JP6603213B2 - 心臓状態に対するピリミジンジオン化合物 - Google Patents
心臓状態に対するピリミジンジオン化合物 Download PDFInfo
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- JP6603213B2 JP6603213B2 JP2016521578A JP2016521578A JP6603213B2 JP 6603213 B2 JP6603213 B2 JP 6603213B2 JP 2016521578 A JP2016521578 A JP 2016521578A JP 2016521578 A JP2016521578 A JP 2016521578A JP 6603213 B2 JP6603213 B2 JP 6603213B2
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- Prior art keywords
- compound
- pharmaceutically acceptable
- phenyl
- dione
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
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Classifications
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- 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
Description
本出願は、それぞれが全体として参照により本明細書に組み込まれている2013年6月21日に出願した米国仮出願第61/838,088号、および2014年2月13日に出願した米国仮出願第61/939,655号、および2014年4月18日に出願した米国仮出願第61/981,366号の35U.S.C.§119(e)に基づく優先権を主張する出願である。
適用されない。
一連のピリミジンジオン化合物およびそれらの薬学的に許容される塩は、アクチンフィラメントを強力に結合し、ホスフェートを放出し、かくして筋収縮サイクルの「パワーストローク」ポーションに関与することが可能であるミオシン分子の割合が減少する以前を除けば、過剰収縮状態における過剰な収縮性を減少することおよび/または拡張機能障害を有する心臓における心臓弛緩をATP加水分解後のベータ心筋ミオシンの立体配座を安定化させることによって促進することが見出されている。そのようなことで、該化合物は、HCMを有する患者において、心臓の弾性を改善し、動的なおよび/または静的な左室流出路閉塞を減少させ、拡張性の左室弛緩を改善し、左室拡張性(充填)圧を低下させ、機能性僧帽弁逆流を減少し、および/または左心房および肺毛細血管の楔入圧を低下させ、多くの場合該疾患を伴う左室流出路閉塞(失神寸前状態または失神)に帰することができる消耗性の労作性呼吸困難および/または症状を克服することを助ける。該化合物は、また、その他の心障害を治療するためにも使用される。
本明細書で使用される用語「アルキル」は、示されている炭素原子の数を有している直鎖のまたは分枝の、飽和した、脂肪族基を指す。アルキルは、任意の数の炭素を、C1〜2、C1〜3、C1〜4、C1〜5、C1〜6、C1〜7、C1〜8、C2〜3、C2〜4、C2〜5、C2〜6、C3〜4、C3〜5、C3〜6、C4〜5、C4〜6およびC5〜6のように含有することができる。例えば、C1〜6アルキルとしては、以下に限定されないが、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、イソペンチル、ヘキシル、などが挙げられる。アルキルは、最高20までの炭素原子を有しているアルキル基、例えば、以下に限定されないが、ヘプチル、オクチル、ノニル、デシル、などを指すことができる。特に指定の無い限り、アルキル基は非置換である。「置換アルキル」基は、ハロ、ヒドロキシ、アミノ、アルキルアミノ、ニトロ、シアノ、およびアルコキシから選択される1つまたはそれ以上の部分により置換されている。
クリルにより置換されているフェニルである。他の実施形態において、R1は、C1〜C4アルキル、−CO2Ra1、または−SO2Ra1により場合によって置換されている4から7員のヘテロシクロアルキルまたは5から6員のヘテロアリールであり;R3は、C3〜C4シクロアルキルまたは4から7員のヘテロシクロアルキルであり;R2は、場合によってオキソにより置換されている5から6員のヘテロアリールまたは5から6員のヘテロシクリルにより置換されているフェニルである。他の実施形態において、R1は、C3〜C8シクロアルキルまたはフェニルであり、R3は、C3〜C4シクロアルキルまたは4から7員のヘテロシクロアルキルであり;R2は、場合によってオキソにより置換されている5から6員のヘテロアリールまたは5から6員のヘテロシクリルにより置換されているフェニルである。
(S)−3−イソプロピル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−5−フルオロ−3−イソプロピル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−5−ブロモ−3−イソプロピル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−クロロフェニル)エチル)アミノ)−5−フルオロ−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3,5−ジフルオロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((シクロプロピル(フェニル)メチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((シクロプロピル(3−メトキシフェニル)メチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((シクロブチル(フェニル)メチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−フルオロフェニル)エチル)アミノ)−3−(テトラヒドロ−2H−ピラン−4−イル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−メトキシフェニル)エチル)アミノ)−3−(テトラヒドロ−2H−ピラン−4−イル)ピリミジン−2,4(1H,3H)−ジオン;
