JP2016539995A - キナーゼ阻害剤としての置換ニコチンアミド誘導体 - Google Patents
キナーゼ阻害剤としての置換ニコチンアミド誘導体 Download PDFInfo
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- JP2016539995A JP2016539995A JP2016538520A JP2016538520A JP2016539995A JP 2016539995 A JP2016539995 A JP 2016539995A JP 2016538520 A JP2016538520 A JP 2016538520A JP 2016538520 A JP2016538520 A JP 2016538520A JP 2016539995 A JP2016539995 A JP 2016539995A
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- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- DUVOZUPPHBRJJO-UHFFFAOYSA-N ethyl 2-isocyanatoacetate Chemical compound CCOC(=O)CN=C=O DUVOZUPPHBRJJO-UHFFFAOYSA-N 0.000 description 1
- XBSGYVHOINMTIM-UHFFFAOYSA-N ethyl 3-isocyanatopropanoate Chemical compound CCOC(=O)CCN=C=O XBSGYVHOINMTIM-UHFFFAOYSA-N 0.000 description 1
- GVDRIEURYWMQNO-UHFFFAOYSA-N ethyl 4-isocyanatobutanoate Chemical compound CCOC(=O)CCCN=C=O GVDRIEURYWMQNO-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 229940051306 eylea Drugs 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229940076783 lucentis Drugs 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- CJSCVGMGFVSANX-UHFFFAOYSA-N methyl 6-amino-5-iodopyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(N)C(I)=C1 CJSCVGMGFVSANX-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- XLZQTGMPRVUBIT-UHFFFAOYSA-N n-(3-ethynylphenyl)-3-methylfuran-2-carboxamide Chemical compound C1=COC(C(=O)NC=2C=C(C=CC=2)C#C)=C1C XLZQTGMPRVUBIT-UHFFFAOYSA-N 0.000 description 1
- QNVWVVVDOSYKBN-UHFFFAOYSA-N n-(5-tert-butyl-1,2-oxazol-3-yl)-3-iodobenzamide Chemical compound O1C(C(C)(C)C)=CC(NC(=O)C=2C=C(I)C=CC=2)=N1 QNVWVVVDOSYKBN-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- DCWXELXMIBXGTH-QMMMGPOBSA-N phosphonotyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-QMMMGPOBSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- VUPQHSHTKBZVML-UHFFFAOYSA-J rhodium(3+);tetraacetate Chemical compound [Rh+3].[Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O VUPQHSHTKBZVML-UHFFFAOYSA-J 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- VLPTXXBXFKEJTN-UHFFFAOYSA-N tert-butyl 1-[6-amino-5-[2-[3-[(3-methylfuran-2-carbonyl)amino]phenyl]ethynyl]pyridine-3-carbonyl]imino-1-oxo-1,4-thiazinane-4-carboxylate Chemical compound NC1=C(C=C(C=N1)C(=O)N=S1(CCN(CC1)C(=O)OC(C)(C)C)=O)C#CC1=CC(=CC=C1)NC(=O)C=1OC=CC=1C VLPTXXBXFKEJTN-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本出願は、2013年12月12日に出願された米国仮特許出願第61/915,186号及び第61/915,209号のそれぞれの優先権及びその利益を主張するものであり、それらの開示はその全てが参照によって本願に組み込まれる。
本発明は、チロシンキナーゼシグナル伝達を調節、制御及び/または阻害することができる新規な化合物に関する。また、本発明は、受容体型または非受容体型にかかわらず、細胞増殖、代謝的及び血管増殖性疾患を含む無調節チロシンキナーゼシグナル伝達に関する疾患の予防及び/または治療のためにチロシンキナーゼを制御、調節または阻害する方法も対象とする。
タンパク質チロシンキナーゼ(PTK)は、酵素活性を有した多数かつ多様な種類の蛋白質を含む。PTKは、細胞増殖及び細胞分化の制御で重要な役割を担う。
上式において、
R1は、水素またはNH2であり、
R2は、水素またはNH2であり
X=
Yは、CHまたはNであり、
Ar1は、アリール、すなわち炭素環式アリールまたはヘテロアリール基あり、
