフタレン環に連結され、ここで、Zは残基であり、5~10員アリール又はN、O及びSから選択される1つ又は複数のヘテロ原子を任意により含有してもよい5~10員ヘテロアリールから選択され、前記5~10員アリール又は5~10員ヘテロアリールはR4によって置換されており、かつ任意にさらにR5によって置換され、かつ
R4は-COOH、-CH2COOH、-NHSO2CF3、-SO2NH-C1~6アルキル、-SO3H、-CONHSO2-C1~6アルキル、-CONHSO2-C3~6シクロアルキル、-CONHSO2-5~10員アリール、及びアリールをC1~6アルキルで置換した-CONHSO2-5~10員アリールから選択され、かつ、R5はH、C1~6アルキル、ハロゲン、C1~6ハロアルキル、-O-(C1~6アルキル)、及び-NH-(C1~6アルキル)から選択される。) - R1、R2及びR3は、それぞれ独立に、H、ハロゲン、及びC1~3ペルフルオロアルコキシから選択され、かつ、R0はイソプロピル又はシクロプロピルから選択され、
Zは、R4によって置換されておりかつ任意にR5によって置換されるフェニルであるか、又は、N、O及びSから選択される1つ又は複数のヘテロ原子を有する、R4によって置換されておりかつ任意にR5によって置換される5~10員ヘテロアリールであり、かつ
前記ハロゲンはフッ素又は塩素である、請求項1に記載の方法。 - R1、R2及びR3は、それぞれ独立に、H、Cl、F、及び-O-CF3から選択され、かつ
Zは、N、O及びSから選択される1つ又は複数のヘテロ原子を有する、R4によって置換されておりかつ任意にR5によって置換される5~6員ヘテロアリールであり、R4は-COOH、-CH2COOH、-CONHSO2-C1~6アルキル、及び-CONHSO2-C3~6シクロアルキルから選択される1種であり、R5はH、C1~3アルキル、及びハロゲンから選択される1種である、請求項2に記載の方法。 - Zはピリジルであり、R4は-COOHであり、かつ、R5はH又はハロゲンである、請求項3に記載の方法。
- 前記式(I)構造を有するフェニルイソキサゾリルメチレン-ナフタレン-エーテル誘導体、その薬学的に許容される塩、及びエステル又は立体異性体を、1種又は複数種の他の抗-HBV剤と組み合わせて使用することを含む、請求項1に記載の方法。
- 前記他の抗-HBV剤は、HBVワクチン、HBVDNAポリメラーゼ阻害剤、免疫調節剤、TOLL様受容体(TLR)調節剤、インターフェロンα受容体リガンド、B型肝炎表面抗原(HBsAg)阻害剤、シクロフィリン阻害剤、HBVウイルス侵入阻害剤、ウイルスmRNAを標的とするアンチセンスオリゴヌクレオチド、短い干渉RNA(siRNA)及びddRNAiエンドヌクレアーゼ調節剤、リボヌクレオチドレダクターゼ阻害剤、HBVE抗原阻害剤、共有結合的に閉じた環状DNA(cccDNA)阻害剤、脂肪酸シンターゼ阻害剤、HBV抗体、CCR2ケモカイン拮抗剤、レチノイン酸誘導性遺伝子1刺激剤、NOD2刺激剤、PD-1阻害剤、PD-L1阻害剤、KDM阻害剤、及びHBV複製阻害剤から選択される1種又は複数種である、請求項7に記載の方法。
- 前記HBVDNAポリメラーゼ阻害剤はエンテカビル又はテノホビルであり、
前記PD-1阻害剤は、ニボルマブ、ペムブロリズマブ、ピジリズマブ、BGB-108、SHR-1210、PDR-001、PF-06801591、IBI-308、セミプリマブ、カムレリズマブ、シンチリマブ、ティスレリズマブ(BGB-A317)、BCD-100、JNJ-63723283、Zimberelimab(GLS-010、WBP-3055)、Balstilimab(AGEN2034)及びドスタルリマブ(TSR-042)から選択される1種又は複数種であり、
前記PD-L1阻害剤は、アテゾリズマブ(RG-7446)、アベルマブ、BGB-A333、BMS-936559(MDX-1105)、デュルバルマブ、CX-072、GX-P2、KN035(ASC022)、GS-4224、及びINCB086550から選択される1種又は複数種であり、
前記アンチセンスオリゴヌクレオチドはIonis-HBVRx又はIonis-HBV-LRxであり、
前記短い干渉RNAはJNJ-3989、又はVir-2218、又はDCR-HBVSであり、
前記脂肪酸シンターゼ阻害剤はTVB-2640及び/又はTVB-3567であり、
