JP6463366B2 - 12−リポキシゲナーゼ阻害物質としての4−((2−ヒドロキシ−3−メトキシベンジル)アミノ)ベンゼンスルホンアミド誘導体 - Google Patents
12−リポキシゲナーゼ阻害物質としての4−((2−ヒドロキシ−3−メトキシベンジル)アミノ)ベンゼンスルホンアミド誘導体 Download PDFInfo
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Classifications
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
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- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
- C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C07—ORGANIC CHEMISTRY
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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- C—CHEMISTRY; METALLURGY
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
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- C07D235/30—Nitrogen atoms not forming part of a nitro radical
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/69—Benzenesulfonamido-pyrimidines
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/14—Nitrogen atoms
- C07D261/16—Benzene-sulfonamido isoxazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
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- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/50—Nitrogen atoms bound to hetero atoms
- C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Description
本特許出願は、2013年10月10日提出の米国特許仮出願第61/889,396号、および2014年5月1日提出の米国特許仮出願第61/987,129号の恩典を主張し、これらはいずれも参照により本明細書に組み入れられる。
本発明は、米国立先進トランスレーショナル科学センター(National Center for Advancing Translational Sciences)の施設内研究プログラムならびに医学研究のための米国立衛生研究所ロードマップ(National Institutes of Health Roadmap for Medical Research)主導の分子ライブラリ助成金番号U54MH084681、米国立衛生研究所助成金番号R01 GM56062、医学研究のための米国立衛生研究所ロードマップ主導の分子ライブラリ助成金番号R03 MH081283、NIH助成金番号S10-RR20939、米国立心肺血液研究所(National Heart, Lung, and Blood Institute(NHBLI))助成金番号HL114405、および米国立一般医科学研究所(National Institute of General Medical Sciences(NIGMS))助成金番号GM105671の下での政府支援により行った。政府は本発明においてある特定の権利を有する。
