JP6424399B2 - 置換ベンズアルデヒド化合物および組織酸素化の増加におけるそれらの使用方法 - Google Patents
置換ベンズアルデヒド化合物および組織酸素化の増加におけるそれらの使用方法 Download PDFInfo
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- JP6424399B2 JP6424399B2 JP2017077318A JP2017077318A JP6424399B2 JP 6424399 B2 JP6424399 B2 JP 6424399B2 JP 2017077318 A JP2017077318 A JP 2017077318A JP 2017077318 A JP2017077318 A JP 2017077318A JP 6424399 B2 JP6424399 B2 JP 6424399B2
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Description
本出願は、2011年12月28日に出願された米国仮出願第61/581,053号、および2012年6月18日に出願された米国仮出願第61/661,320号に対する優先権を主張するものであり、その全体は参照することによって本明細書に組み込まれる。
本発明は、全体として、ヘモグロビンのアロステリック調節因子として作用する置換ベンズアルデヒドおよびその誘導体、それらの製造方法および中間体、該調節因子を含む医薬組成物、ならびにヘモグロビンによって媒介される障害および組織酸素化の増加が有効となりうる障害の治療におけるそれらの使用方法に関する。
ヘモグロビン(Hb)は赤血球中にある四量体タンパク質であり、最大4個の酸素分子を、肺から全身の様々な組織および臓器へ輸送する。ヘモグロビンは立体構造変化によって酸素を結合および放出するが、酸素に結合していない時は緊張(T)状態にあり、酸素に結合している時は弛緩(R)状態にある。2つの立体構造状態の間の平衡はアロステリック制御下にある。天然化合物、例えば2,3−ビスホスホグリセリン酸(2,3−BPG)、プロトン、および二酸化炭素はその脱酸素化T状態にあるヘモグロビンを安定化し、一方、酸素はその酸素化R状態にあるヘモグロビンを安定化する。他の弛緩R状態も発見されているが、アロステリック制御におけるそれらの役割は、完全には解明されていない。
本発明は、1つの態様において、ヘモグロビンのアロステリック調節因子を提供する。別の態様において、本明細書に開示されているアロステリック調節因子を含む医薬組成物が提供される。他の態様では、ヘモグロビンによって媒介される障害を治療する方法および酸素化の増加が有効となりうる障害を治療するために組織酸素化を増加する方法であって、それを必要としている対象に本明細書に開示されているアロステリック調節因子を投与することを含む方法が提供される。さらに他の態様では、本明細書に開示されているアロステリック調節因子を製造する方法を提供する。本発明のこれらのおよび他の実施態様は、以下にさらに詳細に記載されている。
I.定義
本明細書で用いられている以下の用語は、特段の定めがない限り以下の意味を有する。
1つの群の実施態様では、式(I):
[式中、Qはアリール、ヘテロアリール、およびヘテロシクロアルキルからなる群から選択され、それぞれ1〜3個のRaで置換されていてもよく;
YはOまたはCR1aR1bであり、ここでR1aはHまたはハロであり、かつ、R1bはH、ハロ、およびOHからなる群から選択され;
XはO、>CH(CH2)nR8、およびC(R9)2からなる群から選択され、ここでnは0または1であり、R8はOHであり、かつ、R9は独立してHもしくはハロであり;または、Y−Xは一緒になって−NHC(O)−もしくは−C(O)NH−を形成し;
R2、R3、R4、およびR5は水素、ハロ、Rb、ORd、O(CH2)zORd、O(CH2)zNRdRd、OC(O)Re、SRd、CN、NO2、CO2Rd、CONRdRd、C(O)Rd、OC(O)NRdRd、NRdRd、NRdC(O)Re、NRdC(O)2Re、NRdC(O)NRdRd、S(O)Re、S(O)2Re、NRdS(O)2Re、S(O)2NRdRd、およびN3からなる群から独立して選択され、ここでzは0、1、2、3、4、5、もしくは6であり;または、R5は−(CH2)pR5aであり、ここでpは0もしくは1であり、かつ、R5aはOHであり;
R6およびR7は一緒になってオキソもしくはアルデヒド保護基を形成し、またはR6はR1b、R8、もしくはR5と一緒になって環状エーテルを形成し、ここでR1b、R8、もしくはR5aの1つはOであり、R6は結合であり、かつR7はOH、C1−8アルコキシ、およびハロC1−8アルコキシからなる群から選択され;
各Raはハロ、Rb、ORd、O(CH2)uORd、O(CH2)uNRdRd、O(CH2)uNRdC(O)Re、O(CH2)uNRdC(O)2Re、O(CH2)uNRdS(O)2Re、NH2、−(CH2)kOC(O)Re、−(CH2)kSRd、CN、NO2、−(CH2)kCO2(C1−8アルキル)OH、−(CH2)kCO2(C1−8アルキル)(ヘテロアリール)C(O)(C1−8アルキル)、−(CH2)kCO2Rd、−(CH2)kCONRdRd、−(CH2)kNRdC(O)Re、−(CH2)kNRdC(O)2Re、−(CH2)kC(O)Rd、−(CH2)kOC(O)NRdRd、−NRd(CH2)uORd、−NRd(CH2)uNRdRd、−NRd(CH2)uNRdC(O)Re、−NRd(CH2)uNRdC(O)2Re、−NRd(CH2)uNRdS(O)2Re、−(CH2)kNRdC(O)Re、−(CH2)kNRdC(O)2Rd、−(CH2)kNRdC(O)NRdRd、−(CH2)kS(O)Re、−(CH2)kS(O)2Re、−(CH2)kNRdS(O)2Re、−(CH2)kS(O)2NRdRd、N3、1〜3個のRcで置換されていてもよい−(CH2)kアリール、1〜3個のRcで置換されていてもよい−NRd(CH2)kアリール、1〜3個のRcで置換されていてもよい−(CH2)kヘテロアリール、1〜3個のRcで置換されていてもよい−NRd(CH2)kヘテロアリール、1〜3個のRcで置換されていてもよい−(CH2)kヘテロシクロアルキル、および1〜3個のRcで置換されていてもよい−NRd(CH2)kヘテロシクロアルキルからなる群から独立して選択され、ここでkは0、1、2、3、4、5、または6であり、かつ、uは1、2、3、4、5、または6であり;