6−(((S)−1−フェニルエチル)アミノ)−3−(テトラヒドロフラン−3−イル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(1−(メチルスルホニル)ピペリジン−4−イル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
メチル(S)−4−(2,6−ジオキソ−4−((1−フェニルエチル)アミノ)−3,6−ジヒドロピリミジン−1(2H)−イル)ピペリジン−1−カルボキシレート;
3−((R)−sec−ブチル)−6−(((S)−1−(3−メトキシフェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−フェニルエチル)アミノ)−3−(ピリジン−3−イル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(イソオキサゾール−3−イル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−(1H−ピラゾール−1−イル)フェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−(2−メトキシフェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−フェニルプロピル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−5−メチル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(2−フルオロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−フルオロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−クロロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(4−フルオロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−5−フルオロ−3−イソプロピル−6−((1−フェニルプロピル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−5−フルオロ−6−((1−(3−フルオロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−5−フルオロ−3−イソプロピル−6−((1−(3−メトキシフェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(2,5−ジフルオロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−ブロモフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−3−エチル−6−((1−フェニルプロピル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−シクロプロピル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−フェニルエチル)アミノ)−3−(ピリジン−2−イル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(1−メチル−1H−ピラゾール−3−イル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−(1H−1,2,4−トリアゾール−1−イル)フェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−(3−(2−メチル−1H−イミダゾール−1−イル)フェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−(3−(2−オキソオキサゾリジン−3−イル)フェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−シクロヘキシル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−フェニル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−エチル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−メチル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−フェニルエチル)アミノ)−3−プロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(3,5−ジフルオロフェニル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−(m−トリル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(4−フルオロフェニル)プロパン−2−イル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(R)−3−イソプロピル−6−((2,2,2−トリフルオロ−1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
