JP2015523369A - N置換ベンズアミド及びその使用方法 - Google Patents
N置換ベンズアミド及びその使用方法 Download PDFInfo
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- JP2015523369A JP2015523369A JP2015520701A JP2015520701A JP2015523369A JP 2015523369 A JP2015523369 A JP 2015523369A JP 2015520701 A JP2015520701 A JP 2015520701A JP 2015520701 A JP2015520701 A JP 2015520701A JP 2015523369 A JP2015523369 A JP 2015523369A
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- alkyl
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Abstract
Description
本願は、2012年7月6日に出願された、米国特許仮出願第61/668951号に対する優先権を主張する。本仮出願の全体の内容は参照によって本明細書に組み込まれる。
選択的ナトリウムチャネル遮断薬を同定する戦略に加えて、神経因性疼痛を治療する治療薬を同定する継続戦略が存在する。ある程度の成功は、神経因性疼痛症状の治療において、ガバペンチン、及びより最近ではプレガバリン等の本来抗痙攣薬として認可された処方の使用によるものである。しかしながら、神経因性疼痛の薬物療法が有する成功は、以下の様々な理由:特に抗痙攣薬若しくは抗うつ薬として最初に開発された薬剤による鎮静、特にアヘン製剤による嗜癖若しくはタキフィラキシー、又は特にNSAID及び抗炎症薬による効果不足、のため一般的に限定的な成功である。結果的に、神経因性疼痛の新規の治療法を探究する必要がいまだ相当存在し、神経因性疼痛は、これらに限定されないが、ヘルペス後神経痛、三叉神経痛、糖尿病性神経障害、慢性腰痛、幻肢痛、並びにがん及び化学療法が原因の疼痛、慢性骨盤痛、複合性局所疼痛症候群、並びに関連する神経痛を含む。
R1は、−NR1AR1B、−X1R−NR1AR1B、−X1R−OR1A、1〜4個の窒素原子を含む5〜10員ヘテロアリール環、及び1〜3個の窒素原子を含む4〜10員C連鎖ヘテロシクロアルキルからなる群から選択され;RIA及びRIBは、各々独立して、水素、C1〜8アルキル、−C(=Y1)ORR1C、−C(=Y1)R1C、−C(=Y1)N(RR1C)2、−(X1R)0〜1RX、及びC1〜8アルコキシからなる群から選択され;又はRIA及びRIBを組み合わせて、環頂点としてN、O、及びSから選択された1〜3個のさらなるヘテロ原子を含んでいてもよい4〜10員複素環を形成してもよく;RR1Cは、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C2〜7ヘテロシクロアルキル、フェニル、ベンジル、及び5〜6員ヘテロアリールからなる群から選択され;X1Rは、独立して、C1〜4アルキレン、C1〜4ヘテロアルキレン、C2〜4アルケニレン、及びC2〜4アルキニレンからなる群から選択され、ここでX1Rは、オキソ及びチオキソから選択される1つ以上の基と置換されていてもよく;Y1は、独立してO又はSであり;RXは、独立して、6〜10員アリール、5〜10員ヘテロアリール、C3〜8シクロアルキル、及びC2〜7ヘテロシクロアルキルからなる群から選択され;並びに式中R1は、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル−(X1R)0〜1−、C3〜8ヘテロシクロアルキル−(X1R)0〜1−、6〜10員アリール−(X1R)0〜1−、5〜10員ヘテロアリール−(X1R)0〜1−、F、Cl、Br、I、−CN、−NO2、−(X1R)0〜1NRR1aRR1b、−(X1R)0〜1ORR1a、−(X1R)0〜1SRR1a、−(X1R)0〜1N(RR1a)C(=Y1)ORR1c、−(X1R)0〜1OC(=O)N(RR1a)(RR1b)、−(X1R)0〜1N(RR1a)C(=O)N(RR1a)(RR1b)、−(X1R)0〜1C(=O)N(RR1a)(RR1b)、−(X1R)0〜1N(RR1a)C(=O)RR1b、−(X1R)0〜1C(=O)ORR1a、−(X1R)0〜1OC(=O)RR1a、−(X1R)0〜1−P(=O)(ORR1a)(ORR1b)、−(X1R)0〜1S(O)1〜2RR1c、−(X1R)0〜1S(O)1〜2N(RR1a)(RR1b)、−(X1R)0〜1N(RR1a)S(O)1〜2N(RR1a)(RR1b)、及び−(X1R)0〜1N(RR1a)S(O)1〜2(RR1c)からなる群から独立して選択される1〜5個の置換基と、さらに置換されていてもよく;RR1a及びRR1bは、各々独立して、水素、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1〜8アルコキシからなる群から選択され;又はRR1a及びRR1bは、それらが付着している窒素と共に、モルホリノ、ピペリジノ、又はピペラジニル環を形成し、ここで前記環は、C1〜8アルキル、ハロ、ヒドロキシ、C1〜8アルキルアミノ、C1〜8ジアルキルアミノ、C1〜8ハロアルキル、及びC1〜8ヒドロキシアルキルから独立して選択される1つ以上の基と置換されていてもよく;RR1cは、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1〜8アルコキシからなる群から選択され;
RNは、水素、C1〜4アルキル、又はC1〜4ハロアルキルであり;
D1は、N又はC(RD1)であり;
D3は、N又はC(RD3)であり;
RD1、RD2、RD3、及びRD4は、各々独立して、H、F、Cl、Br、I、−CN、C1〜8アルキル、C1〜8ハロアルキル、C1〜8アルコキシ、C3〜8シクロアルキル、C2〜7ヘテロシクロアルキル、フェニル、及びN、O、及びSから選択された1〜3個のヘテロ原子を含む5〜6員ヘテロアリールからなる群から選択され、ここで前記5〜6員ヘテロアリールは、F、Cl、Br、I、−CN、C1〜4アルキル、C1〜4ハロアルキル、及びC14アルコキシから選択された1〜3個の置換基とさらに置換されていてもよく;
Lは、C1〜4アルキレン、C2〜4アルケニレン、C2〜4アルキニレン、及びC1〜4ヘテロアルキレンからなる群から選択されるリンカーであり、ここでLは=O、C1〜4アルキル、C1〜4ハロアルキル、及びC1〜4アシルからなる群から独立して選択された1〜3個の置換基と置換されていてもよく;
添字mは、整数0又は1を表し;
X1及びX2は、各々独立して、非存在、−O−、−S−、−S(O)−、−S(O)2−、−N(H)−、及び−N(Rx1)−からなる群から選択され、ここでRx1とはC1〜8アルキル、C1〜8アシル、又は−S(O)2(C1〜8アルキル)であり、添字mが0である場合、X1又はX2のうち1つは非存在であり;
添字nは、0〜5の整数であり;
