JP2018510207A - スルホニル尿素及び関連化合物並びにその使用 - Google Patents
スルホニル尿素及び関連化合物並びにその使用 Download PDFInfo
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- JP2018510207A JP2018510207A JP2017560843A JP2017560843A JP2018510207A JP 2018510207 A JP2018510207 A JP 2018510207A JP 2017560843 A JP2017560843 A JP 2017560843A JP 2017560843 A JP2017560843 A JP 2017560843A JP 2018510207 A JP2018510207 A JP 2018510207A
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- 229940075931 sodium dithionate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
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- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HHGMADGROXARPN-UHFFFAOYSA-M sodium;2h-triazole-4-thiolate Chemical compound [Na+].[S-]C=1C=NNN=1 HHGMADGROXARPN-UHFFFAOYSA-M 0.000 description 1
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- 239000012258 stirred mixture Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- ZVQXQPNJHRNGID-UHFFFAOYSA-N tetramethylsuccinonitrile Chemical compound N#CC(C)(C)C(C)(C)C#N ZVQXQPNJHRNGID-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000000165 tricyclic carbocycle group Chemical group 0.000 description 1
- JFHAGWAOOHJDEP-UHFFFAOYSA-N trifluoromethylcyclopropane Chemical compound FC(F)(F)C1CC1 JFHAGWAOOHJDEP-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 229910052725 zinc Inorganic materials 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
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Abstract
Description
JはS及びSeから選択され、
R1は、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリルからなる群から選択され、それらの全ては場合によって置換されていてもよく、
R2は、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリルからなる群から選択され、それらの全ては場合によって置換されていてもよく、
炭素原子を介してR1はJに直接結合し、R2も隣接する窒素に直接結合している化合物、又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグが提供される。
JはS及びSeから選択され、
R1は、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリルからなる群から選択され、それらの全ては場合によって置換されていてもよく、
R2は、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリルからなる群から選択され、それらの全ては場合によって置換されていてもよく、
炭素原子を介してR1はJに直接結合し、R2も隣接する窒素に直接結合している化合物、又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグが提供される。
式中、Yは出現毎に独立してC、N、S及びOから選択され、それらは適切ならば、場合によって置換されていてもよく、
R5、R11、R12、R13、R14及びR15は独立して、水素、ハロ、シアノ、アミド、スルホンアミド、アシル、ヒドロキシル、C1〜C6アルキル、C1〜C6ハロアルキル、C3〜C5シクロアルキル及びC1〜C6アルコキシからなる群から選択されていてもよく、それらの基は全て、適切ならば、ハロ、シアノ又はC1〜C6アルコキシで場合によって置換されていてもよく、
R11及びR12は組み合わさってフェニル、5若しくは6員含酸素複素環又は5若しくは6員含窒素ヘテロアリールを形成していてもよく、それらのそれぞれは場合によって置換されていてもよく、
R12及びR13は組み合わさって5若しくは6員含窒素ヘテロアリールを形成していてもよく、それは場合によって置換されていてもよく、
R14及びR15は組み合わさって5若しくは6員シクロアルキル環、フェニル、5若しくは6員含酸素複素環又は5若しくは6員含窒素ヘテロアリールを形成していてもよく、それらのそれぞれは場合によって置換されていてもよい。
R12及びR14はHであり、
R13はH又はハロゲン、好ましくは、H又はClである。
各破線は結合を表していてもよく、
R2は式(I)、(Ia)、(Ib)若しくは(Ic)の任意の実施形態について以前に定義した通りであるか、又は蛍光基であってもよく、
R6は出現毎に独立して、水素、ハロ、シアノ、C1〜C6アルキル、C1〜C6アルキルアミノ、C1〜C6アルキルヒドロキシ、C3〜C6シクロアルキル、アルキルフェニル、フェニル、ベンジル、C1〜C6エステル、C2〜C6アルケニル、C1〜C6トリフルオロアルキル及びC1〜C6アルコキシからなる群から選択され、それらのそれぞれは場合によって置換されていてもよく、又はR6は蛍光基であってもよい化合物、又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグから選択することができる。
A、B、D及びEはN及びCから選択され、A、B、D及びEのうちの少なくとも2つはNであり、
R6は出現毎に独立して、水素、ハロゲン化物、シアノ、C1〜C6アルキル、C1〜C6アルキルアミノ、C1〜C6アルキルヒドロキシ、C3〜C6シクロアルキル、アルキルフェニル、フェニル、ベンジル、C1〜C6エステル、C2〜C6アルケニル、C1〜C6トリフルオロアルキル及びC1〜C6アルコキシからなる群から選択され、それらのそれぞれは場合によって置換されていてもよい化合物、又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグから選択することができる。
A、B、D及びEはN及びCから選択され、A、B、D及びEのうちの少なくとも2つはNであり、
R6は出現毎に独立して、水素、ハロゲン化物、シアノ、C1〜C6アルキル、C1〜C6アルキルアミノ、C1〜C6アルキルヒドロキシ、C3〜C6シクロアルキル、アルキルフェニル、フェニル、ベンジル、C1〜C6エステル、C2〜C6アルケニル、C1〜C6トリフルオロアルキル及びC1〜C6アルコキシからなる群から選択され、それらのそれぞれは場合によって置換されていてもよい化合物、又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグから選択することができる。
式中、R40はH、アルキル及びハロから選択され、
R41はH及びアルキルから選択され、
Pは出現毎に独立してC、O又はSから選択され、
R6は、存在する場合、出現毎に独立して式(II)について定義した群から選択される。
R22はH、アルキル、ペルハロアルキル、C3〜C6シクロアルキル、フェニル又はベンジルから選択され、
R18はH又はハロゲンであり、
R16及びR17はH若しくはアルキルであるか、又はR16及びR17は、それらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
R19及びR20はH若しくはアルキルであるか、又はR19及びR20は、それらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
但し、R21及びR22は両方がHであることはなく、
但し、R16、R17、R18、R19及びR20は全てがHであることはない化合物又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグから選択することができる。
R21はH、アルキル、ペルハロアルキル又はヒドロキシルアルキル、好ましくはC1〜6ペルハロアルキル又はヒドロキシルアルキルから選択され、
R22はH、アルキル、ペルハロアルキル、C3〜C6シクロアルキル、フェニル又はベンジルから選択され、
R16及びR17は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R19及びR20は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R18はH又はハロゲンであり、好ましくはR18はHであり、