3−((R)−1−(ベンジルオキシ)プロパン−2−イル)−6−(((S)−1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
3−((R)−1−ヒドロキシプロパン−2−イル)−6−(((S)−1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−(3−(トリフルオロメチル)フェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−2−(1−((1−イソプロピル−2,6−ジオキソ−1,2,3,6−テトラヒドロピリミジン−4−イル)アミノ)エチル)ベンゾニトリル
(S)−3−(2,6−ジフルオロフェニル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(2,6−ジフルオロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−(ピリジン−4−イル)プロパン−2−イル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(4−(ベンジルオキシ)フェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(4−ヒドロキシフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(R)−6−((2−(ベンジルオキシ)−1−フェニルエチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(6−メチルピリジン−2−イル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(2,2−ジフルオロエチル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(ベンゾ[d][1,3]ジオキソール−5−イル)エチル)アミノ)−3−(2,2,2−トリフルオロエチル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−(o−トリル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−シクロブチル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−(2−(トリフルオロメチル)フェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(1−メチルシクロプロピル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−(1H−イミダゾール−1−イル)フェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−フェニルエチル)アミノ)−3−(ピリダジン−4−イル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−フェニルエチル)アミノ)−3−(ピラジン−2−イル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−(ピリジン−3−イル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(1−メチル−1H−ピラゾール−4−イル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−フェニルブチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
6−(((S)−1−フェニルエチル)アミノ)−3−((R)−テトラヒドロ−2H−ピラン−3−イル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−シクロペンチル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((2−メチル−1−フェニルプロピル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(4,4−ジフルオロシクロヘキシル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(ペンタン−3−イル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(1−ベンゾイルピペリジン−4−イル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((4−フェニルブタン−2−イル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
メチル(S)−2−(2,6−ジオキソ−4−((1−フェニルエチル)アミノ)−3,6−ジヒドロピリミジン−1(2H)−イル)アセテート
(S)−3−イソプロピル−6−((1−フェニルプロパン−2−イル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
3−((S)−1−(ベンジルオキシ)プロパン−2−イル)−6−(((S)−1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
3−((S)−1−ヒドロキシプロパン−2−イル)−6−(((S)−1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(R)−6−((2−ヒドロキシ−1−フェニルエチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
6−(((S)−1−フェニルエチル)アミノ)−3−((S)−1,1,1−トリフルオロプロパン−2−イル)ピリミジン−2,4(1H,3H)−ジオン;