R3は水素または低級アルキルであり、または、
であり、
R4は、水素、低級アルキル、(CH2)nCOOR6または(CH2)nCOR7であり、
R5は水素または低級アルキルであり、
R6は水素または低級アルキルであり、
R7はアミン、例えば、
からなる基から選択されてもよい置換アミンであり、nは0、または1〜6の整数であり、更に、そのプロドラッグ、薬剤的に許容される塩、ラセミ混合物及びエナンチオマーを含む。好ましくは、式IにおいてXは−NH−C(O)−である。
好ましくは、式IにおいてYはCHである。
好ましくは、式Iにおいて、R2はHである。
好ましくは、式Iにおいて、R3は、
からなる基から選択され、R4とR5は上記に定義した通りである。式Iで更に好ましくは、R3は−C(O)N(R4)(R5)からなる基から選択され、R4とR5は上記に定義した通りである。
tert−ブチル1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキシラート1−オキシド
1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
エチル3−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)プロパノアート
エチル4−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)ブタノアート
3−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)プロパン酸
4−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)ブタン酸
N−[3−(3−ヒドロキシピロリジン−1−イル)−3−オキソプロピル]−1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
N−[4−(3−ヒドロキシピロリジン−1−イル)−4−オキソブチル]−1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
N−{4−[(2,3−ジヒドロキシプロピル)アミノ]−4−オキソブチル]−1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
エチル({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)アセタート
({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)酢酸
tert−ブチル1−({[6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキシラート1−オキシド
6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル}−N−(1−オキシド−1λ4,4−チアジナン−1−イリデン)ニコチンアミド
1−({[6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
tert−ブチル1−({[6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキシラート1−オキシド
6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)−N−(1−オキシド−1λ4,4−チアジナン−1−イリデン)ニコチンアミド
1−({[6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
6−アミノ−5−[(3−{[2−フルオロ−5−メチルフェニル)アミノ]カルボニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
6−アミノ−5−{[3−[(4−クロロ−3−(トリフルオロメチル)フェニル]アミノ}カルボニル)フェニル]エチニル}−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
6−アミノ−5−[(3−{[(5‐tert−ブチルイソオキサゾール−3−イル)アミノ]カルボニル}フェニル)エチニル]−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
6−アミノ−5−[(3−{[(3−メトキシフェニル)アミノ]カルボニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド、からなる群から選択される。
「BOP」は、ベンゾトリアゾール−1−イルオキシトリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスフェイトを指す。
「BOC」は、ジ‐tert‐ブチルジカーボネートを指す。
「DCM」は、ジクロロメタンを指す。
「DIPEA」は、ジイソプロピルエチルアミンを指す。
「DMAP」は、ジメチルホルムアミドを指す。
「DMF」は、ジメチルホルムアミドを指す。
「EDCI」は、N−(3−ジメチルアミノプロピル)−N′−エチルカルボジイミドを指す。
「PDGF」は、血小板由来成長因子を指す。
「PDGFR」は、血小板由来成長因子受容体を指す。
「Ph」は、フェニルを指す。
「PTK」は、プロテインチロシンキナーゼを指す。
「RT」は、室温を意味する。
「RTK」は、受容体チロシンキナーゼを示す。
「THF」は、テトラヒドロフランを指す。
「VEGF」は、血管内皮増殖因子を指す。
「VEGFR」は、血管内皮細胞増殖因子受容体を指す。
式Iの化合物へのルートは、これらに限定されないが、以下に提示したスキームで説明する。
スキーム1
スキーム2
調製2
tert−ブチルチオモルホリン−4−カルボキシラート1−オキシド
調製3
tert−ブチル1−イミノ−1λ4,4−チアジナン−4−カルボキシラート1−オキシド
実施例1:
tert−ブチル1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキシラート1−オキシド
実施例2
5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)−N−(1−オキシド−1λ4,4−チアジナン−1−イリデン)ニコチンアミド
実施例3
