JP6404717B2 - アミドスピロ環状アミド及びスルホンアミド誘導体 - Google Patents
アミドスピロ環状アミド及びスルホンアミド誘導体 Download PDFInfo
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- JP6404717B2 JP6404717B2 JP2014559065A JP2014559065A JP6404717B2 JP 6404717 B2 JP6404717 B2 JP 6404717B2 JP 2014559065 A JP2014559065 A JP 2014559065A JP 2014559065 A JP2014559065 A JP 2014559065A JP 6404717 B2 JP6404717 B2 JP 6404717B2
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- 238000010833 quantitative mass spectrometry Methods 0.000 description 1
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- 229940005550 sodium alginate Drugs 0.000 description 1
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- 239000000661 sodium alginate Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- IXMINYBUNCWGER-UHFFFAOYSA-M sodium;4-propoxycarbonylphenolate Chemical compound [Na+].CCCOC(=O)C1=CC=C([O-])C=C1 IXMINYBUNCWGER-UHFFFAOYSA-M 0.000 description 1
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- 125000004079 stearyl 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])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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- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
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- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Description
Rは、(a)N、S、及びOから選択されるヘテロ原子1つ、及び1、2、又は3の追加のN原子を含む8−、9−、又は10−員環の二環式ヘテロアリールであり、その際、前記二環式ヘテロアリールは非置換であり、又は重水素、アミノ、アルキルアミノ、ジアルキルアミノ、アルキル、ハロ、シアノ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、及びアルコキシから成る群から選択される1以上の置換基によって置換され、及びその際、前記二環式ヘテロアリールの1以上のN原子は任意でN−オキシドであり;或いは
(b)フェニル又は単環式5−又は6−員環のヘテロアリールに縮合された5−又は6−員環の窒素連結ヘテロシクロアルキル環であり、その際、前記フェニル又はヘテロアリールは非置換であり、又は重水素、アミノ、アルキルアミノ、ジアルキルアミノ、アルキル、ハロ、シアノ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、及びアルコキシから成る群から選択される1以上の置換基によって置換され;
R1は、H、−(C1−4アルキレン)0−1C(O)Ra、−(C1−4アルキレン)0−1CO2Ra、−(C1−4アルキレン)0−1S(O)Ra、−(C1−4アルキレン)0−1SO2Ra、−C(O)NH(Ra)、−C(O)N(Ra)2、又は−C(O)C(O)NH(Ra)であり;
その際、各Raは独立して
(1)非置換であるアルキル、又は1以上のRm置換基によって置換されたアルキルであり、
その際、各Rmは、重水素、ヒドロキシ、−NRbRc、アルコキシ、シアノ、ハロ、−C(O)アルキル、−CO2アルキル、−CONRbRc、−S(O)アルキル、−SO2アルキル、−SO2NRbRc、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、フェノキシ、及び−O−アルキル−OHから成る群から独立して選択され;
その際、Rbは、H又はアルキルであり;
Rcは、H、アルキル、アルコキシアルキル、ハロアルキル、−C(O)アルキル、−CO2アルキル、−SO2アルキル、−C(O)NH2、又はC(O)Hであり;
Rmの中の各アリール基、ヘテロアリール基、シクロアルキル基、及びヘテロシクロアルキル基は、非置換であり、又はアルキル、ハロアルキル、ヒドロキシ、−NRbRc、アルコキシ、ハロアルコキシ、シアノ、ハロ、オキソ、−C(O)アルキル、−CO2アルキル、−C(O)−ヘテロシクロアルキル、−CONRbRc、−S(O)アルキル、−SO2アルキル、−SO2−ハロアルキル、−SO2NRbRc、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルから成る群から独立して選択される1以上の置換基によって置換され;又は2つの置換基は一緒に縮合フェニル環、ヘテロアリール環、シクロアルキル環、又はヘテロシクロアルキル環を形成し;
その際、各アルキル又はアルコキシは非置換であり、又は−NRbRc、ヘテロシクロアルキル、ヘテロアリール、又は−C(O)アルキルによって置換され;
各アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルは非置換であり、又はアルキル、ハロ、オキソ、−C(O)アルキルによって置換され;
(2)それぞれ非置換である、又は1以上のRg置換基によって置換されたフェニル、シクロアルキル、ヘテロアリール、又はヘテロシクロアルキルであり;
その際、各Rgは、アルキル、ハロアルキル、ヒドロキシ、−NRbRc、アルコキシ、ハロアルコキシ、シアノ、ハロ、オキソ、−C(O)アルキル、−CO2アルキル、−C(O)−ヘテロシクロアルキル、−CONRbRc、−S(O)アルキル、−SO2アルキル、−SO2−ハロアルキル、−SO2NRbRc、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルから成る群から独立して選択され;又は2つのRg置換基は一緒に縮合フェニル環、ヘテロアリール環、シクロアルキル環、又はヘテロシクロアルキル環を形成し;
その際、各アルキル又はアルコキシは、非置換であり、又はフェニル、−NRbRc、ヘテロシクロアルキル、ヘテロアリール、又は−C(O)アルキルによって置換され;
各アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルは非置換であり、又はアルキル、ハロ、−CO2アルキル、又は−C(O)アルキルによって置換され;或いは
(3)−NRxRyであり、
その際、RxはH又はアルキルであり;
RyはH、アルキル、アルコキシアルキル、ハロアルキル、−C(O)アルキル、−CO2アルキル、又は−SO2アルキルであり;
R2及びR3はそれぞれ独立してH又は重水素であり;
nは1又は2である。
一般的な定義
化学的な定義
が挙げられるが、これらに限定されない。
が挙げられるが、これらに限定されない。
が挙げられるが、これらに限定されない。
追加の化学的記載
本発明の化合物
スキーム及び実施例
CDCl3 重水素化クロロホルム
CD3OD 重水素化メタノール
δ 化学シフト(ppm)
DCM ジクロロメタン
DIPEA ジイソプロピルエチルアミン
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
EDCI 1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド
ELSD 蒸発光散乱検出器
equiv 分子当量
ESI エレクトロスプレーイオン化
h 時間
H2 水素ガス
HATU ヘキサフルオロリン酸O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウム
1H NMR 陽子核磁気共鳴分光分析
HOBt 1−ヒドロキシベンゾトリアゾール
HPLC 高速液体クロマトグラフィ
LC/MS 液体クロマトグラフィ−質量分光分析
MeOH メタノール
MHz メガヘルツ
min 分
PDA 光ダイオードアレイ検出器
psi 平方インチ当たりのポンド
rt 室温
Raney−Ni ラネーニッケル
Rf 保持因子
TFA トリフルオロ酢酸
Tf2O 無水トリフルオロメタンスルホン酸
THF テトラヒドロフラン
TLC 薄層クロマトグラフィ
実施例化合物の化学分析の方法
機器:SHIMADZU LCMS−2010EV
LCパラメータ:カラム:Shim−packXR−ODS、2.2μm、3.0×50mm;移動相A:水/0.05%TFA;移動相B:アセトニトリル;勾配:2.0分で5%〜100%B、100%Bで1.1分、0.2分で100%〜5%B、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:254nm及びELSD;試料の調製:メタノール中1mg/mL;注入容量:1μL.