A環は、6〜10員アリール又はN、O、及びSから選択された1〜3個のヘテロ原子を含む5〜10員ヘテロアリールを表し;
各々の存在でRAは、独立して、H、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル−(XRA)0〜1、C3〜8ハロシクロアルキル−(XRA)0〜1、C1−8シアノアルキル、C1〜8ヒドロキシアルキル、C3〜8シクロアルキル−C1〜8アルキル、F、Cl、Br、I、−CN、−NO2、C2〜9ヘテロシクロアルキル−(XRA)0〜1−、C6〜10員アリール−(XRA)0〜1−、5〜6員ヘテロアリール−(XRA)0〜1−、−(XRA)0〜1NRA1RA2、−(XRA)0〜1ORA1、−(XRA)0〜1SRA1、−(XRA)0〜1N(RA1)C(=O)ORA3、−(XRA)0〜1OC(=O)N(RA1)(RA2)、−(XRA)0〜1N(RA1)C(=O)N(RAI)(RA2)、−(XRA)0〜1C(=O)N(RA1)(RA2)、−(XRA)0〜1N(RA1)C(=O)RA2、−(XRA)0〜1C(=O)RA1、−(XRA)0〜1C(=O)ORAI、−(XRA)0〜1OC(=O)RA1、−P(=O)(ORAI)(0RA2)、−(XRA)0〜1S(O)1〜2RA3、−(XRA)0〜1S(O)1〜2N(RA1)(RA2)、−(XRA)0〜1N(RA1)S(O)1〜2N(RA1)(RA2)、及び−(XRA)0〜1N(RAI)S(O)1〜2(RA3)からなる群から選択され;各XRAは、独立して、C1〜4アルキレン、C1〜4ヘテロアルキレン、C2〜4アルケニレン、及びC2〜4アルキニレンからなる群から選択され、ここでC1〜4アルキレン、C1〜4ヘテロアルキレン、C2〜4アルケニレン、及びC2〜4アルキニレンはオキソ及びチオキソから選択された1つ以上の基と置換されていてもよく;RAI及びRA2は、独立して、水素、C1〜8アルキル、C1〜8ハロアルキル、C1〜8ヒドロキシアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1〜8アルコキシから選択され;又はRA1及びRA2は、それらが付着している窒素と共に、モルホリノ、ピペリジノ、又はピペラジニル環を形成し、ここで環は1つ以上のC1〜8アルキル、ハロ、ヒドロキシ、C1〜8ハロアルキル、及びC1〜8ヒドロキシアルキルと置換されていてもよく;RA3は、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1〜8アルコキシからなる群から選択され;式中RAは、F、Cl、Br、I、−NH2、−OH、−CN、−NO2、オキソ(=O)、C1〜4アルキル、C1〜4ハロアルキル、C1〜4アルコキシ、C1〜4ハロアルキル−C(=O)−、C1〜4ハロアルキル−S(O)0〜2−、C1〜4ハロアルキル−C(=O)N(H)−、C1〜4ハロアルキル−N(H)−C(=O)−、(ハロアルキル)2N−C(=O)−、C1〜4ハロアルキル−OC(=O)N(H)−、C1〜4ハロアルキル−OC(=O)N(H)−、ハロアルキル−N(H)−C(=O)O−、(ハロアルキル)2N−C(=O)O−、C1〜4アルキルアミノ、C1〜4ジアルキルアミノ、C3〜6シクロアルキル、C3〜6シクロアルコキシ、C2〜5ヘテロシクロアルコキシ、及びテトラヒドロナフタレンからなる群から独立して選択された1〜5個の置換基とさらに置換されていてもよい。
R1は、−NR1AR1B、−X1R−NR1AR1B、−X1R−OR1A、1〜4個の窒素原子を含む5〜10員ヘテロアリール環、及び1〜3個の窒素原子を含む4〜10員C連鎖ヘテロシクロアルキルからなる群から選択され;RIA及びRIBは、各々独立して、水素、C1〜8アルキル、−C(=Y1)ORR1C、−C(=Y1)R1C、−C(=Y1)N(RR1C)2、−(X1R)0〜1RX、及びC1〜8アルコキシからなる群から選択され;又はRIA及びRIBを組み合わせて、環頂点としてN、O、及びSから選択された1〜3個のさらなるヘテロ原子を含んでいてもよい4〜10員複素環を形成してもよく;RR1Cは、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C2〜7ヘテロシクロアルキル、フェニル、ベンジル、及び5〜6員ヘテロアリールからなる群から選択され;X1Rは、独立して、C1〜4アルキレン、C1〜4ヘテロアルキレン、C2〜4アルケニレン、及びC2〜4アルキニレンからなる群から選択され、ここでX1Rは、オキソ及びチオキソから選択される1つ以上の基と置換されていてもよく;Y1は、独立してO又はSであり;RXは、独立して、6〜10員アリール、5〜10員ヘテロアリール、C3〜8シクロアルキル、及びC2〜7ヘテロシクロアルキルからなる群から選択され;並びに式中R1は、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル−(X1R)0〜1−、C3〜8ヘテロシクロアルキル−(X1R)0〜1−、6〜10員アリール−(X1R)0〜1−、5〜10員ヘテロアリール−(X1R)0〜1−、F、Cl、Br、I、−CN、−NO2、−(X1R)0〜1NRR1aRR1b、−(X1R)0〜1ORR1a、−(X1R)0〜1SRR1a、−(X1R)0〜1N(RR1a)C(=Y1)ORR1c、−(X1R)0〜1OC(=O)N(RR1a)(RR1b)、−(X1R)0〜1N(RR1a)C(=O)N(RR1a)(RR1b)、−(X1R)0〜1C(=O)N(RR1a)(RR1b)、−(X1R)0〜1N(RR1a)C(=O)RR1b、−(X1R)0〜1C(=O)ORR1a、−(X1R)0〜1OC(=O)RR1a、−(X1R)0〜1−P(=O)(ORR1a)(ORR1b)、−(X1R)0〜1S(O)1〜2RR1c、−(X1R)0〜1S(O)1〜2N(RR1a)(RR1b)、−(X1R)0〜1N(RR1a)S(O)1〜2N(RR1a)(RR1b)、及び−(X1R)0〜1N(RR1a)S(O)1〜2(RR1c)からなる群から独立して選択される1〜5個の置換基と、さらに置換されていてもよく;RR1a及びRR1bは、各々独立して、水素、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1 〜 8アルコキシからなる群から選択され;又はRR1a及びRR1bは、それらが付着している窒素と共に、モルホリノ、ピペリジノ、又はピペラジニル環を形成し、ここで前記環は、C1〜8アルキル、ハロ、ヒドロキシ、C1〜8アルキルアミノ、C1〜8ジアルキルアミノ、C1〜8ハロアルキル、及びC1〜8ヒドロキシアルキルから独立して選択される1つ以上の基と置換されていてもよく;RR1cは、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1〜8アルコキシからなる群から選択され;
RNは、水素、C1〜4アルキル、又はC1〜4ハロアルキルであり;
D1は、N又はC(RD1)であり;
D3は、N又はC(RD3)であり;