但し、R21及びR22は両方がHであることはない。
R21はH、アルキル、ペルハロアルキル又はヒドロキシルアルキル、好ましくはC1〜6ペルハロアルキル又はヒドロキシルアルキルから選択され、
R22はH、アルキル、ペルハロアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、
R16及びR20は、C1〜6アルキル、好ましくはイソプロピルであり、
R17及びR19はHであり、
R18はH又はハロゲンであり、好ましくはR18はH又はClであり、
但し、R21及びR22は両方がHであることはない。
R18はH又はハロゲンであり、
R16及びR17はH若しくはアルキルであるか、又はR16及びR17はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
R19及びR20はH若しくはアルキルであるか、又はR19及びR20はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
但し、R21及びR22は両方がHであることはなく、
但し、R16、R17、R18、R19及びR20は全てがHであることはない化合物又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグから選択することができる。
R21及びR22はH、アルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、好ましくはペルハロアルキル及びヒドロキシルアルキルはC1〜6ペルハロアルキル及びヒドロキシルアルキルであり、
R16及びR17は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R19及びR20は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R18はH又はハロゲンであり、好ましくはR18はHであり、
但し、R21及びR22は両方がHであることはない。
R21及びR22はH、アルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、好ましくはペルハロアルキル及びヒドロキシルアルキルはC1〜6ペルハロアルキル及びヒドロキシルアルキルであり、
R16及びR20は、C1〜6アルキル、好ましくはイソプロピルであり、
R17及びR19はHであり、
R18はH又はハロゲンであり、好ましくはR18はH又はClであり、
但し、R21及びR22は両方がHであることはない。
R18はH又はハロゲンであり、
R16及びR17はH若しくはアルキルであるか、又はR16及びR17はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
R19及びR20はH若しくはアルキルであるか、又はR19及びR20はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
但し、R21及びR22は両方がHであることはなく、
但し、R16、R17、R18、R19及びR20は全てがHであることはない化合物、又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグから選択することができる。
R21及びR22はH、アルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、好ましくはペルハロアルキル及びヒドロキシルアルキルはC1〜6ペルハロアルキル及びヒドロキシルアルキルであり、
R16及びR17は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R19及びR20は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R18はH又はハロゲンであり、好ましくはR18はHであり、
但し、R21及びR22は両方がHであることはない。
R21及びR22はH、アルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、好ましくはペルハロアルキル及びヒドロキシルアルキルはC1〜6ペルハロアルキル及びヒドロキシルアルキルであり、
R16及びR20は、C1〜6アルキル、好ましくはイソプロピルであり、
R17及びR19はHであり、
R18はH又はハロゲンであり、好ましくはR18はH又はClであり、
但し、R21及びR22は両方がHであることはない。
R18はH又はハロゲンであり、
R16及びR17はH若しくはアルキルであるか、又はR16及びR17はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は、飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
R19及びR20はH若しくはアルキルであるか、又はR19及びR20はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は、飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
但し、R16、R17、R18、R19及びR20は全てがHであることはない化合物、又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグから選択することができる。
R22はアルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、好ましくはペルハロアルキル及びヒドロキシルアルキルはC1〜6ペルハロアルキル及びヒドロキシルアルキルであり、
R16及びR17は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R19及びR20は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R18はH又はハロゲンであり、好ましくはR18はHである。
R22はアルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、好ましくはペルハロアルキル及びヒドロキシルアルキルはC1〜6ペルハロアルキル及びヒドロキシルアルキルであり、
R16及びR20は、C1〜6アルキル、好ましくはイソプロピルであり、
R17及びR19はHであり、
R18はH又はハロゲンであり、好ましくはR18はH又はClである。
R30は出現毎に独立してアルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル及びアルキルアミノから選択され、
R18はH又はハロゲンであり、
R16及びR17はH若しくはアルキルであるか、又はR16及びR17はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は、飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
R19及びR20はH若しくはアルキルであるか、又はR19及びR20はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は、飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
但し、R16、R17、R18、R19及びR20は全てがHであることはなく、
但しQがOであり、R16及びR17、並びにこれとは別にR19及びR20がそれらが結合したそれぞれの炭素原子と一緒にシクロペンチル環を形成するとき、R30はC-3ヒドロキシルアルキルではない化合物、又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグから選択することができる。
QはO又はSであり、
R30は出現毎に独立してアルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル及びアルキルアミノ、好ましくはC1〜6アルキル、ペルハロアルキル、ヒドロキシルアルキル及びアルキルアミノから選択され、
R16及びR17は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R19及びR20は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R18はH又はハロゲンであり、好ましくはR18はHであり、
但し、QがOであるとき、R30はC-3ヒドロキシルアルキルではない。
QはO又はSであり、
R30は出現毎に独立してアルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル及びアルキルアミノ、好ましくはC1〜6アルキル、ペルハロアルキル、ヒドロキシルアルキル及びアルキルアミノから選択され、
R16及びR20は、C1〜6アルキル、好ましくはイソプロピルであり、
R17及びR19はHであり、
R18はH又はハロゲンであり、好ましくはR18はH又はClである。
1. 1-(4-クロロ-2,6-ジイソプロピル-フェニル)-3-[3-(1-ヒドロキシ-1-メチル-エチル)-ベンゼンスルホニル]-尿素;
2. 1-(1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)-3-[4-(1-ヒドロキシ-1-メチル-エチル)-フラン-2-スルホニル]-尿素;
3. 1-(1,2,3,5,6,7-ヘキサヒドロ-4-アザ-s-インダセン-8-イル)-3-[4-(1-ヒドロキシ-1-メチル-エチル)-フラン-2-スルホニル]-尿素;