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:4.5kv;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:1.7kv。
機器:SHIMADZU LCMS−2010EV
LCパラメータ:カラム:Waters XBridgeC18、3.0×50mm、3.5μ;移動相A:水/5mM酢酸アンモニウム;移動相B:メタノール;勾配:1.8分で10%〜100%B、100%で1.3分、0.1分で100%〜10%B、次いで停止;流速:0.9mL/分;カラム温度:40℃;検出器:PDA及びELSD;試料の調製:メタノール中1mg/mL;注入容量:1μL.
MSパラメータ:インターフェース:ESI(陽性&陰性);インターフェース電圧:4.0kv;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:1.5kv。
機器:SHIMADZU LCMS−2010EV
LCパラメータ:カラム:Shim−pack XR−ODS、2.2μm、3.0×50mm;移動相A:水/0.05%TFA;移動相B:アセトニトリル/0.05%TFA;勾配:2.0分で5%〜100%B、100%Bで1.1分、0.2分で100%〜5%B、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:254nm及びELSD;試料の調製:メタノール中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:4.5kv;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:1.5kv。
機器:SHIMADZU LC/MS−2010EV
LCパラメータ:カラム:Waters XselectC18、3.0×50mm、3.5μm;移動相A:水/0.1%蟻酸;移動相B:アセトニトリル/0.05%蟻酸;勾配:2.0分で5%〜100%B、100%Bで1.2分、0.1分で100%〜5%B、次いで停止;流速:0.9mL/分;カラム温度:35℃;検出器:254nm及びELSD;試料の調製:メタノール中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性&陰性);インターフェース電圧:4.5kv;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:1.5kv。
機器:SHIMADZU LCMS−2010EV
LCパラメータ:カラム:Shim−pack XR−ODS、3.0×50mm、2.2μm;移動相A:水/0.05%TFA;移動相B:アセトニトリル;勾配:2.0分で5%〜100%B、100%Bで1分、0.3分で100%〜5%B、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:254nm及びELSD;試料の調製:メタノール中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:4.5kv;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:1.3kv。
機器:SHIMADZU LCMS−2010EV
LCパラメータ:カラム:Shim−pack XR−ODS、3.0×50mm、2.2μm;移動相A:水/0.05%TFA;移動相B:アセトニトリル;勾配:2.0分で5%〜100%B、100%Bで1.2分、0.1分で100%〜5%B、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:254nm及びELSD;試料の調製:メタノール中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:4.5kv;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:70−900(m/z);検出器電圧:1.1kv。
機器:SHIMADZU LC/MS−2020EV
LCパラメータ:カラム:Shim−pack XR−ODS、50mm×3.0mm、2.2μm;移動相A:水/0.05%TFA;移動相B:アセトニトリル;勾配:2.1分で5%〜100%B、100%Bで0.8分、0.1分で100%〜5%B、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:254nm及びELSD;試料の調製:アセトニトリル中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:4.5kv;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:1.05kv。
機器:SHIMADZU LCMS−2020
LCパラメータ:カラム:Shim−pack XR−ODS、2.2μm、3.0×50mm;移動相A;水/0.05%TFA;移動相B:アセトニトリル/0.05%TFA;勾配:2.0分で5%〜100%B、100%Bで1.2分、0.1分で100%〜5%B、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:254nm及びELSD;試料の調製:メタノール中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:4.5kv;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:1.1kv.
機器:SHIMADZU LCMS−2020
LCパラメータ:カラム:Shim−pack XR−ODS、50×3.0nm、2.2μm;移動相A:水/0.05%TFA;移動相B:アセトニトリル/0.05%TFA;勾配:5%B〜100%Bで2.0分、100%Bで1.2分、0.1分で100%B〜5%、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:254nm及びELSD;試料の調製:メタノール中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:4.5kv;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:70−900(m/z);検出器電圧:1.05kv。
機器:SHIMADZU LCMS−2020
LCパラメータ:カラム:Shim−pack XR−ODS、3.0×50mm、2.2μ;移動相A:水/0.05%TFA;移動相B:アセトニトリル;勾配:2.0分で5%〜100%B、100%Bで1.2分、0.2分で100%〜5%B、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:254nm及びELSD;試料の調製:アセトニトリル中1mg/mL;注入容量1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:4.5kv;熱ブロック:200℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:1.05kv.