リポキシゲナーゼは、アラキドン酸(AA)およびリノール酸(LA)などの多価不飽和脂肪酸基質を位置特異的および立体特異的に酸化する、非ヘム鉄含有酵素の1つのクラスである。(Solomon, et al. Chem. Biol. 1997, 4, 795-808;Brash, J. Biol. Chem. 1999, 274, 23679-23682。)これらのcis,cis-1,4-ペンタジエン基質が酸化される位置は、必須のリポキシゲナーゼと一致しており、3つの主要なヒトリポキシゲナーゼ:5-LOX、12-LOX、および15-LOX-1はそれぞれC5、C12、およびC15位を酸化する。リポキシゲナーゼは代謝経路のカスケードにおいて重要な第一段階に関与し、これらの酵素の生成物(エイコサノイド)は、ロイコトリエンおよびリポキシンなどのホルモンの前駆体であり、これらは多くの細胞機能を媒介する。(Serhan, et al. Chem. Rev. 2011, 111, 5922-5943。)したがって、リポキシゲナーゼ酵素およびそれらの生物活性代謝産物(例えば、ヒドロキシエイコサテトラエン酸(HETE)およびロイコトリエンA4)は、様々な炎症性疾患および癌に関与している。
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーを提供し、
式中、R1およびR2は独立して、C1〜C6アルキル、C1〜C6アルケニル、C1〜C6アルキニル、F、Cl、Br、ヒドロキシル、アミン、メトキシからなる群より選択される1つまたは複数の置換基でそれぞれ置換されていてもよい、H、アルキル、アルケニル、アルキニル、F、Cl、Br、アミン、二酸化窒素、インドール、アルコキシ、シクロアルキル、アリール、ヘテロシクロアルキル、ヘテロアリールからなる群より選択され;
R3は、C1〜C6アルキル、C1〜C6アルケニル、C1〜C6アルキニル、F、Cl、Br、ヒドロキシル、アミン、アルコキシ、フェニル、シクロアルキル、アリール、ピペラジン、ピペリジン、ピリジン、モルホリン、ピロリジン、ピラゾリジン、イミダゾリジン、およびチオモルホリンからなる群より選択される1つまたは複数の置換基でそれぞれ置換されていてもよい、フェニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、チアゾール、ベンゾチアゾール、ベンゾキサゾール、イミダゾール、ベンズイミダゾール、チオフェン、1-ナフタレン、2-ナフタレン、ピリジン、キノリン、イソキノリン、4N-boc-ピペリジン-3-フェニル、オキサゾール、ベンゾチオフェン、パラチアジン、フラン、ピラン、クロメン、ベンゾフラン、ピロール、ピラゾール、ピラジン、ピリミジン、トリアジン、インドール、プリン、フタラジンからなる群より選択され、
ただし、化合物は、
ではない。
[本発明1001]
式(I)
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマー:
式中、R 1 およびR 2 は独立して、C 1 〜C 6 アルキル、C 1 〜C 6 アルケニル、C 1 〜C 6 アルキニル、F、Cl、Br、ヒドロキシル、アミン、メトキシからなる群より選択される1つまたは複数の置換基でそれぞれ置換されていてもよい、H、アルキル、アルケニル、アルキニル、F、Cl、Br、アミン、二酸化窒素、インドール、アルコキシ、シクロアルキル、アリール、ヘテロシクロアルキル、ヘテロアリールからなる群より選択され;
R 3 は、C 1 〜C 6 アルキル、C 1 〜C 6 アルケニル、C 1 〜C 6 アルキニル、F、Cl、Br、ヒドロキシル、アミン、アルコキシ、フェニル、シクロアルキル、アリール、ピペラジン、ピペリジン、ピリジン、モルホリン、ピロリジン、ピラゾリジン、イミダゾリジン、およびチオモルホリンからなる群より選択される1つまたは複数の置換基でそれぞれ置換されていてもよい、フェニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、チアゾール、ベンゾチアゾール、ベンゾキサゾール、イミダゾール、ベンズイミダゾール、チオフェン、1-ナフタレン、2-ナフタレン、ピリジン、キノリン、イソキノリン、4N-boc-ピペリジン-3-フェニル、オキサゾール、ベンゾチオフェン、パラチアジン、フラン、ピラン、クロメン、ベンゾフラン、ピロール、ピラゾール、ピラジン、ピリミジン、トリアジン、インドール、プリン、フタラジンからなる群より選択され、
ただし、該化合物は、
ではない。
[本発明1002]
R 2 がHである場合、R 1 が、メトキシおよびClからなる群より選択され;
R 1 がHである場合、R 2 が、BrおよびClからなる群より選択され;かつ