各RbはC1−8アルキル、C2−8アルケニル、およびC2−8アルキニルからなる群から独立して選択され、それぞれ独立して1〜3個のハロ、ORd、またはNRdRdで置換されていてもよく;
各Rcはハロ、C1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、ハロC2−8アルキニル、(CH2)mORf、OC(O)Rg、SRf、CN、NO2、CO2Rf、CONRfRf、C(O)Rf、OC(O)NRfRf、(CH2)mNRfRf、NRfC(O)Rg、NRfC(O)2Rg、NRfC(O)NRfRf、S(O)Rg、S(O)2Rg、NRfS(O)2Rg、S(O)2NRfRf、N3、1〜3個のRhで置換されていてもよいヘテロアリール、および1〜3個のRhで置換されていてもよいヘテロシクロアルキルからなる群から独立して選択され、ここでmは0、1、2、3、4、5、および6からなる群から選択され;
各Rhはハロ、C1−8アルキル、ハロC1−8アルキル、ORj、OC(O)R、SRj、NO2、CO2Rj、CONRjRj、C(O)Rj、OC(O)NRjRj、NRjRj、NRjC(O)Rt、NRjC(O)2Rt、NRjC(O)NRjRj、S(O)Rt、S(O)2Rt、NRjS(O)2Rt、およびS(O)2NRjRjからなる群から独立して選択され;
Rd、Rf、およびRjは水素、C1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、およびハロC2−8アルキニルからなる群からそれぞれ独立して選択され;かつ
Re、Rg、およびRtはC1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、およびハロC2−8アルキニルからなる群からそれぞれ独立して選択される]
の化合物、またはその互変異性体もしくは医薬的に許容される塩を提供する。
Wはピリジン−2−イル、ピリジン−3−イル、およびピリジン−4−イル、
[式中、Qはアリール、ヘテロアリール、およびヘテロシクロアルキルからなる群から選択され、それぞれ1〜3個のRaで置換されていてもよく;
YはOまたはCR1aR1bであり、ここでR1aはHまたはハロであり、かつ、R1bはH、ハロ、およびOHからなる群から選択され;
XはO、>CH(CH2)nR8、およびC(R9)2からなる群から選択され、ここでnは0または1であり、R8はOHであり、かつ、R9は独立してHまたはハロであり;
R2、R3、R4、およびR5は水素、ハロ、Rb、ORd、OC(O)Re、SRd、CN、NO2、CO2Rd、CONRdRd、C(O)Rd、OC(O)NRdRd、NRdRd、NRdC(O)Re、NRdC(O)2Re、NRdC(O)NRdRd、S(O)Re、S(O)2Re、NRdS(O)2Re、S(O)2NRdRd、およびN3からなる群から独立して選択され;または、R5は−(CH2)pR5aであり、ここでpは0もしくは1であり、かつ、R5aはOHであり;
R6およびR7は一緒になってオキソもしくはアルデヒド保護基を形成し、またはR6はR1b、R8、もしくはR5と一緒になって環状エーテルを形成し、ここでR1b、R8、もしくはR5aの1つは−O−であり、R6は結合であり、かつR7はOH、C1−8アルコキシ、およびハロC1−8アルコキシからなる群から選択され;
各Raはハロ、Rb、ORd、OC(O)Re、SRd、CN、NO2、CO2Rd、CONRdRd、C(O)Rd、OC(O)NRdRd、NRdC(O)Re、NRdC(O)2Rd、NRdC(O)NRdRd、S(O)Re、S(O)2Re、NRdS(O)2Re、S(O)2NRdRd、N3、1〜3個のRcで置換されていてもよいアリール、1〜3個のRcで置換されていてもよいヘテロアリール、および1〜3個のRcで置換されていてもよいヘテロシクロアルキルからなる群から独立して選択され;
各RbはC1−8アルキル、C2−8アルケニル、およびC2−8アルキニルからなる群から独立して選択され、それぞれ独立して1〜3個のハロ、ORd、またはNRdRdで置換されていてもよく;
各Rcはハロ、C1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、ハロC2−8アルキニル、(CH2)mORf、OC(O)Rg、SRf、CN、NO2、CO2Rf、CONRfRf、C(O)Rf、OC(O)NRfRf、(CH2)mNRfRf、NRfC(O)Rg、NRfC(O)2Rg、NRfC(O)NRfRf、S(O)Rg、S(O)2Rg、NRfS(O)2Rg、S(O)2NRfRf、およびN3からなる群から独立して選択され、ここでmは0、1、2、3、4、5、および6からなる群から選択され;
各RdおよびRfは水素、C1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、およびハロC2−8アルキニルからなる群から独立して選択され;かつ
各ReおよびRgはC1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、およびハロC2−8アルキニルからなる群から独立して選択され;
ただし、
XとYの両方がOになることはなく;
XがOである場合、R1bはOHではなく;
YがOであり、かつnがOである場合、R8はOHではなく;かつ
R6およびR7が一緒になってオキソを形成し、YがCH2であり、XがOまたはCH2であり、かつ、R5がH、ハロ、OH、CHO、またはOCH3である場合、QはVまたはWであり;
Vは