RD1、RD2、RD3、及びRD4は、各々独立して、H、F、Cl、Br、I、−CN、C1〜8アルキル、C1〜8ハロアルキル、C1〜8アルコキシ、C3〜8シクロアルキル、C2〜7ヘテロシクロアルキル、フェニル、及びN、O、及びSから選択された1〜3個のヘテロ原子を含む5〜6員ヘテロアリールからなる群から選択され、ここで前記5〜6員ヘテロアリールは、F、Cl、Br、I、−CN、C1〜4アルキル、C1〜4ハロアルキル、及びC14アルコキシから選択された1〜3個の置換基とさらに置換されていてもよく;
Lは、C1〜4アルキレン、C2〜4アルケニレン、C2〜4アルキニレン、及びC1〜4ヘテロアルキレンからなる群から選択されるリンカーであり、ここでLは=0、C1〜4アルキル、C1〜4ハロアルキル、及びC1〜4アシルからなる群から独立して選択された1〜3個の置換基と置換されていてもよく;
添字mは、整数0又は1を表し;
X1及びX2は、各々独立して、非存在、−O−、−S−、−S(O)−、−S(O)2−、−N(H)−、及び−N(Rx1)−からなる群から選択され、ここでRx1とはC1〜8アルキル、C1〜8アシル、又は−S(O)2(C1〜8アルキル)であり、添字mが0である場合、X1又はX2のうち1つは非存在であり;
添字nは、0〜5の整数であり;
A環は、6〜10員アリール又はN、O、及びSから選択された1〜3個のヘテロ原子を含む5〜10員ヘテロアリールを表し;
各々の存在でRAは、独立して、H、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル−(XRA)0〜1、C3〜8ハロシクロアルキル−(XRA)0〜1、C1−8シアノアルキル、C1〜8ヒドロキシアルキル、C3〜8シクロアルキル−C1〜8アルキル、F、Cl、Br、I、−CN、−NO2、C2〜9ヘテロシクロアルキル−(XRA)0〜1−、C6〜10員アリール−(XRA)0〜1−、5〜6員ヘテロアリール−(XRA)0〜1−、−(XRA)0〜1NRA1RA2、−(XRA)0〜1ORA1、−(XRA)0〜1SRA1、−(XRA)0〜1N(RA1)C(=O)ORA3、−(XRA)0〜1OC(=O)N(RA1)(RA2)、−(XRA)0〜1N(RA1)C(=O)N(RAI)(RA2)、−(XRA)0〜1C(=O)N(RA1)(RA2)、−(XRA)0〜1N(RA1)C(=O)RA2、−(XRA)0〜1C(=O)RA1、−(XRA)0〜1C(=O)ORAI、−(XRA)0〜1OC(=O)RA1、−P(=O)(ORAI)(0RA2)、−(XRA)0〜1S(O)1〜2RA3、−(XRA)0〜1S(O)1〜2N(RA1)(RA2)、−(XRA)0〜1N(RA1)S(O)1〜2N(RA1)(RA2)、及び−(XRA)0〜1N(RAI)S(O)1〜2(RA3)からなる群から選択され;各XRAは、独立して、C1〜4アルキレン、C1〜4ヘテロアルキレン、C2〜4アルケニレン、及びC2〜4アルキニレンからなる群から選択され、ここでC1〜4アルキレン、C1〜4ヘテロアルキレン、C2〜4アルケニレン、及びC2〜4アルキニレンはオキソ及びチオキソから選択された1つ以上の基と置換されていてもよく;RAI及びRA2は、独立して、水素、C1〜8アルキル、C1〜8ハロアルキル、C1〜8ヒドロキシアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1〜8アルコキシから選択され;又はRA1及びRA2は、それらが付着している窒素と共に、モルホリノ、ピペリジノ、又はピペラジニル環を形成し、ここで環は1つ以上のC1〜8アルキル、ハロ、ヒドロキシ、C1〜8ハロアルキル、及びC1〜8ヒドロキシアルキルと置換されていてもよく;RA3は、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1〜8アルコキシからなる群から選択され;式中RAは、F、Cl、Br、I、−NH2、−OH、−CN、−NO2、オキソ(=O)、C1〜4アルキル、C1〜4ハロアルキル、C1〜4アルコキシ、C1〜4ハロアルキル−C(=O)−、C1〜4ハロアルキル−S(O)0〜2−、C1〜4ハロアルキル−C(=O)N(H)−、C1〜4ハロアルキル−N(H)−C(=O)−、(ハロアルキル)2N−C(=O)−、C1〜4ハロアルキル−OC(=O)N(H)−、C1〜4ハロアルキル−OC(=O)N(H)−、ハロアルキル−N(H)−C(=O)O−、(ハロアルキル)2N−C(=O)O−、C1〜4アルキルアミノ、C1〜4ジアルキルアミノ、C3〜6シクロアルキル、C3〜6シクロアルコキシ、C2〜5ヘテロシクロアルコキシ、及びテトラヒドロナフタレンからなる群から独立して選択された1〜5個の置換基とさらに置換されていてもよい。
は、以下:
から選択される。
1) そう痒作動性刺激薬(pruritinergic stimulants)が電位開口型ナトリウムチャンネルを通じてナトリウム流入を必要とするC線維における電気的活動の伝播
2) NaV1.7がヒトの皮膚上のC線維及びケラチノサイトにおいて発現する(Zhao,P.,et al.,Pain(2008),139:90−105)。
3) 肢端紅痛症を引き起こすNaV1.7(L858F)の機能突然変異の獲得が、慢性的なかゆみもまた引き起こす(Li,Y.,et al.,Clinical and Experimental Dermatology(2009),34:e313−e4)。
4) 慢性的なかゆみを局所麻酔性リドカイン等のナトリウムチャネル遮断薬による治療で軽減することができる(Oaklander,A.L.,et al.,Pain(2002),96:9−12;Villamil,A.G.,et al.,The American Journal of Medicine(2005),118:1160−3)。これらの報告では、静脈内又は局所的(Lidodermパッチ)のいずれかで投与した場合、リドカインが効果的であった。全身的に投与した場合に達した血漿中濃度でリドカインは複数の活性を有することができるが、but 局所的に投与した場合、血漿中濃度はわずか約1μMである(Center for Drug Evaluation and Research NDA 20−612)。これらの濃度で、リドカインはナトリウムチャネル遮断に選択的であり、かつ動物モデルにおいてC線維での自発的な電気的活動及び疼痛反応を阻害する(Xiao,W.H.,and Bennett,G.J..Pain(2008),137:218−28)。かゆみ又は皮膚刺激の型として、これらに限定されないが、以下が挙げられる:
a) 乾癬性そう痒、血液透析によるかゆみ、水原性そう痒症、及び皮膚障害が原因のかゆみ(例えば、接触性皮膚炎)、全身性疾患、神経障害、心因性要因、又はそれらの混合;
b) アレルギー反応が原因のかゆみ、虫刺され、過敏症(例えば、皮膚乾燥、挫創、湿疹、乾癬)、炎症状態、又は外傷;
c) 外陰部前庭炎と関連するかゆみ;並びに
d) 例えば、抗生物質、抗ウイルス剤、及び抗ヒスタミン剤等の別の治療の投与による皮膚刺激又は炎症効果。
・麻薬性鎮痛剤、例えば、モルヒネ、ヘロイン、コカイン、オキシモルヒネ、レボルファノール、レバロルファン、オキシコドン、コデイン、ジヒドロコデイン、プロポキシフェン、ネルメフェン、フェンタニル、ヒドロコドン、ヒドロモルホン、メリピジン(meripidine)、メサドン、ナロルフィン、ナロキソン、ナルトレキソン、ブプレノルフィン、ブトルファノール、ナルブフィン、及びペンタゾシン;