R 3 が、チアゾール、2-ベンゾチアゾール、2-ベンゾキサゾール、2-ベンズイミダゾール、4-メチル-2-ベンゾチアゾール、チオフェン、4-メチル-2-チアゾール、5-メチル-2-チアゾール、4,5-メチル-2-チアゾール、フェニル、1-ナフタレン、2-ナフタレン、1,4-ビ-フェニル、3-ピペラジン-フェニル、4-ピペリジン-フェニル、4-ピペラジン-3-ピリジン、6-メチル-3-ピリジン、3-キノリン、8-イソキノリン、2-ピリジン、3-ピリジン、3-tertブチル-フェニル、6-メトキシ-2-ベンゾチアゾール、6-フルロ(fluro)-2-ベンゾチアゾール、4-フェニル-2-チアゾール、3-モルホリン-フェニル、4N-boc-ピペリジン-3-フェニル、3-ピペリジン-フェニル、3-イソプロピル-フェニル、および4-ビ-フェニルからなる群より選択される、
本発明1001の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマー。
[本発明1003]
R 1 がメトキシであり、かつR 2 がHである、本発明1002の化合物。
[本発明1004]
プロドラッグである、本発明1001の化合物。
[本発明1005]
R 3 が、2-ベンゾチアゾール、2-ベンゾキサゾール、2-ベンズイミダゾール、4-メチル-2-ベンゾチアゾール、3-キノリン、8-イソキノリン、フェニル、および3-イソプロピル-フェニルからなる群より選択される、本発明1003の化合物。
[本発明1006]
R 3 が、2-ベンゾチアゾール、2-ベンゾキサゾール、2-ベンズイミダゾール、4-メチル-2-ベンゾチアゾール、チオフェン、フェニル、1-ナフタレン、2-ナフタレン、3-キノリン、8-イソキノリン、3-tertブチル-フェニル、6-メトキシ-2-ベンゾチアゾール、6-フルロ-2-ベンゾチアゾール、4-フェニル-2-チアゾール、4N-boc-ピペリジン-3-フェニル、および3-イソプロピル-フェニルからなる群より選択される、本発明1003の化合物。
[本発明1007]
R 3 が、2-ベンゾチアゾール、2-ベンゾキサゾール、2-ベンズイミダゾール、4-メチル-2-ベンゾチアゾール、チオフェン、フェニル、1-ナフタレン、2-ナフタレン、3-キノリン、8-イソキノリン、3-tertブチル-フェニル、4N-boc-ピペリジン-3-フェニル、および3-イソプロピル-フェニルからなる群より選択される、本発明1003の化合物。
[本発明1008]
R 3 が、2-ベンゾチアゾール、2-ベンゾキサゾール、2-ベンズイミダゾール、および3-イソプロピル-フェニルからなる群より選択される、本発明1003の化合物。
[本発明1009]
R 3 が、2-ベンゾチアゾール、2-ベンゾキサゾール、2-ベンズイミダゾール、4-メチル-2-ベンゾチアゾール、チオフェン、フェニル、6-メトキシ-2-ベンゾチアゾール、6-フルロ-2-ベンゾチアゾール、および4-フェニル-2-チアゾールからなる群より選択される、本発明1003の化合物。
[本発明1010]
R 3 が、2-ベンゾチアゾール、2-ベンゾキサゾール、2-ベンズイミダゾール、4-メチル-2-ベンゾチアゾール、チオフェン、およびフェニルからなる群より選択される、本発明1003の化合物。
[本発明1011]
R 3 が、2-ベンゾチアゾール、2-ベンゾキサゾール、2-ベンズイミダゾール、4-メチル-2-ベンゾチアゾール、チオフェン、フェニル、1-ナフタレン、2-ナフタレン、3-キノリン、8-イソキノリン、2-ピリジン、および3-ピリジンからなる群より選択される、本発明1003の化合物。
[本発明1012]
である化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマー。
[本発明1013]
である化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマー。
[本発明1014]
である化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマー。
[本発明1015]
式(II)
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマー:
式中、Xは、O、S、NH、およびCからなる群より選択され;
R 1 およびR 2 は独立して、H、ハロゲン、ヒドロキシル、アルコキシ、およびアルキルからなる群より選択され;
R 3 からR 6 は独立して、H、ハロゲン、アルコキシ、およびアルキルからなる群より選択される。
[本発明1016]
式(III)
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマー:
式中、R 1 およびR 2 は独立して、H、ハロゲン、およびアルコキシからなる群より選択され、かつさらにR 1 およびR 2 は両方ともHであることはなく;
R 4 およびR 5 は独立して、H、アルキル、フェニル、および置換されていてもよいフェニルからなる群より選択され;
