JP2019532932A - 高血圧症及び/又は線維症を処置するための組成物 - Google Patents
高血圧症及び/又は線維症を処置するための組成物 Download PDFInfo
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- JP2019532932A JP2019532932A JP2019515792A JP2019515792A JP2019532932A JP 2019532932 A JP2019532932 A JP 2019532932A JP 2019515792 A JP2019515792 A JP 2019515792A JP 2019515792 A JP2019515792 A JP 2019515792A JP 2019532932 A JP2019532932 A JP 2019532932A
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- pharmaceutically acceptable
- stereoisomer
- acceptable salt
- compound according
- fibrosis
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
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- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract
Description
したがって、BPを有意に低下し、そしてより多くの割合の患者が単剤療法でBP標的を達成すること及び/若しくは存在している線維症を逆行させること、並びに/又は正常な組織構造を回復することを可能にする効力を有する薬剤が必要である。
Xは、
R1〜R9は、独立して、C、N、O又はSであり、
R10は、独立して、C1〜6アルキル、ハロ、C0〜6アルキルカルボン酸、アミノ、ヒドロキシ及びC1〜6アルコキシから選択され、
Yは、A、CH2−A又はCH=Aであり、
Aは、任意選択により置換された飽和、部分飽和若しくは不飽和5又は6員ヘテロシクリル、任意選択により置換されたC1〜6アルコキシルアミン、任意選択により置換されたC1〜6アルキルアミン、任意選択により置換されたC0〜6アルキルカルボン酸、任意選択により置換されたC1〜6アルキルヒドロキシル、任意選択により置換された飽和又は不飽和C0〜6アルキル二環式ヘテロシクリル、及び任意選択により置換された飽和又は不飽和C1〜6アルコキシル二環式ヘテロシクリルから選択され、
Zは、
R11は、独立して、ハロ、アルキル、ヒドロキシ、アミノ及び置換アミノから選択され、
R12、R14及びR15は、独立して、C、CH、CH2、O、N、NH又はSであり、
R13は、C、CH、CH2、N、NH、C−CF3、CH−CF3又はC=Oであり、
mは、0、1、2、3、4又は5であり、及び
nは、0、1、2、3又は4である、
又はその立体異性体若しくは薬学的に許容される塩を提供する。
R16は、−CN、−SO2(R17)aR18及び−CO(R17)aR18から選択され、
aは、0又は1であり、
R17は、−NH−及び−O−から選択され、及び
R18は、−H、−CH3、−CH2CH3、−CH2OH及び−CH2CH2OHから選択される。
なる群から選択されるアルキルである。
効である。これらは、本発明の化合物で処置することができる状態の範囲及び重症度に関する重要な発見である。
Xは、
R1〜R9は、独立して、C、N、O又はSであり、
R10は、独立して、C1〜6アルキル、ハロ、C0〜6アルキルカルボン酸、アミノ、ヒドロキシ及びC1〜6アルコキシから選択され、
Yは、A、CH2−A又はCH=Aであり、
Aは、任意選択により置換された飽和、部分飽和若しくは不飽和5又は6員ヘテロシクリル、任意選択により置換されたC1〜6アルコキシルアミン、任意選択により置換されたC1〜6アルキルアミン、任意選択により置換されたC0〜6アルキルカルボン酸、任意選択により置換されたC1〜6アルキルヒドロキシル、任意選択により置換された飽和又は不飽和C0〜6アルキル二環式ヘテロシクリル、及び任意選択により置換された飽和又は不飽和C1〜6アルコキシル二環式ヘテロシクリルから選択され、
Zは、
R11は、独立して、ハロ、アルキル、ヒドロキシ、アミノ及び置換アミノから選択され、
R12、R14及びR15は、独立して、C、CH、CH2、O、N、NH又はSであり、
R13は、C、CH、CH2、N、NH、C−CF3、CH−CF3又はC=Oであり、
mは、0、1、2、3、4又は5であり、及び
nは、0、1、2、3又は4である、
又はその立体異性体若しくは薬学的に許容される塩である。