機器:SHIMADZU LCMS−2020
LCパラメータ:カラム:Gemini−N×3uC18 110A;移動相A:水/0.04%アンモニア;移動相B:アセトニトリル;勾配:2.0分で5%〜100%B、100%Bで1.1分、0.1分で100%〜5%B、次いで停止;流速:1.0mL/分;カラム温度:35℃;検出器:254nm及びELSD;試料の調製:メタノール中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性&陰性);インターフェース電圧:4.5kv;熱ブロック:200℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:0.75kv。
機器 Waters 質量依存性
移動相A 0.1%H2O w/NH4OH
移動相B アセトニトリル
カラム PhenomeneX Gemini N−X C18、10μm、21.5×100mm
カラム温度 25℃
LC勾配 10分で5〜85%
LC流速 35mL/分
UV波長 254nm
質量分光計 Waters3100
イオン化 ES+
HPLC Waters 質量依存性
移動相A 0.1%H2O w/NH4OH
移動相B アセトニトリル
カラム PhenomeneX Gemini N−X C18、10μm、30×100mm
カラム温度 25℃
LC勾配 15分で5〜50%
LC流速 60mL/分
UV波長 254nm
質量分光計 Waters3100
イオン化 ES+
機器:SHIMADZU LC/MS−2020
LCパラメータ:カラム:Shim−pack XR−ODS、2.2μm、3.0×50mm;移動相A:水/0.05%TFA;移動相B:アセトニトリル;勾配:5%B〜100%Bで2.0分、100%Bで1.2分、0.1分で100%B〜5%、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:UV及びELSD;試料の調製:メタノール中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:4.5kv;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:70−900(m/z);検出器電圧:1.1kv。
機器:SHIMADZU UHPLCMS−2020EV(LC−30AD ポンプ、 2成分溶媒マネージャー、SIL−AC自動試料、SPDM20A検出器、Alltech 3300ELSD検出器
LCパラメータ:カラム:Shim−pack XR−ODS、1.6μm、2.0×50mm;移動相A:水/0.1%蟻酸;移動相B:アセトニトリル/0.1%蟻酸;勾配:5%B〜100%Bで2.0分、100%Bで1.1分、0.1分で100%B〜5%、次いで停止;流速:0.7mL/分;カラム温度:40℃;検出器:ダイオードアレイ検出器(DAD)及びELSD;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:4.0kv;熱ブロック:200℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:0.9kv。
機器:SHIMADZU LC/MS−2020
LCパラメータ:カラム:Shim−pack XR−ODS、2.2μm、3.0×50mm;移動相A:水/0.1%蟻酸;移動相B:アセトニトリル/0.05%蟻酸;勾配:5%B〜100%Bで2.0分、100%Bで1.1分、0.1分で100%B〜5%、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:PDA及びELSD;試料の調製:アセトニトリル中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:チューニングファイル;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:0.9kv。
機器:SHIMADZU LC/MS−2020
LCパラメータ:カラム:Shim−pack XR−ODS、2.2μm、3.0×50mm;移動相A:水/0.1%蟻酸;移動相B:アセトニトリル/0.05%蟻酸;勾配:5%B〜100%Bで2.0分、100%Bで1.2分、0.2分で100%B〜5%、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:UV及びELSD;試料の調製:アセトニトリル中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:4.5kv;熱ブロック:200℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:0.95kv。
機器:SHIMADZU LC/MS−2020
LCパラメータ:カラム:Shim−pack XR−ODS、2.2μm、3.0×50mm;移動相A:水/0.05%TFA;移動相B:アセトニトリル/0.05%TFA;勾配:5%B〜100%Bで1.2分、100%Bで0.9分、0.2分で100%B〜5%、次いで停止;流速:1.0mL/分;カラム温度:40℃;検出器:PDA及びELSD;試料の調製:アセトニトリル中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:チューニングファイル;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:1.1kv。
機器:SHIMADZU UHPLC/MS−2020
LCパラメータ:カラム:Shim−pack XR−ODS、1.6μm、2.0×50mm;移動相A:水/0.1%蟻酸;移動相B:アセトニトリル/0.05%蟻酸;勾配:5%B〜100%Bで2.0分、100%Bで1.1分、0.1分で100%B〜5%、次いで停止;流速:0.7mL/分;カラム温度:40℃;検出器:PDA及びELSD;試料の調製:アセトニトリル中1mg/mL;注入容量:1μL。
MSパラメータ:インターフェース:ESI(陽性);インターフェース電圧:チューニングファイル;熱ブロック:250℃;霧化ガス:1.50L/分;走査範囲:90−900(m/z);検出器電圧:0.85kv.
機器:HPLC Agilent 1200
LCパラメータ:カラム:Agilent SB C18、2.1×30mm、1.8μm;移動相A:水/0.05%TFA;移動相B:アセトニトリル;勾配:3%Bで0.3分、6.5分で3%B〜95%B、95%Bで1.5分、0.1分で95%〜3%B、次いで停止;流速:0.4mL/分;カラム温度:25℃;検出器:254nm。
MSパラメータ:Agilent6140四重極LC/MS;インターフェース:ESI(陽性);走査範囲:90−1300amu。
機器:Waters Acquity UPLC