・非麻薬性鎮痛剤、例えば、アセトメニフェン(acetomeniphen)、サリチレート(例えば、アスピリン);
・非ステロイド性抗炎症薬(NSAID)、例えば、イブプロフェン、ナプロキセン、フェノプロフェン、ケトプロフェン、セレコキシブ、ジクロフェナク、ジフルシナル、エトドラク、フェンブフェン、フェノプロフェン、フルフェニサル、フルルビプロフェン、イブプロフェン、インドメタシン、ケプトロフェン、ケトロラク、メクロフェナム酸、メフェナム酸、メロキシカム、ナブメトン、ナプロキセン、ニメスリド、ニトロフルルビプロフェン、オルサラジン、オキサプロジン、フェニルブタゾン、ピロキシカム、スルファサラジン、スリンダク、トルメチン、及びゾメピラック;
・抗痙攣薬、例えば、カルバマゼピン、オキシカルバゼピン、ラモトリジン、バルプロ酸、トピラメート、ガバペンチン、及びプレガバリン;
・三環系抗うつ薬等の抗うつ薬、例えば、アミトリプチリン、クロミプラミン、デシプラミン(despramine)、イミプラミン、及びノルトリプチリン;
・COX−2選択的阻害薬、例えば、セレコキシブ、ロフェコキシブ、パレコキシブ、バルデコキシブ、デラコキシブ、エトリコキシブ、及びルミラコキシブ;
・α−アドレナリン作動性神経薬、例えば、ドキサゾシン、タムスロシン、クロニジン、グアンファシン、デキシメタトミジン(dexmetatomidine)、モダニフィル、及び4−アミノ−6,7−ジメトキシ−2−(5−メタンスルホンアミド−1,2,3,4−テトラヒドロイソキノール−2−イル)−5−(2−ピリジル)キナゾリン;
・バルビツール系鎮静薬、例えば、アモバルビタール、アプロバルビタール、ブタバルビタール、ブタビタール(butabital)、メホバルビタール、メタルビタール、メトヘキシタール、ペントバルビタール、フェノバルチタール(phenobartital)、セコバルビタール、タルブタール、テアミラール(theamylal)、及びチオペンタール;
・タキキニン(NK)遮断薬、特にNK−3、NK−2、又はNK−1遮断薬、例えば、(aR、9R)−7−[3,5−ビス(トリフルオロメチル)ベンジル)]−8,9,10,11−テトラヒドロ−9−メチル−5−(4−メチルフェニル)−7H−[1,4]ジアゾシノ[2,1−g][1,7]−ナフチリジン−6−13−ジオン(TAK−637)、5−[[2R,3S)−2−[(1R)−143,5−ビス(トリフルオロメチルフェニル]エトキシ−3−(4−フルオロフェニル)−4−モルホリニルl−メチル]−1,2−ジヒドロ−3H−1,2,4−トリアゾール−3−オン(MK−869)、アプレピタント、ラネピタント(lanepitant)、ダピタント(dapitant)、又は3−[[2−メトキシ5−(トリフルオロメトキシ)フェニル]−メチルアミノ]−2−フェニルピペリジン(2S,3S);
・コールタール鎮痛剤、特にパラセタモール;
・セロトニン再取り込み阻害薬、例えば、パロキセチン、セルトラリン、ノルフルオキセチン(フルオキセチンデスメチル代謝産物)、デメチルセルトラリン代謝産物、‘3フルボキサミン、パロキセチン、シタロプラム、シタロプラム代謝産物デスメチルシタロプラム、エシタロプラム、d,l−フェンフルラミン、フェモキセチン、イフォキセチン、シアノドチエピン、リトキセチン、ダポキセチン、ネファゾドン、セリクラミン、トラゾドン、及びフルオキセチン;
・ノルアドレナリン(ノルエピネフリン)再取り込み阻害薬、例えば、マプロチリン、ロフェプラミン、ミルタゼピン(mirtazepine)、オキサプロチリン、フェゾラミン、トモキセチン、ミアンセリン、ブプロプリオン、ブプロプリオン代謝産物ヒドロキシブプロプリオン、ノミフェンシン、及びビロキサジン(Vivalan(登録商標)))、ロボキセチン、特に(S,S)−レボキセチン、及びベンラファキシンデュロキセチン神経遮断薬鎮痛剤/抗不安薬等の、特に選択的ノルアドレナリン再取り込み阻害薬;
・ベンラファキシン、ベンラファキシン代謝産物O−デスメチルベンラファキシン、クロミプラミン、クロミプラミン代謝産物デスメチルクロミプラミン、デュロキセチン、ミルナシプラン、及びイミプラミン等の、二重セトロニン・ノルアドレナリン再取り込み阻害薬;
・ドネペジル等のアセチルコリエステラーゼ阻害剤;
・オンダンセトロン等の5−HT3遮断薬;
・代謝型グルタミン酸受容体(mGluR)遮断薬;
・メキシレチン及びリドカイン等の局所麻酔;
・デキサメタゾン等の副腎皮質ステロイド;
・例えば、メキシレチン及びフェニトイン等の抗不整脈薬;
・ムスカリン受容体遮断薬、例えば、トルテロジン、プロピベリン、トロプシウム t 塩化物(tropsium t chloride)、ダリフェナシン、ソリフェナシン、テミベリン、及びイプラトロピウム;
・カンナビノイド;
・バニロイド受容体作動薬(例えば、レシンフェラトキシン(resinferatoxin))又は遮断薬(例えば、カプサゼピン);
・鎮痛剤、例えば、グルテチミド、メプロバメート、メタカロン、及びジクロラルフェナゾン;
・ベンゾジアゼピン等の抗不安薬、
・ミルタザピン等の抗うつ薬、
・局所用剤(例えば、リドカイン、カプサイシン、及びレシニフェロトキシン(resiniferotoxin));
・ベンゾジアゼピン、バクロフェン、カリソプロドール、クロルゾキサゾン、シクロベンザプリン、メトカルバモール、及びオルフレナジン(orphrenadine)等の筋弛緩剤;
・抗ヒスタミン又はHl遮断薬;
・NMDA受容体遮断薬;
・5−HT受容体作動薬/遮断薬;
・PDEV阻害薬;
・Tramadol(登録商標);
・コリン作動性(ニコチン性)鎮痛剤;
・α−2−δリガンド;
・プロスタグランジンE2サブタイプ遮断薬;
・ロイコトリエンB4遮断薬;
・5−リポキシゲナーゼ阻害薬;並びに
・5−HT3遮断薬。
これらの実施例は、本発明の化合物、組成物および方法を調製し、使用するためのガイダンスを当業者に提供するために提示した。本発明の特定の実施形態を記載するが、本発明の精神および範囲から逸脱することなく様々な変化例および変形例を作製することができることを当業者は理解するだろう。
EtOAc 酢酸エチル
DBU 1,8−ジアザビシクロ[5.4.0]ウンデカ−7−エン
DCE ジクロロエタン
DCM ジクロロメタン
DIPEA ジイソプロピルエチルアミン
DME エチレングリコールジメチルエーテル
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
HC1 塩酸
HPLC 高速液体クロマトグラフィー
IMS 工業用変性アルコール
LCMS 液体クロマトグラフィー質量分析
MeOH メタノール
RPHPLC 逆相高圧液体クロマトグラフィー
RT 保持時間
THE テトラヒドロフラン
TFA トリフルオロ酢酸
ホルマリン試験は、急性痛の動物モデルに使用される。ホルマリンテストでは、実験日の前に、20分間プレキシガラス試験室に動物を慣らす。試験日に試験物を無作為に動物に注射する。投薬から30分で、50μLの10%のホルマリンを、ラットの左後足の足底表面に皮下注射する。ホルマリン投与後すぐにビデオデータの取得を開始し、90分間続ける。