1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
1H NMR (DMSO−d6) δ: 10.21 (s, 1H), 9.12 (d, J = 2.0 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.44 (t, J = 2.1 Hz, 1H), 8.13 (t, J = 1.6 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.78 − 7.81 (m, 1H), 7.39 − 7.43 (m, 1H), 7.34 (dt, J = 7.7, 1.1 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H), 6.35 (s, 2H), 4.05 − 4.12 (m, 2H), 3.77 − 3.83 (m, 2H), 3.56 − 3.64 (m, 2H), 3.46 − 3.53 (m, 2H), 2.35 (s, 3H)
実施例4
エチル3−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)プロパノアート
1H NMR (DMSO−d6) δ: 10.21 (s, 1H), 9.12 (d, J = 2.0 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.44 (t, J = 2.0 Hz, 1H), 8.13 (t, J = 1.7 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.78 − 7.81 (m, 1H), 7.39 − 7.43 (m, 1H), 7.34 (dt, J = 7.6, 1.1 Hz, 1H), 7.02 (t, J = 5.3 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H), 4.02 − 4.10 (m, 4H), 3.77 − 3.83 (m, 2H), 3.56 − 3.64 (m, 2H), 3.44 − 3.51 (m, 2H), 3.26 − 3.30 (m, 2H), 2.45 − 2.49 (m, 2H), 2.35 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H)
実施例5
エチル4−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)ブタノアート
1H NMR (DMSO−d6) δ: 10.21 (s, 1H), 9.12 (d, J = 2.1 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.44 (t, J = 2.0 Hz, 1H), 8.13 (t, J = 1.7 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.78 − 7.81 (m, 1H), 7.39 − 7.43 (m, 1H), 7.34 (dt, J = 7.7, 1.2 Hz, 1H), 6.90 (t, J = 5.4 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 4.01 − 4.12 (m, 4H), 3.76 − 3.83 (m, 2H), 3.62 (dd, J = 13.1, 9.4 Hz, 2H), 3.46 − 3.53 (m, 2H), 3.04 − 3.09 (m, 2H), 2.35 (s, 3H), 2.31 (t, J = 7.5 Hz, 2H), 1.68 (quin, J = 7.2 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H)
実施例6
3−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)プロパン酸
1H NMR (DMSO−d6) δ: 12.09 (br. s., 1H), 10.21 (s, 1H), 9.12 (d, J = 2.0 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.44 (t, J = 2.0 Hz, 1H), 8.13 (t, J = 1.6 Hz, 1H), 7.77 − 7.83 (m, 2H), 7.39 − 7.43 (m, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.00 (t, J = 5.0 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 4.04 − 4.11 (m, 2H), 3.76 − 3.83 (m, 2H), 3.56 − 3.64 (m, 2H), 3.44 − 3.52 (m, 2H), 3.23 − 3.29 (m, 2H), 2.40 (t, J = 7.0 Hz, 2H), 2.35 (s, 3H)
実施例7
4−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)ブタン酸
1H NMR (DMSO−d6) δ: 12.00 (br. s., 1H), 10.21 (s, 1H), 9.12 (d, J = 2.1 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.44 (t, J = 2.0 Hz, 1H), 8.13 (dt, J = 6.8, 1.6 Hz, 1H), 7.78 − 7.83 (m, 2H), 7.39 − 7.44 (m, 1H), 7.34 (dd, J = 7.6, 1.2 Hz, 1H), 6.90 (t, J = 5.3 Hz, 1H), 6.61 (d, J = 1.1 Hz, 1H), 4.05 − 4.13 (m, 2H), 3.77 − 3.84 (m, 2H), 3.57 − 3.65 (m, 2H), 3.45 − 3.52 (m, 2H), 3.03 − 3.09 (m, 2H), 2.35 (s, 3H), 2.23 (t, J = 7.3 Hz, 2H), 1.66 (quin, J = 7.2 Hz, 2H).