周知のように、賦形剤には、希釈剤、緩衝剤、結合剤、滑沢剤、崩壊剤、着色剤、酸化防止剤/防腐剤、pH調整剤などが含まれる。賦形剤は、最終形態の所望の物理的態様、例えば、素早く分散可能で容易に飲み込こめるなどの所望の硬さ及び破砕性を有する錠剤を得ることに基づいて選択される。摂取後における組成物からの活性物質の所望の放出速度はまた、賦形剤の選択において役割を果たす。医薬組成物は、錠剤、カプセル剤、散剤、液体製剤、遅延放出剤又は徐放剤、パッチ剤、嗅剤(snuffs)、点鼻薬(nasal sprays)などの任意の種類の剤形を含み得る。企図される医薬組成物の物理的形態及び含有量は、医薬製剤分野の当業者によって製剤化することができる従来の調製であり、例えば、Remington:The Science and Practice of Pharmacy,19th Edition,1995;British Pharmacopoeia 2000に記載されている十分に確立された原理及び組成、並びに類似の製剤化テキスト
及びマニュアルに基づく。
2−[4−ベンジル−1−(3−ヒドロキシベンジル)−1H−イミダゾール−5−イル]アセトアミド(VB0002)の調製に使用する合成経路を図1に示す。1,1’−カルボニルジイミダゾール(CDI)により促進されるBoc−フェニルアラニンとマロ
ン酸メチルカリウム塩との間の縮合反応により、中間体4を得た。次いでBoc基を除去することにより、塩酸塩として化合物5を得た。塩5をイソチオシアネートBと反応させて、環状チオ尿素6を低収率で得た。環状チオ尿素6のイミダゾール7への変換を酸化条件下で達成した。イミダゾール7をアンモニア水で処理することにより、VB0002を得た。
及び酢酸エチル(300mL)を加えた。層を分離し、次いで水層を酢酸エチルでさらに2回抽出した。合わせた有機層を飽和重炭酸ナトリウム(2×300mL)及び食塩水(300mL)で洗浄し、乾燥し、真空中で濃縮して、4−(tert−ブトキシカルボニルアミノ)−3−オキソ−5−フェニルペンタン酸メチル(22.22g、92%)を淡い粘性油として得て、これを固化した。1H NMR(400MHz、CDCl3)δ7.33−7.08(m、5H)、5.20−4.80(m、1H)、4.62−4.48(m、1H)、3.69(s、3H)、3.52(d、J=16.0Hz、1H)、3.45(d、J=16.0Hz、1H)、3.25−2.88(m、2H)、1.39(s、9H)。13C NMR(100MHz、CDCl3)δ201.8、167.3、155.2、136.1、129.2、128.6、126.9、80.1、60.4、52.3、46.5、36.7、28.2。EIMS:m/z321[M]+。C17H23NO5のHRMS計算値321.1576、実測値321.1555。
5−ベンジル−3−[3−(tert−ブチルジメチルシリルオキシ)ベンジル]−2−チオキソ−2,3−ジヒドロ−1H−イミダゾール−4−イル}酢酸メチル(1.00g、2.1mmol)に、窒素下、30%過酸化水素(941μL)をゆっくり加えた。10分後、反応溶液を氷浴中で冷却し、次いで10%炭酸ナトリウム(20mL)でクエンチした。pHを1M水酸化ナトリウムで9〜10に調整し、次いで酢酸エチル(3×20mL)で抽出し、乾燥し、真空中で濃縮して、2−{4−ベンジル−1−[3−(tert−ブチルジメチルシリルオキシ)ベンジル]−1H−イミダゾール−5−イル}酢酸メチル(0.86g、91%)を黄褐色の油状物として得た。1H NMR(400MHz、CDCl3)δ7.50(s、1H)、7.27−7.10(m、6H)、6.80−6.74(m、1H)、6.69−6.60(m、1H)、6.50−6.47(m、1H)、5.06(s、2H)、3.93(s、2H)、3.55(s、3H)、3.38(s、2H)、0.95(s、9H)、0.14(s、6H)。13C NMR(50MHz、CDCl3)δ170.0、156.3、139.9、139.6、137.3、136.2、130.1、128.6、128.4、126.0、120.4、119.8、118.4、117.4、52.2、48.9、33.5、29.1、25.6、18.0、−4.5。EIMS:m/z450[M]+。C26H34N2O3SiのHRMS計算値450.2333、実測値450.2323。
S:m/z233[M]+。C13H19NOSiのHRMS計算値233.1236、実測値233.1227。
MHz、CDCl3)δ7.89(m、2H)7.58(s、1H)、7.21−7.7.44(m、9H)、6.90(m、1H)、6.65(m、2H)、5.31(s、2H)、5.01(s、2H)、3.83(m、2H)、3.59(m、2H)、3.02(s、2H),1.33(s、3H)。13C NMR(50MHz、CDCl3)δ159.2、138.5、137.6、136.6、135.3、130.0、128.6、128.3、128.0、127.4、127.2、126.5、119.0、114.0、113.1、109.9、69.9、65.0、48.8、33.9、29.7、25.5。ESIMS:m/z441[M+H]+。C28H28N2O3のHRMS計算値440.2094、実測値440.2075。
7。HPLC純度=98%。
(ベンジルオキシ)ベンジルアジド(5.28g、95%)を無色透明の油状物として得た。1H NMR(200MHz、CDCl3)δ7.48−7.22(m、6H);6.99−6.86(m、3H);5.07(s、2H);4.30(s、2H)。13C