Wはピリジン−2−イル、ピリジン−3−イル、およびピリジン−4−イル、
の化合物、またはその互変異性体もしくは医薬的に許容される塩を提供する。
[式中、R10はH、C1−8アルキル、およびハロC1−8アルキルからなる群から選択される]を有する化合物、またはその互変異性体もしくは医薬的に許容される塩を提供する。
[式中、Qはアリール、ヘテロアリール、およびヘテロシクロアルキルからなる群から選択され、それぞれ1〜3個のRaで置換されていてもよく;
YはOまたはCH2であり;
XはOまたはCH2であり;
R2およびR3は水素、ハロ、Rb、ORd、−O(CH2)zORd、−O(CH2)zNRdRd、OC(O)Re、SRd、CN、NO2、CO2Rd、CONRdRd、C(O)Rd、OC(O)NRdRd、NRdRd、NRdC(O)Re、NRdC(O)2Re、NRdC(O)NRdRd、S(O)Re、S(O)2Re、NRdS(O)2Re、S(O)2NRdRd、およびN3からなる群から独立して選択され、ここでzは0、1、2、3、4、5、もしくは6であり;または、R5は−(CH2)pR5aであり、ここでpは0もしくは1であり、かつ、R5aはOHであり;
R4は水素およびORdからなる群から選択され;
R5は水素、ハロ、およびORdからなる群から選択され;
R6およびR7は一緒になってオキソまたはアルデヒド保護基を形成し;
各Raはハロ、Rb、ORd、O(CH2)uORd、O(CH2)uNRdRd、O(CH2)uNRdC(O)Re、O(CH2)uNRdC(O)2Re、O(CH2)uNRdS(O)2Re、NH2、−(CH2)kOC(O)Re、−(CH2)kSRd、CN、NO2、−(CH2)kCO2(C1−8アルキル)OH、−(CH2)kCO2(C1−8アルキル)(ヘテロアリール)C(O)(C1−8アルキル)、−(CH2)kCO2Rd、−(CH2)kCONRdRd、−(CH2)kNRdC(O)Re、−(CH2)kNRdC(O)2Re、−(CH2)kC(O)Rd、−(CH2)kOC(O)NRdRd、−NRd(CH2)uORd、−NRd(CH2)uNRdRd、−NRd(CH2)uNRdC(O)Re、−NRd(CH2)uNRdC(O)2Re、−NRd(CH2)uNRdS(O)2Re、−(CH2)kNRdC(O)Re、−(CH2)kNRdC(O)2Rd、−(CH2)kNRdC(O)NRdRd、−(CH2)kS(O)Re、−(CH2)kS(O)2Re、−(CH2)kNRdS(O)2Re、−C(O)(CH2)kNRdS(O)2Re、−(CH2)kC(O)NRdS(O)2Re、−(CH2)kS(O)2NRdRd、N3、1〜3個のRcで置換されていてもよい−(CH2)kアリール、1〜3個のRcで置換されていてもよい−NRd(CH2)kアリール、1〜3個のRcで置換されていてもよい−(CH2)kヘテロアリール、1〜3個のRcで置換されていてもよい−NRd(CH2)kヘテロアリール、1〜3個のRcで置換されていてもよい−(CH2)kヘテロシクロアルキル、および1〜3個のRcで置換されていてもよい−NRd(CH2)kヘテロシクロアルキルからなる群から独立して選択され、ここでkは0、1、2、3、4、5、または6であり、かつ、uは1、2、3、4、5、または6であり;
各RbはC1−8アルキル、C2−8アルケニル、およびC2−8アルキニルからなる群から独立して選択され、それぞれ独立して1〜3個のハロ、ORd、またはNRdRdで置換されていてもよく;
各Rcはハロ、C1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、ハロC2−8アルキニル、(CH2)mORf、OC(O)Rg、SRf、CN、NO2、(CH2)mCO2Rf、CONRfRf、C(O)Rf、OC(O)NRfRf、(CH2)mNRfRf、NRfC(O)Rg、NRfC(O)2Rg、NRfC(O)NRfRf、S(O)Rg、S(O)2Rg、NRfS(O)2Rg、S(O)2NRfRf、N3、(Rf)mSiC1−8アルキル、1〜3個のRhで置換されていてもよいヘテロアリール、1〜3個のRhで置換されていてもよいシクロアルキル、および1〜3個のRhで置換されていてもよいヘテロシクロアルキルからなる群から独立して選択され、ここでmは0、1、2、3、4、5、および6からなる群から選択され;
各Rhはハロ、C1−8アルキル、ハロC1−8アルキル、ORj、OC(O)R、SRj、NO2、CO2Rj、CONRjRj、C(O)Rj、OC(O)NRjRj、NRjRj、NRjC(O)Rt、NRjC(O)2Rt、NRjC(O)NRjRj、S(O)Rt、S(O)2Rt、NRjS(O)2Rt、およびS(O)2NRjRjからなる群から独立して選択され;
Rd、Rf、およびRjは水素、C1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、およびハロC2−8アルキニルからなる群からそれぞれ独立して選択され;かつ
Re、Rg、およびRtはC1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、およびハロC2−8アルキニルからなる群からそれぞれ独立して選択され;
ただし、
XとYの両方がOになることはなく;
R4およびR5の少なくとも1つはHであり;
R4がORdである場合、Qはフェニル、ピリジニル、またはイミダゾ[1,2−a]ピリジン−2−イルではなく、Raはオキソ、オキシド、またはハロではなく、かつ、XはOであり、
R5がORdである場合、Raはオキソ、オキシド、またはハロではなく;かつ
R2〜R5がHである場合、Qはフェニルではない]
の化合物、またはその互変異性体もしくは医薬的に許容される塩を提供する。
[式中:
YはOまたはCH2であり;
XはOまたはCH2であり;
Qは、下記i)およびii)からなる群から選択され
i)イミダゾピリジニル、メチルイミダゾピリジニル、インダゾリル、ピロロピリジニル、ピロロピラジニル、ピラゾロピリジニル、ピラゾロピラジニル、およびキノリニルであって、そのそれぞれは1〜3個のRaで置換されていてもよい;(ここで