6−(((S)−1−フェニルエチル)アミノ)−3−(4,4,4−トリフルオロブタン−2−イル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−フェニルエチル)アミノ)−3−(2,2,2−トリフルオロエチル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(tert−ブチル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(2−メトキシエチル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
6−(((S)−1−フェニルプロピル)アミノ)−3−((S)−1,1,1−トリフルオロプロパン−2−イル)ピリミジン−2,4(1H,3H)−ジオン;
3−((R)−1−シクロプロピルエチル)−6−(((S)−1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
3−((S)−1−シクロプロピルエチル)−6−(((S)−1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((シクロブチル(フェニル)メチル)アミノ)−3−エチルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(ベンゾ[d][1,3]ジオキソール−5−イル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(ベンゾ[d][1,3]ジオキソール−5−イル)エチル)アミノ)−3−エチルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−フェニルプロピル)アミノ)−3−(2,2,2−トリフルオロエチル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(シクロプロピルメチル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((シクロプロピル(フェニル)メチル)アミノ)−3−(2,2,2−トリフルオロエチル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((シクロブチル(フェニル)メチル)アミノ)−3−(2,2,2−トリフルオロエチル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(1,3−ジヒドロキシプロパン−2−イル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−ヒドロキシフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
6−((1−(2−ヒドロキシフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−フェニルエチル)アミノ)−3−(1−(トリフルオロメチル)シクロプロピル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(3,5−ジフルオロフェニル)−6−((1−(4−フルオロフェニル)プロパン−2−イル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(2−クロロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−3−イソプロピル−6−((1−(4−メトキシフェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((シクロプロピル(フェニル)メチル)アミノ)−3−エチルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−クロロフェニル)エチル)アミノ)−3−エチルピリミジン−2,4(1H,3H)−ジオン;
(S)−3−エチル−6−((1−(3−(トリフルオロメチル)フェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(シクロプロピルメチル)−6−((1−(3−フルオロフェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−(シクロプロピルメチル)−6−((1−(3−(トリフルオロメチル)フェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−クロロフェニル)エチル)アミノ)−3−(シクロプロピルメチル)ピリミジン−2,4(1H,3H)−ジオン;
(S)−5−クロロ−6−((1−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3−クロロフェニル)エチル)アミノ)−3−プロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−3−プロピル−6−((1−(3−(トリフルオロメチル)フェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−3−シクロブチル−6−((1−(4−フルオロフェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(2−ヒドロキシフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(3,4−ジフルオロフェニル)エチル)アミノ)−3−エチルピリミジン−2,4(1H,3H)−ジオン;
3−((S)−sec−ブチル)−6−(((S)−1−(4−フルオロフェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン;
(S)−6−((1−(4−フルオロフェニル)エチル)アミノ)−3−プロピルピリミジン−2,4(1H,3H)−ジオン;および