NMR(50MHz、CDCl3)δ159.4、137.2、137.0、130.1、128.8、128.3、127.7、120.9、114.9、114.9、70.3、54.9。UN=N=N/cm−12101。
ン(14.47mL、103.8mmol)をシリンジにより滴下して加えた。冷却浴を取り除き、反応混合物をさらに30分間撹拌した。次いで水(70mL)を加え、さらに10分間撹拌を続けた。有機相を分離し、水相をジクロロメタン(70mL)で洗浄した。合わせた有機物を水(4×70mL)で洗浄し、乾燥し、溶媒を真空中で除去した。残渣をシリカゲルの小プラグ(ジクロロメタン)を通して濾過することにより精製して、2−(2−メチル−[1,3]−ジオキソラン−2−イル)アセトアルデヒド(1.40g、42%)を淡黄色の油状物として得た。1H NMR(200MHz、CDCl3)δ9.75(t、1H、J=2.8Hz)、4.04−3.98(m、4H)、2.71(d、2H、J=2.8Hz)、1.43(s、3H)。
周囲温度で2日間撹拌した。次いで反応混合物を、シリカゲルを充填した短いカラムに注ぎ、セライト層を上に載せた。粗生成物をクロロホルムで溶出し、粗生成物を含有する画分を合わせた。粗物質をセライトに予め吸着させ、次いでPE中のクロロホルム(60〜100%クロロホルム)の勾配で溶出するシリカゲルDCVCにより精製して、(S)−tert−ブチル4−[(3−ベンジルオキシ)フェニルアミノ]−5−オキソ−5−(フェニルアミノ)ペンタノエート(3.35g、50%)を淡黄褐色の油状物として得た。1H NMR(400MHz、CDCl3)δ8.69(brs、1H)、7.57−7.48(m、2H)、7.46−7.23(m、7H)、7.15−7.06(m、2H)、6.49−6.42(m、1H)、6.33−6.24(m、2H)、5.06−5.02(m、1H)、5.00(s、2H)、3.80−3.72(m、1H)、2.67−2.54(m、1H)、2.49−2.37(m、1H)、2.36−2.24(m、1H)、2.21−2.09(m、1H)、1.46(s、9H)。13C NMR(50MHz、CDCl3)δ173.6、171.3、160.0、148.2、137.3、136.9、130.2、128.9、128.5、127.8、127.4、124.4、119.9、106.8、105.5、100.8、81.3、69.8、61.1、32.7、28.0、27.8。EIMS:m/z460[M]+。C28H32N2O4のHRMS計算値460.2357、実測値460.2341。
た。混合物を分液漏斗に移し、層を分離した。水相を酢酸エチルでさらに2回抽出した。合わせた有機層を10%クエン酸(100mL)、飽和重炭酸ナトリウム(100mL)及び食塩水(100mL)で洗浄し、乾燥し、溶媒を真空中で除去した。残渣をセライトに予め吸着させ、次いでシリカゲルDCVCにより精製した。同様の画分を合わせ、次いでジエチルエーテルとともに粉砕して、(S)−tert−ブチル3−[1−(3−ベンジルオキシ)フェニル−3,6−ジオキソ−4−フェニルピペラジン−2−イル]プロパノエート(4.18g、59%)を無色の固体として得た;融点141.6〜143.6℃。1H NMR(400MHz、CDCl3)δ7.48−7.29(m、11H)、7.03−6.95(m、3H)、5.08(s、2H)、4.55(dd、J=17.6、17.0Hz、2H)、4.45(dd、J=9.1、5.2Hz、1H)、2.52−2.14(m、4H)、1.37(s、9H)。13C NMR(50MHz、CDCl3)δ171.4、165.7、163.8、159.6、139.9、139.8、136.5、130.4、129.3、128.6、128.1、127.6、127.4、125.1、119.3、114.7、113.7、81.0、70.25、63.9、52.9、30.6、28.0、26.9。EIMS:m/z500[M]+。C31H32N2O5のHRMS計算値500.2306、実測値500.2294。
、溶媒を真空中で除去した。暗黄褐色油状物をセライトに予め吸着させ、次いでクロロホルム中のメタノール(0〜5%MeOH)の勾配で溶出するクロマトグラフィー処理(DCVC)を行って、(S)−3−[1−(3−ヒドロキシ)フェニル−4−フェニルピペラジン−2−イル]プロパン酸(418mg、70%)を黄褐色の油状物として得た。1H NMR(400MHz、CDCl3)δ7.37−7.31(m、2H)、7.30−7.24(m、2H)、7.17(brs、1H)、7.08−7.00(m、3H)、6.92−6.79(m、2H)、3.99−3.89(m、1H)、3.70−3.37(m、6H)、2.42−2.18(m、2H)、2.02−1.88(m、2H)。13C NMR(50MHz、MeOH−d4)δ175.8、160.6、151.0、144.0、132.6、130.6、123.0、118.5、116.7、112.7、109.3、63.7、55.6、53.7、49.2、30.8、25.0。EIMS:m/z326[M]+。C19H22N2O3のHRMS計算値326.1625、実測値326.1620。
値325.1776。[α]D=−13.5°(CHCl3、c=0.005)。