R2、R3、R4、およびR5は水素、ハロ、Rb、ORd、O(CH2)zORd、O(CH2)zNRdRd、OC(O)Re、SRd、CN、NO2、CO2Rd、CONRdRd、C(O)Rd、OC(O)NRdRd、NRdRd、NRdC(O)Re、NRdC(O)2Re、NRdC(O)NRdRd、S(O)Re、S(O)2Re、NRdS(O)2Re、S(O)2NRdRd、およびN3からなる群から独立して選択され、ここでzは1、2、または3である);ならびに
ii)ピリジニルおよびピペリジニルであって、そのそれぞれは1〜3個のRaで置換されていてもよい;(ここで
R2、R3、およびR4は水素、ハロ、Rb、ORd、O(CH2)zORd、O(CH2)zNRdRd、OC(O)Re、SRd、CN、NO2、CO2Rd、CONRdRd、C(O)Rd、OC(O)NRdRd、NRdRd、NRdC(O)Re、NRdC(O)2Re、NRdC(O)NRdRd、S(O)Re、S(O)2Re、NRdS(O)2Re、S(O)2NRdRd、およびN3からなる群から独立して選択され、ここでzは1、2、または3であり;かつ
R5はハロおよびORdからなる群から選択される);
R6およびR7は一緒になってオキソまたはアルデヒド保護基を形成し;
各Raはハロ、オキソ、Rb、ORd、O(CH2)uORd、O(CH2)uNRdRd、O(CH2)uNRdC(O)Re、O(CH2)uNRdC(O)2Re、O(CH2)uNRdS(O)2Re、NH2、−(CH2)kOC(O)Re、−(CH2)kSRd、CN、NO2、−(CH2)kCO2(C1−8アルキル)OH、−(CH2)kCO2(C1−8アルキル)(ヘテロアリール)C(O)(C1−8アルキル)、−(CH2)kCO2Rd、−(CH2)kCONRdRd、−(CH2)kNRdC(O)Re、−(CH2)kNRdC(O)2Re、−(CH2)kC(O)Rd、−(CH2)kOC(O)NRdRd、−NRd(CH2)uORd、−NRd(CH2)uNRdRd、−NRd(CH2)uNRdC(O)Re、−NRd(CH2)uNRdC(O)2Re、−NRd(CH2)uNRdS(O)2Re、−(CH2)kNRdC(O)Re、−(CH2)kNRdC(O)2Rd、−(CH2)kNRdC(O)NRdRd、−(CH2)kS(O)Re、−(CH2)kS(O)2Re、−(CH2)kNRdS(O)2Re、−C(O)(CH2)kNRdS(O)2Re、−(CH2)kC(O)NRdS(O)2Re、−(CH2)kS(O)2NRdRd、N3、1〜3個のRcで置換されていてもよい−(CH2)kアリール、1〜3個のRcで置換されていてもよい−NRd(CH2)kアリール、1〜3個のRcで置換されていてもよい−(CH2)kヘテロアリール、1〜3個のRcで置換されていてもよい−NRd(CH2)kヘテロアリール、1〜3個のRcで置換されていてもよい−(CH2)kヘテロシクロアルキル、および1〜3個のRcで置換されていてもよい−NRd(CH2)kヘテロシクロアルキルからなる群から独立して選択され、ここでkは0、1、2、3、4、5、または6であり、かつ、uは1、2、3、4、5、または6であり;
各RbはC1−8アルキル、C2−8アルケニル、およびC2−8アルキニルからなる群から独立して選択され、それぞれ独立して1〜3個のハロ、ORd、またはNRdRdで置換されていてもよく;
各Rcはハロ、C1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、ハロC2−8アルキニル、(CH2)mORf、OC(O)Rg、SRf、CN、NO2、(CH2)mCO2Rf、CONRfRf、C(O)Rf、OC(O)NRfRf、(CH2)mNRfRf、NRfC(O)Rg、NRfC(O)2Rg、NRfC(O)NRfRf、S(O)Rg、S(O)2Rg、NRfS(O)2Rg、S(O)2NRfRf、N3、(Rf)mSiC1−8アルキル、1〜3個のRhで置換されていてもよいヘテロアリール、1〜3個のRhで置換されていてもよいシクロアルキル、および1〜3個のRhで置換されていてもよいヘテロシクロアルキルからなる群から独立して選択され、ここでmは0、1、2、3、4、5、および6からなる群から選択され;
各Rhはハロ、C1−8アルキル、ハロC1−8アルキル、ORj、OC(O)R、SRj、NO2、CO2Rj、CONRjRj、C(O)Rj、OC(O)NRjRj、NRjRj、NRjC(O)Rt、NRjC(O)2Rt、NRjC(O)NRjRj、S(O)Rt、S(O)2Rt、NRjS(O)2Rt、およびS(O)2NRjRjからなる群から独立して選択され;
Rd、Rf、およびRjは水素、C1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、およびハロC2−8アルキニルからなる群からそれぞれ独立して選択され;かつ
Re、Rg、およびRtはC1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、およびハロC2−8アルキニルからなる群からそれぞれ独立して選択される]
の化合物、またはその互変異性体もしくは医薬的に許容される塩を提供する。
R2がHおよびORdからなる群から選択され;
R3がH、CN、ハロ、およびORdからなる群から選択され;
R4がH、CN、およびORdからなる群から選択され;かつ
R5がHである
式Icの化合物を提供する。
2−(イミダゾ[1,2−a]ピリジン−8−イルメトキシ)−5−メトキシベンズアルデヒド、
2−(イミダゾ[1,2−a]ピリジン−2−イルメトキシ)−5−メトキシベンズアルデヒド、
2−(イミダゾ[1,5−a]ピリジン−8−イルメトキシ)−5−メトキシベンズアルデヒド、
5−メトキシ−2−(キノリン−5−イルメトキシ)ベンズアルデヒド、
5−メトキシ−2−((1−メチル−1H−インダゾール−4−イル)メトキシ)ベンズアルデヒド、
5−メトキシ−2−((8−メチルイミダゾ[1,2−a]ピリジン−2−イル)メトキシ)ベンズアルデヒド、
2−((1H−インダゾール−4−イル)メトキシ)−5−メトキシベンズアルデヒド、
