JP6849618B2 - 中性エンドペプチダーゼの阻害剤(NEP阻害剤)および/またはアンジオテンシンII拮抗薬と組み合わせた可溶性グアニル酸シクラーゼ(sGC)の刺激薬および/または活性化薬ならびにその使用 - Google Patents
中性エンドペプチダーゼの阻害剤(NEP阻害剤)および/またはアンジオテンシンII拮抗薬と組み合わせた可溶性グアニル酸シクラーゼ(sGC)の刺激薬および/または活性化薬ならびにその使用 Download PDFInfo
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- JP6849618B2 JP6849618B2 JP2017567712A JP2017567712A JP6849618B2 JP 6849618 B2 JP6849618 B2 JP 6849618B2 JP 2017567712 A JP2017567712 A JP 2017567712A JP 2017567712 A JP2017567712 A JP 2017567712A JP 6849618 B2 JP6849618 B2 JP 6849618B2
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Description
国際公開第00/06569号の実施例16として開示される、2−[1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]−5−(4−モルホリニル)−4,6−ピリミジンジアミン(1)、
国際公開第02/42301号の実施例1として開示される、2−[1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]−5−(4−ピリジニル)−4−ピリミジンアミン(2)、
国際公開第03/095451号の実施例8として開示される、メチル4,6−ジアミノ−2−[1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]−5−ピリミジニル(メチル)カルバメート(3)、
国際公開第03/095451号の実施例5として開示される、メチル4,6−ジアミノ−2−[1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]−5−ピリミジニルカルバメート(4)、
国際公開第01/019780号の実施例8aとして開示される、4−({(4−カルボキシブチル)[2−(2−{[4−(2−フェニルエチル)ベンジル]オキシ}フェニル)エチル]アミノ}メチル)カルボン酸(5)、
国際公開第2011/147809号に開示される、メチル{4,6−ジアミノ−2−[5−フルオロ−1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]ピリミジン−5−イル}カルバメート(6)、メチル{4,6−ジアミノ−2−[5−フルオロ−1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]ピリミジン−5−イル}メチルカルバメート(7)、メチル{4,6−ジアミノ−2−[5−フルオロ−1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]ピリミジン−5−イル}(2,2,2−トリフルオロエチル)カルバメート(8)、
国際公開第00/02851号に開示される、ナトリウム塩(9)としての5−クロロ−2−(5−クロロチオフェン−2−スルホニルアミノ−N−(4−(モルホリン−4−スルホニル)フェニル)ベンズアミド、
国際公開第00/02851号に開示される、2−(4−クロロフェニルスルホニルアミノ)−4,5−ジメトキシ−N−(4−(チオモルホリン−4−スルホニル)フェニル)ベンズアミド(10)、
国際公開第2009/032249号に開示される、1−{6−[5−クロロ−2−({4−トランス−4−}トリフルオロメチル)シクロヘキシル]ベンジル}オキシ)フェニル]ピリジン−2−イル}−5−(トリフルオロメチル)−1H−ピラゾール−4−カルボン酸(11)、
国際公開第2009/071504号に開示される、1−[6−(2−(2−メチル−4−(4−トリフルオロメトキシフェニル)ベンジルオキシ)フェニル)ピリジン−2−イル]−5−トリフルオロメチルピラゾール−4−カルボン酸(12)、
国際公開第2009/068652号に開示される、1[6−(3,4−ジクロロフェニル)−2−ピリジニル−5−(トリフルオロメチル)−1H−ピラゾール−4−カルボン酸(13)、
国際公開第2009/123316号に開示される、1−({2−[3−クロロ−5−(トリフルオロメチル)フェニル]−5−メチル−1,3−チアゾール−4−イル}メチル)−1H−ピラゾール−4−カルボン酸(14)、4−({2−[3−(トリフルオロメチル)フェニル]−1,3−チアゾール−4−イル}メチル)安息香酸(15)および1−({2−[2−フルオロ−3−(トリフルオロメチル)フェニル]−5−メチル−1,3−チアゾール−4−イル}メチル)−1H−ピラゾール−4−カルボン酸(16)、