2.2%塩分食(Glenn Forrest Stockfeeders、西オーストラリア州(WA))を与えた14週齢の自然発症高血圧ラット(SHR;オーストラリア動物資源センター(Australian Animal Resources Centre)、西オーストラリア州)を以下の処置群に無作為に分けた:14週目の対照、又は4週間のVB0002注入(20%DMSO中20pmol/kg/分)若しくはビヒクル対照注入(20%DMSO)。VB0002及びビヒクル対照の注入は、14週目に全身麻酔下(イソフルラン3%、酸素中)で挿入されたAlzet浸透圧ミニポンプにより行った。
o Plus V.5(Media Cybernetics、メリーランド州ベセスダ、米国)を用いて各デジタル化画像の視野面積のパーセントとして決定し、次いで平均化して、各ラットの線維症のレベルを決定した。
Claims (25)
- 下記式の化合物:
Xは、
R1〜R9は、独立して、C、N、O又はSであり、
R10は、独立して、C1〜6アルキル、ハロ、C0〜6アルキルカルボン酸、アミノ、ヒドロキシ及びC1〜6アルコキシから選択され、
Yは、A、CH2−A又はCH=Aであり、
Aは、任意選択により置換された飽和、部分飽和若しくは不飽和5又は6員ヘテロシクリル、任意選択により置換されたC1〜6アルコキシルアミン、任意選択により置換されたC1〜6アルキルアミン、任意選択により置換されたC0〜6アルキルカルボン酸、任意選択により置換されたC1〜6アルキルヒドロキシル、任意選択により置換された飽和又は不飽和C0〜6アルキル二環式ヘテロシクリル、及び任意選択により置換された飽和又は不飽和C1〜6アルコキシル二環式ヘテロシクリルから選択され、
Zは、
R11は、独立して、ハロ、アルキル、ヒドロキシ、アミノ及び置換アミノから選択され、
R12、R14及びR15は、独立して、C、CH、CH2、O、N、NH又はSであり、
R13は、C、CH、CH2、N、NH、C−CF3、CH−CF3又はC=Oであり、
mは、0、1、2、3、4又は5であり、及び
nは、0、1、2、3又は4である、
又はその立体異性体若しくは薬学的に許容される塩。 - R10が、独立して、−CH3、−C(O)OH、−F、−NH2、−OH及び−OCH3から選択される、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- R5〜R9が、独立して、C又はNである、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- 前記C0〜6アルキルカルボン酸が、カルボン酸である、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- 前記飽和、部分飽和若しくは不飽和5又は6員ヘテロシクリルが、1つ以上のオキソ、C1〜6アルキル、アミノ、ヒドロキシル又はハロ置換基で任意選択により置換された、N、S又はOのうちの1つ以上を含む、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- 前記飽和、部分飽和若しくは不飽和5又は6員ヘテロシクリルが、1つ以上のオキソ、C1〜6アルキル、アミノ、ヒドロキシル又はハロ置換基で任意選択により置換された、ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、イミダゾリジニル、ピロリジニル、ピロリジニリデン、ジヒドロピロリル、イソオキサゾリル、ジヒドロオキサゾリル、イソオキサゾリジニル、オキサゾリジニル及びオキサゾリルから選択される、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- 前記C1〜6アルコキシルアミンが、アミノオキシメチルである、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- 前記C1〜6アルキルアミンが、C1〜6アルキル、C1〜6ハロアルキル、ヒドロキシル又はハロのうちの1つ以上、好ましくは一置換、二置換又は三置換されたハロアルキル、最も好ましくはトリフルオロメタンで任意選択により置換された、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- 前記C1〜6アルキルヒドロキシルが、メチルヒドロキシル又はプロパン−2−オールである、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- 前記C0〜6アルキル二環式ヘテロシクリルが、1つ以上のオキソ、好ましくはジオキソで任意選択により置換された、インドリル、イソインドリル、インソリニル及びイソインドリニルから選択される、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- 前記C1〜6アルコキシル二環式ヘテロシクリルが、1つ以上のオキソで任意選択により置換されたインドリル、イソインドリル、インソリニル及びイソインドリニルから選択され、前記C1〜6アルコキシルが、メトキシ又はエトキシである、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- R11が、F、Cl、Br及びIからなる群から選択されるハロである、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- R11が、式−NHR16の置換アミノであり、