LCパラメータ:カラム:Acquity UPLC BEH C181.7mm2.1×50 mm;移動相A:水/0.05%TFA;移動相B:アセトニトリル;勾配:17.5分で2%〜98%B、98%Bで1.5分、1.5分間平衡化、次いで停止;流速:0.6mL/分;カラム温度:40℃;検出器:254nm及び220nm。
MSパラメータ:Waters LCT Premier XE;インターフェース:ESI(陽性);走査範囲:80−1300amu;検出器:飛行時間型。
I.中間体の調製
中間体1:フロ[2,3−c]ピリジン−2−カルボン酸
0℃にて撹拌した6−[(tert−ブトキシ)カルボニル]−6−アザスピロ[2.5]オクタン−1−カルボン酸(129g,505.27ミリモル,1.00当量)、DIPEA(196g,1.52モル,6.02当量)及び(S)−(−)−1−フェニルエタンアミン(87g,717.94ミリモル,1.10当量)のDMF(2L)溶液にヘキサフルオロリン酸O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウム(231g,607.89ミリモル,1.20当量)を小分けして加えた。得られた溶液を室温で一晩撹拌し、次いで4.5Lの水/氷の添加によって反応を止めた。得られた混合物を2Lの酢酸エチルで3回抽出した。合わせた有機層を800mLのブラインで2回洗浄し、無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。酢酸エチル/石油エーテル(1/4)によって溶出するシリカゲルカラムで残留物を精製して白色固形物としてのジアステレオマーの混合物として83.15g(46%)のtert−ブチル 1−[[(1S)−1−フェニルエチル]カルバモイル]−6−アザスピロ[2.5]オクタン−6−カルボキシレートを得た。LC/MS(方法I,ESI):RT1=4.63分,RT2=4.73分,m/z=359.1[M+H]+。キラル超臨界流体クロマトグラフィ(Column:3×25cm,5μm Chiralpak AD;移動相A:CO2;移動相B:MeOH中0.1%NH4OH;定組成条件:87:13A:B;流速:200g/分;UV:220nm;背圧:100バール;カラム温度:40℃)によってジアステレオマーの得られた混合物を分離した。最初に溶出するジアステレオマーを次の工程に進めた。
tert−ブチル (1S)−1−[[(1S)−1−フェニルエチル]カルバモイル]−6−アザスピロ[2.5]オクタン−6−カルボキシレート(20g,55.79ミリモル,1.00当量)のMeOH(200mL)溶液に0℃にて30分間、塩化水素ガスを吹き込んだ。得られた溶液を室温で一晩撹拌し、次いで真空下で濃縮した。残留物を100mLのH2Oで希釈し、2Nの水酸化ナトリウム溶液で溶液のpHを12に合わせた。得られた混合物を100mLのDCMで3回抽出した。合わせた有機層を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮して淡黄色の固形物として15gの(1S)−N−[(1S)−1−フェニルエチル]−6−アザスピロ[2.5]オクタン−1−カルボキサミドを得た。LC/MS(方法I,ESI):RT=1.03分,m/z=259.0[M+H]+
室温で窒素のもとで維持された撹拌した(1S)−N−[(1S)−1−フェニルエチル]−6−アザスピロ[2.5]オクタン−1−カルボキサミド(8g,30.96ミリモル,1.00当量)のTHF(800mL)溶液にTHF(100mL,100ミリモル,3.3当量)中1Mのボラン溶液を一滴ずつ加えた。得られた溶液を一晩還流した。得られた混合物を真空下で濃縮し、次いで水(50mL)を残留物に加えた。5%HCl(5%)で溶液のpHを1に合わせた。得られた溶液を還流で4時間撹拌した。反応混合物を室温に冷却し、10%水酸化ナトリウム溶液で溶液のpHを12に合わせた。溶液を室温に冷却し、次いで撹拌しながら、二炭酸ジ−tert−ブチル(6.7g,30.70ミリモル,0.68当量)の20mLのTHF溶液を一滴ずつ加えた。反応混合物を室温で一晩撹拌した。得られた混合物を200mLの酢酸エチルで2回抽出した。合わせた有機層を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。酢酸エチル/石油エーテル(1:3)によって溶出するシリカゲルカラムで残留物を精製して淡茶色の油として2.9g(19%)のtert−ブチル (1S)−1−([[(1S)−1−フェニルエチル]アミノ]メチル)−6−アザスピロ[2.5]オクタン−6−カルボキシレートを得た。TLC:DCM:MeOH=10:1,Rf=0.3
MeOH(30mL)におけるtert−ブチル (1S)−1−([[(1S)−1−フェニルエチル]アミノ]メチル)−6−アザスピロ[2.5]オクタン−6−カルボキシレート(700mg,2.03ミリモル,1.00当量)とPd(OH)2(100mg)の混合物を50mLの加圧反応器にて5気圧の水素のもとで室温にて一晩撹拌した。濾液を真空下で濃縮して淡黄色の油として400mg(82%)のtert−ブチル (1S)−1−(アミノメチル)−6−アザスピロ[2.5]オクタン−6−カルボキシレートを得た。LC/MS(方法F,ESI):RT=1.25分,m/z=241.0[M+H]+
tert−ブチル (1S)−1−(アミノメチル)−6−アザスピロ[2.5]オクタン−6−カルボキシレート(5g,20.80ミリモル,1.00当量)、クロロ蟻酸4−ニトロフェニル(4.4g,21.83ミリモル,1.05当量)及びDIPEA(10mL)のTHF(200mL)溶液を室温にて一晩撹拌した。次いでジヒドロ塩化1H,2H,3H−ピロロ[3,4−c]ピリジン(4.4g,22.79ミリモル,9.24当量)を加え、反応混合物を室温にて一晩撹拌した。得られた混合物を真空下で濃縮した。DCM/MeOH(20/1)のよって溶出するシリカゲルカラムで残留物を精製して淡黄色の固形物として2.3gのtert−ブチル (1S)−1−[[([1H,2H,3H−ピロロ[3,4−c]ピリジン−2−イル]カルボニル)アミノ]メチル]−6−アザスピロ[2.5]オクタン−6−カルボキシレートを得た。TLC:DCM:MeOH=10:1,Rf=0.4
MEOH溶液(100mL)中の飽和塩化水素におけるtert−ブチル (1S)−1−[[([1H,2H,3H−ピロロ[3,4−c]ピリジン−2−イル]カルボニル)アミノ]メチル]−6−アザスピロ[2.5]オクタン−6−カルボキシレート(2.3g,5.95ミリモル,1.00当量)の溶液を室温で2時間撹拌した。得られた混合物を真空下で濃縮して茶色の固形物として1.7gの粗精製のN−[(1S)−6−アザスピロ[2.5]オクタン−1−イルメチル]−1H,2H,3H−ピロロ[3,4−c]ピリジン−2−カルボキサミド 塩酸塩を得た。