国際公開第2010/065275号に開示される、4−アミノ−2−[5−クロロ−3(3,3,3−トリフルオロプロピル)−1H−インダゾール−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(17)、4−アミノ−2[5−クロロ−3−(2,3,6−トリフルオロベンジル)−1H−インダゾール−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(18)、4−アミノ−5,5−ジメチル−2−[3−(2,3,6−トリフルオロベンジル)1H−チエノ[3,4−c]ピラゾール−1−イル]−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(19)、4−アミノ−5,5−ジメチル−2−[3−(2,3,6−トリフルオロベンジル)−1H−チエノ[2,3−d]ピラゾール−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(20)、4−アミノ−5,5−ジメチル−2−[7−(2,3,6−トリフルオロベンジル)イミダゾ[1,5−b]ピリダジン−5−イル]−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(21)、4−アミノ−2−[6−クロロ−3−(2,3,6−トリフルオロベンジル)イミダゾ[1,5−a]ピリジン−1−イル]]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(22)、4−アミノ−2−[6−フルオロ−3−(2,3,6−トリフルオロベンジル)イミダゾ[1,5−a]ピリジン−1−イル]]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(23)、4−アミノ−2−[6−フルオロ−3−(2,3,6−トリフルオロベンジル)6−フルオロイミダゾ[1,5−a]ピリジン−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(24)、4−アミノ−5,5−ジメチル−2−[3−(2,4,6−トリフルオロベンジル)イミダゾ[1,5−a]ピリジン−1−イル]]−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(25)、4−アミノ−2−[3−(2−シクロペンチルエチル)イミダゾ[1,5−a]ピリジン−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(26)、
国際公開第00/06568号の実施例1として開示されるBAY 41−2272として公知の、3−(4−アミノ−5−シクロプロピルピリミジン−2−イル)−1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン(27)、
国際公開第2014/131760号の実施例1として開示される、2−{5−フルオロ−1−[(3−フルオロピリジン−2−イル)メチル]−1H−ピラゾロ[3,4−b]ピリジン−3−イル}−5−メチル−5−(トリフルオロメチル)−4−[(3,3,3−トリフルオロプロピル)アミノ]−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(28)、
国際公開第2012/139888号の実施例22として開示される、3−(4−クロロ−3−{[(2S,3R)−2−(4−クロロフェニル)−4,4,4−トリフルオロ−3−メチルブタノイル]アミノ}フェニル)−3−シクロプロピルプロパン酸(29)、
国際公開第2014/012934号の例として開示される、5−{[2−(4−カルボキシフェニル)エチル][2−(2−{[3−クロロ−4’−(トリフルオロメチル)ビフェニル−4−イル]メトキシ}フェニル)エチル]アミノ}−5,6,7,8−テトラヒドロキノリン−2−カルボン酸の式(32)および5−{(4−カルボキシブチル)[2−(2−{[3−クロロ−4’−(トリフルオロメチル)ビフェニル−4−イル]メトキシ}フェニル)エチル]アミノ}−5,6,7,8−テトラヒドロキノリン−2−カルボン酸の式(33)、