R16が、−CN、−SO2(R17)aR18及び−CO(R17)aR18から選択され、
aが、0又は1であり、
R17が、−NH−及び−O−から選択され、並びに
R18が、−H、−CH3、−CH2CH3、−CH2OH及び−CH2CH2OHから選択される、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。 - R11が、−NHSO2CH3、−NHCOH、−NHCONHCH3、−NHCONHCH2CH3、−NHSO2NHCH3、−NHSO2NHCH2CH3、−NHCOCH3、−NHCOOCH3、−NHCOOCH2CH2OH、−NHCONH2及び−NHCNからなる群から選択される置換アミノである、請求項1に記載の化合物又はその
立体異性体若しくは薬学的に許容される塩。 - R11が、メチル、エチル、プロピル、ブチル及びペンチルからなる群から選択されるアルキルである、請求項1に記載の化合物又はその立体異性体若しくは薬学的に許容される塩。
- 請求項1〜18のいずれか一項に記載の化合物又はその立体異性体若しくは薬学的に許容される塩及び薬学的に許容される賦形剤を含む、医薬組成物。
- 対象における高血圧症又は高血圧前症の治療的処置方法であって、請求項1〜18のいずれか一項に記載の化合物若しくはその立体異性体若しくは薬学的に許容される塩又は請求項19に記載の組成物を前記対象に投与することを含む方法。
- 対象における線維症の予防的処置方法であって、請求項1〜18のいずれか一項に記載の化合物若しくはその立体異性体若しくは薬学的に許容される塩又は請求項19に記載の組成物を前記対象に投与することを含む方法。
- 対象における線維症の治療的処置方法であって、請求項1〜18のいずれか一項に記載の化合物若しくはその立体異性体若しくは薬学的に許容される塩又は請求項19に記載の組成物を前記対象に投与することを含む方法。
- 対象における高血圧症及び線維症の治療的処置方法であって、請求項1〜18のいずれか一項に記載の化合物若しくはその立体異性体若しくは薬学的に許容される塩又は請求項19に記載の組成物を前記対象に投与することを含む方法。
- 対象における高血圧前症及び線維症の処置方法であって、請求項1〜18のいずれか一項に記載の化合物若しくはその立体異性体若しくは薬学的に許容される塩又は請求項19に記載の組成物を前記対象に投与することを含む方法。
- 前記線維症が、心筋線維症、腎線維症、肝線維症及び肺線維症から選択される、請求項21〜24のいずれか一項に記載の方法。
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Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0753548A (ja) * | 1993-07-23 | 1995-02-28 | Adir | 新規置換ピペラジン類、それらの製造方法および医薬組成物 |
JPH0987255A (ja) * | 1995-07-19 | 1997-03-31 | Toray Ind Inc | ラセミ2−ピペラジンカルボン酸誘導体の製造法 |
JPH09512521A (ja) * | 1994-03-24 | 1997-12-16 | メルク エンド カンパニー インコーポレーテッド | 子宮収縮抑制オキシトシン受容体拮抗剤 |
FR2759698A1 (fr) * | 1997-02-20 | 1998-08-21 | Synthelabo | Derives de 1,4-diphenylimidazole-5-acetamide, leur preparation et leur application en therapeutique |
JP2002539121A (ja) * | 1999-03-08 | 2002-11-19 | シェーリング コーポレイション | ヒスタミンh3リガンドとしてのイミダゾール化合物 |
JP2009501185A (ja) * | 2005-07-14 | 2009-01-15 | エフ.ホフマン−ラ ロシュ アーゲー | V1a受容体アンタゴニストとしてのインドール−3−イル−カルボニル−スピロ−ピペリジン誘導体 |
JP2009526764A (ja) * | 2006-01-27 | 2009-07-23 | ブリストル−マイヤーズ スクイブ カンパニー | ケモカインレセプター活性のモジュレータとしてのピペリジニル誘導体 |
JP2010529137A (ja) * | 2007-06-08 | 2010-08-26 | アボット・ラボラトリーズ | キナーゼ阻害薬としての5−ヘテロアリール置換インダゾール類 |
JP2010535834A (ja) * | 2007-08-13 | 2010-11-25 | エフ.ホフマン−ラ ロシュ アーゲー | 新規ピペラジンアミド誘導体 |
JP2012524797A (ja) * | 2009-04-23 | 2012-10-18 | アボット・ラボラトリーズ | 5−ht受容体調節物質およびその使用方法 |