MPIE(%)=100−[(治療の和/平均ビヒクル値)X100%]。
痛み評価=[0(To)+1(T1)+2(T2)+3(T3)]/(To+T1+T2+T3)
(1)L5脊髄神経の結紮
(2)L5およびL6脊髄神経の結紮
(3)L5脊髄神経の結紮および切断
(4)L5およびL6脊髄神経の結紮および切断
(5)上述(1)〜(4)のいずれか1つと組み合わせてL4脊髄神経の軽度刺激性
Claims (63)
- 式Iの化合物:
又はその薬剤的に許容可能な塩であって、式I中:
R1は、−NR1AR1B、−X1R−NR1AR1B、−X1R−OR1A、1〜4個の窒素原子を含む5〜10員ヘテロアリール環、及び1〜3個の窒素原子を含む4〜10員C連鎖ヘテロシクロアルキルからなる群から選択され;RIA及びRIBは、各々独立して、水素、C1〜8アルキル、−C(=Y1)ORR1C、−C(=Y1)RR1C、−C(=Y1)N(RR1C)2、−(X1R)0〜1RX、及びC1〜8アルコキシからなる群から選択され;又はRIA及びRIBを組み合わせて、環頂点としてN、O、及びSから選択された1〜3個のさらなるヘテロ原子を含んでいてもよい4〜10員複素環を形成してもよく;RR1Cは、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C2〜7ヘテロシクロアルキル、フェニル、ベンジル、及び5〜6員ヘテロアリールからなる群から選択され;X1Rは、独立して、C1〜4アルキレン、C1〜4ヘテロアルキレン、C2〜4アルケニレン、及びC2〜4アルキニレンからなる群から選択され、ここでX1Rは、オキソ及びチオキソから選択される1つ以上の基と置換されていてもよく;Y1は、独立してO又はSであり;RXは、独立して、6〜10員アリール、5〜10員ヘテロアリール、C3〜8シクロアルキル、及びC2〜7ヘテロシクロアルキルからなる群から選択され;並びに式中R1は、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル−(X1R)0〜1−、C3〜8ヘテロシクロアルキル−(X1R)0〜1−、6〜10員アリール−(X1R)0〜1−、5〜10員ヘテロアリール−(X1R)0〜1−、F、Cl、Br、I、−CN、−NO2、−(X1R)0〜1NRR1aRR1b、−(X1R)0〜1ORR1a、−(X1R)0〜1SRR1a、−(X1R)0〜1N(RR1a)C(=Y1)ORR1c、−(X1R)0〜1OC(=O)N(RR1a)(RR1b)、−(X1R)0〜1N(RR1a)C(=O)N(RR1a)(RR1b)、−(X1R)0〜1C(=O)N(RR1a)(RR1b)、−(X1R)0〜1N(RR1a)C(=O)RR1b、−(X1R)0〜1C(=O)ORR1a、−(X1R)0〜1OC(=O)RR1a、−(X1R)0〜1−P(=O)(ORR1a)(ORR1b)、−(X1R)0〜1S(O)1〜2RR1c、−(X1R)0〜1S(O)1〜2N(RR1a)(RR1b)、−(X1R)0〜1N(RR1a)S(O)1〜2N(RR1a)(RR1b)、及び−(X1R)0〜1N(RR1a)S(O)1〜2(RR1c)からなる群から独立して選択される1〜5個の置換基と、さらに置換されていてもよく;RR1a及びRR1bは、各々独立して、水素、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1〜8アルコキシからなる群から選択され;又はRR1a及びRR1bは、それらが付着している窒素と共に、モルホリノ、ピペリジノ、又はピペラジニル環を形成し、ここで前記環は、C1〜8アルキル、ハロ、ヒドロキシ、C1〜8アルキルアミノ、C1〜8ジアルキルアミノ、C1〜8ハロアルキル、及びC1〜8ヒドロキシアルキルから独立して選択される1つ以上の基と置換されていてもよく;RR1cは、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1〜8アルコキシからなる群から選択され;
RNは、水素、C1〜4アルキル、又はC1〜4ハロアルキルであり;
D1は、N又はC(RD1)であり;
D3は、N又はC(RD3)であり;
RD1、RD2、RD3、及びRD4は、各々独立して、H、F、Cl、Br、I、−CN、C1〜8アルキル、C1〜8ハロアルキル、C1〜8アルコキシ、C3〜8シクロアルキル、C2〜7ヘテロシクロアルキル、フェニル、及びN、O、及びSから選択された1〜3個のヘテロ原子を含む5〜6員ヘテロアリールからなる群から選択され、ここで前記5〜6員ヘテロアリールは、F、Cl、Br、I、−CN、C1〜4アルキル、C1〜4ハロアルキル、及びC1-4アルコキシから選択された1〜3個の置換基とさらに置換されていてもよく;
Lは、C1〜4アルキレン、C2〜4アルケニレン、C2〜4アルキニレン、及びC1〜4ヘテロアルキレンからなる群から選択されるリンカーであり、ここでLは=O、C1〜4アルキル、C1〜4ハロアルキル、及びC1〜4アシルからなる群から独立して選択された1〜3個の置換基と置換されていてもよく;
添字mは、整数0又は1を表し;
X1及びX2は、各々独立して、非存在、−O−、−S−、−S(O)−、−S(O)2−、−N(H)−、及び−N(Rx1)−からなる群から選択され、ここでRx1とはC1〜8アルキル、C1〜8アシル、又は−S(O)2(C1〜8アルキル)であり、添字mが0である場合、X1又はX2のうち1つは非存在であり;
添字nは、0〜5の整数であり;
A環は、6〜10員アリール又はN、O、及びSから選択された1〜3個のヘテロ原子を含む5〜10員ヘテロアリールを表し;
各々の存在でRAは、独立して、H、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル−(XRA)0〜1、C3〜8ハロシクロアルキル−(XRA)0〜1、C1−8シアノアルキル、C1〜8ヒドロキシアルキル、C3〜8シクロアルキル−C1〜8アルキル、F、Cl、Br、I、−CN、−NO2、C2〜9ヘテロシクロアルキル−(XRA)0〜1−、C6〜10員アリール−(XRA)0〜1−、5〜6員ヘテロアリール−(XRA)0〜1−、−(XRA)0〜1NRA1RA2、−(XRA)0〜1ORA1、−(XRA)0〜1SRA1、−(XRA)0〜1N(RA1)C(=O)ORA3、−(XRA)0〜1OC(=O)N(RA1)(RA2)、−(XRA)0〜1N(RA1)C(=O)N(RAI)(RA2)、−(XRA)0〜1C(=O)N(RA1)(RA2)、−(XRA)0〜1N(RA1)C(=O)RA2、−(XRA)0〜1C(=O)RA1、−(XRA)0〜1C(=O)ORAI、−(XRA)0〜1OC(=O)RA1、−P(=O)(ORAI)(0RA2)、−(XRA)0〜1S(O)1〜2RA3、−(XRA)0〜1S(O)1〜2N(RA1)(RA2)、−(XRA)0〜1N(RA1)S(O)1〜2N(RA1)(RA2)、及び−(XRA)0〜1N(RAI)S(O)1〜2(RA3)からなる群から選択され;各XRAは、独立して、C1〜4アルキレン、C1〜4ヘテロアルキレン、C2〜4アルケニレン、及びC2〜4アルキニレンからなる群から選択され、ここでC1〜4アルキレン、C1〜4ヘテロアルキレン、C2〜4アルケニレン、及びC2〜4アルキニレンはオキソ及びチオキソから選択された1つ以上の基と置換されていてもよく;RAI及びRA2は、独立して、水素、C1〜8アルキル、C1〜8ハロアルキル、C1〜8ヒドロキシアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1〜8アルコキシから選択され;又はRA1及びRA2は、それらが付着している窒素と共に、モルホリノ、ピペリジノ、又はピペラジニル環を形成し、ここで環は1つ以上のC1〜8アルキル、ハロ、ヒドロキシ、C1〜8ハロアルキル、及びC1〜8ヒドロキシアルキルと置換されていてもよく;RA3は、C1〜8アルキル、C1〜8ハロアルキル、C3〜8シクロアルキル、C3〜8シクロアルキル−C1〜8アルキル、C3〜8シクロアルキル−C1〜8アルコキシ、テトラヒドロナフタレン、フェニル、フェニル−C1〜8アルキル、フェニル−C1〜8アルコキシ、5〜6員ヘテロアリール、5〜6員ヘテロアリール−C1〜8アルキル、5〜6員ヘテロアリール−C1〜8アルコキシ、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル−C1〜8アルキル、3〜7員ヘテロシクロアルキル−C1〜8アルコキシからなる群から選択され;式中RAは、F、Cl、Br、I、−NH2、−OH、−CN、−NO2、オキソ(=O)、C1〜4アルキル、C1〜4ハロアルキル、C1〜4アルコキシ、C1〜4ハロアルキル−C(=O)−、C1〜4ハロアルキル−S(O)0〜2−、C1〜4ハロアルキル−C(=O)N(H)−、C1〜4ハロアルキル−N(H)−C(=O)−、(ハロアルキル)2N−C(=O)−、C1〜4ハロアルキル−OC(=O)N(H)−、C1〜4ハロアルキル−OC(=O)N(H)−、ハロアルキル−N(H)−C(=O)O−、(ハロアルキル)2N−C(=O)O−、C1〜4アルキルアミノ、C1〜4ジアルキルアミノ、C3〜6シクロアルキル、C3〜6シクロアルコキシ、C2〜5ヘテロシクロアルコキシ、及びテトラヒドロナフタレンからなる群から独立して選択された1〜5個の置換基とさらに置換されていてもよい、式Iの化合物又はその薬剤的に許容可能な塩。 - RD1、RD2、RD3、及びRD4が、各々独立して、H、F、Cl、及び−CNからなる群から選択される、請求項1記載の化合物。
- RD1、RD2、RD3、及びRD4が、N、O、及びSから選択された1〜3個のヘテロ原子を含む5〜6員ヘテロアリールであり、ここで前記5〜6員ヘテロアリールがF、Cl、−CN、C1〜4アルキル、C1〜4ハロアルキル、及びC1〜4アルコキシから独立して選択された1〜3個の置換基とさらに置換されていてもよい、請求項1記載の化合物。
- RD1、RD2、RD3、及びRD4のうち1つが、独立して、H、F、及びClからなる群から選択されるか、又はRD1、RD2、RD3、及びRD4のうち1つが、N、O、及びSから選択された1〜3個のヘテロ原子を含む5〜6員ヘテロアリールであって、ここで前記5〜6員ヘテロアリールは、F、Cl、−CN、C1〜4アルキル、C1〜4ハロアルキル、及びC1〜4アルコキシから独立して選択された1〜3個の置換基とさらに置換されていてもよい、請求項1記載の化合物。
- RD1、RD2、RD3、及びRD4のうち1つが、N、O、及びSから選択された1〜3個のヘテロ原子を含む5〜6員ヘテロアリールであって、ここで前記5〜6員ヘテロアリールは、F、Cl、−CN、C1〜4アルキル、C1〜4ハロアルキル、及びC1〜4アルコキシから独立して選択された1〜3個の置換基とさらに置換されていてもよい、請求項1記載の化合物。
- RD1、RD2、RD3、及びRD4が、独立して、H、F、Cl、−CN、−CF3、及びピリジルからなる群から選択され、ここで前記ピリジルは、F、Cl、−CN、及びC1〜4アルコキシから選択された1〜3個の置換基とさらに置換されていてもよい、請求項1記載の化合物。
- D1がC(RD1)であり、D3がC(RD3)である、請求項1記載の化合物。
- D1がNであり、D3がC(RD3)である、請求項1記載の化合物。
- D1がC(RD1)であり、D3がNである、請求項1記載の化合物。
- D1及びD3が各々Nである、請求項1記載の化合物。
- 式Iの化合物が式Iaの化合物:
であって、式中、D1はCH又はNである、請求項1記載の化合物。 - 式Iaの化合物が式Ibの化合物:
である、請求項11記載の化合物。 - RD2、RD3、及びRD4の1つ以上が、各々独立して、F、Cl、−CN、C1〜8アルキル、C1〜8ハロアルキル、C1〜8アルコキシ、C3〜8シクロアルキル、C2〜7ヘテロシクロアルキル、フェニル、及びN、O、及びSから選択された1〜3個のヘテロ原子を含む5〜6員ヘテロアリールからなる群から選択され、前記5〜6員ヘテロアリールは、F、Cl、−CN、C1〜4アルキル、C1〜4ハロアルキル、及びC1〜4アルコキシから選択された1〜3個の置換基とさらに置換されていてもよく;かつRD2、RD3、及びRD4の残部が各々Hである、請求項11又は12記載の化合物。
- RD2、RD3、及びRD4の2つ以上が、各々独立して、F、Cl、−CN、C1〜8アルキル、C1〜8ハロアルキル、C1〜8アルコキシ、C3〜8シクロアルキル、C2〜7ヘテロシクロアルキル、フェニル、及びN、O、及びSから選択された1〜3個のヘテロ原子を含む5〜6員ヘテロアリールからなる群から選択され、ここで前記5〜6員ヘテロアリールは、F、Cl、−CN、C1〜4アルキル、C1〜4ハロアルキル、及びC1〜4アルコキシから選択された1〜3個の置換基とさらに置換されていてもよく;かつRD2、RD3、及びRD4の残部がHである、請求項11又は12記載の化合物。
- A環が6〜10員アリールである、請求項1〜14のいずれか1項に記載の化合物。
- A環がフェニルである、請求項1〜14のいずれか1項に記載の化合物。
- A環が5〜6員ヘテロアリールである、請求項1〜14のいずれか1項に記載の化合物。
- A環がピリジルである、請求項1〜14のいずれか1項に記載の化合物。
- nが2又は3である、請求項1〜18のいずれか1項に記載の化合物。
- 式Iの化合物が式Icの化合物:
であって、式中、D1はCH又はNであり;EはC(RA)又はNである、請求項1記載の化合物。 - 式Iの化合物が式Idの化合物:
であって、式中、D1はCH又はNであり;EはC(RA)又はNである、請求項1記載の化合物。 - 式Iの化合物が式Ieの化合物:
であって、式中、D1はCH又はNであり;EはC(RA)又はNである、請求項1記載の化合物。 - 式Iの化合物が式Ifの化合物:
であって、式中、D1はCH又はNであり;EはC(RA)又はNである、請求項1記載の化合物。 - R1が:−NH2、−NH(CH3)、−N(CH3)2、
- R1が:
- X1が−O−又は−N(H)−であり;X2が非存在であり;添字mが1であり;−(L)−がC1〜4アルキレン、C2〜4アルケニレン、又はC2〜4アルキニレンからなる群から選択され、かつ置換されていてもよい、請求項1〜11、13〜20、22、及び24〜25のいずれか1項に記載の化合物。