4. 1-(1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)-3-[4-(1-ヒドロキシ-1-メチル-エチル)-チオフェン-2-スルホニル]-尿素;
5. 1-(4-[1,3]ジオキソラン-2-イル-フラン-2-スルホニル)-3-(1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)-尿素;
6. 1-(2,6-ジイソプロピル-フェニル)-3-[4-(1-ヒドロキシ-1-メチル-エチル)-フラン-2-スルホニル]-尿素;
7. 1-(2,6-ジイソプロピル-フェニル)-3-[4-(1-ヒドロキシ-1-メチル-エチル)-チオフェン-2-スルホニル]-尿素;
8. 1-(4-アセチル-チオフェン-2-スルホニル)-3-(1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)-尿素;
9. 1-(1H-ベンゾイミダゾール-5-スルホニル)-3-(1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)-尿素;
10. 1-(1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)-3-[4-(1-ヒドロキシ-1-メチル-エチル)-チオフェン-2-スルホニル]-尿素;
11. 1-(8-クロロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)-3-[4-(1-ヒドロキシ-1-メチル-エチル)-フラン-2-スルホニル]-尿素;
12. 1-(4-アセチル-フラン-2-スルホニル)-3-(1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)-尿素;
13. 1-(8-フルオロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)-3-[4-(1-ヒドロキシ-1-メチル-エチル)-フラン-2-スルホニル]-尿素;
14. 1-(4-フルオロ-2,6-ジイソプロピル-フェニル)-3-[3-(1-ヒドロキシ-1-メチル-エチル)-ベンゼンスルホニル]-尿素;及び
15. 1-(6-フルオロ-1H-ベンゾイミダゾール-5-スルホニル)-3-(1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)-尿素;
16. 1-(4-クロロ-2,6-ジイソプロピル-フェニル)-3-(1H-インドール-6-スルホニル)-尿素;
17. 1-(4-クロロ-2,6-ジイソプロピル-フェニル)-3-(5-フルオロ-1H-インドール-6-スルホニル)-尿素;
18. 1-[1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-u-イル)-3-(1H-インドール-6-スルホニル)-尿素;
19. 1-(5-フルオロ-1H-インドール-6-スルホニル)-3-(1,2,3,5,6,7-ヘキサンヒドロ-5-インダセン-4-イル)-尿素;
20. 1-[4-クロロ-2,6-ジイソプロピル-フェニル]-3-[2-フルオロ-5-(2-メチル-(1,3)ジオキソラン-2-イル)-ベンゼンスルホニル]-尿素;
21. 3-[3-[4-クロロ-2,6-ジイソプロピル-フェニル]-ウレイドスルホニル]-N-メチル-ベンゼンスルホンアミド;
22. 1-[2-フルオロ-5-(2-メチル-(1,3)ジオキソラン-2-イル)ベンゼンスルホニル]-3-1,2,3,5,6,7-ヘキサヒドロ-インダセン-4-イル)-尿素;
23. 3-[3-(1,2,3,5,6,7-ヘキサヒドロ-S-インダセン-4-イル)-ウレイドスルホニル]-N-メチル-ベンゼンスルホンアミド;
24. 4-(1-ヒドロキシ-1-メチル-エチル)-フラン-2-スルホンアミド
からなる群から選択される化合物ではない。
i) 個々の鏡像異性体の肉眼的結晶を手動で分離する、結晶の物理的な分離。この技術は特に、別々の鏡像異性体の結晶が存在する場合(すなわち、その物質が集合体である場合)、及び結晶が視覚的に区別できる場合に使用することができる。
ii)個々の鏡像異性体がラセミ体の溶液から別々に結晶化され、後者が固形状の集合体である場合にのみ可能である、同時結晶化。
iii)鏡像異性体と酵素との反応速度の違いによるラセミ体の部分的又は完全な分離を行う、酵素的分割。
iv)少なくとも1つの合成工程で、所望する鏡像異性体の鏡像異性的に純粋又は豊富な合成前駆体を得るための酵素反応を使用した合成技術である酵素的不斉合成。
v)生成物中において非対称(すなわち不斉性)を生じる条件下で、所望する鏡像異性体を光学不活性な前駆体から合成し、それはキラル触媒又はキラル助剤を使用して実現することができる、化学的不斉合成。
vi)ラセミ化合物を、個々の鏡像異性体をジアステレオマーに変換する鏡像異性的に純粋な試薬(キラル助剤)と反応させるジアステレオマー分離。得られたジアステレオマーは次に、より明確なそれらの構造的な違いによってクロマトグラフィー又は結晶化によって分離され、その後キラル助剤を除去して所望する鏡像異性体が得られる。
vii)原則として、最終的に全物質が所望する鏡像異性体から結晶性ジアステレオマーに変換されるように、ラセミ体から得られたジアステレオマーが所望する鏡像異性体から得られたジアステレオマーの溶液中において優勢となるように平衡化するか、又は所望する鏡像異性体から得られたジアステレオマーの優先的な結晶化によって平衡が傾く、第1次及び第2次不斉転換。次いで、所望する鏡像異性体はジアステレオマーから放出される。
viii)速度論的条件下で鏡像異性体とキラル、非ラセミ試薬又は触媒との反応速度の違いによって、ラセミ体を部分的又は完全に分割する(又は部分的に分割された化合物を更に分割する)ことを含む速度論的分割。
ix)所望する鏡像異性体が非キラル出発物質から得られ、立体化学的完全性が合成過程中損なわれないか、又は最小限にのみ損なわれる、非ラセミ前駆体からのエナンチオ選択的合成。
x)固定相との異なる相互作用によって、ラセミ体の鏡像異性体を液体移動相中に分離させる。異なる相互作用を引き起こすために、固定相はキラル物質によって作製されていてもよく、又は移動相は追加の不斉物質を含有していてもよい、キラル液体クロマトグラフィー。
xi)ラセミ体を揮発させ、気体移動相中において、固定された非ラセミキラル吸着相を含有するカラムとの相互作用の違いによって鏡像異性体を分離する、キラルガスクロマトグラフィー。
xii)ある鏡像異性体を特定のキラル溶媒に優先的に溶解させることによって鏡像異性体を分離する、キラル溶媒による抽出。
xiii)ラセミ体を薄い膜バリアに接触させるように配置する、キラル膜を横断する輸送。バリアは典型的に2種類の混和可能な流体を分離し、一方がラセミ体を含有し、濃度差又は圧力差等の推進力によって膜バリアを横断する優先的輸送を引き起こす。分離は、ラセミ体の1鏡像異性体だけの通過を可能にする膜の非ラセミキラル性の結果として生じる。
一般的な合成方法
A1:限定するものではないがテトラヒドロフラン又はジクロロメタン等の無水非プロトン性溶媒中の、限定するものではないがトリエチルアミン等の塩基(1.2当量)を有する又は有しないR2アミン中間体(1当量)の溶液に、トリホスゲン(0.4から1.1当量)を添加した。反応物を室温で撹拌し、又は必要な場合には、完了まで、典型的には2から18時間加熱還流した。
A2:無水アセトニトリル又はTHF中のジ-t-ブチルジカーボネート(1.2〜1.4当量)に、DMAP(15〜100mol%)を添加し、5分後、アセトニトリル中のR2アミン中間体(1.0当量)の溶液を添加した。反応混合物を室温で30〜60分間撹拌した。
B1:R2カルボン酸中間体(1当量)を、2滴のDMFを有する又は有しないトルエン等の非プロトン性溶媒に溶解し、塩化チオニル等の塩素化剤(2当量)を添加した。反応混合物を完了まで加熱還流し、次いで真空中で濃縮して、対応するR2酸塩化物中間体を得た。
代替方法又は酸塩化物を形成することもここでは同様に有用であり、例えば、トルエン及びDMFを用いず、そのため塩化チオニルを溶媒及び塩素化剤の両方として使用して、上記手順を実行することができる。
R2酸塩化物中間体をアセトンに溶解し、0℃の水:アセトン(50:50)溶液中のアジ化ナトリウム(1.5当量)の溶液に滴下添加した。氷水を添加して、得られたR2アシルアジド中間体を沈殿させ、これをトルエンに溶解し、乾燥(MgSO4)させた後、不活性ガスの一定流量を維持しながら、溶液を還流下で無水トルエンに滴下添加した。反応物を完了まで、典型的には2時間加熱して、R2イソシアネートを得た。
B2:乾燥CH2Cl2中のR2酸塩化物(方法B1に示した通りに形成した)に、NaN3(2.0当量)を0℃で添加した。反応混合物を室温で1時間撹拌し、EtOAc中に抽出した。有機層をH2O(15mL)で洗浄し、乾燥させ(MgSO4)、慎重に蒸発させて、アシルアジドを得た。アシルアジドを乾燥トルエンに溶解し、100℃に2時間加熱した。溶媒を除去して、粗製のR2イソシアネートを得た。
C1:R1スルホンアミド中間体(1当量)を無水THFに溶解し、減圧下、NaH(1当量)で処理した。混合物を2時間加熱還流し、次いで室温に冷却し、THF中のR2イソシアネート中間体を窒素雰囲気下で添加した。反応混合物を完了まで撹拌還流した。
C2:R1スルホンアミド中間体(1当量)を無水THF又は無水メタノールに溶解し、減圧下、NaH(1当量)で処理した。発泡が止んだら、R2イソシアネート中間体を添加し、反応混合物を室温で終夜撹拌した。
C3:無水THF(5mL/mmol)中のR1スルホンアミド中間体(1当量)に、NaH(1当量)を0℃で添加し、窒素雰囲気下室温で30分間から2時間、又は完了まで撹拌した。再度0℃に冷却し、THF中のR2イソシアネート(1.0当量)を添加し、室温で完了まで、典型的には2から16時間撹拌した。
C4:無水THF又はDCM(5〜11mL/mmol)中の粗製のR2イソシアネート(1.0当量)に、R1スルホンアミド(1.0当量)、続いてトリエチルアミン、DIPEA又はDBU等の塩基(1〜2当量)を添加し、反応混合物を室温で終夜撹拌した。
C5:無水MeOH(5mL/mmol)中のR1スルホンアミド中間体(1当量)に、NaOMe(1当量)を添加した[或いは:新たに調製したナトリウムメトキシド(1当量)の1.0mM溶液を、無水メタノール中のR1スルホンアミド(1当量)の1.0mM溶液に添加した]。次いで、溶媒を真空中で除去した。塩をアセトニトリル又はTHF等の無水非プロトン性溶媒中に懸濁させ、アセトニトリル又はTHF等の無水非プロトン性溶媒中のR2イソシアネート(1.0当量)を添加し、混合物を室温で終夜撹拌した。次いで、溶液を完了まで、典型的には90分間加熱還流した。
C6:R1スルホンアミド(1.0当量)を窒素雰囲気下で無水THFに溶解した。固体ナトリウムメトキシド(1.0当量mmol)を一度に添加した。この混合物を室温で3時間撹拌した。THF中のR2イソシアネート(1.17当量)の溶液を滴下添加した。反応混合物を室温で終夜撹拌した。
0℃のアセトニトリル(7〜12mL/mmol)中のアミン(1.0当量)の溶液を、H2O(0.5〜1.2mL/mmol)中のc.HCl(1.25〜2.25mL/mmol)、続いてH2Oに溶解したNaNO2(1.2当量)の水溶液(0.3〜0.5mL/mmolのNaNO2)で処理した。得られた溶液を0℃で45分間撹拌した。AcOH(0.5〜1.2mL/mmol)、CuCl2.2H2O(0.5当量)及びCuCl(0.05当量)を上記混合物に順次添加し、0℃にて20分間、SO2ガスでパージした。得られた反応混合物を0℃〜10℃で完了まで撹拌した。
E1:THF(10〜20mL/mmol)中のスルホニルクロリド(1当量)の溶液を-78℃に冷却し、アンモニアガスを溶液に通して15分間バブリングし、更に30分間撹拌を続け、次いで室温に加温し、2時間又は完了まで撹拌した。
E2:アセトン(20mL/mmol)中のスルホニルクロリド(1当量)の溶液を、室温にて、水に溶解したNH4HCO3(4当量)の溶液(1.5mL/mmolのNH4HCO3)で処理し、4時間又は完了まで撹拌した。
E3:アセトン(2.5mL/mmol)中のスルホニルクロリド(1当量)の溶液を、0℃にてNH3(3.5mL/mmol、H2O中NH4OH、28%NH3ベース)で処理し、2時間又は完了まで撹拌した。
アルキン(1当量)及びアジド(1.2当量)、5mol%CuSO4、10mol%NaAscのDMSO中溶液(500μL)を室温で完了まで、典型的には12時間撹拌した。
R1スルホンアミド中間体の合成:
DME(15mL)中のピリジニウム5-エチルフラン-2-スルホネート(3.2g、12.5mmol)のスラリーに、塩化オキサリル(1.62mL、27.0mmol)、次いでDMF(0.97mL、12.5mmol)をアルゴン雰囲気下0℃で添加し、得られた反応混合物を室温で完了まで撹拌した。反応混合物を氷水でクエンチし、次いでトルエン(2×50mL)で抽出し、有機層を飽和NaHCO3水溶液(20mL)及びブライン(20mL)で洗浄し、乾燥させ(MgSO4)、真空中で濃縮して、5-エチルフラン-2-スルホニルクロリドを薄褐色油状物(510mg、21%)として得た。
THF(5mL)中の1-イソプロピル-1H-1,2,3-トリアゾール-4-スルホニルクロリド(100mg)の溶液を-40℃に冷却した。アンモニアガスを前述の溶液に通して15分間パージした。反応混合物を室温に加温し、2時間撹拌した。完了したら、反応混合物を真空中で濃縮し、得られた残留物を酢酸エチル(25mL)及び水(10mL)で希釈した。有機抽出物を水、ブラインで洗浄し、乾燥させ(Na2SO4)、真空中で濃縮して、1-イソプロピル-1H-1,2,3-トリアゾール-4-スルホンアミド(0.07g、78%)を褐色固体として得た。
MeOH(10mL)-EtOAc(4mL)中の粗製の1-メチル-5-(プロパ-1-エン-2-イル)-1H-ピラゾール-3-スルホンアミド(0.12g、0.6mmol)の溶液を、窒素雰囲気下、10%パラジウム炭素(30mg)で処理した。反応フラスコを排気し、水素(バルーン)で充填し、4時間撹拌した。反応混合物を酢酸エチル(25mL)で希釈し、セライトのパッドに通して濾過し、乾燥させ(Na2SO4)、真空中で濃縮した。得られた固体をジエチルエーテルで更に洗浄して、5-イソプロピル-1-メチル-1H-ピラゾール-3-スルホンアミドをオフホワイトの固体(0.11g、91%)として得た。
アセトン(5mL)中の5-(ジメチルアミノ)ナフタレン-1-スルホニルクロリド(0.12g、0.44mmol)の溶液を、水(1.0mL)中の重炭酸アンモニウム(0.17g、1.76mmol)の溶液に滴下添加し、反応物を室温で2時間又は完了まで撹拌した。pHを、c.HClを用いてpH2.0に調整した。有機相を分離し、水性相をNaClで飽和させ、酢酸エチルで抽出した。合わせた有機相をブラインで洗浄し、乾燥させ(MgSO4)、真空中で濃縮して、表題化合物を白色固体(0.075g、収率67%)として得た。
2-(メチル(7-ニトロベンゾ[c][1,2,5]オキサジアゾール-4-イル)アミノ)酢酸(1.00g、3.96mmol)を、窒素雰囲気下で無水テトラヒドロフラン(25mL)に溶解し、溶液を0℃に冷却した。ジイソプロピルエチルアミン(0.76g、5.55mmol)及び1,1'-カルボニルジイミダゾール(0.90g、4.75mmol)を添加し、2-(メチル(7-ニトロベンゾ[c][1,2,5]オキサジアゾール-4-イル)アミノ)酢酸が全て反応するまで混合物を50℃で撹拌した。次いで、反応混合物を0℃に冷却し、4-(2-アミノエチル)ベンゼンスルホンアミド(0.95g、4.75mmol)を添加し、室温で完了まで、典型的には6時間撹拌した。溶媒を真空中で除去し、残留物を逆相分取HPLCにより精製して、表題化合物を赤レンガ色固体(1.20g、70%)として得た。LCMS (m/z): 435.4 (M +1)+.
メチル4-クロロブタンイミデート塩酸塩(25g、146.1mmol)をDCM(250mL)に溶解し、Et3N(44.3g、4.38mmol)で処理し、得られた溶液を0℃に冷却した。2,2-ジメトキシエタン-1-アミン(12.2g、116.9mmol)を上記混合物に5分間かけて滴下添加した。得られた反応混合物を60℃に加温し、3時間撹拌した。反応混合物を真空中で濃縮し、得られた残留物をギ酸(150mL)で処理し、80℃で24時間加熱した。完了したら、反応混合物を真空中で濃縮し、得られた残留物をトルエン(2×100mL)と共沸させた。粗混合物を飽和NaHCO3溶液で塩基性化し、DCM(3×200mL)で抽出した。合わせた有機抽出物を水、ブラインで洗浄し、乾燥させ(Na2SO4)、真空中で濃縮して、6,7-ジヒドロ-5H-ピロロ[1,2-a]イミダゾール(3工程にわたって8g、39%)を低融点の暗色固体として得た。
THF(15mL)中の6,7-ジヒドロ-5H-ピロロ[1,2-a]イミダゾール-2-スルホニルクロリド(300mg)の溶液を-40℃に冷却した。アンモニアガスを前述の溶液に通して15分間パージし、溶液を-40℃で1時間撹拌した。反応混合物を室温に加温し、1時間撹拌し、次いで完了したら、真空中で濃縮した。粗生成物を、10%MeOH-CHCl3溶離液を用いるシリカゲル(60〜120メッシュ)上でのカラムクロマトグラフィーにより精製して、6,7-ジヒドロ-5H-ピロロ[1,2-a]イミダゾール-2-スルホンアミド(117mg、88%)を白色固体として得た。
1-メチル-1H-ピラゾール-3-アミンHCl
DMSO(10mL)中の4-ブロモ-3,5,6,7-テトラヒドロ-2H-インデノ[5,6-b]フラン(0.28g、1.18mmol)を、ヨウ化銅(0.22g、1.18mmol)、L-プロリン(0.21g、1.88mmol)及びアジ化ナトリウム(0.19g、2.94mmol)で処理した。反応混合物を密封管内135℃で36時間加熱した。反応混合物を冷却し、水で希釈し、EtOAc(2×25mL)を用いて抽出した。合わせた有機抽出物を水(25mL)、ブライン(25mL)で洗浄し、乾燥させ(Na2SO4)、真空中で濃縮した。粗生成物を、10%EtOAc-ヘキサン溶離液を用いるシリカゲル上でのカラムクロマトグラフィーにより精製して、3,5,6,7-テトラヒドロ-2H-インデノ[5,6-b]フラン-4-アミンを灰色固体(0.17g、85%)として得た。
4-クロロ-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-6-(トリフルオロメチル)アニリン(500mg、1.55mmol)を、THF(5mL)及びH2O(2mL)に室温で溶解した。NaBO3.H2O(0.62g、6.23mmol)を少量ずつ添加し、反応物を室温で4時間撹拌した。完了したら、反応混合物を水で希釈し、EtOAc(2×50mL)で抽出し、合わせた有機抽出物を水、ブラインで洗浄し、乾燥させ(Na2SO4)、真空中で濃縮した。粗生成物を、15%EtOAc-ヘキサン溶離液を用いるシリカゲル(60〜120メッシュ)上でのカラムクロマトグラフィーにより精製して、2-アミノ-5-クロロ-3-(トリフルオロメチル)フェノール(0.5g、100%)を黄色液体として得た。
2,3,6,7-テトラヒドロベンゾ[1,2-b:4,5-b']ジフラン-4-カルボン酸