JP2013542255A (ja) * | 2010-11-10 | 2013-11-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ミネラルコルチコイド受容体アンタゴニストとしてのピリジル尿素 |
JP2016507502A (ja) * | 2012-12-21 | 2016-03-10 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | カゼインキナーゼ1δ/ε阻害剤としての新規な置換イミダゾール |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8823475D0 (en) * | 1988-10-06 | 1988-11-16 | Merck Sharp & Dohme | Chemical compounds |
JP2001294572A (ja) * | 2000-02-09 | 2001-10-23 | Dai Ichi Seiyaku Co Ltd | 新規スルホニル誘導体 |
GB0119797D0 (en) | 2001-08-14 | 2001-10-03 | Glaxo Group Ltd | Chemical compounds |
US7795267B2 (en) * | 2003-08-29 | 2010-09-14 | Takeda Pharmaceutical Company Limited | Bicyclic piperazine compound having TGR23 antagonistic activity |
US20100121048A1 (en) | 2006-02-16 | 2010-05-13 | Takanobu Kuroita | Cyclic Amine Compound and Use Thereof for the Prophylaxis or Treatment of Hypertension |
WO2009022731A1 (ja) | 2007-08-10 | 2009-02-19 | Nippon Chemiphar Co., Ltd. | P2x4受容体拮抗剤 |
US8546377B2 (en) * | 2009-04-23 | 2013-10-01 | Abbvie Inc. | Modulators of 5-HT receptors and methods of use thereof |
CN103517386B (zh) | 2012-06-26 | 2017-06-20 | 华为技术有限公司 | 无线局域网的数据传输方法及设备 |
WO2016105448A1 (en) | 2014-12-22 | 2016-06-30 | Darryl Rideout | Imidazoline receptor type 1 ligands for use as therapeutics |
-
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Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0753548A (ja) * | 1993-07-23 | 1995-02-28 | Adir | 新規置換ピペラジン類、それらの製造方法および医薬組成物 |
JPH09512521A (ja) * | 1994-03-24 | 1997-12-16 | メルク エンド カンパニー インコーポレーテッド | 子宮収縮抑制オキシトシン受容体拮抗剤 |
JPH0987255A (ja) * | 1995-07-19 | 1997-03-31 | Toray Ind Inc | ラセミ2−ピペラジンカルボン酸誘導体の製造法 |
FR2759698A1 (fr) * | 1997-02-20 | 1998-08-21 | Synthelabo | Derives de 1,4-diphenylimidazole-5-acetamide, leur preparation et leur application en therapeutique |
JP2002539121A (ja) * | 1999-03-08 | 2002-11-19 | シェーリング コーポレイション | ヒスタミンh3リガンドとしてのイミダゾール化合物 |
JP2009501185A (ja) * | 2005-07-14 | 2009-01-15 | エフ.ホフマン−ラ ロシュ アーゲー | V1a受容体アンタゴニストとしてのインドール−3−イル−カルボニル−スピロ−ピペリジン誘導体 |
JP2009526764A (ja) * | 2006-01-27 | 2009-07-23 | ブリストル−マイヤーズ スクイブ カンパニー | ケモカインレセプター活性のモジュレータとしてのピペリジニル誘導体 |
JP2010529137A (ja) * | 2007-06-08 | 2010-08-26 | アボット・ラボラトリーズ | キナーゼ阻害薬としての5−ヘテロアリール置換インダゾール類 |