- X1が−O−又は−N(H)−であり;X2が非存在であり;添字mが1であり;−(L)−が、−CH2−、−C(=O)−、−C(H)(CH3)−、−CH2−CH2−、−CH2−C(H)(CH3)−、−C(H)(CH3)−C(H2)−、−CH2CH2CH2−、−CH2−C(H)(CH3)−CH2−、又は−CH2CH2CH2CH2−からなる群から選択される、請求項1〜11、13〜20、22、及び24〜25のいずれか1項に記載の化合物。
- X1が−O−であり;添字mが1であり、−(L)−が−CH2−又は−CH2−CH2−である、請求項1〜11、13〜20、22、及び24〜25のいずれか1項に記載の化合物。
- X1が非存在であり;X2が−O−又は−N(H)−であり;添字mが1であり;−(L)−が、−C(H)2−、−C(=O)−、C(H)(CH3)−、−CH2−CH2−、−CH2−C(H)(CH3)−、−C(H)(CH3)−C(H2)−、−CH2CH2CH2−、−CH2−C(H)(CH3)−CH2−、又は−CH2CH2CH2CH2−からなる群から選択される、請求項1〜11、13〜20、22、及び24〜25のいずれか1項に記載の化合物。
- X1及びX2が非存在であり;添字mが1であり;−(L)−が、−C(H)2−、−C(=O)−、−C(H)(CH3)−、CH2−CH2−、−CH2−C(H)(CH3)−、−C(H)(CH3)−C(H2)−、−CH2CH2CH2−、−CH2−C(H)(CH3)−CH2−、又は−CH2CH2CH2CH2−からなる群から選択される、請求項1〜11、13〜20、22、及び24〜25のいずれか1項に記載の化合物。
- X1及びX2が非存在であり;添字mが1であり;−(L)−が置換されていてもよいC1〜4ヘテロアルキレンである、請求項1〜11、13〜20、22、及び24〜25のいずれか1項に記載の化合物。
- mが0であり;X1が−O−及び−N(H)−から選択され;X2が非存在である、請求項1〜11、13〜20、22、及び24〜25のいずれか1項に記載の化合物。
- RAが、C1〜4アルキル、C1〜4ハロアルキル、C3〜5シクロアルキル、3〜5員ヘテロシクロアルキル、C1〜4ハロアルコキシ、C3〜5ハロシクロアルキル、F、Cl、Br、I、−OH、−NH2、−CN、−NO2、C1〜4アルコキシ、−C(=O)−N(RA1)(RA2)、及び−N(RA1)(RA2)からなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- RAが、C1〜4アルキル、C1〜4ハロアルキル、C3〜5シクロアルキル、C1〜4ハロアルコキシ、C3〜5ハロシクロアルキル、F、Cl、及びC1〜4アルコキシからなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- RAが、メチル、トリフルオロメチル、ジフルオロメチル、モノフルオロメチル、エチル、ペンタフルオロエチル、シクロプロピル、−F、Cl、−OH、−NH2、又は−CNである、請求項1〜32のいずれか1項に記載の化合物。
- RAが、トリフルオロメチル、ペンタフルオロエトキシ、エチル、イソプロピル、2−フルオロエトキシ、フルオロメチル、3,3−ジフルオロシクロブチル、シクロブチル、イソプロピル、F、Cl、イソプロポキシ、トリフルオロメトキシ、及びシクロプロピルからなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- RAが、H、C1〜4アルキル、C1〜4ハロアルキル、C3〜5シクロアルキル、3〜5員ヘテロシクロアルキル、C1〜4ハロアルコキシ、C3〜5ハロシクロアルキル、F、Cl、Br、I、−OH、−NH2、−CN、−NO2、C1〜4アルコキシ、−C(=O)−N(RA1)(RA2)、及び−N(RA1)(RA2)からなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- RAが、H、C1〜4アルキル、C1〜4ハロアルキル、C3〜5シクロアルキル、C1〜4ハロアルコキシ、C3〜5ハロシクロアルキル、F、Cl、及びC1〜4アルコキシからなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- RAが、H、メチル、トリフルオロメチル、ジフルオロメチル、モノフルオロメチル、エチル、ペンタフルオロエチル、シクロプロピル、−F、Cl、−OH、−NH2、又は−CNである、請求項1〜32のいずれか1項に記載の化合物。
- RAが、H、トリフルオロメチル、ペンタフルオロエトキシ、エチル、イソプロピル、2−フルオロエトキシ、フルオロメチル、3,3−ジフルオロシクロブチル、シクロブチル、イソプロピル、F、Cl、イソプロポキシ、トリフルオロメトキシ、及びシクロプロピルからなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- 少なくとも1つのRAが、C1〜4アルキル、C1〜4ハロアルキル、C3〜5シクロアルキル、C2〜4ヘテロシクロアルキル、C1〜4ハロアルコキシ、C3〜5ハロシクロアルキル、F、Cl、Br、I、−OH、−NH2、−CN、−NO2、C1〜4アルコキシ、−C(=O)−N(RA1)(RA2)、及び−N(RA1)(RA2)からなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- 少なくとも1つのRAが、C1〜4アルキル、C1〜4ハロアルキル、C3〜5シクロアルキル、C1〜4ハロアルコキシ、C3〜5ハロシクロアルキル、F、Cl、及びC1〜4アルコキシからなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- 少なくとも1つのRAが、メチル、トリフルオロメチル、ジフルオロメチル、モノフルオロメチル、エチル、ペンタフルオロエチル、シクロプロピル、−F、Cl、−OH、−NH2、及び−CNからなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- 少なくとも1つのRAが、トリフルオロメチル、ペンタフルオロエトキシ、エチル、イソプロピル、2−フルオロエトキシ、フルオロメチル、3,3−ジフルオロシクロブチル、シクロブチル、イソプロピル、F、Cl、イソプロポキシ、トリフルオロメトキシ、及びシクロプロピルからなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- 各RAが、独立して、C1〜8ハロアルキル、C3〜8シクロアルキル、C3〜8ハロシクロアルキル、F、Cl、−(XRA)0〜1ORA1、及び−(XRA)0〜1NRA1RA2からなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- 各RAが、独立して、フルオロ、クロロ、トリフルオロメチル、フルオロメチル、ペンタフルオロエトキシ、トリフルオロメトキシ、シクロプロピル、シクロブチル、2,2−ジフルオロシクロブチル、2−メチルプロポキシ、及びピペリジノからなる群から選択される、請求項1〜32のいずれか1項に記載の化合物。