5−メトキシ−2−(ピリジン−3−イルメトキシ)ベンズアルデヒド、
2−((2−(1−イソプロピル−1H−ピラゾール−5−イル)ピリジン−3−イル)メトキシ)−5−メトキシベンズアルデヒド、
2−ヒドロキシ−6−((2−(1−イソプロピル−1H−ピラゾール−5−イル)ピリジン−3−イル)メトキシ)ベンズアルデヒド、
2−((3−(2H−テトラゾール−5−イル)ベンジル)オキシ)−6−ヒドロキシベンズアルデヒド、
2−((4−(2H−テトラゾール−5−イル)ベンジル)オキシ)−6−ヒドロキシベンズアルデヒド、
4−((2−ホルミルフェノキシ)メチル)安息香酸メチル、
4−((2−ホルミルフェノキシ)メチル)安息香酸、
3−((2−ホルミルフェノキシ)メチル)安息香酸メチル、
2−ブロモ−3−((2−(1−イソプロピル−1H−ピラゾール−5−イル)ピリジン−3−イル)メトキシ)ベンズアルデヒド、
2−ヒドロキシ−6−((2−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−5−イル)ピリジン−3−イル)メトキシ)ベンズアルデヒド、
2−ヒドロキシ−6−((2−(1−(3,3,3−トリフルオロプロピル)−1H−ピラゾール−5−イル)ピリジン−3−イル)メトキシ)ベンズアルデヒド、
2−フルオロ−6−((2−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−5−イル)ピリジン−3−イル)メトキシ)ベンズアルデヒド、
2−フルオロ−6−((2−(1−(3,3,3−トリフルオロプロピル)−1H−ピラゾール−5−イル)ピリジン−3−イル)メトキシ)ベンズアルデヒド、
2−フルオロ−6−((2−(1−イソプロピル−1H−ピラゾール−5−イル)ピリジン−3−イル)メトキシ)ベンズアルデヒド、および
1−(2−ホルミル−3−ヒドロキシフェネチル)ピペリジン−4−カルボン酸、
から選択される化合物、またはその互変異性体もしくは医薬的に許容される塩を提供する。
スキームI
スキームII
スキームIII
スキームIV
意図する投与様式に依存して、医薬組成物は固体、半固体または液体剤形の形態であってよく、好ましくは正確な投与量の単回投与に適切な単位剤形であってよい。活性化合物の有効量に加えて、組成物は、活性化合物を医薬的に用いることができる製剤に加工することを容易にするアジュバントを含む適切な医薬的に許容される賦形剤を含有してもよい。「医薬的に許容される賦形剤」は、活性化合物の生物学的活性の有効性を妨げず、かつ、投与された対象にとって有毒でも有害でもない賦形剤または賦形剤の混合物を指す。
1つの群の実施態様では、組織酸素化を増加させる方法であって、上記実施態様のいずれかの化合物、またはその互変異性体もしくは医薬的に許容される塩の治療的有効量を、それを必要としている対象に投与することを含む方法を提供する。
[式中、Qはアリール、ヘテロアリール、およびヘテロシクロアルキルからなる群から選択され、それぞれ1〜3個のRaで置換されていてもよく;
YはOまたはCR1aR1bであり、ここでR1aはHまたはハロであり、かつ、R1bはH、ハロ、およびOHからなる群から選択され;
XはO、>CH(CH2)nR8、およびC(R9)2からなる群から選択され、ここでnは0もしくは1であり、R8はOHであり、かつ、R9は独立してHもしくはハロであり;または、Y−Xは一緒になって−NHC(O)−もしくは−C(O)NH−を形成し;
R2、R3、R4、およびR5は水素、ハロ、Rb、ORd、−O(CH2)zORd、−O(CH2)zNRdRd、OC(O)Re、SRd、CN、NO2、CO2Rd、CONRdRd、C(O)Rd、OC(O)NRdRd、NRdRd、NRdC(O)Re、NRdC(O)2Re、NRdC(O)NRdRd、S(O)Re、S(O)2Re、NRdS(O)2Re、S(O)2NRdRd、およびN3からなる群から独立して選択され、ここでzは0、1、2、3、4、5、もしくは6であり;または、R5は−(CH2)pR5aであり、ここでpは0もしくは1であり、かつ、R5aはOHであり;
R6およびR7は一緒になってオキソもしくはアルデヒド保護基を形成し、またはR6はR1b、R8、もしくはR5と一緒になって環状エーテルを形成し、ここでR1b、R8、もしくはR5aの1つはOであり、R6は結合であり、かつR7はOH、C1−8アルコキシ、およびハロC1−8アルコキシからなる群から選択され;
各Raはハロ、Rb、ORd、O(CH2)uORd、O(CH2)uNRdRd、O(CH2)uNRdC(O)Re、O(CH2)uNRdC(O)2Re、O(CH2)uNRdS(O)2Re、NH2、−(CH2)kOC(O)Re、−(CH2)kSRd、CN、NO2、−(CH2)kCO2(C1−8アルキル)OH、−(CH2)kCO2(C1−8アルキル)(ヘテロアリール)C(O)(C1−8アルキル)、−(CH2)kCO2Rd、−(CH2)kCONRdRd、−(CH2)kNRdC(O)Re、−(CH2)kNRdC(O)2Re、−(CH2)kC(O)Rd、−(CH2)kOC(O)NRdRd、−NRd(CH2)uORd、−NRd(CH2)uNRdRd、−NRd(CH2)uNRdC(O)Re、−NRd(CH2)uNRdC(O)2Re、−NRd(CH2)uNRdS(O)2Re、−(CH2)kNRdC(O)Re、−(CH2)kNRdC(O)2Rd、−(CH2)kNRdC(O)NRdRd、−(CH2)kS(O)Re、−(CH2)kS(O)2Re、−(CH2)kNRdS(O)2Re、−(CH2)kS(O)2NRdRd、N3、1〜3個のRcで置換されていてもよい−(CH2)kアリール、1〜3個のRcで置換されていてもよい−NRd(CH2)kアリール、1〜3個のRcで置換されていてもよい−(CH2)kヘテロアリール、1〜3個のRcで置換されていてもよい−NRd(CH2)kヘテロアリール、1〜3個のRcで置換されていてもよい−(CH2)kヘテロシクロアルキル、および1〜3個のRcで置換されていてもよい−NRd(CH2)kヘテロシクロアルキルからなる群から独立して選択され、ここでkは0、1、2、3、4、5、または6であり、かつ、uは1、2、3、4、5、または6であり;