JP2010535834A (ja) * | 2007-08-13 | 2010-11-25 | エフ.ホフマン−ラ ロシュ アーゲー | 新規ピペラジンアミド誘導体 |
JP2012524797A (ja) * | 2009-04-23 | 2012-10-18 | アボット・ラボラトリーズ | 5−ht受容体調節物質およびその使用方法 |
JP2013542255A (ja) * | 2010-11-10 | 2013-11-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ミネラルコルチコイド受容体アンタゴニストとしてのピリジル尿素 |
JP2016507502A (ja) * | 2012-12-21 | 2016-03-10 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | カゼインキナーゼ1δ/ε阻害剤としての新規な置換イミダゾール |
Non-Patent Citations (7)
Title |
---|
BIOORGANIC & MEDICINAL CHEMISTRY, vol. 12, JPN6021027587, 2004, pages 3299 - 3311, ISSN: 0004550260 * |
DATABASE REGISTRY ON STN, JPN7021002704, 21 March 2011 (2011-03-21), ISSN: 0004550258 * |
DATABASE REGISTRY ON STN, JPN7021002705, 21 March 2011 (2011-03-21), ISSN: 0004550257 * |
DATABASE REGISTRY ON STN, JPN7021002706, 21 March 2011 (2011-03-21), ISSN: 0004550256 * |
DATABASE REGISTRY ON STN, JPN7021002707, 21 March 2011 (2011-03-21), ISSN: 0004550255 * |
INDIAN J. CHEM., vol. 16B(11), JPN6021027588, 1978, pages 1012 - 1014, ISSN: 0004550259 * |
TETRAHEDRON LETTERS, vol. 46, JPN6021027589, 2005, pages 7315 - 7319, ISSN: 0004550254 * |
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CA3223869A1 (en) | 2018-03-29 |
BR112019005297A2 (pt) | 2019-06-04 |
EP3640243A1 (en) | 2020-04-22 |
RU2752088C1 (ru) | 2021-07-22 |
US11834417B2 (en) | 2023-12-05 |
AU2017329111A1 (en) | 2019-04-18 |
IL265242B (en) | 2021-09-30 |
CA3037222A1 (en) | 2018-03-29 |
AU2017329111B9 (en) | 2021-03-04 |
CN110234631A (zh) | 2019-09-13 |
NZ752196A (en) | 2022-05-27 |
EP3515895A4 (en) | 2019-12-18 |
DK3515895T3 (da) | 2021-10-18 |
US11053202B2 (en) | 2021-07-06 |
AU2017329111B2 (en) | 2021-01-28 |
JP2023002841A (ja) | 2023-01-10 |
IL265242A (en) | 2019-05-30 |
ES2890924T3 (es) | 2022-01-25 |
KR102640385B1 (ko) | 2024-02-23 |
CA3037222C (en) | 2024-02-13 |
EP3640243B1 (en) | 2021-05-26 |
JP7381136B2 (ja) | 2023-11-15 |
DK3640243T3 (da) | 2021-08-09 |
US20200255384A9 (en) | 2020-08-13 |
US20210284612A1 (en) | 2021-09-16 |
EP3515895B1 (en) | 2021-08-11 |
KR20190049884A (ko) | 2019-05-09 |
JP7177495B2 (ja) | 2022-11-24 |
US20190225588A1 (en) | 2019-07-25 |
EP3515895A1 (en) | 2019-07-31 |
WO2018053588A1 (en) | 2018-03-29 |
CN110234631B (zh) | 2023-02-28 |
ES2884945T3 (es) | 2021-12-13 |
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