(S)−3−(6−フルオロピリジン−2−イル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン、または上記のいずれかの薬学的に許容される塩から選択される。
さらに提供されるのは、本明細書に記載されている化合物または薬学的に許容される塩および薬学的に許容される添加剤を含んでいる医薬組成物である。その組成物は、ヒトおよび他の対象における肥大型心筋症を治療するために役立つ。
HCMにつながる突然変異は、ミオシン構造における重要な動揺を引き起こす。これらの突然変異は、ミオシン遺伝子中のそれらの位置に応じた独特の機構によりそれらに影響を与える。よく研究されたHCM突然変異、R403QおよびR453Cは、モータードメインの異なるセクションに位置づけられており、増大された力発生の共通の結果をもたらす独特の機構的な動揺を引き起こす。何らかの特定の理論に制約されることは望まないが、本明細書に記載されている化合物または薬学的に許容される塩は、シスにおいて(同じ特定の機能に影響をおよぼすことによって)またはトランスにおいて(補足的な機能を改めることによって)突然変異サルコメアタンパク質に直接結合して、それらの異常機能を是正することができるものと考えられる。そのようなものとして、それらはHCM患者に対し、この疾患と関連する過剰収縮性のおよび/または障害性の弛緩を是正することによって治療利益を提供することができる。
略語:
aq:水性の(aqueous)
BBr3:三臭化ホウ素
CH2Cl2:ジクロロメタン
CH3CN:アセトニトリル
CH3OH:メタノール
DIAD:アゾジカルボン酸ジイソプロピル
DIEA:ジイソプロピルエチルアミン
DMF:ジメチルホルムアミド
DMSO:ジメチルスルホキシド
equiv.:当量
Et3N:トリエチルアミン
Et2O:ジエチルエーテル
EtOH:エタノール
FeSO4:硫酸第一鉄
h:時間
HCl:塩化水素
H2O:水
K2CO3:炭酸カリウム
KHSO4:硫酸水素カリウム
KNCO:イソシアン酸カリウム
LiBr:臭化リチウム
MgSO4:硫酸マグネシウム
mL:ミリリットル
MW:マイクロ波(マイクロ波反応器中で行われる反応)
NaCl:塩化ナトリウム
NaH:水素化ナトリウム
NaHCO3:重炭酸ナトリウム
NaOEt:ナトリウムエトキシド
NaOH:水酸化ナトリウム
NaOMe:ナトリウムメトキシド
Na2SO4:硫酸ナトリウム
NH4Cl:塩化アンモニウム
NMP:n−メチルピロリジノン
pH:−log[H+]
POCl3:三塩化ホスホリル
PPTS:p−トルエンスルホン酸ピリジニウム
RP−HPLC:逆相高圧液体クロマトグラフィー
RT:室温
SEMCl:2−(トリメチルシリル)エトキシメチルクロリド
TEBAC:トリエチルベンジルアンモニウムクロリド
TFA:トリフルオロ酢酸
THF:テトラヒドロフラン
TLC:薄層クロマトグラフィー
(S)−3−イソプロピル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−5−ブロモ−3−イソプロピル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン(3)の調製。
(S)−6−((1−(3−クロロフェニル)エチル)アミノ)−5−フルオロ−3−イソプロピルピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−6−((1−(3,5−ジフルオロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−6−((シクロプロピル(フェニル)メチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−6−((シクロプロピル(3−メトキシフェニル)メチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−6−((シクロブチル(フェニル)メチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−6−((1−フェニルエチル)アミノ)−3−(テトラヒドロ−2H−ピラン−4−イル)ピリミジン−2,4(1H,3H)−ジオンの調製
(S)−6−((1−(3−メトキシフェニル)エチル)アミノ)−3−(テトラヒドロ−2H−ピラン−4−イル)ピリミジン−2,4(1H,3H)−ジオン(10)の調製。
6−(((S)−1−フェニルエチル)アミノ)−3−(テトラヒドロフラン−3−イル)ピリミジン−2,4(1H,3H)−ジオンの調製
(S)−3−(1−(メチルスルホニル)ピペリジン−4−イル)−6−(1−フェニルエチルアミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−メチル4−(2,6−ジオキソ−4−(1−フェニルエチルアミノ)−2,3−ジヒドロピリミジン−1(6H)−イル)ピペリジン−1−カルボキシレートの調製。
3−(R)−sec−ブチル−6−((S)−1−(3−メトキシフェニル)エチルアミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−6−(1−フェニルエチルアミノ)−3−(ピリジン−3−イル)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−3−(イソオキサゾール−3−イル)−6−(1−フェニルエチルアミノ)ピリミジン−2,4(1H,3H)−ジオン(16)の調製。
(S)−6−((1−(3−(1H−ピラゾール−1−イル)フェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン(17)の調製。
さらなるピリミジンジオン化合物の調製。
表1の化合物が、上記のような実施例に従って調製された。