ただし、該化合物は、
ではない。
[本発明1017]
式(IV)
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマー:
式中、R 1 およびR 2 は独立して、H、ハロゲン、およびアルコキシからなる群より選択され;
R 3 およびR 4 は独立して、H、フェニル、置換されていてもよいフェニル、tert-ブチル、イソプロピル、および
からなる群より選択され;
Xは、NH、O、および
からなる群より選択される。
[本発明1018]
哺乳動物に、本発明1006の化合物、その塩、その鏡像異性体、その鏡像異性体の混合物、またはそのジアステレオマーの治療的または予防的に有効な量を投与する段階を含む、12-リポキシゲナーゼ媒介性の疾患または障害を処置または予防するための方法。
[本発明1019]
前記12-リポキシゲナーゼがヒト12-リポキシゲナーゼである、本発明1018の方法。
[本発明1020]
前記12-リポキシゲナーゼ媒介性の疾患または障害が、1型糖尿病、2型糖尿病、糖尿病性腎疾患、糖尿病性神経疾患、心血管疾患、アルツハイマー病、非アルコール性脂肪性肝炎、血小板性血流遮断、皮膚疾患、ヘパリン起因性血小板減少症、血栓症、抗リン脂質抗体症候群、敗血症症候群、治療用または診断用モノクローナル抗体に関連する血栓症、および血栓性血小板減少性紫斑病、ならびに癌からなる群より選択される、本発明1018の方法。
[本発明1021]
前記癌が、前立腺癌、直腸結腸癌、乳癌、および肺癌からなる群より選択される、本発明1020の方法。
[本発明1022]
前記心血管疾患が、うっ血性心不全、心筋梗塞、および脳卒中からなる群より選択される、本発明1020の方法。
[本発明1023]
前記12-リポキシゲナーゼ媒介性の疾患または障害が、1型糖尿病および2型糖尿病からなる群より選択される、本発明1020の方法。
[本発明1024]
前記12-リポキシゲナーゼ媒介性の疾患または障害が、血栓症、ヘパリン起因性血小板減少症、抗リン脂質抗体症候群、敗血症症候群、治療用または診断用モノクローナル抗体に関連する血栓症、および血栓性血小板減少性紫斑病からなる群より選択される、本発明1020の方法。
[本発明1025]
前記化合物が、
またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーである、本発明1018の方法。
[本発明1026]
前記化合物が、
またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーである、本発明1020の方法。
[本発明1027]
前記化合物が、
またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーである、本発明1020の方法。
[本発明1028]
前記化合物が、
またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーである、本発明1020の方法。
[本発明1029]
哺乳動物に、本発明1006の化合物、その塩、その鏡像異性体、その鏡像異性体の混合物、またはそのジアステレオマーの治療的または予防的に有効な量を投与する段階を含む、PAR4-AP誘導性血小板凝集を減少させるための方法。
[本発明1030]
哺乳動物に、本発明1006の化合物、その塩、その鏡像異性体、その鏡像異性体の混合物、またはそのジアステレオマーの治療的または予防的に有効な量を投与する段階を含む、PAR4-AP誘導性カルシウム動員を減少させるための方法。
本明細書に記載の特定の方法論などは変動し得るため、本発明は、これらに限定されないことが理解される。本明細書において用いられる用語は、特定の態様を記載するために用いられるにすぎず、本発明の範囲を限定する意図はないことも理解されるべきである。
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーを含み、
式中、R1およびR2は独立して、C1〜C6アルキル、C1〜C6アルケニル、C1〜C6アルキニル、F、Cl、Br、ヒドロキシル、アミン、メトキシからなる群より選択される1つまたは複数の置換基でそれぞれ置換されていてもよい、H、アルキル、アルケニル、アルキニル、F、Cl、Br、アミン、二酸化窒素、インドール、アルコキシ、シクロアルキル、アリール、ヘテロシクロアルキル、ヘテロアリールからなる群より選択され;