式(34)のent−N−[(2S)−アミノ−2−メチルブチル]−8−[(2,6−ジフルオロベンジル)オキシ]−2,6−ジメチルイミダゾ[1,2−a]ピリジン−3−カルボキサミド(エナンチオマーA)、式(35)のent−N−(2−アミノ−2−メチルブチル)−8−[(2,6−ジフルオロベンジル)オキシ]−2,6−ジメチルイミダゾ[1,2−a]ピリジン−3−カルボキサミド(エナンチオマーB)、式(36)のent−N−(2−アミノ−5,5,5−トリフルオロ−2−メチルペンチル)−2,6−ジメチル−8−[(2,3,6−トリフルオロベンジル)オキシ]イミダゾ[1,2−a]ピリジン−3−カルボキサミド(エナンチオマーB)、式(37)のent−N−(2−アミノ−5,5,5−トリフルオロ−2−メチルペンチル)−8−[(2,6−ジフルオロベンジル)オキシ]−2,6−ジメチルイミダゾ[1,2−a]ピリジン−3−カルボキサミド(エナンチオマーB)、式(38)のent−N−(2−アミノ−5,5,5−トリフルオロ−2−メチルペンチル)−8−[(2,6−ジフルオロベンジル)オキシ]−2,6−ジメチルイミダゾ[1,2−a]ピリジン−3−カルボキサミド(エナンチオマーA)、式(39)のent−N−(2−アミノ−3−フルオロ−2−メチルプロピル)−2,6−ジメチル−8−[(2,3,6−トリフルオロベンジル)オキシ]イミダゾ[1,2−a]ピリジン−3−カルボキサミド(エナンチオマーB)、式(40)のent−N−(2−アミノ−3−フルオロ−2−メチルプロピル)−8−[(2,6−ジフルオロベンジル)オキシ]−2,6−ジメチルイミダゾ[1,2−a]ピリジン−3−カルボキサミド(エナンチオマーB)、式(41)のent−N−(2−アミノ−3−フルオロ−2−メチルプロピル)−8−[(2,6−ジフルオロベンジル)オキシ]−2,6−ジメチルイミダゾ[1,2−a]ピリジン−3−カルボキサミド(エナンチオマーA)、式(42)のrac−N−(2−アミノ−3−フルオロ−2−メチルプロピル)−8−[(2,6−ジフルオロベンジル)オキシ]−2,6−ジメチルイミダゾ[1,2−a]ピリジン−3−カルボキサミドホルメート、式(43)のent−N−(2−アミノ−3−フルオロ−2−メチルプロピル)−2,6−ジメチル−8−[(2,3,6−トリフルオロベンジル)オキシ]イミダゾ[1,2−a]ピリジン−3−カルボキサミド(エナンチオマーA)、式(44)のent−N−(2−アミノ−3−フルオロ−2−メチルプロピル)−8−[(2,6−ジフルオロベンジル)オキシ]−6−(ジフルオロメチル)−2−メチルイミダゾ[1,2−a]ピリジン−3−カルボキサミド(エナンチオマーB)、式(45)のent−N−(2−アミノ−3−フルオロ−2−メチルプロピル)−8−[(2,6−ジフルオロベンジル)オキシ]−6−(ジフルオロメチル)−2−メチルイミダゾ[1,2−a]ピリジン−3−カルボキサミド(エナンチオマーA)であり、式(46)のent−N−(2−アミノ−3−フルオロ−2−メチルプロピル)−8−[(2,6−ジフルオロベンジル)オキシ]−6−(フルオロメチル)−2−メチルイミダゾ[1,2−a]ピリジン−3−カルボキサミドは、国際公開第2014/068099号に例として開示される。
降圧活性成分、例として、好ましくはアンジオテンシンII拮抗薬、ACE阻害剤、カルシウム拮抗薬、エンドセリン拮抗薬、レニン阻害剤、α受容体遮断薬、β受容体遮断薬、ミネラルコルチコイド受容体拮抗薬およびまた利尿薬の群のもの;
有機硝酸塩およびNO供与体、例えばナトリウムニトロプルシド、ニトログリセリン、一硝酸イソソルビド、硝酸イソソルビド、モルシドミンまたはSIN−1、および吸入NO;
環状グアノシン一リン酸(cGMP)の分解を阻害する化合物、例えばホスホジエステラーゼ(PDE)1、2、5および/または9の阻害剤、特にシルデナフィル、バルデナフィルおよびタダラフィルなどのPDE5阻害剤;
抗血栓薬、例として、好ましくは血小板凝集阻害剤、抗凝固薬または線維素溶解促進性物質の群のもの;
脂質代謝を変更する活性化合物、例として、好ましくは甲状腺受容体アゴニスト、コレステロール合成阻害剤(好ましい例はHMG−CoAレダクターゼ阻害剤またはスクアレン合成阻害剤)、ACAT阻害剤、CETP阻害剤、MTP阻害剤、PPAR−α、PPAR−γおよび/またはPPAR−δアゴニスト、コレステロール吸収阻害剤、リパーゼ阻害剤、高分子胆汁酸吸着剤、胆汁酸再吸収阻害剤およびリポタンパク質(a)アンタゴニストの群のもの。
以下の実施例は、本発明を例示する。本発明は実施例に限定されない。
本発明による組合せの心血管障害の処置への適合性は、以下のアッセイ系で示すことができる:
Data Sciences International DSI、USAから市販されているテレメトリーシステムを、覚醒ラット(ウィスター系Unilever/WUまたは自然発症高血圧ラット/SHR)での測定に用いた。このシステムは、3つの主な構成要素:(1)埋め込み型送信器(PhysioTel(登録商標)テレメトリー送信器)、(2)受信器(PhysioTel(登録商標)受信器)と、受信器が多重化装置(DSI Data Exchange Matrix)を経由して連結されている(3)データ収集コンピュータからなる。テレメトリーシステムは、覚醒動物の血圧、心拍および身体の動きをその通常の生育地で連続的に記録することを可能にする。
使用したテレメトリー送信器(例えば、PA−C40 HD−S10、DSI)は、最初の実験使用の少なくとも14日前に無菌条件下で実験動物に外科的に埋め込まれた。
別段の規定のない限り、調査する物質は、各例の動物の群(n=6)に経口的に投与される。2ml/体重kgの投与量に従って、試験物質を適した溶媒混合物に溶解する。溶媒で処置した群の動物を対照として使用する。