前記インターフェロンはPegasysであり、かつ
前記カプシド阻害剤は、ABI-H0731、ABI-H2158、ABI-H3733、CB-HBV-001、JNJ-6379、JNJ-0440、QL-007、RG-7907及びRO7049389から選択される1種又は複数種である、請求項8に記載の方法。 - 抗B型肝炎ウイルス医薬組成物の製造における、式(I)構造を有するフェニルイソキサゾリルメチレン-ナフタレン-エーテル誘導体、又はその薬学的に許容される塩、エステル又は立体異性体の使用。
R1、R2及びR3は、それぞれ独立に、H、ハロゲン、非置換又はハロゲン置換C1~6アルキル、及び非置換又はハロゲン置換C1~6アルコキシから選択され、条件としては、R1、R2及びR3のうちの少なくとも1つは水素ではなく、R0は非置換又はハロゲン置換C1~6アルキル、C3~6シクロアルキル、及びC4~7アルキルシクロアルキルから選択され、
X1及びX2は、独立に、H及びハロゲンから選択され、
-O-Z基はナフタレン環に連結され、ここで、Zは残基であり、5~10員アリール又はN、O及びSから選択される1つ又は複数のヘテロ原子を任意により含有してもよい5~10員ヘテロアリールから選択され、前記5~10員アリール又は5~10員ヘテロアリールはR4によって置換されておりかつ任意にさらにR5によって置換され、かつ
R4は、-COOH、-CH2COOH、-NHSO2CF3、-SO2NH-C1~6アルキル、-SO3H、-CONHSO2-C1~6アルキル、-CONHSO2-C3~6シクロアルキル、-CONHSO2-5~10員アリール、及びアリールをC1~6アルキルで置換した-CONHSO2-5~10員アリールから選択され、かつR5はH、C1~6アルキル、ハロゲン、C1~6ハロアルキル、-O-(C1~6アルキル)、及び-NH-(C1~6アルキル)から選択される。) - R1、R2及びR3は、それぞれ独立に、H、ハロゲン、及びC1~3ペルフルオロアルコキシから選択され、かつR0はイソプロピル又はシクロプロピルから選択され、かつ
Zは、R4によって置換されておりかつ任意にR5によって置換されるフェニルであるか、又は、N、O及びSから選択される1つ又は複数のヘテロ原子を有する、R4によって置換されておりかつ任意にR5によって置換される5~10員ヘテロアリールであり、かつ
前記ハロゲンはフッ素又は塩素である、請求項10に記載の使用。 - R1、R2及びR3は、それぞれ独立に、H、Cl、F、及び-O-CF3から選択され、かつ
ZはN、O及びSから選択される1つ又は複数のヘテロ原子を有する、R4によって置換されておりかつ任意にR5によって置換される5~6員ヘテロアリールであり、ここで、R4は-COOH、-CH2COOH、-CONHSO2-C1~6アルキル、及び-CONHSO2-C3~6シクロアルキルから選択される1種であり、R5はH、C1~3アルキル、及びハロゲンから選択される1種である、請求項11に記載の使用。 - Zはピリジルであり、R4は-COOHであり、かつR5はH又はハロゲンである、請求項12に記載の使用。
- 治療有効量の式(I)構造を有するフェニルイソキサゾリルメチレン-ナフタレン-エーテル誘導体、又はその薬学的に許容される塩、エステル又は立体異性体又はその薬学的に許容される塩、エステル又は立体異性体と、1種又は複数種の他の抗-HBV剤と、薬学的に許容される補助材料とを含む、抗B型肝炎ウイルス医薬組成物。
R1、R2及びR3は、それぞれ独立に、H、ハロゲン、非置換又はハロゲン置換C1~6アルキル、及び非置換又はハロゲン置換C1~6アルコキシから選択され、条件としては、R1、R2及びR3のうちの少なくとも1つは水素ではなく、R0は非置換又はハロゲン置換C1~6アルキル、C3~6シクロアルキル、及びC4~7アルキルシクロアルキルから選択され、
X1及びX2は、独立に、H及びハロゲンから選択され、
-O-Z基はナフタレン環に連結され、ここで、Zは残基であり、5~10員アリール又はN、O及びSから選択される1つ又は複数のヘテロ原子を任意により含有してもよい5~10員ヘテロアリールから選択され、前記5~10員アリール又は5~10員ヘテロアリールはR4によって置換されておりかつ任意にさらにR5によって置換され、かつ