R3は、C1〜C6アルキル、C1〜C6アルケニル、C1〜C6アルキニル、F、Cl、Br、ヒドロキシル、アミン、アルコキシ、フェニル、シクロアルキル、アリール、ピペラジン、ピペリジン、ピリジン、モルホリン、ピロリジン、ピラゾリジン、イミダゾリジン、およびチオモルホリンからなる群より選択される1つまたは複数の置換基でそれぞれ置換されていてもよい、フェニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、チアゾール、ベンゾチアゾール、ベンゾキサゾール、イミダゾール、ベンズイミダゾール、チオフェン、1-ナフタレン、2-ナフタレン、ピリジン、キノリン、イソキノリン、4N-boc-ピペリジン-3-フェニル、オキサゾール、ベンゾチオフェン、パラチアジン、フラン、ピラン、クロメン、ベンゾフラン、ピロール、ピラゾール、ピラジン、ピリミジン、トリアジン、インドール、プリン、フタラジンからなる群より選択され、
ただし、化合物は、
ではない。
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーを含み、
式中、Xは、O、S、NH、およびCからなる群より選択され;
R1およびR2は独立して、H、ハロゲン、ヒドロキシル、アルコキシ、およびアルキルからなる群より選択され;
R3からR6は独立して、H、ハロゲン、アルコキシ、およびアルキルからなる群より選択される。
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーを含み、
式中、R1およびR2は独立して、H、ハロゲン、およびアルコキシからなる群より選択され、かつさらに、R1およびR2は両方ともHであることはなく;
R4およびR5は独立して、H、アルキル、フェニル、および置換されていてもよいフェニルからなる群より選択され;
ただし、化合物は
ではない。
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーを含み、
式中、R1およびR2は独立して、H、ハロゲン、およびアルコキシからなる群より選択され;
R3およびR4は独立して、H、フェニル、置換されていてもよいフェニル、tert-ブチル、イソプロピル、および
からなる群より選択され;
Xは、NH、O、および
からなる群より選択される。
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーを含み、
式中、Xは、N、C、S、およびOからなる群より選択され;
R1からR6は独立して、H、アルキル、およびアルコキシからなる群より選択される。
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーを含み、
式中、Xは、N、C、S、およびOからなる群より選択され;
R1からR6は独立して、H、アルキル、およびアルコキシからなる群より選択される。
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマーを含み、
式中、Xは、N、C、S、およびOからなる群より選択され;
R1からR3は独立して、H、アルキル、およびアルコキシからなる群より選択される。
一般手順:(段階iv)1,4-ジオキサン(1.5mL)中の4-(2-ヒドロキシ-3-メトキシベンジルアミノ)ベンゼンスルホンアミド(5)(0.58mmol)、臭化アリール(0.70mmol)、K2CO3(1.45mmol)、N,N'-ジメチルエチレンジアミン(0.29mmol)、およびヨウ化銅(I)(0.03mmol)をN2雰囲気下におき、5mL密封チューブに入れて密封した。反応混合物を70℃で6〜8時間加熱し、LC/MS分析によりモニターした。完了後、不均質混合物を室温まで冷却し、ろ過し、ジオキサンで洗浄した。溶液をチオールカートリッジ(金属捕捉)に通し、AcOEtで希釈し、NH4Cl(2×)、水、および食塩水で洗浄した。粗製材料を分取HPLC(10〜100%アセトニトリル+0.1%TFA/水+0.1%TFAの勾配)により精製して、所望の生成物を得た。
a1、35、36、および37の選択性プロファイリング。bIC50値はμMで報告している。c化合物を15μMで試験し、10%を超える阻害を示す化合物はなかった。dUV-vis偽ペルオキシダーゼ(pseudoperoxidase)活性アッセイ法を35および36で実施し、234nmでヒドロペルオキシド生成物の分解は観察されず、非還元的阻害メカニズムを示した;NI=阻害なし、およびNT=未試験。
aこれらの実験はPharmaron Inc.で行った。他の試験はすべてNCATSで行った。bNADPH存在下での安定性を表す。NADPHなしの35および36は1時間の間に分解を示さなかった。cpH7.4での人工膜透過性試験法(Parallel Artificial Membrane Permeability Assay)(PAMPA)における透過性を表す。