テレメトリー測定システムを、24匹の動物用に設定する。
実験終了後、分析ソフトウェア(Dataquest(商標)A.R.T.4.1 AnalysisまたはPonemah、DSI)を用いて収集した個々のデータを選別した。物質の投与前2時間の時点をブランク値と仮定した。
K.Witte,K.Hu,J.Swiatek,C.Mussig,G.ErtlおよびB.Lemmer,Experimental heart failure in rats:effects on cardiovascular circadiam thythms and on myocardial β−adrenergic signaling,Cardiovasc.Res.47(2):203−405,2000。
sGC調節薬、ネプリライシン阻害剤、アンジオテンシンII拮抗薬ならびにその二重および三重の組合せの投与後の心血管作用は、ラットの高レニン、低NOの血圧モデルでの血行動態およびホルモンパラメータへの長期的な作用を求めることによって実証される。
sGC調節薬(sGC刺激薬またはsGC活性化薬)、ネプリライシン阻害剤、アンジオテンシンII拮抗薬ならびにその二重および三重の組合せの投与後の心血管作用を、アンジオテンシンII拮抗薬誘発性急性高血圧症によって起こる「軽度」収縮期心不全のイヌモデルで評価する。左心室機能不全の実験動物モデルは、180bpmで10日間の右室の「頻拍ペーシング」によって引き起こされる。このモデルの実験での実施は、詳細に記載されている。[Redfield et al.,Circulation 1993;87:2016−2022]
sGC調節薬(sGC刺激薬またはsGC活性化薬)、ネプリライシン阻害剤、アンジオテンシンII拮抗薬、ならびにその二重および三重の組合せの血圧および心拍への作用を高血圧性「腎ラップ」イヌモデルで試験する。このモデルでは、1つの腎臓が絹で巻かれ、一方2つ目の腎臓は主腎動脈の閉塞に付される。[Page et al.,Science 1939;89:2307−2308;Goldblatt et al.,Proc Natl Acad Sci 1976;73:1722−1724]。手術の約4週後、イヌは安定した高血圧になる。
結果は、ネプリライシン阻害剤とアンジオテンシンII拮抗薬との三重の組合せ中の式(6)の化合物について、式(6)の化合物の単回投与およびネプリライシン阻害剤とアンジオテンシンII拮抗薬の二重の組合せと比較して図1および2に示される。
Claims (13)
- 心血管障害、腎障害、肺障害の処置および/または予防のための、さらに線維性疾患の処置および/または予防のための方法に使用するための、請求項1から5のいずれか一項に記載のキット。
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Publication number | Publication date |
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US11166932B2 (en) | 2021-11-09 |
EP3325013B1 (de) | 2020-09-23 |
CA2989740A1 (en) | 2017-01-26 |
CN113712969A (zh) | 2021-11-30 |
WO2017013010A1 (de) | 2017-01-26 |
CN113750102A (zh) | 2021-12-07 |
EP3325013B2 (de) | 2023-07-19 |
HRP20201932T1 (hr) | 2021-02-05 |
CA2989740C (en) | 2023-07-11 |
US20220023246A1 (en) | 2022-01-27 |
CN108430510B (zh) | 2021-10-29 |
DK3325013T3 (da) | 2020-12-14 |
ES2839248T3 (es) | 2021-07-05 |
DK3325013T4 (da) | 2023-10-16 |
FI3325013T4 (fi) | 2023-10-11 |
CN108430510A (zh) | 2018-08-21 |
HRP20201932T4 (hr) | 2024-02-16 |
JP2018520151A (ja) | 2018-07-26 |
LT3325013T (lt) | 2020-11-10 |
HUE052337T2 (hu) | 2021-04-28 |
SI3325013T2 (sl) | 2023-11-30 |
US20190125709A1 (en) | 2019-05-02 |
EP3325013A1 (de) | 2018-05-30 |
ES2839248T5 (es) | 2024-02-22 |
SI3325013T1 (sl) | 2020-11-30 |
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