−50℃にて窒素のもとで維持された撹拌したオキセタン−3−オン(9g,124.89ミリモル,1.00当量)のTHF(200mL)溶液に1.6Mのメチルリチウムのエーテル(150mL,240ミリモル,1.9当量)溶液を一滴ずつ加えた。反応混合物を0℃に温め、2時間撹拌した。次いで0℃にてクロロ蟻酸4−ニトロフェニル(26g,128.99ミリモル,1.03当量)のTHF(100mL)溶液を一滴ずつ加えた。添加が完了した後、得られた溶液を室温でさらに2時間撹拌した。次いで200mLの水の添加によって反応を止めた。得られた混合物を200mLの酢酸エチルで2回抽出した。合わせた有機層を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。酢酸エチル/石油エーテル(1:5)によって溶出するシリカゲルカラムで残留物を精製して白色固形物として4.5g(14%)の炭酸3−メチルオキセタン−3−イル 4−ニトロフェニルを得た。TLC:石油エーテル:酢酸エチル=2:1、Rf=0.6
N−[(1S)−6−アザスピロ[2.5]オクタン−1−イルメチル]−1H,2H,3H−ピロロ[3,4−c]ピリジン−2−カルボキサミド 塩酸塩(1.7g,5.27ミリモル,1.00当量)、炭酸3−メチルオキセタン−3−イル 4−ニトロフェニル(1.7g,6.71ミリモル,1.27当量及びDIPEA(2mL)のエタノール(50mL)溶液を室温にて一晩撹拌した。得られた混合物を真空下で濃縮した。残留物を150mLのDCMに溶解し、次いで100mLのH2Oで洗浄した。有機層を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。DCM/MeOH(20/1)によって溶出するシリカゲルカラムで残留物を精製して白色固形物として1.43g(68%)の3−メチルオキセタン−3−イル (1S)−1−[[([1H,2H,3H−ピロロ[3,4−c]ピリジン−2−イル]カルボニル)アミノ]メチル]−6−アザスピロ[2.5]オクタン−6−カルボキシレートを得た。LC/MS(方法I,ESI):RT=1.24分,m/z=401.1[M+H]+.1H−NMR(300MHz,DMSO−d6,ppm):δ8.56(s,1H),8.47(d,J=5.1Hz,1H),7.39(d,J=5.1Hz,2H),6.42(t,J=5.2Hz,1H),4.63−4.59(m,6H),4.38(d,J=7.5Hz,2H),3.48(s,2H),3.31(s,2H),3.12(t,J=6.0Hz,2H),1.62(s,3H),1.59−1.55(m,1H),1.42−1.39(m,2H),1.37−1.34(m,1H),1.21−1.17(m,1H),1.01−0.96(m,1H),0.54−0.48(m,1H),0.27−0.21(m,1H)
解析評価
アッセイ1:生化学的な阻害アッセイ
組換えHisタグ付きのNAMPTを大腸菌で作出し、Niカラムで精製し、XTAL Biostructuresによるサイズ排除カラムでさらに精製した。
96穴V底プレートにて緩衝液A(50mMのHepes、pH7.5、50mMのNaCl、5mMのMgCl2及び1mMのTHP)でNAMPTの酵素反応を行った。DMSOにて化合物を連続希釈して100×ストックを作製することによって別の希釈プレートで化合物の滴定を行った。33nMのNAMPTタンパク質を含有する緩衝液A(89μL)を、対照(たとえば、DMSO又はブランク)を含有する100×化合物1μLに加えた。化合物と酵素の混合物を室温で15分間インキュベートし、次いで緩衝液Aにおける10×基質及び補因子10μLを試験ウェルに加え、1μMのNAM、100μMの5−ホスホ−D−リボース1−ジホスフェート(PRPP)及び2.5mMのアデノシン−5’−三リン酸(ATP)の最終濃度とした。室温で30分間、反応を進め、次いで、1%の蟻酸及び10μMのL−シスタチオニンの最終濃度とする蟻酸とL−シスタチオニンの溶液11μLの添加によって反応を止めた。事前に反応を止めた酵素及び補因子のミックスにNMNの連続希釈を添加する(添加しない)ことによってバックグランド及びシグナルの強度を測定した。
質量分光分析に基づくアッセイを用いてNAMPTの反応生成物、β−ニコチンアミドモノヌクレオチド(NMN)及び内部対照(L−シスタチオニン)を測定した。RapidFireシステムと共にBiocius Lifesciencesのサービスを用いてNMN及びL−シスタチオニンを検出した。手短に言えば、0.1%の蟻酸にて黒鉛炭素カートリッジにNMN及びL−シスタチオニンを結合させ、30%アセトニトリル緩衝液で溶出し、Sciex4000質量分光計に注入した。試料の成分をエレクトロスプレーイオン化によってイオン化し、陽イオンを検出した。NMNのQ1(親イオン)及びQ3(断片イオン)の質量はそれぞれ334.2及び123.2だった。L−シスタチオニンのQ1及びQ3は、それぞれ223.1及び134.1だった。以下の方法によって断片を定量し、解析した。
先ず、各ウェルについてNMNのシグナルをL−シスタチオニンのシグナルで割ることによってNMNのシグナルをL−シスタチオニンのシグナルに対して標準化した。バックグランドのウェルからのシグナルを平均し、試験プレートから差し引いた。次いで以下の式:
%阻害=100−100×x/y
を用いてパーセント阻害について化合物処理した細胞をアッセイした。
尚、式中、xは化合物処理したウェルの平均シグナルを示し、yはDMSO処理したウェルの平均シグナルを示す。
IC50=10^(LOG10(X)+(((50−化合物濃度1での%阻害)/(XX−YY)*(LOG10(X)−LOG10(Y))))
を用いてIC50値を決定した。式中、Xは化合物濃度1を示し、Yは化合物濃度2を示し、XXは化合物濃度1(X)での%阻害を示し、YYは化合物濃度2(Y)での%阻害を示す。
アッセイ2.試験管内での細胞増殖アッセイ
NMN又はニコチンアミド(NAM)の添加を伴って又は伴わずに180μLの培養培地(10%FBS、1%のPen/StrepアンホテリシンB、RPMI)にて1×103個/ウェルで96穴プレートにA2780細胞を播いた。37℃及び5%CO2にて一晩インキュベートした後、DMSO中の化合物を連続希釈して1000×ストックを作製することによって化合物の滴定を行った。次いで培養培地にて化合物をさらに10×最終濃度に希釈し、その際、対照(たとえば、DMSO及びブランク)を伴ってプレートに入れた細胞に20μLの各希釈物を加え、200μLの最終容量にした。各ウェルにおけるDMSOの最終濃度は0.1%だった。次いで5%CO2インキュベータにて37℃でプレートを72時間インキュベートした。次いでスルホローダミンB(SRB)アッセイを用いて生細胞の数を評価した。6%TCAの最終濃度にした30%トリクロロ酢酸(TCA)50μLの添加によって細胞を4℃で1時間固定した。プレートをH2Oで4回洗浄し、少なくとも1時間乾燥させ、1%酢酸中の4%SRB100μLを各ウェルに加え、室温で少なくとも30分間インキュベートした。次いでプレートを1%酢酸で3回洗浄し、乾燥させ、10mMのトリス塩基溶液100μLで処理した。次いで570nmの吸収でマイクロプレートリーダーにてプレートを読み取った。バックグランドは培地のみの別のプレートで生成した。