R4は-COOH、-CH2COOH、-NHSO2CF3、-SO2NH-C1~6アルキル、-SO3H、-CONHSO2-C1~6アルキル、-CONHSO2-C3~6シクロアルキル、-CONHSO2-5~10員アリール、及びアリールをC1~6アルキルで置換した-CONHSO2-5~10員アリールから選択され、かつR5はH、C1~6アルキル、ハロゲン、C1~6ハロアルキル、-O-(C1~6アルキル)、及び-NH-(C1~6アルキル)から選択される。) - R1、R2及びR3は、それぞれ独立に、H、ハロゲン、及びC1~3ペルフルオロアルコキシから選択され、かつR0はイソプロピル又はシクロプロピルから選択され、
Zは、R4によって置換されておりかつ任意にR5によって置換されるフェニルであるか、N、O及びSから選択される1つ又は複数のヘテロ原子を有する、R4によって置換されておりかつ任意にR5によって置換される5~10員ヘテロアリールであり、かつ
前記ハロゲンはフッ素又は塩素である、請求項16に記載の医薬組成物。 - R1、R2及びR3は、それぞれ独立に、H、Cl、F、及び-O-CF3から選択され、かつ
Zは、N、O及びSから選択される1つ又は複数のヘテロ原子を有する、R4によって置換されておりかつ任意にR5によって置換される5~6員ヘテロアリールであり、ここで、R4は-COOH、-CH2COOH、-CONHSO2-C1~6アルキル、及び-CONHSO2-C3~6シクロアルキルから選択され、R5はH、C1~3アルキル、及びハロゲンから選択される、請求項17に記載の医薬組成物。 - Zはピリジルであり、R4は-COOHであり、かつR5はH又はハロゲンである、請求項18に記載の医薬組成物。
- 前記方法は、前記式(I)構造を有するフェニルイソキサゾリルメチレン-ナフタレン-エーテル誘導体、その薬学的に許容される塩、及びエステル又は立体異性体を、1種又は複数種の他の抗-HBV剤と組み合わせて投与することを含む、請求項16に記載の医薬組成物。
- 前記他の抗-HBV剤は、HBVワクチン、HBVDNAポリメラーゼ阻害剤、免疫調節剤、TOLL様受容体(TLR)調節剤、インターフェロンα受容体リガンド、B型肝炎表面抗原(HBsAg)阻害剤、シクロフィリン阻害剤、HBVウイルス侵入阻害剤、ウイルスmRNAを標的とするアンチセンスオリゴヌクレオチド、短い干渉RNA(siRNA)及びddRNAiエンドヌクレアーゼ調節剤、リボヌクレオチドレダクターゼ阻害剤、HBVE抗原阻害剤、共有結合的に閉じた環状DNA(cccDNA)阻害剤、脂肪酸シンターゼ阻害剤、HBV抗体、CCR2ケモカイン拮抗剤、レチノイン酸誘導性遺伝子1刺激剤、NOD2刺激剤、PD-1阻害剤、PD-L1阻害剤、KDM阻害剤、及びHBV複製阻害剤から選択される、請求項22に記載の医薬組成物。
- 前記HBVDNAポリメラーゼ阻害剤はエンテカビル又はテノホビルであり、
前記PD-1阻害剤は、ニボルマブ、ペムブロリズマブ、ピジリズマブ、BGB-108、SHR-1210、PDR-001、PF-06801591、IBI-308、セミプリマブ、カムレリズマブ、シンチリマブ、ティスレリズマブ(BGB-A317)、BCD-100、JNJ-63723283、Zimberelimab(GLS-010、WBP-3055)、Balstilimab(AGEN2034)及びドスタルリマブ(TSR-042)から選択される1種又は複数種であり、
前記PD-L1阻害剤は、アテゾリズマブ(RG-7446)、アベルマブ、BGB-A333、BMS-936559(MDX-1105)、デュルバルマブ、CX-072、GX-P2、KN035(ASC022)、GS-4224、及びINCB086550から選択される1種又は複数種であり、
前記アンチセンスオリゴヌクレオチドはIonis-HBVRx又はIonis-HBV-LRxであり、
前記短い干渉RNAはJNJ-3989、Vir-2218又はDCR-HBVSであり、
前記脂肪酸シンターゼ阻害剤はTVB-2640及び/又はTVB-3567であり、
前記インターフェロンはPegasysであり、かつ
前記カプシド阻害剤はABI-H0731、ABI-H2158、ABI-H3733、CB-HBV-001、JNJ-6379、JNJ-0440、QL-007、RG-7907及びRO7049389から選択される1種又は複数種である、請求項23に記載の医薬組成物。
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