aすべての実験はPharmaron Inc.で雄CD1マウス(6〜8週齢)を用いて行った。データは24時間にわたり8つの時点において三つ組で収集した。b溶液(5%DMSO、10%Solutol、20%PEG400、65%水)として製剤化。c静脈内用量の63.2%を排出する時間を表す。
実施例:血小板12-LOXはFcγRIIa媒介性血小板活性化のために必須である
ヒト血小板における12-LOXの薬理学的阻害は、FcγRIIa媒介性凝集の有意な減弱をもたらした。12-LOXは、FcγRIIa誘導性PLCγ2活性のために必須であり、カルシウム動員の活性化、Rap1およびPKC活性化、ならびに続くインテグリンαIIbβ3活性化につながることが判明した。加えて、ヒトFcγRIIaを発現するが血小板12-LOXを欠損しているトランスジェニックマウス由来の血小板は、FcγRIIa受容体の刺激後に、正常な血小板凝集塊を形成することができず、Rap1およびαIIbβ3活性化の欠損を示した。これらの結果は、FcγRIIa媒介性血小板機能を制御する際の12-LOXの必須の役割を裏付け、免疫媒介性血栓症を制限するための治療標的として12-LOXを同定している。
12-LOXは以前、GPVI媒介性血小板凝集を制御することが示された。血小板において、FcγRIIaはGPVI-FcRγと同じ下流シグナル伝達エフェクターの多くを用いる(4)。12-LOXがFcγRIIa媒介性血小板凝集において役割を果たすかどうかを調べるために、洗浄ヒト血小板をML355、選択的な12-LOX阻害物質、またはDMSO(ビヒクル対照)で処理した後、FcγRIIaにより凝集を誘導した。血小板12-LOX活性の阻害は、抗CD9刺激(図11A)またはFcγRIIa抗体架橋(図11B)を介したFcγRIIa媒介性血小板凝集を減弱した。FcγRIIa媒介性血小板凝集の減少が12-LOXの薬理学的阻害によるものであり、ML355の非特異的効果ではないことを確認するために、エクスビボでの血小板凝集を、12-LOXを発現する(ALOX12+/+)または12-LOXを欠損している(ALOX12-/-)ヒト化FcγRIIa(hFcR)トランスジェニックマウスにおいて抗CD9刺激後に測定した。12-LOXを欠損しているマウス(hFcR/ALOX12-/-)からの血小板は、機能的12-LOXを発現するマウス(hFcR/ALOX12+/+)からの血小板と比べると、抗CD9刺激(0.125および0.25μg/mL)に反応した凝集の遅延(図12B)および減弱(図12C)を示した。これらのデータは、薬理学的または遺伝的除去を通じて12-LOX活性を欠いている血小板は、FcγRIIa活性化に反応した凝集の有意な減弱を示すことを示唆している。
図11および12は、12-LOXが正常なFcγRIIa媒介性血小板凝集のために必須であると示唆しているが;12-LOXによって制御されるFcγRIIa経路における構成要素は不明のままである。インテグリンαIIbβ3の活性化は血小板凝集に必要とされるため、FcγRIIa刺激血小板におけるαIIbβ3活性化を媒介する際の12-LOXの可能な役割を調査し、ML355で処理したFcγRIIa刺激血小板においてαIIbβ3活性化をフローサイトメトリーにより測定した。Rap1は、その活性化がαIIbβ3の活性化のために必須である、小さいGTPアーゼである。したがって、Rap1活性化をML355での処置または非処置後の血小板におけるFcγRIIa刺激後に測定した。図13Bに示すとおり、前処理非存在下(対照)の血小板の刺激は、Rap1-GTPの有意な増大をもたらし、ML355で処理した血小板はRap1を活性化することができなかった。DMSO処理した血小板凝は、対照に比べて活性Rap1の減弱を示さなかった。
活性化血小板からのα顆粒および密顆粒の放出は、血小板凝集を増幅するのに役立つ。P-セレクチンの表面発現を、FcγRIIa刺激血小板におけるα顆粒分泌を測定するための代替マーカーとして用いた。ML355による処理は、対照条件に比べて、P-セレクチンのアゴニスト誘導性表面発現の減弱を引き起こさなかった(図14A)。しかし、ML355で処理したFcγRIIa刺激血小板は、DMSO処理血小板に比べて、ATP放出の有意な減少を示した(図14B)。これらのデータは、12-LOXが血小板におけるFcγRIIa刺激の下流の密分泌の制御因子であることを示唆している。