各RbはC1−8アルキル、C2−8アルケニル、およびC2−8アルキニルからなる群から独立して選択され、それぞれ独立して1〜3個のハロ、ORd、またはNRdRdで置換されていてもよく;
各Rcはハロ、C1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、ハロC2−8アルキニル、(CH2)mORf、OC(O)Rg、SRf、CN、NO2、CO2Rf、CONRfRf、C(O)Rf、OC(O)NRfRf、(CH2)mNRfRf、NRfC(O)Rg、NRfC(O)2Rg、NRfC(O)NRfRf、S(O)Rg、S(O)2Rg、NRfS(O)2Rg、S(O)2NRfRf、N3、1〜3個のRhで置換されていてもよいヘテロアリール、および1〜3個のRhで置換されていてもよいヘテロシクロアルキルからなる群から独立して選択され、ここでmは0、1、2、3、4、5、および6からなる群から選択され;
Rd、Rf、およびRjは水素、C1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、およびハロC2−8アルキニルからなる群からそれぞれ独立して選択され;かつ
Re、Rg、およびRtはC1−8アルキル、ハロC1−8アルキル、C2−8アルケニル、ハロC2−8アルケニル、C2−8アルキニル、およびハロC2−8アルキニルからなる群からそれぞれ独立して選択され;
ただし、
XとYの両方がOになることはなく;
XがOである場合、R1bはOHではなく;
YがOであり、かつnがOである場合、R8はOHではなく;かつ
R6およびR7が一緒になってオキソを形成し、R2、R3、R4、およびR5の1つがメトキシまたはエトキシであり、かつR2、R3、R4、およびR5のもう一方がHである場合、Qは非置換ピリジン−2−イル、ピリジン−3−イル、またはピリジン−4−イルではない]
の化合物、またはその互変異性体もしくは医薬的に許容される塩の治療的有効量を、それを必要としている対象に投与することを含む方法を提供する。
以下の実施例は説明目的で提供されているが、特許請求の範囲に記載の発明を限定する意図はない。
これらの化合物の製造に用いられる出発物質および試薬は、一般的に民間の業者、例えばアルドリッチ・ケミカル社から入手可能であり、または参考文献、例えばFieser and Fieser’s Reagents for Organic Synthesis;Wiley & Sons: New York, 1967-2004, Volumes 1-22;Rodd’s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals;およびOrganic Reactions, Wiley & Sons: New York, 2005, Volumes 1-65に記載されている手順に従って当業者に既知の方法によって製造される。
実施例1.2−(イミダゾ[1,5−a]ピリジン−8−イルメトキシ)−5−メトキシベンズアルデヒドの製造
1H NMR(400MHz,DMSO) δ10.39(s,1H),8.53(d,J=6.8Hz,1H),8.06(s,1H),7.54(d,J=9.1Hz,1H),7.42(d,J=9.1Hz,1H),7.29−7.22(m,2H),7.17(d,J=3.3Hz,1H),6.90(t,J=6.8Hz,1H),5.35(s,2H),3.76(s,3H)。
1H NMR(400MHz,CDCl3) δ9.09(s,1H),7.73(dd,J=4.0,1.3Hz,1H),7.19(d,J=8.4Hz,1H),6.92(d,J=8.4Hz,1H),6.48(t,J=8.4Hz,1H),6.40(d,J=6.9Hz,1H),6.24(dd,J=8.5,4.2Hz,1H),6.10(d,J=2.6Hz,1H),5.95−5.85(m,2H),4.32(s,2H),2.56(s,3H)。
1H NMR(400MHz,CD3CN) δ10.32(s,1H),8.01(d,J=6.8Hz,1H),7.68(s,1H),7.19(d,J=9.0Hz,1H),7.13(d,J=3.2Hz,1H),7.08(dd,J=9.0,3.3Hz,1H),6.90(td,J=6.8,1.2H 1H),6.62(t,J=6.sHz,1H),5.21(s,2H),3.67(s,3H),2.39(s,3H)。
2,6−ジヒドロキシベンズアルデヒド(1.58g、11.47mmol、2当量)とK2CO3(2.4g、17.22mmol、3当量)のDMF(150mL)中混合物を、室温で10分間攪拌した。この混合物に、室温で3−(クロロメチル)−2−(1−イソプロピル−1H−ピラゾール−5−イル)ピリジン塩酸塩(1.56g、5.74mmol、1当量)を添加した。混合物を50℃で2時間加熱し、濾過し、濃縮し、溶離液としてEtOAcとヘキサンの混合物を用いてシリカゲルで精製し、2−ヒドロキシ−6−((2−(1−イソプロピル−1H−ピラゾール−5−イル)ピリジン−3−イル)メトキシ)ベンズアルデヒド(1.71g、88%)を淡黄色固体として得た。1H NMR(400MHz,CDCl3) δ11.96(s,1H),10.40(s,1H),8.77(dd,J=4.8,1.5Hz,1H),8.00(d,J=7.8Hz,1H),7.63(d,J=1.8Hz,1H),7.49−7.34(m,2H),6.59(d,J=8.5Hz,1H),6.37(d,J=1.8Hz,1H),6.29(d,J=8.2Hz,1H),5.10(s,2H),4.67(sep,J=6.7Hz,1H),1.50(d,J=6.6Hz,6H)。LRMS(M+H+)m/z338.1
工程1:
工程2:
1H NMR(400MHz,CD3CN) δ11.95(s,1H),10.45(s,1H),8.17(s,1H),8.05(d,J=7.7Hz,1H),7.69(d,J=7.8Hz,1H),7.62(t,J=7.7Hz,1H),7.49(t,J=8.4Hz,1H),6.62(d,J=8.3Hz,1H),6.54(d,J=8.5Hz,1H),5.30(s,2H)。