(S)−6−((1−フェニルエチル)アミノ)−3−プロピルピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−3−(3,5−ジフルオロフェニル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−3−イソプロピル−6−((1−(m−トリル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−6−((1−(4−フルオロフェニル)プロパン−2−イル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオンの調製。
(R)−3−イソプロピル−6−((2,2,2−トリフルオロ−1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン(52)の調製。
3−((R)−1−(ベンジルオキシ)プロパン−2−イル)−6−(((S)−1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
3−((R)−1−ヒドロキシプロパン−2−イル)−6−(((S)−1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン(54)の調製。
(S)−3−イソプロピル−6−((1−(3−(トリフルオロメチル)フェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−3−イソプロピル−6−((1−(2−シアノフェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン(56)の調製。
(S)−3−ベンジル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−3−(2,6−ジフルオロフェニル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオン(58)の調製。
(S)−6−((1−(2,6−ジフルオロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオンの調製。
(R)−6−((1−(2,6−ジフルオロフェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオン(60R)の調製。
(S)−3−イソプロピル−6−((1−(ピリジン−4−イル)プロパン−2−イル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−6−((1−(4−(ベンジルオキシ)フェニル)エチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオンの調製。
(R)−6−((2−(ベンジルオキシ)−1−フェニルエチル)アミノ)−3−イソプロピルピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−3−(6−メチルピリジン−2−イル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−3−(2,2−ジフルオロエチル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−6−((1−(ベンゾ[d][1,3]ジオキソール−5−イル)エチル)アミノ)−3−(2,2,2−トリフルオロエチル)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−3−イソプロピル−6−((1−(o−トリル)エチル)アミノ)ピリミジン−2,4−(1H,3H)−ジオン(68)の調製。
(S)−3−シクロブチル−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−3−イソプロピル−6−((1−(2−(トリフルオロメチル)フェニル)エチル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
(S)−3−(1−メチルシクロプロピル)−6−((1−フェニルエチル)アミノ)ピリミジン−2,4(1H,3H)−ジオンの調製。
さらなるピリミジンジオン化合物の調製。
表1B内の化合物が、上に記載されている実施例(「参照例番号」として提供されている例示的方法)に従って調製された。
ミオシン阻害アッセイ
小分子薬剤が、ウシの心臓ミオシンの酵素活性を阻害するそれらの能力について、心臓ミオシンからのADP(アデノシン二リン酸)の放出をピルビン酸キナーゼおよび乳酸脱水素酵素(PK/LDH)からなる酵素のカップリングシステムに連結する生化学アッセイを用い、時間の関数としてのNADHの吸光度減少(340nmにおける)を監視して評価された。PKは、PEP(ホスホエノールピルビン酸塩)をピルビン酸塩に変換することによってADPをATP(アデノシン三リン酸)に変換する。ピルビン酸塩は、その時、LDHにより、NADH(ニコチンアミドアデニンジヌクレオチド)をNAD(酸化されたニコチンアミドアデニンジヌクレオチド)に変換することによって乳酸塩に変換される。その心臓ミオシンの源は、除膜した筋原線維の形をしているウシの心臓からであった。小分子薬剤を試験する前に、そのウシの筋原線維は、それらのカルシウム応答性が評価され、その小分子薬剤の阻害活性を評価するための最終条件として筋原線維系の50%(pCa50)または75%(pCa75)の活性化を達成するカルシウム濃度が選択された。全ての酵素活性は、12mMのPIPES(ピペラジン−N,N’−ビス(2−エタンスルホン酸))、2mMの塩化マグネシウムを含んでいるpH6.8の緩衝液(PM12緩衝液)中で測定された。最終のアッセイ条件は、1mg/mLのウシ心臓筋原線維、0.4mMのPK/LDH、50μMのATP、0.1mg/mLのBSA(ウシ血清アルブミン)、10ppmの消泡剤、1mMのDTT、0.5mMのNADH、PEP筋原線維の50%または75%活性化を達成するために必要とされる望ましい遊離カルシウム濃度の1.5mMのPEPであった。
活性に対する立体化学的優先度
立体異性体の調和したペアが、上記のようなミオシン活性を阻害するそれらの能力について試験された。その結果は表3にまとめられている。全ての場合において、該(R)立体異性体は、該(S)立体異性体より著しく低い活性である。