図13に示すとおり、12-LOX活性は、FcγRIIa経路の正常な遠位シグナル伝達構成要素(Rap1、αIIbβ3、および血小板活性化)のために必要である。FcγRIIaの免役グロブリンとの架橋も、最終的に血小板凝集につながる近位シグナル伝達構成要素の活性化を開始する。FcγRIIaはITAMリン酸化を開始し、Syk活性化をもたらす。Syk活性化は、ホスホリパーゼγ2(PLCγ2)の活性化につながり、カルシウム放出およびPKC活性化をもたらし、これらはいずれも血小板活性化にとって非常に重要である。この複雑なシグナル伝達環境のどこで12-LOXが血小板中のFcγRIIaシグナル伝達において必須の役割を果たすかを調べるために、FcγRIIa開始の直接的に下流にある個々のシグナル伝達構成要素をML355存在下または非存在下で評価した。
12-LOXは最近、GPVI媒介性血小板活性化の重要な制御因子であることが明らかにされた。FcγRIIaおよびGPVIは保存経路を介してシグナル伝達するとされているため、12-LOXはヒト血小板におけるFcγRIIaシグナル伝達の制御において必須の役割を果たしうる。本試験は、12-LOXがFcγRIIa免疫媒介性血小板活性化の必須の構成要素であることを示す最初のものである。12-LOX阻害物質、ML355で処理したヒト血小板、または12-LOXを欠損しているFcγRIIaトランスジェニックマウス血小板は、FcγRIIa媒介性活性化に反応した凝集の有意な減弱を示した。12-LOXがFcγRIIa媒介性血小板活性化を制御する根元的メカニズムを調査するために、FcγRIIa経路における複数のシグナル伝達中間体の活性を、12-LOX阻害物質ML355存在下で評価した。刺激後、ML355で処理した血小板は、αIIbβ3、Rap1、Ca2+、PLCγ2、PKC、および密顆粒分泌を含む免疫媒介性FcγRIIa活性化経路における複数のシグナル伝達段階に沿って有意に減弱した(図17)。
マウスおよび血小板調製:FcγRIIAトランスジェニックマウス(hFcR/ALOX12+/+)を血小板12-リポキシゲナーゼノックアウト(ALOX12-/-)マウスと繁殖させて、血小板12-リポキシゲナーゼを欠損しているFcγRIIAトランスジェニックマウス(hFcR/ALOX12-/-)を作製した。すべてのマウスをThomas Jefferson University(TJU)のマウス施設に収容した。実験手順はAnimal Care and Use Committee of TJUによって認可された。血液を12週齢の麻酔したマウスの下大静脈からクエン酸ナトリウムを含むシリンジを用いて採取した。マウス血小板調製物を(Yeung et al., 2012)に記載のとおりに調製した。マウス血小板を、フィブリノゲン(75μg/mL)およびCaCl2(1mM)を含むタイロード緩衝液に再懸濁した。
Claims (21)
- 式(I)
の化合物、またはその薬学的に許容される塩、その鏡像異性体、その鏡像異性体の混合物、もしくはそのジアステレオマー:
式中、R1はメトキシであり;
R2はHであり;
R3は、2−ベンゾチアゾール、4−メチル−2−ベンゾチアゾール、6−フルオロ−2−ベンゾチアゾール、6−メトキシ−2−ベンゾチアゾール、2−ベンゾキサゾール、2−ベンズイミダゾール、2−チオフェン、4−メチル−2−チアゾール、5−メチル−2−チアゾール、4,5−メチル−2−チアゾール、4−フェニル−2−チアゾール、3−キノリン、8−イソキノリン、フェニル、1,4−ビフェニル、1−ナフタレン、2−ナフタレン、3−ピペラジン−フェニル、4−ピペリジン−フェニル、3−ピペリジン−フェニル、2−ピリジン、3−ピリジン、4−ピペラジン−3−ピリジン、3−tert−ブチル−フェニル、3−モルホリン−フェニル、4N−tert-ブトキシカルボニル(boc)−ピペリジン−3−フェニル、および3−イソプロピル−フェニルからなる群から選択される。 - R3が、1−ナフタレン、2−ナフタレン、および2−ベンゾチアゾールからなる群から選ばれる、請求項2に記載の化合物。
- R3が、2−ベンゾチアゾール、2−ベンゾキサゾール、2−ベンズイミダゾール、4−メチル−2−ベンゾチアゾール、2−チオフェン、4−フェニル−2−チアゾール、3−キノリン、8−イソキノリン、フェニル、1−ナフタレン、2−ナフタレン、3−tert−ブチル−フェニル、4N−boc−ピペリジン−3−フェニル、6−メトキシ−2−ベンゾチアゾール、および3−イソプロピル−フェニルからなる群より選択される、請求項1に記載の化合物。
- R3が、2−ベンゾチアゾール、2−ベンゾキサゾール、2−ベンズイミダゾール、および3−イソプロピル−フェニルからなる群より選択される、請求項1に記載の化合物。