1H NMR(400MHz,DMSO) δ11.77(s,1H),10.40(s,1H),8.06(d,J=8.2Hz,2H),7.69(d,J=8.0Hz,2H),7.54(t,J=8.4Hz,1H),6.73(d,J=8.4Hz,1H),6.56(d,J=8.5Hz,1H),5.33(s,2H)。
工程1:
工程2:
1H NMR(400MHz,CDCl3) δ10.51(s,1H),8.01(d,J=8.3Hz,2H),7.81(dd,J=7.7,1.8Hz,1H),7.51−7.40(m,3H),7.00(t,J=7.5Hz,1H),6.94(d,J=8.4Hz,1H),5.19(s,2H),3.86(s,3H)。
1H NMR(400MHz,CDCl3) δ10.52(s,1H),8.09(d,J=8.2Hz,2H),7.81(dd,J=7.7,1.6Hz,1H),7.53−7.43(m,3H),7.01(t,J=7.5Hz,1H),6.95(d,J=8.4Hz,1H),5.21(s,2H)。
1H NMR(400MHz,CDCl3) δ10.58(s,1H),8.14(s,1H),8.06(d,J=7.8Hz,1H),7.90(dd,J=7.7,1.8Hz,1H),7.69(d,J=7.7Hz,1H),7.60−7.48(m,2H),7.08(dd,J=14.4,7.9Hz,2H),5.26(s,2H),3.96(s,3H)。
工程1:
工程1:
メチルマグネシウムブロミド(3M/エーテル、41.0mL、123.4mmol)を、−78℃で3−((tert−ブチルジメチルシリルオキシ)メチル)ピコリノニトリル(20.4g、82.25mmol)のTHF(100.0mL)中攪拌溶液に添加した。反応混合物を室温まで温め、クエン酸水溶液でクエンチし、EtOAc(50mL)で2回抽出した。合わせた有機層をNaHCO3(飽和)溶液と食塩水で洗浄し、Na2SO4で乾燥し、濃縮し、溶離液としてEtOAc/ヘキサンの混合液を用いてシリカゲルで精製し、1−(3−((tert−ブチルジメチルシリルオキシ)メチル)ピリジン−2−イル)エタノン(12.9g、59%)を無色油状物として得た。LRMS(M+H+)m/z266.2。
1−(3−((tert−ブチルジメチルシリルオキシ)メチル)ピリジン−2−イル)エタノン(10.8g、40.75mmol)のジメトキシ−N,N−ジメチルメタンアミン(15.0mL)溶液を、3日間加熱還流した。混合物を濃縮し、さらに精製することなく次の工程に用いた。LRMS(M+H+)m/z321.1。
実施例27に記載されている手順に従って表題化合物を製造した。
工程1:
工程1:
ヒドラジンカルボン酸ベンジル(5.0g、30.3mmol、1当量)とDIEA(15.0mL、90.9mmol、3当量)のDMF(20mL)中混合物に、室温で3,3,3−トリフルオロプロピルブロミド(10.7g 60.6mmol、2当量)を添加した。混合物を80℃で20時間加熱し、濃縮し、溶離液としてEtOAcとヘキサンの混合液を用いてシリカゲルで精製し、2−(3,3,3−トリフルオロプロピル)ヒドラジンカルボン酸ベンジル(4.2g;53%)を白色固体として得た。1H NMR(400MHz,CDCl3) δ7.33−7.17(m,5H),6.11(s,1H),5.01(s,2H),4.00(s,1H),3.00(dd,J=12.2,7.1Hz,2H),2.17(qt,J=10.8,7.3Hz,2H)。LRMS(M+H+)m/z263.1
2−(3,3,3−トリフルオロプロピル)ヒドラジンカルボン酸ベンジル(1.7g、6.49mmol、1当量)のEtOH(30mL)の混合液中溶液に、Pd/C(1.0g)とHCl(12N、2.0mL)を添加した。混合物にH2(60psi)を満たし、室温で1時間攪拌し、濾過し、濃縮し、(3,3,3−トリフルオロプロピル)ヒドラジン二塩酸塩(1.07g)を黄色固体として得た。LRMS(M+H)m/z129.1。
化合物52〜55は、上記方法に従って製造した。
実施例33.置換ベンズアルデヒド化合物によるヘモグロビン酸素親和性の調節−アッセイ手順
精製ヘモグロビンS(HbS)の酸素平衡曲線(OEC)をp50(HbSサンプル内のヘム結合部位が酸素で50%飽和する酸素分圧)の変化によって測定した。HbSは、小児病院オークランド研究所(CHORI)の異常ヘモグロビン症センターを通じて、施設内治験審査委員会の承認を得て、ホモ接合型鎌状赤血球患者から得られた血液から、修正手順(Antonini and Brunori, 1971; Heomoglobin and Myoglobin in their Reactions with Ligands; North Holland Publishing Company; Amsterdam, London)によって精製した。酸素平衡曲線は、HEMOXアナライザー(TCS Scientific社、ニューホープ、ペンシルベニア州)で実行した。250μMの精製HbSの500μLを4.5mLのHEMOX緩衝液(30mM TES、130mM NaCl、5mM KCl、pH=7.4)で希釈し、最終ヘモグロビン濃度を25μMとした。所望の最終濃度で化合物を添加した。混合物を37℃で45分間インキュベートし、次いでHemoxサンプルチャンバーに移した。圧縮空気で10分間フラッシングすることによってサンプルを酸素で飽和した。次いでサンプルを純窒素でフラッシングし、デオキシHbの吸収度を溶液pO2の関数として記録した。次いで酸素平衡データをヒル・モデルにフィットし、p50の値を得た。HbS単独(コントロール)および化合物存在下のHbSの両方について、TCSソフトウェアで脱酸素化曲線を収集した。精製Hbsについてのp50は、典型的には13.8±1.6であった。Δp50値は、コントロールのp50値から化合物で処理したHbSのp50値を引き、コントロールのp50値で割ることによって得た。正のΔp50値は、左シフト曲線およびコントロールよりも低いp50値に対応し、化合物がその酸素に対する親和性を増加させるようにHbSを調節する作用をしていることを示すものである。