或いは、アセトン(5.0mL)中の該アルデヒド(0.5g、2.77mmol)を、0℃にて2回に分けてスルファミン酸(0.4g、4.17mmol)で処理した。2分後、水(1.0mL)中の亜塩素酸ナトリウム(0.32g、3.6mmol)の溶液を滴下添加し、0℃で4時間撹拌を続けた。反応混合物を水(20mL)で希釈し、10%IPA/クロロホルム(2×20mL)を用いて抽出した。合わせた有機物を水(25mL)、ブライン(25mL)で洗浄し、乾燥させ(Na2SO4)、真空中で濃縮した。粗固体をジエチルエーテルとすり混ぜて、2,3,6,7-テトラヒドロベンゾ[1,2-b:4,5-b']ジフラン-4-カルボン酸(0.4g;70%)を得た。
無水メタノール(50mL)中の2,3-ジヒドロキシ安息香酸(5.0g、32.4mmol)を濃硫酸(10滴)で処理し、終夜加熱還流した。反応混合物を真空中で濃縮し、EtOAc(100mL)を用いて希釈し、飽和NaHCO3水溶液(2×50mL)、ブライン(50mL)を用いて洗浄し、次いで乾燥させ(MgSO4)、真空中で濃縮して、メチル2,3-ジヒドロキシベンゾエート(2.92g;54%)を得た。
脂肪族化合物
N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)シクロヘキサンスルホンアミド
0℃のTHF(5mL)中の4-(2-ヒドロキシプロパン-2-イル)フラン-2-スルホンアミド(0.2g、0.98mmol)を水素化ナトリウム(3当量)で少量ずつ処理し、懸濁液を室温で45分間(発泡が止むまで)撹拌した。粗製のフェニルキノリン-8-イルカルバメートをTHF(5mL)に溶解し、次いでゆっくりと反応物に添加し、溶液を室温で完了まで、典型的には4時間撹拌した。反応物を飽和NH4Cl水溶液でクエンチし、酢酸エチル(×2)で抽出し、水、ブラインで洗浄し、乾燥させ(Na2SO4)、真空中で濃縮した。粗生成物を、逆相HPLCを用いて精製して、表題化合物である4-(2-ヒドロキシプロパン-2-イル)-N-(キノリン-8-イルカルバモイル)フラン-2-スルホンアミドを白色固体(40mg、11%)として得た。
4-(2-ヒドロキシプロパン-2-イル)フラン-2-スルホンアミド、3(150mg、0.731mmol)を無水THF(50mL)に溶解し、窒素雰囲気下0℃にてNaH(44mg、1.096mmol)で慎重に処理した。得られた反応混合物を室温で30分間撹拌し、窒素雰囲気下、THF(30mL)中の5-クロロ-2-イソシアナト-1-メチル-3-(トリフルオロメチル)ベンゼン(0.2g)の溶液で処理した。得られた反応混合物を室温で2時間撹拌した。完了したら、反応混合物を飽和NH4Cl溶液で希釈し、EtOAc(2×50mL)で抽出し、合わせた有機抽出物を水、ブラインで洗浄し、乾燥させ(Na2SO4)、真空中で濃縮した。粗生成物を、40%EtOAc-ヘキサン溶離液を用いるシリカゲル(60〜120メッシュ)上でのカラムクロマトグラフィーにより精製した。次いで、生成物をジエチルエーテル及びn-ペンタンとすり混ぜて、N-((2,4-ジメチル-6-(トリフルオロメチル)フェニル)カルバモイル)-4-(2-ヒドロキシプロパン-2-イル)フラン-2-スルホンアミド(15mg、5%)を白色固体として得た。
無水THF(1mL)中の4-(2-ヒドロキシプロパン-2-イル)フラン-2-スルホンアミド中間体(100mg、0.48mmol)に、NaH(18.3mg、0.48mmol)を0℃で添加し、窒素雰囲気下室温で30分間撹拌した。再度0℃に冷却し、8-イソシアナト-3,5,6,7-テトラヒドロ-s-インダセン-1(2H)-オン(前工程の反応混合物)を添加し、室温で16時間撹拌した。反応混合物に0.5mLのH2Oを添加し、移動相として10mM (NH4)HCO3水溶液及びアセトニトリルを用いる精製のためC18カラム上に直接ロードして、4-(2-ヒドロキシプロパン-2-イル)-N-((3-オキソ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)フラン-2-スルホンアミドを白色固体(150mg、67%)として得た。
無水THF(1mL)中の4-(2-ヒドロキシプロパン-2-イル)フラン-2-スルホンアミド中間体(50mg、0.24mmol)に、NaH(9.3mg、0.24mmol)を0℃で添加し、窒素雰囲気下室温で30分間撹拌した。再度0℃に冷却し、4-イソシアナト-3,5,6,7-テトラヒドロ-s-インダセン-1(2H)-オン(前工程の反応混合物)を添加し、室温で16時間撹拌した。反応混合物に0.5mLのH2Oを添加し、移動相として10mM (NH4)HCO3水溶液及びアセトニトリルを用いる精製のためC18カラム上に直接ロードして、4-(2-ヒドロキシプロパン-2-イル)-N-((1-オキソ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)フラン-2-スルホンアミド(70mg、63%)を得た。
N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)-4-(2-ヒドロキシプロパン-2-イル)-5-メチルフラン-2-スルホンアミド
N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)-4-(2-ヒドロキシプロパン-2-イル-1,1,1,3,3,3-d6)フラン-2-スルホンアミド
或いは、-10℃の無水THF(30mL)中のエチル2-メチル-5-スルファモイルフラン-3-カルボキシレート(0.4g、0.96mmol)を、激しく撹拌しながらd3-メチルマグネシウムヨージド溶液(Et2O中1.0M、10当量)で10分間かけて滴下処理した。次いで、溶液を室温で12時間撹拌し、次いで0℃に冷却し、飽和塩化アンモニウムの溶液を滴下してクエンチした。水溶液を、EtOAc(2×20mL)を用いて抽出し、合わせた有機物をブライン(20mL)で洗浄し、乾燥させ(Na2SO4)、真空中で濃縮した。粗生成物を逆相分取HPLCにより精製して、表題化合物を白色固体(5mg、1%)として得た。
N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)チオフェン-2-スルホンアミド
N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)チアゾール-2-スルホンアミド
1-ベンジル-N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)-1H-1,2,4-トリアゾール-3-スルホンアミド
N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)-1-メチル-1H-ピラゾール-5-スルホンアミド
N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)ベンゼンスルホンアミド
メチル3-(N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)スルファモイル)ベンゾエート(0.06g、0.144mmol)を無水THFに溶解し、溶液を0℃に冷却した。メチルマグネシウムブロミド(ジエチルエーテル中3M溶液、0.14mL、0.42mmol、3.0当量)を添加し、混合物を室温で4時間撹拌した。完了したら、飽和塩化アンモニウム水溶液を反応混合物に添加し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、乾燥させ(Na2SO4)、真空中で濃縮した。粗残留物を逆相分取HPLCにより精製して、表題化合物をオフホワイトの固体(0.015g、25%)として得た。
窒素雰囲気下のTHF(5.0mL)中の5-((3aS,4S,6aR)-2-オキソヘキサヒドロ-1H-チエノ[3,4-d]イミダゾール-4-イル)-N-((1-(3-スルファモイルフェニル)-1H-1,2,3-トリアゾール-4-イル)メチル)ペンタンアミド(15mg、0.031mmol)の溶液に、DIPEA(605μL、0.037mmol)を添加した。この混合物を室温で15分間撹拌した。THF中の4-イソシアナト-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン(一般方法A2を用いて調製した)(705mg、0.037mmol)の溶液を滴下添加した。反応混合物を室温で終夜撹拌し、次いで溶媒を真空中で除去して、粗化合物を得、これを、10mM (NH4)2CO3水溶液及びMeCNの移動相を用いる逆相カラムクロマトグラフィーにより精製して、表題化合物を白色固体(5.2mg、24%)として単離した。
0℃のTHF(30mL)中の3-(3-(トリフルオロメチル)-3H-ジアジリン-3-イル)ベンゼンスルホンアミド(0.185g、0.69mmol)を水素化ナトリウム(3当量)で少量ずつ処理し、懸濁液を30分間(発泡が止むまで)撹拌した。粗製のフェニルキノリン-6-イルカルバメートをTHF(20mL)に溶解し、次いで反応物にゆっくりと添加し、室温で完了まで、典型的には2時間撹拌を続けた。反応物を飽和NH4Cl水溶液でクエンチし、酢酸エチル(×2)で抽出し、水(100mL)、ブライン(100mL)で洗浄し、乾燥させ(Na2SO4)、真空中で濃縮した。粗生成物を、ジエチルエーテル、次いでペンタンを用いてすり混ぜて、表題化合物であるN-(キノリン-6-イルカルバモイル)-3-(3-(トリフルオロメチル)-3H-ジアジリン-3-イル)ベンゼンスルホンアミドを白色固体(10mg、3%)として得た。
N-(1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イルカルバモイル)-4-(2-ヒドロキシプロパン-2-イル)ピリジン-2-スルホンアミド