先ず、バックグランドのプレートからのシグナルを平均し、試験プレートから差し引いた。次いで次いで以下の式:
%阻害=100−100×x/y
を用いてパーセント阻害について化合物処理した細胞をアッセイした。
尚、式中、xは化合物処理した細胞の平均シグナルを示し、yはDMSO処理した細胞の平均シグナルを示す。
IC50=10^(LOG10(X)+(((50−化合物濃度1での%阻害)/(XX−YY)*(LOG10(X)−LOG10(Y))))
を用いてIC50値を決定した。式中、Xは化合物濃度1を示し、Yは化合物濃度2を示し、XXは化合物濃度1(X)での%阻害を示し、YYは化合物濃度2(Y)での%阻害を示す。
NAMPTの阻害はNAM又はNMNの添加によって無効にすることができた。化合物の特異性は、化合物及びNAM又はNMNのいずれかの存在下で細胞生存率アッセイを介して決定した。パーセント阻害は上記の方法を用いて決定した。
Claims (21)
- 式Iの化合物
(式中、
Rは、
(a)N、S、及びOから選択されるヘテロ原子1つ、及び1、2、又は3の追加のN原子を含む8−、9−、又は10−員環の二環式ヘテロアリールであり、その際、前記二環式ヘテロアリールは非置換であり、又は重水素、アミノ、アルキルアミノ、ジアルキルアミノ、アルキル、ハロ、シアノ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、及びアルコキシから成る群から選択される1以上の置換基によって置換され、及びその際、前記二環式ヘテロアリールの1以上のN原子は任意でN−オキシドであり;或いは
(b)フェニル又は単環式5−又は6−員環のヘテロアリールに縮合された5−又は6−員環の窒素連結ヘテロシクロアルキル環であり、その際、前記フェニル又はヘテロアリールは非置換であり、又は重水素、アミノ、アルキルアミノ、ジアルキルアミノ、アルキル、ハロ、シアノ、ハロアルキル、ヒドロキシ、ヒドロキシアルキル、及びアルコキシから成る群から選択される1以上の置換基によって置換され;
R1は、H、−(C1−4アルキレン)0−1C(O)Ra、−(C1−4アルキレン)0−1CO2Ra、−(C1−4アルキレン)0−1S(O)Ra、−(C1−4アルキレン)0−1SO2Ra、−C(O)NH(Ra)、 −C(O)N(Ra)2、又は−C(O)C(O)NH(Ra)であり;
その際、各Raは独立して
(1)非置換であるアルキル、又は1以上のRm置換基によって置換されたアルキルであり、
その際、各Rmは、ヒドロキシ、−NRbRc、アルコキシ、シアノ、ハロ、−C(O)アルキル、−CO2アルキル、−CONRbRc、−S(O)アルキル、−SO2アルキル、−SO2NRbRc、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、フェノキシ、及び−O−アルキル−OHから成る群から独立して選択され;
その際、Rbは、H又はアルキルであり;
Rcは、H、アルキル、アルコキシアルキル、ハロアルキル、−C(O)アルキル、−CO2アルキル、−SO2アルキル、−C(O)NH2、又はC(O)Hであり;
Rmの中の各アリール基、ヘテロアリール基、シクロアルキル基、及びヘテロシクロアルキル基は、非置換であり、又はアルキル、ハロアルキル、ヒドロキシ、−NRbRc、アルコキシ、ハロアルコキシ、シアノ、ハロ、オキソ、−C(O)アルキル、−CO2アルキル、−C(O)−ヘテロシクロアルキル、−CONRbRc、−S(O)アルキル、−SO2アルキル、−SO2−ハロアルキル、−SO2NRbRc、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルから成る群から独立して選択される1以上の置換基によって置換され;
その際、各アルキル又はアルコキシは非置換であり、又は−NRbRc、ヘテロシクロアルキル、ヘテロアリール、又は−C(O)アルキルによって置換され;
各アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルは非置換であり、又はアルキル、ハロ、−C(O)アルキルによって置換され;
(2)それぞれ非置換のフェニル、シクロアルキル、ヘテロアリール、又はヘテロシクロアルキルであり、又はアルキル、ハロアルキル、ヒドロキシ、−NRbRc、アルコキシ、ハロアルコキシ、シアノ、ハロ、オキソ、−C(O)アルキル、−CO2アルキル、−C(O)−ヘテロシクロアルキル、−CONRbRc、−S(O)アルキル、−SO2アルキル、−SO2−ハロアルキル、−SO2NRbRc、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルから成る群から独立して選択される1以上の置換基により置換されたフェニル、シクロアルキル、ヘテロアリール、又はヘテロシクロアルキルであり;
その際、各アルキル又はアルコキシは、非置換であり、又は−NRbRc、ヘテロシクロアルキル、ヘテロアリール、又は−C(O)アルキルによって置換され;
各アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルは非置換であり、又はアルキル、ハロ、又は−C(O)アルキルによって置換され;或いは
(3)−NRxRyであり、
その際、RxはH又はアルキルであり;
RyはH、アルキル、アルコキシアルキル、ハロアルキル、−C(O)アルキル、−CO2アルキル、又は−SO2アルキルであり;
R2及びR3はそれぞれ独立してH又は重水素であり;
nは1又は2である)。 - Rが、請求項1について記載されたように非置換である又は置換された8−又は9−員環のヘテロアリールである請求項1の化合物。
- Rが、請求項1で定義されたように非置換の又は置換されたフェニル又は単環式のヘテロアリールに縮合された5−又は6−員環の窒素連結ヘテロシクロアルキルである請求項1の化合物。
- R1がH
、−C(O)Ra、−CO2Ra、−S(O)Ra又は−SO2Raである請求項1の化合物。 - Raが、それぞれ非置換である又は置換されたメチル、エチル、プロピル、イソプロピル、tert−ブチル、イソブチル、イソペンチル、フェニル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、ピロリル、フラニル、チオフェニル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、チアゾリル、トリアゾリル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、イソインドリニル、アゼチジニル、オキセタニル、ピロリジニル、ピペリジニル、モルフォリニル、ピペラジニル、テトラヒドロフラニル、テトラヒドロピラニル、又はテトラヒドロチオフェニルである請求項1〜5のいずれか1項に記載の化合物。