心筋細胞収縮力アッセイ
成体ラット心室筋細胞の収縮力が、IonOptix収縮力システムによるエッジ検出によって測定される。タイロード緩衝液(137mMのNaCl、3.7mMのKCl、0.5mMのMgCl2、1.5mMのCaCl2、4mMのHEPES、11mMのグルコース)中の筋細胞のアリコートが、灌流チャンバー(シリーズ20RC−27NE;Warner Instruments)中に配置され、カバースリップに付着するままにされ、次いで37℃のタイロード緩衝液と共に灌流される。筋細胞は1Hzおよび10Vで刺激されてファイルされる。120〜180ミクロンの細胞長、細胞長の3〜8%に等しい基底短縮率、および1秒当たり100ミクロンより大きい収縮速度を有するペーシング前の静止状態の透明な条線を有する筋細胞のみが収縮実験のために使用される。化合物に対する反応を測定するために、筋細胞は、最初60秒間タイロード緩衝液により還流され、次に5分間の化合物が続き、タイロード緩衝液による140秒間の洗い流しが続く。データは、IonOptixソフトウェアを用いて連続的に記録される。収縮力データはIonwizardソフトウェア(IonOptix)を用いて分析される。各細胞に対して、10〜20の収縮力過渡応答が平均化され、基本条件(化合物無し)および化合物で処理された条件の下で比較された。化合物の活性は、短縮率(FS)に対する効果によって測定され、ここで短縮率は、未処理の細胞に対して100%に標準化された基本の細胞長さにより割られた収縮の際の細胞のピークの長さの割合である。
ラットにおける急性薬力学的効果。
代表的な化合物が、インビボのターゲットエンゲージメントの尺度として、ラットにおいて心筋収縮力を調節するそれらの能力について試験された。収縮性の評価尺度の短縮率は、左心室拡張末期径(LVEDd)に対する左心室収縮末期径(LVESd)の変化を記録し、この変化をその割合FS=(LVEDd−LVESd)/LVEDdとして表わすことによって測定された。餌を与えられた雄のSprague−Dawleyラットが、イソフルランにより軽く麻酔をかけられ、ベースライン短縮率が傍胸骨の位置で経胸壁心エコー法(TTE)を用いて測定された。この測定の後に、動物は回収され、経口強制投与により化合物の単回投与(4mg/kg)を受けた。投与3時間後に、第2および第3の心エコー図が、収縮性への薬物作用を測定するために軽い麻酔の下で収集された。効果は、表5にベースライン短縮率のパーセント減少として表されている。
Claims (31)
- 式:
R1は、C3−C4アルキル、C3〜C5シクロアルキル、フェニルおよび5から6員のヘテロアリールからなる群から選択される構成要素であり、ここで各R1は、場合によって1〜3個のRaにより置換されており;
R2は、フェニル、フェニル−C1〜C4アルキルおよびピリジルからなる群から選択される構成要素であり、ここで各R2は、場合によって1〜5個のRbにより置換されており;
R3は、C1〜C4アルキルおよびC3〜C4シクロアルキルからなる群から選択される構成要素であり、ここで各R3は、場合によって1〜3個のRcにより置換されており;
R4は、Hであり;
Xは、HおよびFからなる群から選択される構成要素であり;
各Raは、ハロ、CN、ヒドロキシル、C1〜C4アルキル、C1〜C4ハロアルキル、C1〜C4アルコキシ、フェニル、フェニル−C1〜C4アルキル、フェニル−C1〜C4アルコキシ、フェノキシ、−CORa1、−CO2Ra1、−SO2Ra1、−SO2NRa1Ra2、および−CONRa1Ra2からなる群から独立して選択され、ここで各Ra1およびRa2は、H、C1〜C4アルキルおよびフェニルからなる群から独立して選択され、または場合によってRa1およびRa2は、窒素原子に結合しているとき、組み合わされて4から6員の環を形成しており;
各Rbは、ハロ、CN、ヒドロキシル、C1〜C4アルキル、C1〜C4ハロアルキル、C1〜C4アルコキシ、フェノキシ、フェニル−C1〜C4アルコキシ、メチレンジオキシ、ジフルオロメチレンジオキシ、−CORb1、−CO2Rb1、−SO2Rb1、−SO2NRb1Rb2、−CONRb1Rb2、NRb1Rb2、5から6員のヘテロアリール、および場合によってオキソにより置換されている5から6員のヘテロシクリルからなる群から独立して選択され、ここで各Rb1およびRb2は、HおよびC1〜C4アルキルからなる群から独立して選択され、または場合によってRb1およびRb2は、窒素原子に結合しているとき、組み合わされて4から6員の環を形成しており;
各Rcは、ハロ、ヒドロキシルおよびC1〜C2アルコキシからなる群から独立して選択される、
前記式を有する化合物または薬学的に許容されるその塩。 - R1が、C3〜C4アルキル、C3〜C5シクロアルキル、フェニル、および5から6員のヘテロアリールからなる群から選択される構成要素であり、ここで各R1は、場合によって1〜3個のRaにより置換されており;
R2が、場合によって1〜5個のRbにより置換されているフェニルであり;
R3が、C1〜C4アルキルおよびC3〜C4シクロアルキルからなる群から選択される構成要素であり、ここで各R3は、場合によって1〜2個のRcにより置換されており;
R4が、Hであり;
Xが、HおよびFからなる群から選択される構成要素であり;
各Raが、ハロ、CN、C1〜C4アルキル、C1〜C4アルコキシ、−CORa1、−CO2Ra1、−SO2Ra1、−SO2NRa1Ra2、および−CONRa1Ra2からなる群から独立して選択され、ここで各Ra1およびRa2は、HおよびC1〜C4アルキルからなる群から独立して選択され、または場合によってRa1およびRa2は、窒素原子に結合しているとき、組み合わされて4から6員の環を形成しており;
各Rbが、ハロ、CN、C1〜C4アルキル、C1〜C4アルコキシ、−CORb1、−CO2Rb1、−SO2Rb1、−SO2NRb1Rb2、−CONRb1Rb2、NRb1Rb2、5から6員のヘテロアリール、および場合によってオキソにより置換されている5から6員のヘテロシクリルからなる群から独立して選択され、ここで各Rb1およびRb2は、HおよびC1〜C4アルキルからなる群から独立して選択され、または場合によって Rb1およびRb2は、窒素原子に結合しているとき、組み合わされて4か