- 請求項1に記載の化合物、その塩、その鏡像異性体、その鏡像異性体の混合物、またはそのジアステレオマーを含む、12−リポキシゲナーゼ媒介性の疾患または障害を処置または予防するための薬学的組成物。
- 前記12−リポキシゲナーゼがヒト12−リポキシゲナーゼである、請求項9に記載の薬学的組成物。
- 前記12−リポキシゲナーゼ媒介性の疾患または障害が、1型糖尿病、2型糖尿病、糖尿病性腎疾患、糖尿病性神経疾患、心血管疾患、アルツハイマー病、非アルコール性脂肪性肝炎、血小板性血流遮断、皮膚疾患、ヘパリン起因性血小板減少症、血栓症、抗リン脂質抗体症候群、敗血症症候群、治療用または診断用モノクローナル抗体に関連する血栓症、および血栓性血小板減少性紫斑病、ならびに癌からなる群より選択される、請求項9に記載の薬学的組成物。
- 前記癌が、前立腺癌、直腸結腸癌、乳癌、および肺癌からなる群より選択される、請求項11に記載の薬学的組成物。
- 前記心血管疾患が、うっ血性心不全、心筋梗塞、および脳卒中からなる群より選択される、請求項11に記載の薬学的組成物。
- 前記12−リポキシゲナーゼ媒介性の疾患または障害が、1型糖尿病および2型糖尿病からなる群より選択される、請求項11に記載の薬学的組成物。
- 前記12−リポキシゲナーゼ媒介性の疾患または障害が、血栓症、ヘパリン起因性血小板減少症、抗リン脂質抗体症候群、敗血症症候群、治療用または診断用モノクローナル抗体に関連する血栓症、および血栓性血小板減少性紫斑病からなる群より選択される、請求項11に記載の薬学的組成物。
- 請求項1に記載の化合物、その塩、その鏡像異性体、その鏡像異性体の混合物、またはそのジアステレオマーを含む、PAR4−AP誘導性血小板凝集を減少させるための薬学的組成物。
- 請求項1に記載の化合物、その塩、その鏡像異性体、その鏡像異性体の混合物、またはそのジアステレオマーを含む、PAR4−AP誘導性カルシウム動員を減少させるための薬学的組成物。
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CN104364751A (zh) | 2012-06-08 | 2015-02-18 | Nec卡西欧移动通信株式会社 | 电子设备及其控制方法和程序 |
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US9115122B2 (en) | 2012-12-20 | 2015-08-25 | University Of Maryland, Baltimore | Non-ATP dependent inhibitors of extracellular signal-regulated kinase (ERK) |
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WO2015035325A1 (en) | 2013-09-06 | 2015-03-12 | The Regents Of University Of California | Intermolecular c-h silylation of unactivated arenes |
EP3046561B1 (en) | 2013-09-20 | 2023-02-22 | University of Pittsburgh - Of the Commonwealth System of Higher Education | Compounds for treating prostate cancer |
CA2926950C (en) | 2013-10-10 | 2022-10-11 | Eastern Virginia Medical School | 4-((2-hydroxy-3-methoxybenzyl)amino) benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase |
CN104163794A (zh) | 2013-10-17 | 2014-11-26 | 中国药科大学 | 2-氨基芳环类血管内皮生长因子受体(vegfr)抑制剂及其制备方法和用途 |
AU2015226881A1 (en) | 2014-03-07 | 2016-09-29 | Intonation Research Laboratories | Inhibitors of histone lysine specific demethylase (LSD1) and histone deacetylases (HDACs) |
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