メチル2-(N-(1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イルカルバモイル)スルファモイル)イソニコチネート(0.30g、0.72mmol)を無水THF(8mL)に溶解し、溶液を0℃に冷却した。メチルマグネシウムブロミド(ジエチルエーテル中3M溶液、0.96mL、2.88mmol、4.0当量)を窒素雰囲気下0℃で添加し、室温で3時間撹拌を続けた。完了したら、反応混合物を飽和塩化アンモニウム水溶液に注ぎ入れ、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、乾燥させ(Na2SO4)、真空中で濃縮した。粗残留物を逆相分取HPLCにより精製して、表題化合物を白色固体(0.016g、5%)として得た。
N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモチオイル)-4-(2-ヒドロキシプロパン-2-イル)フラン-2-スルホンアミド
NLRP3阻害アッセイ
以下のアッセイは、アデノシン三リン酸、ナイジェリシン、LeuLeu-OMe又は尿酸ナトリウム結晶(MSU)等の通常の刺激を使用して、NLRP3インフラマソームに対する試験化合物の阻害活性を測定するために使用することができる。
HMDMを生成するために、Ficoll-Plaque Plus(GE Healthcare社)及び密度遠心分離を使用してヒト単核球をバフィーコート血液から単離する。CD14+細胞選択は、MACS磁気ビーズ(Miltenyl Biotec社)を使用して実施する。単離したCD14+単核球は、Croker等、2013年 Immunol Cell Biol 91:625頁によって記載されたように、10%FBS及び1%ペニシリン/ストレプトマイシン(Life Technologies社)を補給したL-グルタミンを含有するイスコフ改変ダルベッコ培地(IMDM)中で、ヒトCSF-1(Miltenyl Biotec社)10ng/mlと共に7日間培養して分化させる。
HMDMは、1×105/mlで播種する。翌日、一晩経った培地を交換し、細胞を大腸菌(Escherichia coli)血清型0111:B4(Sigma Aldrich社)で3時間刺激する。培地を除去し、NLRP3刺激の30分前に試験化合物を含有する無血清培地(SFM)と交換する。次に、細胞を、アデノシン5’-三リン酸二ナトリウム塩水和物(5mM、1時間)、ナイジェリシン(10μM、1時間)、LeuLeu-OMe(1mM、2時間)又はMSU(200μg/ml、15時間)で刺激する。ATPは、Sigma Aldrich社から、ナイジェリシン及びMSUはInvivogen社から、LeuLeu-OmeはChem-Impex International社から入手することができる。
ELISA及び細胞死アッセイのために、細胞を96ウェルプレートに播種する。上清を除去し、製造元の指示に従ってELISAキットを使用して分析する(DuoSet(登録商標)R&D Systems社、ReadySetGo!(登録商標)eBioscience、BD OptEIA(商標)又はPerkin Elmer AlphaLISA(登録商標))。細胞死は、CytoTox96(登録商標)非放射活性細胞傷害性アッセイ(Promega社)を使用して、100%細胞溶解物対照に対するLDH放出を測定することによって評価する。
一般的実験:カルブタミドは、Sigma Aldrich社(カタログ番号381578)から購入した。アセトニトリルは、Chromasolv(登録商標)HPLC等級(Sigma Aldrich社、Sydney、Australia)であり、ギ酸はAR等級99%〜100%Normapur(VWR International Pty Ltd社、Brisbane、Australia)であり、DMSOはReagentPlus(登録商標)等級(D5879、Sigma Aldrich社、Sydney、Australia)であり、H2O Milli-Qを濾過した。HPLCバイアル及びポリプロピレン挿入物は、Agilent Technologies社(Melbourne、Australia)から、一方、エッペンドルフ管タンパク質LoBind管1.5mLはVWR International Pty Ltd社(Brisbane、Australia)から入手した。
投与:20mg/kgでの強制経口投与
時点:2時間
4mg/mlで投与するために保存化合物を滅菌したPBSで調製する。マウスの体重を測定し、各化合物20mg/kgを強制経口投与によって投与した。2時間後、ゾレチル(50mg/kg)及びキシラジン(10mg/kg)の組合せを使用してマウスを麻酔し、心臓穿刺によって血液をEDTA 100mM 20μLを含有する試験管に収集した。血液を4℃で2000×gで15分間遠心分離し、血漿を収集した。
tPSA全体及び生物学的結果を以下の表に挙げるが、本発明のある種の化合物のために選択したデータを以下に提示する。
4mg/Kgのiv投与及び20mg/Kgのpo投与を使用したN-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)-4-(2-ヒドロキシプロパン-2-イル)フラン-2-スルホンアミド(MCC950)と比較したN-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)-1-イソプロピル-1H-ピラゾール-3-スルホンアミド(MCC7840であり、第1の態様の化合物である)の単回投与の薬物動態研究によって、フランに対するピラゾール誘導体の半減期の延長、最大濃度(Cmax)及び曲線下面積(AUC)の増加が明らかに示された。これは、比較的低い用量又は少ない投与頻度につながり、有利である。
Claims (57)
- 式(I)の化合物であって、
JはS及びSeから選択され、
R1は、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリルからなる群から選択され、それらの全ては場合によって置換されていてもよく、
R2は、シクロアルキル、アリール、ヘテロアリール及びヘテロシクリルからなる群から選択され、それらの全ては場合によって置換されていてもよく、
炭素原子を介してR1はJに直接結合し、R2も隣接する窒素に直接結合している化合物、又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグ。 - R1は、C5又はC6シクロアルキル、5員又は6員ヘテロアリール、少なくとも1個の環がヘテロアリール、フェニル、ビフェニル、フェニルヘテロシクリル、5員又は6員ヘテロシクリル、及びヘテロシクリルシクロアルキルである2環式ヘテロアリールからなる群から選択され、それらの全ては場合によって置換されていてもよい、請求項1に記載の化合物。
- R1は、ピラゾール、フラン、テトラヒドロフラン、テトラヒドロピラン、ピラン、ピロリジン、ピロール、トリアゾール、テトラゾール、イミダゾール、ピリジン、モルホリン、ピペラジン、ピペリジン、置換フェニル、フェニルヘテロアリール、フェニルヘテロシクリル、ビフェニル、キノリン、イソキノリン、ナフチル、ピラジン及びピリミジンからなる群から選択され、それらの全ては適切ならば、場合によって置換されていてもよい、請求項1又は請求項2に記載の化合物。
- R1は5員ヘテロシクリル又はヘテロアリールであり、それらのそれぞれは場合によって置換されていてもよく、N、O及びSから選択される少なくとも1個の環ヘテロ原子を含む、請求項1から3のいずれか一項に記載の化合物。
- R1は5員含窒素ヘテロシクリル又は5員含窒素ヘテロアリールであり、それらのそれぞれは場合によって置換されていてもよい、請求項4に記載の化合物。
- R1は5員ヘテロシクリル又は5員ヘテロアリールであり、それらのそれぞれは場合によって置換されていてもよく、少なくとも2個の環窒素原子を含む、請求項4又は請求項5に記載の化合物。
- R2は、それぞれが場合によって置換されていてもよい2環式及び3環式炭化水素、5、6及び7員複素環又はヘテロアリール、並びに置換フェニルからなる群から選択される、請求項1から6のいずれか一項に記載の化合物。
- R2は、
式中、Yは出現毎に独立してC、N、S及びOから選択され、それらは適切ならば、場合によって置換されていてもよく、
R5、R11、R12、R13、R14及びR15は独立して、水素、ハロ、シアノ、アミド、スルホンアミド、アシル、ヒドロキシル、C1〜C6アルキル、C1〜C6ハロアルキル、C3〜C5シクロアルキル、C1〜C6アルコキシからなる群から選択され、それらの基は全て、適切ならば、ハロ、シアノ又はC1〜C6アルコキシで場合によって置換されていてもよく、
R11及びR12は組み合わさってフェニル、5若しくは6員含酸素複素環又は5若しくは6員含窒素ヘテロアリールを形成していてもよく、それらのそれぞれは場合によって置換されていてもよく、
R12及びR13は組み合わさって5若しくは6員含窒素ヘテロアリールを形成していてもよく、それらは場合によって置換されていてもよく、
R14及びR15は組み合わさって5若しくは6員シクロアルキル環、フェニル、5若しくは6員含酸素複素環又は5若しくは6員含窒素ヘテロアリールを形成していてもよく、それらのそれぞれは場合によって置換されていてもよい、請求項1から7のいずれか一項に記載の化合物。 - R1は、
このようなR1基それぞれと組み合わせて、R2は独立して、
- R2は置換又は水素化インダセン、2,6-ジアルキルフェニル、2,6-ジアルキル-4-ハロフェニル、2,6-ジシクロアルキルフェニル及び2,6-ジシクロアルキル-4-ハロフェニルから選択される、請求項1から9のいずれか一項に記載の化合物。