ら6員の環を形成しており;
各Rcが、ハロおよびC1〜C2アルコキシからなる群から独立して選択される、
請求項1に記載の化合物または薬学的に許容されるその塩。 - Xが、Hである請求項1もしくは2に記載の化合物、または薬学的に許容されるその塩。
- 各R1は、1〜2個のRaにより場合によって置換されている請求項1もしくは2に記載の化合物、または薬学的に許容されるその塩。
- R1が、フェニルおよび5から6員のヘテロアリールからなる群から選択され、ここで各R1は、1〜3個のRaにより場合によって置換されている請求項1もしくは2に記載の化合物、または薬学的に許容されるその塩。
- R1が、C3〜C4アルキルおよびC3〜C5シクロアルキルからなる群から選択される請求項1もしくは2に記載の化合物、または薬学的に許容されるその塩。
- R1が、シクロブチル、イソプロピル、イソブチル、1−メトキシプロパン−2−イル
、シクロペンチル、フェニル、2−ピリジル、3−ピリジル、3−イソオキサゾリル、5−イソオキサゾリル、および1−メチル−3−ピラゾリルからなる群から選択される請求項1もしくは2に記載の化合物、または薬学的に許容されるその塩。 - R2が、1〜2個のRbにより場合によって置換されている請求項1もしくは2に記載の化合物、または薬学的に許容されるその塩。
- R2が、フェニル、3−メチルフェニル、2−フルオロフェニル、3−フルオロフェニル、4−フルオロフェニル、2,5−ジフルオロフェニル、3,5−ジフルオロフェニル、3−クロロフェニル、3−メトキシフェニル、3−(3−オキサゾリジン−2−オンイル)フェニル、3−(2−メチル−1−イミダジル)フェニル、3−(1−ピラゾリル)フェニル、および3−(1,2,4−トリアゾール−1−イル)フェニルからなる群から選択される請求項1もしくは2に記載の化合物、または薬学的に許容されるその塩。
- R3が、C1〜C4アルキル、C1〜C4アルコキシアルキル、およびC3〜C4シクロアルキルからなる群から選択される請求項1もしくは2に記載の化合物、または薬学的に許容されるその塩。
- R3が、メチル、エチル、プロピル、シクロプロピル、シクロブチルおよび2−メトキシメチルからなる群から選択される請求項1もしくは2に記載の化合物、または薬学的に許容されるその塩。
- R3が、メチルである請求項1〜9のいずれか1項に記載の化合物、または薬学的に許容されるその塩。
- R1が、イソプロピルであり;R2が、1〜2個のRbにより場合によって置換されており;R3が、メチルである請求項1もしくは2に記載の化合物、または薬学的に許容されるその塩。
- R1が、フェニルおよび5から6員のヘテロアリールからなる群から選択され、ここで各R1は、1〜3個のRaにより場合によって置換されており;R2が、1〜2個のRbにより場合によって置換されており;R3が、メチルである請求項1もしくは2に記載の化合物、または薬学的に許容されるその塩。
- 請求項1〜14のいずれか1項に記載の化合物、または薬学的に許容されるその塩、および薬学的に許容される添加剤を含んでいる医薬組成物。
- 肥大型心筋症(HCM)を治療するための医薬であって、請求項1〜14、もしくは17〜18のいずれか1項に記載の化合物または薬学的に許容されるその塩の有効量を含む前記医薬。
- 左室流出路閉塞を減少させる、請求項20に記載の医薬。
- 駆出率が保たれた拡張期心不全、虚血性心疾患、狭心症、および拘束型心筋症からなる群から選択される疾患または障害を治療するための医薬であって、請求項1〜14、もしくは17〜18のいずれか1項に記載の化合物または薬学的に許容されるその塩の有効量を含む前記医薬。
- 容積または圧力過負荷が原因の左室肥大を特徴とし、慢性僧帽弁閉鎖不全、慢性大動脈弁狭窄、および慢性全身性血圧上昇からなる群から選択される疾患または障害を、容積または圧力過負荷の根本原因を是正または軽減することを狙った弁修復/置換または効果的な降圧療法を含む治療と併せて治療するための医薬であって、請求項1〜14、もしくは17〜18のいずれか1項に記載の化合物または薬学的に許容されるその塩の有効量を含む前記医薬。
- 肥大型心筋症(HCM)を治療するための医薬であって、心不全の進行を心臓の神経ホルモンの刺激を下方制御することによって遅らせ、心臓リモデリングを防ぐことを試みる治療剤と組み合わせた請求項1〜14、もしくは17〜18のいずれか1項に記載の化合物または薬学的に許容されるその塩の有効量を含み、該治療剤がACE阻害剤、アンジオテンシン受容体遮断剤(ARB)、β遮断剤、アルドステロン受容体アンタゴニストおよび神経エンドペプチダーゼ阻害剤からなる群より選択される前記医薬。
- 心臓の収縮性を刺激することにより、心機能を改善する治療剤と組み合わされた、有効量の請求項1〜14、もしくは17〜18のいずれか1項に記載の化合物またはその薬学的に許容される塩を含む肥大性心筋症(HCM)を治療するための医薬であって、該治療剤が1つ以上の陽性変力剤である前記医薬。
- 前記陽性変力剤が、β−アドレナリン性アゴニストのドブタミンまたはホスホジエステラーゼ阻害剤ミルリノンである、請求項27に記載の医薬。
- 心前負荷または後負荷を減少させる治療剤と組み合わせた、有効量の請求項1〜14、もしくは17〜18のいずれか1項に記載の化合物またはその医薬上許容される塩を含む、肥大性心筋症(HCM)を治療するための医薬であって、
心前負荷を減少させる治療剤が利尿薬であり、後負荷を減少させる治療剤が血管拡張剤である、前記医薬。 - 前記利尿剤がフロセミドである、請求項29に記載の医薬。
- 前記血管拡張剤が、カルシウムチャネル遮断剤、ホスホジエステラーゼ阻害剤、エンドセリン受容体アンタゴニスト、レニン阻害剤および平滑筋ミオシンモジュレーターからなる群より選択される、請求項29に記載の医薬。
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