- 基:
が、以下:
- 表1に記載の化合物又はその薬剤的に許容可能な塩からなる群から選択される、請求項1記載の化合物。
- 請求項1〜48のいずれか1項に記載の式Iの化合物又はその薬剤的に許容可能な塩、及び薬剤的に許容可能な賦形剤を含む医薬組成物。
- 疼痛、うつ病、循環器疾患、呼吸器疾患、及び精神疾患、並びにそれらの組み合わせからなる群から選択される、哺乳類における疾患又は状態を治療する方法であって、ここで方法は、それらを必要とする前記哺乳類に、治療効果のある量の請求項1〜48のいずれか1項に記載の式Iの化合物、又はその薬剤的に許容可能な塩を投与することを含む、方法。
- 前記疾患又は状態が、神経因性疼痛、炎症性疼痛、内臓痛、がん疼痛、化学療法性疼痛、外傷性疼痛、外科的疼痛、術後疼痛、出産疼痛、陣痛、神経因性膀胱、潰瘍性大腸炎、慢性疼痛、持続性疼痛、末梢性媒介疼痛、中枢性媒介疼痛、慢性頭痛、片頭痛、副鼻腔炎性頭痛、緊張型頭痛、幻肢痛、歯痛、末梢神経損傷、又はそれらの組み合わせからなる群から選択される、請求項50記載の方法。
- 前記疾患又は状態が、HIV、HIV治療誘導性神経障害、三叉神経痛、ヘルペス後神経痛、急性痛(eudynia)、熱感受性、トサルコイドーシス(tosarcoidosis)、過敏性腸症候群、クローン氏病と関連する疼痛、多発性硬化症(MS)、筋萎縮性側索硬化症(ALS)、糖尿病性神経障害、末梢神経障害、関節炎、リウマチ性関節炎、変形性関節炎、アテローム、発作性ジストニア、筋無力症症候群、筋強直症、悪性高熱症、嚢胞性線維症、偽アルドステロン症、横紋筋融解症、甲状腺機能低下症、双極性うつ病、不安症、統合失調症、ナトリウムチャネル毒素関連疾病、家族性肢端紅痛症、原発性肢端紅痛症、家族性直腸痛、がん、てんかん、部分的及び全身強直性発作、下肢静止不能症候群、不整脈、線維筋痛症、脳卒中又は神経性外傷が原因の虚血性状態下における神経保護、頻脈性不整脈、心房細動、並びに心室細動と関連する疼痛からなる群から選択される、請求項50記載の方法。
- 哺乳類における電位依存性ナトリウムチャネルを介するイオン流束の阻害によって、哺乳類の疼痛を治療する方法であって、前記方法は、それを必要とする前記哺乳類に、治療効果のある量の請求項1〜48のいずれか1項に記載の式Iの化合物又はその薬剤的に許容可能な塩を投与することを含む、方法。
- 哺乳類の細胞において電位依存性ナトリウムチャネルを介してイオン流束を減少させる方法であって、前基方法は、前記細胞と、請求項1〜48のいずれか1項に記載の式Iの化合物又はその薬剤的に許容可能な塩を接触させることを含む、方法。
- 哺乳類におけるそう痒症を治療する方法であって、前記方法は、それを必要とする前記哺乳類に、治療効果のある量の請求項1〜48のいずれか1項に記載の式Iの化合物又はその薬剤的に許容可能な塩を投与することを含む、方法。
- 哺乳類におけるがんを治療する方法であって、前記方法は、それを必要とする前記哺乳類に、治療効果のある量の請求項1〜48のいずれか1項に記載の式Iの化合物又はその薬剤的に許容可能な塩を投与することを含む、方法。
- 哺乳類における疼痛を、予防ではなく治療する方法であって、前記方法は、それを必要とする前記哺乳類に、治療効果のある量の請求項1〜48のいずれか1項に記載の式Iの化合物又はその薬剤的に許容可能な塩を投与することを含む、方法。
- 前記疼痛が、神経因性疼痛、炎症性疼痛、内臓痛、がん疼痛、化学療法による疼痛、外傷性疼痛、外科的疼痛、術後疼痛、出産疼痛、陣痛、神経因性膀胱、潰瘍性大腸炎、慢性疼痛、持続性疼痛、末梢性媒介疼痛、中枢性媒介疼痛、慢性頭痛、片頭痛、副鼻腔炎性頭痛、緊張型頭痛、幻肢痛、歯痛、末梢神経損傷またはそれらの組み合わせからなる群から選択される、請求項57記載の方法。
- 前記疼痛が、HIV、HIV治療誘導神経障害、三叉神経痛、ヘルペス後神経痛、急性痛(eudynia)、熱感受性、トサルコイドーシス(tosarcoidosis)、過敏性腸症候群、クローン氏病、多発性硬化症(MS)と関連する疼痛、筋萎縮性側索硬化症(ALS)、糖尿病性神経障害、末梢神経障害、関節炎、リウマチ性関節炎、変形性関節炎、アテローム、発作性ジストニア、筋無力症症候群、筋強直症、悪性高熱症、嚢胞性線維症、偽アルドステロン症、横紋筋融解症、甲状腺機能低下症、双極性うつ病、不安症、統合失調症、ナトリウムチャネル毒素関連疾病、家族性肢端紅痛症、原発性肢端紅痛症、家族性直腸痛、がん、てんかん、部分的及び全身強直性発作、下肢静止不能症候群、不整脈、線維筋痛症、脳卒中又は神経性外傷が原因の虚血性状態下における神経保護、頻脈性不整脈、心房細動並びに心室細動からなる群から選択される、疾患又は状態と関連する、請求項57記載の方法。
- 疼痛、うつ病、循環器疾患、呼吸器疾患、及び精神疾患、並びにそれらの組み合わせを前記治療する又は予防する方法であって、方法は、有効量の請求項1〜48のいずれか1項に記載の式Iの化合物又はその薬剤的に許容可能な塩を投与することを含む、方法。
- 疼痛、うつ病、循環器疾患、呼吸器疾患、及び精神疾患、又はそれらの組み合わせからなる群から選択される疾患及び障害の前記治療のための薬物として使用するための、請求項1〜48のいずれか1項に記載の式Iの化合物又はその薬剤的に許容可能な塩。
- 疼痛、うつ病、循環器疾患、呼吸器疾患、及び精神疾患、又はそれらの組み合わせからなる群から選択される疾患及び障害の前記治療のための薬物を生産するための、請求項1〜48のいずれか1項に記載の式Iの化合物又はその薬剤的に許容可能な塩の使用。
- 上記に記載の発明。
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CN104797555A (zh) | 2015-07-22 |
CA2878478A1 (en) | 2014-01-09 |
KR101663436B1 (ko) | 2016-10-06 |
MX2015000164A (es) | 2015-08-12 |
JP6309519B2 (ja) | 2018-04-11 |
CN104797555B (zh) | 2017-12-22 |
EP2870138A2 (en) | 2015-05-13 |
WO2014008458A3 (en) | 2014-04-17 |
HK1209736A1 (en) | 2016-04-08 |
KR20150036367A (ko) | 2015-04-07 |
US20180346416A1 (en) | 2018-12-06 |
US20150322002A1 (en) | 2015-11-12 |
US10071957B2 (en) | 2018-09-11 |
RU2015103913A (ru) | 2016-08-27 |
WO2014008458A2 (en) | 2014-01-09 |
EP2870138B1 (en) | 2018-08-22 |
BR112015000187A2 (pt) | 2017-06-27 |
EP2870138A4 (en) | 2016-02-17 |
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