- R2はヘキサヒドロインダセン、2,6-ジイソプロピルフェニル、2,6-ジイソプロピル-4-クロロフェニル、2,6-ジシクロプロピルフェニル及び2,6-ジシクロプロピル-4-クロロフェニルから選択される、請求項1から10のいずれか一項に記載の化合物。
- Jはイオウ原子である、請求項1から11のいずれか一項に記載の化合物。
- Wは酸素原子である、請求項1から12のいずれか一項に記載の化合物。
- 式(Ia)、(Ib)又は(Ic)の化合物であって、
- R1は、ピラゾール、フラン、テトラヒドロフラン、テトラヒドロピラン、ピラン、ピロリジン、ピロール、トリアゾール、テトラゾール、イミダゾール、ピリジン、モルホリン、ピペラジン、ピペリジン、置換フェニル、フェニルヘテロアリール、フェニルヘテロシクリル、ビフェニル、キノリン、イソキノリン、ナフチル、ピラジン及びピリミジンからなる群から選択され、それらの全ては適切ならば、場合によって置換されていてもよい、請求項14に記載の化合物。
- R1は、
- 式(II)の化合物であって、
各破線は結合を表していてもよく、
R2は請求項1から16のいずれか一項で規定した通りであるか、又はR2は蛍光基であってもよく;
R6は出現毎に独立して、水素、ハロゲン化物、シアノ、C1〜C6アルキル、C1〜C6アルキルアミノ、C1〜C6アルキルヒドロキシ、C3〜C6シクロアルキル、アルキルフェニル、フェニル、ベンジル、C1〜C6エステル、C2〜C6アルケニル、C1〜C6トリフルオロアルキル及びC1〜C6アルコキシからなる群から選択され、それらのそれぞれは、適切ならば、場合によって置換されていてもよいか、又はR6は蛍光基であってもよい化合物、又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグである、請求項1から16のいずれか一項に記載の化合物。 - 式(II)の化合物は、
式中、R40はH、アルキル及びハロから選択され、
R41はH、アルキル及びシクロアルキルから選択され、
Pは出現毎に独立してC、O又はSから選択され、
R6は存在するならば出現毎に独立して、請求項17で規定した群から選択される、請求項17に記載の化合物。 - 式(IIa)の化合物であって、
A、B、D及びEはN及びCから選択され、A、B、D及びEのうちの少なくとも2つはNであり、
R6は出現毎に独立して、水素、ハロゲン化物、シアノ、C1〜C6アルキル、C1〜C6アルキルアミノ、C1〜C6アルキルヒドロキシ、C3〜C6シクロアルキル、アルキルフェニル、フェニル、ベンジル、C1〜C6エステル、C2〜C6アルケニル、C1〜C6トリフルオロアルキル及びC1〜C6アルコキシからなる群から選択され、それらのそれぞれは場合によって置換されていてもよい化合物又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグから選択される、請求項1から18のいずれか一項に記載の化合物。 - 式(IIb)の化合物であって、
A、B、D及びEはN及びCから選択され、A、B、D及びEのうちの少なくとも2つはNであり、
R6は出現毎に独立して、水素、ハロゲン化物、シアノ、C1〜C6アルキル、C1〜C6アルキルアミノ、C1〜C6アルキルヒドロキシ、C3〜C6シクロアルキル、アルキルフェニル、フェニル、ベンジル、C1〜C6エステル、C2〜C6アルケニル、C1〜C6トリフルオロアルキル及びC1〜C6アルコキシからなる群から選択され、それらのそれぞれは場合によって置換されていてもよい化合物又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグである、請求項1から19のいずれか一項に記載の化合物。 - 式(IIIa)、(IIIb)若しくは(IIIc)の化合物であって、
R22はH、アルキル、ペルハロアルキル、C3〜C6シクロアルキル、フェニル又はベンジルから選択され、
R18はH又はハロゲンであり、
R16及びR17はH、アルキル若しくはシクロアルキルであるか、又はR16及びR17はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
R19及びR20はH若しくはアルキルであるか、又はR19及びR20はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
但し、R21及びR22は両方がHであることはなく、
但し、R16、R17、R18、R19及びR20は全てがHであることはない化合物又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグである、請求項1から20のいずれか一項に記載の化合物。 - R21はH、アルキル、ペルハロアルキル又はヒドロキシルアルキルから選択され、
R22はH、アルキル、ペルハロアルキル、C3〜C6シクロアルキル、フェニル又はベンジルから選択され、
R16及びR17は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R19及びR20は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R18はH又はハロゲンであり、
但し、R21及びR22は両方がHであることはない、請求項21に記載の化合物。 - R21はH、アルキル、ペルハロアルキル又はヒドロキシルアルキルから選択され、
R22はH、アルキル、ペルハロアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、
R16及びR20は、C1〜6アルキル又はC3〜5シクロアルキルであり、
R17及びR19は、Hであり、
R18はH又はハロゲンであり、
但し、R21及びR22は両方がHであることはない、請求項21に記載の化合物。 - 式(IVa)、(IVb)若しくは(IVc)の化合物であって、
R18はH又はハロゲンであり、
R16及びR17はH、アルキル若しくはシクロアルキルであるか、又はR16及びR17はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
R19及びR20はH若しくはアルキルであるか、又はR19及びR20はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
但し、R21及びR22は両方がHであることはなく、
但し、R16、R17、R18、R19及びR20は全てがHであることはない化合物又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグである、請求項1から23のいずれか一項に記載の化合物。 - R21及びR22は、H、アルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、
R16及びR17は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R19及びR20は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R18はH又はハロゲンであり、
但し、R21及びR22は両方がHであることはない、請求項24に記載の化合物。 - R21及びR22はH、アルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、好ましくはペルハロアルキル及びヒドロキシルアルキルはC1〜6ペルハロアルキル及びヒドロキシルアルキルであり、
R16及びR20は、C1〜6アルキル又はC3〜5シクロアルキルであり、
R17及びR19はHであり、
R18はH又はハロゲンであり、
但し、R21及びR22は両方がHであることはない、請求項24に記載の化合物。 - 式(Va)、(Vb)若しくは(Vc)の化合物であって、
R18はH又はハロゲンであり、
R16及びR17はH、アルキル若しくはシクロアルキルであるか、又はR16及びR17はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
R19及びR20はH若しくはアルキルであるか、又はR19及びR20はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
但し、R21及びR22は両方がHであることはなく、
但し、R16、R17、R18、R19及びR20は全てがHであることはない化合物又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグである、請求項1から26のいずれか一項に記載の化合物。 - R21及びR22は、H、アルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、
R16及びR17は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R19及びR20は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R18はH又はハロゲンであり、
但し、R21及びR22は両方がHであることはない、請求項27に記載の化合物。 - R21及びR22はH、アルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、
R16及びR20は、C1〜6アルキル又はC3〜5シクロアルキルであり、
R17及びR19は、Hであり、
R18はH又はハロゲンであり、
但し、R21及びR22は両方がHであることはない、請求項27に記載の化合物。 - 式(VIa)若しくは(VIb)の化合物であって、
R18はH又はハロゲンであり、
R16及びR17はH、アルキル若しくはシクロアルキルであるか、又はR16及びR17はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