- Raが、それぞれ非置換である、又はフルオロ、オキソ、メチル、−CONH2、アセチル、−SO2メチル、−C(O)−イソプロピル、ピリダジニル、トリアゾリル、ジメチルアミノメチル、シアノ、メチル−トリアゾリル−メトキシ、トリフルオロメトキシ、ピロリジニルメチル、アセチルアミノ、テトラゾリルメチル、メチル−テトラゾリル−メチル、メチル−イミダゾリル−メチル、−NHSO2メチル、1,1−ジオキソチオモルフォリニル、4−メチル−ピペラジニルメチル、−NHCONH2、−SO2CF3、モルフォリニルメチル、イミダゾリル、−SO2NH2、メチルピペリジニル、メチル−ピペラジニル、−C(O)(4−メチル−ピペラジニル)、モルフォリニル、トリフルオロメチル、シクロプロピル、エチル、イソオキサゾリル、テトラゾリル、イソプロピル、フェニル、フルオロ−フェニル、tert−ブチル、ベンジル、N−メチルピロリジニル、N−アセチル−ピロリジニル、イソブチル、プロピル、メチルピラゾリル、トリフルオロエチル、ピリミジニル、オキソ、アセチル、シアノ、−CO2−tert−ブチル、及びアミノから成る群から選択される1以上の置換基で置換されたフェニル、シクロアルキル、ヘテロアリール、又はヘテロシクロアルキルである請求項1〜6のいずれか1項に記載の化合物。
- Raが、非置換のアルキル、又はフルオロ、tert−ブトキシ、−C(O)NMe2、−NHCHO、メトキシ、フェノキシ、シアノ、アセチル、ヒドロキシ、−OCH2C(CH3)=OH、−NH(アセチル)、及び−N(Me)(アセチル)から成る群から選択される1以上の置換基で置換されたアルキルである請求項1〜6のいずれか1項に記載の化合物。
- R1が−SO2Raであり、式中、Raがメチル、エチル、フェニル、ベンジル又は2,2−ジメチルプロピルである請求項1の化合物。
- R1が−C(O)NHRaであり、式中、Raがメチル、エチル、プロピル、イソプロピル、tert−ブチル、シクロヘキシル、−CH2−シクロヘキシル、オキセタニル若しくはメチルオキセタニルである、又はRaがそれぞれ任意で、シアノ、メチル、フルオロ、メトキシ及びクロロから成る群から選択される1以上の置換基で置換されたフェニル基若しくはベンジル基である請求項1の化合物。
- (a)有効量の少なくとも1つの請求項1の化合物と、(b)薬学上許容可能なキャリアを含む医薬組成物。
- ニコチンアミド、ニコチン酸、及びニコチンアミドモノヌクレオチド(NMN)からなる群から選択される救援剤又は治療上有効な量の1以上の追加の補助的な活性剤を含む請求項12に記載の医薬組成物であって、
前記1以上の追加の補助的な活性剤が、シスプラチン、ドキソルビシン、タキソテレ、タキソール、エトポシド、イリノテカン、カンプトスター、トポテカン、パクリタキセル、ドセタキセル、エポチロン、タモキシフェン、5−フルオロウラシル、メソトレキセート、テモゾロミド、サイクロホスファミド、SCH66336、チピファルニブ(Zarnestra(登録商標))、L778,123、BMS214662、イレッサ(登録商標)、タルセバ(登録商標)、グリベック(登録商標)、イントロン(登録商標)、ペグ−イントロン(登録商標)、アドリアマイシン、シトキサン、ゲムシタビン、ウラシルマスタード、クロルメチン、イフォスファミド、メルファラン、クロラムブシル、ピポブロマン、トリエチレンメラミン、トリエチレンチオホスホルアミン、ブスルファン、カルムスチン、ロムスチン、ストレプトゾシン、ダカルバジン、フロクスウリジン、シタラビン、6−メルカプトプリン、6−チオグアニン、フルダラビンリン酸塩、オキサリプラチン、ロイコボリン、オキサリプラチン(フロキサチン(登録商標))、ペントスタチン、ビンブラスチン、ビンクリスチン、ビンデシン、ブレオマイシン、ダクチノマイシン、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、ミトラマイシン(商標)、ドキシコホルマイシン、
マイトマイシン−C、L−アスパラギナーゼ、テニポシド、17α−エチニルエストラジオール、ジエチルスチルベストロール、テストステロン、プレドニゾロン、フルオキシメステロン、ドロモスタノロンプロピオン酸塩、テストラクトン、メゲストロール酢酸塩、メチルプレドニゾロン、メチルテストステロン、プレドニゾロン、トリアムシノロン、クロロトリアニセン、ヒドロキシプロゲステロン、アミノグルテチミド、エストラムスチンメドロキシプロゲステロン酢酸塩、リュープライド、フルタミド、トレミフェン、ゴセレリン、カルボプラチン、ヒドロキシ尿素、アムサクリン、プロカルバジン、ミトタン、ミトキサントロン、レバミソール、ナベルベン、アナストラゾール、レトラゾール、カペシタビン、レロキサフィン、ドロロキサフィン、ヘキサメチルメラミン、アバスチン、ヘルセプチン、ベキサール、ベルケード、ゼバリン、トリセノックス、キセロダ、ビノレルビン、ポルフィマー、アービタックス、リポソマール、チオテパ、アルトレタミン、メルファラン、トラスツズマブ、レロゾール、フルベストラント、エキセメスタン、イフォスフォミド、リツキシマブ、キャンパス、ロイコボリン、及びデキサメタゾン、ビカルタミド、カルボプラチン、クロラムブシル、シスプラチン、レトロゾール、メゲストロール、バルルビシン、ビンブラスチン、及びNIASPAN(登録商標)から成る群から選択される、医薬組成物。 - 請求項1に記載の化合物、又はその薬学的に許容可能な塩を含有する治療剤であって、前記治療剤は、疾患又は医学的状態を患う又はそうであると診断された対象を治療する治療剤であって、
前記疾患又は医学的状態は、固形及び液状の腫瘍、非小細胞肺癌、白血病、リンパ腫、卵巣癌、神経膠腫、乳癌、子宮癌、結腸癌、子宮頸癌、肺癌、前立腺癌、皮膚癌、鼻−胃腫瘍、結腸直腸癌、CNSの癌、膀胱癌、膵臓癌、ホジキン病、関節リウマチ、糖尿病、アテローム性硬化症、敗血症、加齢、又は炎症を含む、治療剤。 - 請求項14に記載の治療剤であって、前記治療剤は、ニコチンアミド、ニコチン酸及びニコチンアミドモノヌクレオチド(NMN)からなる群から選択される救援剤を更に含有し、又は、シスプラチン、ドキソルビシン、タキソテレ、タキソール、エトポシド、イリノテカン、カンプトスター、トポテカン、パクリタキセル、ドセタキセル、エポチロン、タモキシフェン、5−フルオロウラシル、メソトレキセート、テモゾロミド、サイクロホスファミド、SCH66336、チピファルニブ(Zarnestra(登録商標))、L778,123、BMS214662、イレッサ(登録商標)、タルセバ(登録商標)、グリベック(登録商標)、イントロン(登録商標)、ペグ−イントロン(登録商標)、アドリアマイシン、シトキサン、ゲムシタビン、ウラシルマスタード、クロルメチン、イフォスファミド、メルファラン、クロラムブシル、ピポブロマン、トリエチレンメラミン、トリエチレンチオホスホルアミン、ブスルファン、カルムスチン、ロムスチン、ストレプトゾシン、ダカルバジン、フロクスウリジン、シタラビン、6−メルカプトプリン、6−チオグアニン、フルダラビンリン酸塩、ロイコボリン、オキサリプラチン(フロキサチン(登録商標))、ペントスタチン、ビンクリスチン、ビンデシン、ブレオマイシン、ダクチノマイシン、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、ミトラマイシン(商標)、ドキシコホルマイシン、マイトマイシン−C、L−アスパラギナーゼ、テニポシド、17α−エチニルエストラジオール、ジエチルスチルベストロール、テストステロン、プレドニゾロン、フルオキシメステロン、ドロモスタノロンプロピオン酸塩、テストラクトン、メゲストロール酢酸塩、メチルプレドニゾロン、メチルテストステロン、プレドニゾロン、トリアムシノロン、クロロトリアニセン、ヒドロキシプロゲステロン、アミノグルテチミド、エストラムスチン、メドロキシプロゲステロン酢酸塩、リュープライド、フルタミド、トレミフェン、ゴセレリン、カルボプラチン、ヒドロキシ尿素、アムサクリン、プロカルバジン、ミトタン、ミトキサントロン、レバミソール、ナベルベン、アナストラゾール、レトラゾール、カペシタビン、レロキサフィン、ドロロキサフィン、ヘキサメチルメラミン、アバスチン、ヘルセプチン、ベキサール、ベルケード、ゼバリン、トリセノックス、キセロダ、ビノレルビン、ポルフィマー、アービタックス、リポソマール、チオテパ、アルトレタミン、メルファラン、トラスツズマブ、レロゾール、フルベストラント、エキセメスタン、イフォスフォミド、リツキシマブ、キャンパス、ロイコボリン、デキサメタゾン、ビカルタミド、クロラムブシル、レトロゾール、メゲストロール、バルルビシン、ビンブラスチン、及びNIASPAN(登録商標)から成る群から選択される有効量の少なくとも1つの化合物を更に含有することを特徴とする、治療剤。
- 前記化合物が、N-[[6-(2,4-ジメチルオキサゾール-5-カルボニル)-6-アザスピロ[2.5]オクタン-2-イル]メチル]-1,3-ジヒドロピロロ[3,4-c]ピリジン-2-カルボキサミドである、請求項11に記載の化合物。
- 前記化合物が、(3-メチルオキセタン-3-イル) (2S)-2-[(1,3-ジヒドロピロロ[3,4-c]ピリジン-2-カルボニルアミノ)メチル]-6-アザスピロ[2.5]オクタン-6-カルボキシレートである、請求項11に記載の化合物。
- 前記化合物が、N-[[6-(3-メチルブタノイル)-6-アザスピロ[2.5]オクタン-2-イル]メチル]-1,3-ジヒドロピロロ[3,4-c]ピリジン-2-カルボキサミドである、請求項11に記載の化合物。
- 前記化合物が、tert-ブチル 2-[(1,3-ジヒドロピロロ[3,4-c]ピリジン-2-カルボニルアミノ)メチル]-6-アザスピロ[2.5]オクタン-6-カルボキシレートである、請求項11に記載の化合物。
- 前記化合物が、イソプロピル 2-[(1,3-ジヒドロピロロ[3,4-c]ピリジン-2-カルボニルアミノ)メチル]-6-アザスピロ[2.5]オクタン-6-カルボキシレートである、請求項11に記載の化合物。
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MX347459B (es) | 2011-05-09 | 2017-04-26 | Forma Tm Llc | Nuevos compuestos y composiciones para la inhibición de nampt. |
CA2865509A1 (en) | 2012-03-02 | 2013-09-06 | Genentech, Inc. | Amido-benzyl sulfone and sulfoxide derivatives |
PL2820008T3 (pl) | 2012-03-02 | 2018-04-30 | Genentech, Inc. | Pochodne amidów amido-spirocyklicznych i sulfonamidów |
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KR20180022826A (ko) * | 2015-07-02 | 2018-03-06 | 얀센 사이언시즈 아일랜드 유씨 | 항균 화합물 |
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US10730889B2 (en) | 2020-08-04 |
AU2017254876A1 (en) | 2017-11-23 |
US20210171545A1 (en) | 2021-06-10 |
AU2013225533A8 (en) | 2014-10-16 |
PL2820008T4 (pl) | 2018-04-30 |
US11485745B2 (en) | 2022-11-01 |
CY1118869T1 (el) | 2018-01-10 |
CN104520290B (zh) | 2020-10-09 |
CA2865525A1 (en) | 2013-09-06 |
PL2820008T3 (pl) | 2018-04-30 |
EP2820008A4 (en) | 2015-08-26 |
EP2820008A1 (en) | 2015-01-07 |
US20180339998A1 (en) | 2018-11-29 |
HRP20170411T1 (hr) | 2017-06-16 |
JP2015508786A (ja) | 2015-03-23 |
US20170216262A1 (en) | 2017-08-03 |
AU2013225533B2 (en) | 2017-08-03 |
LT2820008T (lt) | 2017-06-12 |
CA2865525C (en) | 2019-05-21 |
DK2820008T3 (en) | 2017-03-27 |
WO2013127269A1 (en) | 2013-09-06 |
CN104520290A (zh) | 2015-04-15 |
US9822129B2 (en) | 2017-11-21 |
EP2820008B1 (en) | 2016-12-14 |
SI2820008T1 (sl) | 2017-06-30 |
US20160002266A1 (en) | 2016-01-07 |
RS55807B1 (sr) | 2017-08-31 |
ES2620668T3 (es) | 2017-06-29 |
SG11201405056UA (en) | 2014-09-26 |
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