上記アッセイにて試験した第1表の化合物は、全て正のΔp50値を有することが分かった。Δp50%は[[p50(HbS)−p50(化合物で処理したHbS)]/p50(HbS)]X100で計算した。下記第2表はΔp50%値を記載しており、+は0〜29の間のΔp50%を示し、++は30以上のΔp50%を示している。別段の記載がない限り、第2表の化合物は30μMで試験した。
1.8Mリン酸カリウム緩衝液pH7.4に交換した精製HBSを用いて、インビトロで重合アッセイを実行した。若干修正したプロトコール(Antonini and Brunori, 1971)を用いて、HbSは、小児病院オークランド研究所(CHORI)の異常ヘモグロビン症センターを通じて、施設内治験審査委員会の承認を得て、ホモ接合型鎌状赤血球患者から得られた血液から、CRO VIRUSYSによって精製した。100%DMSO中で化合物を製造し、所望の量を50μMの精製HBSに最終DMSO濃度0.3%で添加した。2.5Mのリン酸カリウムストック溶液およびpH7.4の水の組み合わせを用いて、最終リン酸カリウム濃度を1.8Mに調整した。反応混合物を37℃で1時間インキュベートし、次いで99.5%窒素と0.5%酸素を含有するグローブ・ボックス内で脱酸素化するために24ウェルプレートに移した。24ウェルプレートにはカバーをせず、グローブ・ボックス内のプレートクーラー上で、4℃で1.5時間インキュベートした。50μLの反応混合物を96ウェルプレートに移し、700nmでの吸光度をグローブ・ボックス内のプレートリーダーにて37℃で1時間毎分測定した。ボルツマン・シグモイド・フィットを用いて時間に対する吸光度のプロットをフィットし、遅延時間(0からVmaxの半分までの時間)を測定した。化合物を比較およびランク付けするために、遅延時間は遅延パーセント(%DT)(HBS/化合物とHBS単独の遅延時間の差に100を掛け、HBS単独の遅延時間で割ったものとして定義される)として表した。
弛緩/緊張遷移アッセイ(「R/Tアッセイ」)を用いて、置換ベンズアルデヒド化合物が脱酸素化条件下でヘモグロビンの高酸素親和性弛緩(R)状態を維持する能力を決定した。この能力は「ΔR」値(すなわち、化合物で処理しなかった場合の時間と比較した、ヘモグロビンを化合物で処理した後のR状態の時間の変化)として表すことができる。ΔRは未処理と比較した化合物処理後の残量の%Rである(例えば、処理なしのR%が8%で、一方、標的化合物で処理したR%が30μMで48%Rである場合、%Rはその化合物について40%である)。
異なる濃度の置換ベンズアルデヒド化合物で処理する前および後の全血の酸素平衡曲線(OEC)は、HEMOXアナライザー(TCS Scientific社、ニューホープ、ペンシルベニア州)を用いて次のように行った。ホモ接合型鎌状赤血球患者由来の血液サンプルは、小児病院オークランド研究所(CHORI)の異常ヘモグロビン症センターを通じて、施設内治験審査委員会の承認を得て入手した。自己血漿を用いてヘマトクリットを20%に調整し、化合物の非存在下または存在下で血液サンプルを37℃で1時間インキュベートした。100μlのこれらのサンプルを5mLのHemox緩衝液(30mM TES、130mM NaCl、5mM KCl、pH=7.4)に37℃で添加し、次いでHemoxサンプルチャンバーに移した。圧縮空気で10分間フラッシングすることによってサンプルを酸素で飽和した。次いでサンプルを純窒素でフラッシングし、オキシHbおよびデオキシHbのそれぞれの吸収度を溶液pO2の関数として記録した。次いで酸素平衡データをヒル・モデルにフィットし、p50の値を得た。全血単独(コントロール)および化合物の存在下の全血の両方についての脱酸素化曲線を、TCSソフトウェアで収集した。
静脈内研究
スプラーグ・ドーリー・ラットを、10%DMA:50%PEG:16%ca vitronに溶解した7.8mg/Kgの化合物43で処置した。特定の時点で、10uLの全血/血漿をラットから除去し、490ulのpH3緩衝液+500uLのACN/ISで処理し、次いで1時間振盪し、4℃にて57rpmで10分間遠心分離した。上清をフィルタープレートに移し、4℃にて2000rpmで1分間遠心分離した。次いでサンプルをLC−MS/MSによって分析し、親アルデヒドをモニターした。血液および血漿中の濃度を第5表に示す。キーとなるP/Kパラメーターは第6表に示している。
10%DMA:90%PEGに溶解した44mg/kgおよび100mg/kgを強制経口投与することによってSDラットを処置した。特定の時点で血液を採取し、上記静脈内研究で記載されているようなワークアップを行った。キーとなるパラメーターは、第7表に示している。
Claims (13)
- 請求項1または請求項2に記載の化合物、またはその互変異性体もしくは医薬的に許容される塩、および医薬的に許容される賦形剤を含む医薬組成物。
- 組織酸素化を増加させるための薬剤の製造のための、請求項1または請求項2に記載の化合物、またはその互変異性体もしくは医薬的に許容される塩の使用。
- 酸素欠乏と関連する状態を治療するための薬剤の製造のための、請求項1または請求項2に記載の化合物、またはその互変異性体もしくは医薬的に許容される塩の使用。
- 状態が癌、肺障害、脳卒中、高山病、潰瘍、褥瘡、アルツハイマー病、急性呼吸器疾患症候群、および創傷からなる群から選択される、請求項7または請求項8に記載の使用。
- 状態が肺障害である、請求項9に記載の使用。
- 状態が急性呼吸器疾患症候群である、請求項9に記載の使用。
- 鎌状赤血球症を治療するための薬剤の製造のための、請求項1または請求項2に記載の化合物、またはその互変異性体もしくは医薬的に許容される塩の使用。
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