R19及びR20はH若しくはアルキルであるか、又はR19及びR20はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
但し、R16、R17、R18、R19及びR20は全てがHであることはない化合物又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグである、請求項1から29のいずれか一項に記載の化合物。 - R22は、アルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、
R16及びR17は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R19及びR20は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R18はH又はハロゲンである、請求項30に記載の化合物。 - R22はアルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル、フェニル及びベンジルから選択され、
R16及びR20は、C1〜6アルキル又はC3〜5シクロアルキルであり、好ましくはイソプロピル又はシクロペンチルであり、
R17及びR19は、Hであり、
R18はH又はハロゲンである、請求項30に記載の化合物。 - 式(VII)の化合物であって、
R30は出現毎に独立してアルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル及びアルキルアミノから選択され、
R18はH又はハロゲンであり、
R16及びR17はH若しくはアルキルであるか、又はR16及びR17はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
R19及びR20はH若しくはアルキルであるか、又はR19及びR20はそれらが結合した炭素原子と一緒に5若しくは6員環を形成し、前記環は飽和、部分的に不飽和又は不飽和であり、前記環は、N、O及びSから選択される1個又は2個のヘテロ原子を場合によって含み、
但し、R16、R17、R18、R19及びR20は全てがHであることはなく、
但し、QがOであり、R16及びR17、並びにこれとは別にR19及びR20がそれらが結合したそれぞれの炭素原子と一緒にシクロペンチル環を形成するとき、R30はC-3ヒドロキシルアルキルではない化合物又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグである、請求項1から32のいずれか一項に記載の化合物。 - QはO又はSであり、
R30は出現毎に独立してアルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル及びアルキルアミノから選択され、
R16及びR17は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R19及びR20は、それらが結合した原子と一緒にシクロペンチル環を形成し、
R18はH又はハロゲンであり、
但し、QがOであるとき、R30はC-3ヒドロキシルアルキルではない、請求項33に記載の化合物。 - QはO又はSであり、
R30は出現毎に独立してアルキル、ペルハロアルキル、ヒドロキシルアルキル、C3〜C6シクロアルキル及びアルキルアミノから選択され、
R16及びR20は、C1〜6アルキル、好ましくはイソプロピルであり、
R17及びR19はHであり、
R18はH又はハロゲンである、請求項33又は請求項34に記載の化合物。 -
- 化合物又はその薬学的に有効な塩、溶媒和物若しくはプロドラッグはNLRP3インフラマソームの阻害剤である、請求項1から36のいずれか一項に記載の化合物。
- 請求項1から請求項37のいずれか一項に記載の化合物又はその薬学的に許容される塩、溶媒和物若しくはプロドラッグ並びに薬学的に許容される担体、希釈剤及び/又は賦形剤を含む医薬組成物。
- 有効量の、請求項1から請求項37のいずれか一項に記載の化合物又はその薬学的に有効な塩、溶媒和物若しくはプロドラッグ、或いは請求項38に記載の医薬組成物を投与して、それによって疾患、障害又は状態を治療又は予防する工程を含む、疾患、障害又は状態の治療又は予防方法。
- 疾患、障害又は状態は、NLRP3インフラマソームの活性化の阻害に応答するものである、請求項39に記載の方法。
- 疾患、障害又は状態は、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-33及びTh17細胞の1つ又は複数の調節に応答する、請求項39又は請求項40に記載の方法。
- 疾患、障害又は状態は、免疫系の疾患、障害又は状態である、請求項39から請求項41のいずれか一項に記載の方法。
- 疾患、障害又は状態は、炎症性の疾患、障害若しくは状態か、又は自己免疫疾患、障害若しくは状態である、請求項39から請求項41のいずれか一項に記載の方法。
- 疾患、障害又は状態は、皮膚の疾患、障害又は状態である、請求項39から請求項41のいずれか一項に記載の方法。
- 疾患、障害又は状態は、心血管系の疾患、障害又は状態である、請求項39から請求項41のいずれか一項に記載の方法。
- 疾患、障害又は状態は、癌、腫瘍又はその他の悪性病変である、請求項39から請求項41のいずれか一項に記載の方法。
- 疾患、障害又は状態は、腎臓系の疾患、障害又は状態である、請求項39から請求項41のいずれか一項に記載の方法。
- 疾患、障害又は状態は、胃腸管の疾患、障害又は状態である、請求項39から請求項41のいずれか一項に記載の方法。
- 疾患、障害又は状態は、呼吸器系の疾患、障害又は状態である、請求項39から請求項41のいずれか一項に記載の方法。
- 疾患、障害又は状態は、内分泌系の疾患、障害又は状態である、請求項39から請求項41のいずれか一項に記載の方法。
- 疾患、障害又は状態は、中枢神経系(CNS)の疾患、障害又は状態である、請求項39から請求項41のいずれか一項に記載の方法。
- 疾患、障害又は状態は、クリオパイリン関連周期性症候群(CAPS):マックルウェルズ症候群(MWS)、家族性寒冷自己炎症性症候群(FCAS)及び新生児期発症多臓器性炎症性疾患(NOMID)を含む恒常的炎症;自己炎症性疾患を含む:家族性地中海熱(FMF)、TNF受容体関連周期性症候群(TRAPS)、メバロン酸キナーゼ欠損症(MKD)、高グロブリン血症D及び周期熱症候群(HIDS)、インターロイキン1受容体アンタゴニストの欠損症(DIRA)、マジード症候群、化膿性関節炎、壊疽性膿皮症及びざ瘡(PAPA)、A20のハプロ不全(HA20)、小児肉芽腫性動脈炎(PGA)、PLCG2関連抗体不全及び免疫調節異常(PLAID)、PLCG2関連自己炎症、抗体不全及び免疫調節異常(APLAID)、B細胞免疫不全を伴う鉄芽球性貧血、周期熱及び発育遅延(SIFD);スイート症候群、慢性非細菌性骨髄炎(CNO)、慢性再発性多巣性骨髄炎(CRMO)及び滑膜炎、ざ瘡、膿疱症、骨増殖症、骨炎症候群(SAPHO);多発硬化症(MS)、1型糖尿病、乾癬、関節リウマチ、ベーチェット病、シェーグレン症候群及びシュニッツラー症候群を含む自己免疫疾患;慢性閉塞性肺疾患(COPD)、ステロイド耐性喘息、石綿肺、珪肺症及び嚢胞性線維症を含む呼吸器疾患;パーキンソン病、アルツハイマー病、運動ニューロン疾患、ハンチントン病、脳性マラリア及び肺炎球菌性髄膜炎による脳損傷を含む中枢神経系疾患;2型糖尿病、アテローム性動脈硬化、肥満、痛風、偽痛風を含む代謝疾患;眼の上皮の疾患、加齢黄斑変性(AMD)、角膜感染症、ブドウ膜炎及びドライアイを含む眼の疾患;慢性腎臓疾患、シュウ酸腎症及び糖尿病性腎症を含む腎臓疾患;非アルコール性脂肪性肝炎及びアルコール性肝臓疾患を含む肝臓疾患;接触過敏症及び日焼けを含む皮膚における炎症反応;骨関節炎、若年性原因不明の全身炎症、成人発症スチル病、再発性多発軟骨炎を含む関節における炎症反応;チクングニア及びロスリバーを含むアルファウイルス並びにデング及びジカウイルスを含むフラビウイルス、インフルエンザ、HIVを含むウイルス感染;化膿性汗腺炎(HS)及びその他の嚢胞が原因の皮膚疾患;肺癌転移、膵臓癌、胃癌、骨髄異形成症候群、白血病を含む癌;多発性筋炎;脳卒中;心筋梗塞;移植片対宿主病;高血圧;大腸炎;蠕虫感染;細菌感染;腹部大動脈瘤;創傷治癒;鬱病、心理的ストレス;ドレスラー症候群を含む心膜炎、虚血再灌流傷害並びに個体がNLRP3に生殖系列又は体細胞の非サイレント突然変異を有することが決定された任意の疾患からなる群から選択される、請求項39から請求項41のいずれか一項に記載の方法。
- 疾患、障害又は状態の治療又は予防は、ほ乳類に対して実施される、請求項39から請求項52のいずれか一項に記載の方法。
- ほ乳類はヒト対象である、請求項53に記載の方法。
- ほ乳類における疾患、障害又は状態の診断を容易にするために、請求項1から請求項37のいずれか一項に記載の標識化合物、又はその薬学的に有効な塩、溶媒和物若しくはプロドラッグ、又はその金属イオンキレート複合体を、ほ乳類又はほ乳類から得た生物学的試料に投与する工程を含む、ほ乳類における疾患、障害又は状態を診断する方法。
- 生物学的標的を請求項1から請求項37のいずれか一項に記載の化合物又はその薬学的に有効な塩、溶媒和物若しくはプロドラッグに曝露する工程を含む、生物学的標的の活性を調節する方法。
- 生物学的標的は、NLRP3インフラマソーム、IL-1β、IL-17、IL-18、IL-1α、IL-37、IL-33及びTh17細胞からなる群から選択することができる、請求項56に記載の方法。
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