実施例8
N−[3−(3−ヒドロキシピロリジン−1−イル)−3−オキソプロピル]−1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
1H NMR (DMSO−d6) δ: 10.21 (s, 1H), 9.12 (d, J = 2.0 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.44 (t, J = 2.1 Hz, 1H), 8.13 (t, J = 1.6 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.78 − 7.81 (m, 1H), 7.39 − 7.43 (m, 1H), 7.34 (dt, J = 7.6, 1.1 Hz, 1H), 6.96 (t, J = 5.3 Hz, 1H), 6.61 (d, J = 1.3 Hz, 1H), 4.88 − 4.99 (m, 1H), 4.20 − 4.31 (m, 1H), 4.07 (dd, J = 16.0, 2.8 Hz, 2H), 3.77 − 3.83 (m, 2H), 3.60 (dd, J = 13.9, 9.0 Hz, 2H), 3.36 − 3.52 (m, 4H), 3.21 − 3.29 (m, 4H), 2.37 − 2.46 (m, 2H), 2.35 (s, 3H), 1.72 − 1.96 (m, 2H)
実施例9
N−[4−(3−ヒドロキシピロリジン−1−イル)−4−オキソブチル]−1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
1H NMR (DMSO−d6) δ: 10.21 (s, 1H), 9.12 (d, J = 2.0 Hz, 1H), 8.93 (d, J = 2.2 Hz, 1H), 8.44 (t, J = 2.1 Hz, 1H), 8.13 (t, J = 1.6 Hz, 1H), 7.78 − 7.83 (m, 2H), 7.39 − 7.43 (m, 1H), 7.34 (dt, J = 7.6, 1.1 Hz, 1H), 6.91 (t, J = 4.9 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H), 4.87 − 4.98 (m, 1H), 4.20 − 4.31 (m, 1H), 4.09 (d, J = 16.1 Hz, 2H), 3.77 − 3.82 (m, 2H), 3.62 (dd, J = 13.6, 9.4 Hz, 2H), 3.35 − 3.52 (m, 4H), 3.20 − 3.30 (m, 2H), 3.07 (q, J = 5.9 Hz, 2H), 2.35 (s, 3H), 2.18 − 2.28 (m, 2H), 1.63 − 1.93 (m, 4H).
実施例10
N−{4−[(2,3−ジヒドロキシプロピル)アミノ]−4−オキソブチル}−1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
1H NMR (DMSO−d6) δ: 10.21 (s, 1H), 9.12 (d, J = 2.0 Hz, 1H), 8.93 (d, J = 2.2 Hz, 1H), 8.44 (t, J = 2.1 Hz, 1H), 8.13 (t, J = 1.6 Hz, 1H), 7.76 − 7.83 (m, 3H), 7.39 − 7.43 (m, 1H), 7.34 (d, J = 7.8 Hz, 1H), 6.90 (t, J = 5.1 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H), 4.72 (d, J = 4.9 Hz, 1H), 4.50 (t, J = 5.9 Hz, 1H), 4.06 − 4.12 (m, 2H), 3.77 − 3.83 (m, 2H), 3.61 (dd, J = 13.4, 9.8 Hz, 2H), 3.44 − 3.52 (m, 3H), 3.26 (dtd, J = 10.5, 5.5, 5.3 Hz, 2H), 3.18 (ddd, J = 13.3, 5.6, 5.5 Hz, 1H), 3.01 − 3.07 (m, 2H), 2.93 − 2.99 (m, 1H), 2.35 (s, 3H), 2.11 (t, J = 7.5 Hz, 2H), 1.65 (dt, J = 14.5, 7.3 Hz, 2H)
実施例11
エチル({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)アセタート
1H NMR (DMSO−d6) δ: 10.21 (s, 1H), 9.12 (d, J = 2.0 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.45 (t, J = 2.0 Hz, 1H), 8.13 (s, 1H), 7.78 − 7.83 (m, 2H), 7.39 − 7.47 (m, 2H), 7.34 (d, J = 7.7 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 4.05 − 4.14 (m, 4H), 3.81 − 3.87 (m, 2H), 3.78 (d, J = 5.7 Hz, 2H), 3.65 (dd, J = 13.3, 9.7 Hz, 2H), 3.44 − 3.51 (m, 2H), 2.35 (s, 3H), 1.17 − 1.21 (m, 3H)
実施例12
({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)酢酸
1H NMR (DMSO−d6) δ: 10.21 (s, 1H), 9.12 (d, J = 2.1 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.45 (t, J = 2.0 Hz, 1H), 8.13 (t, J = 1.6 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.78 − 7.81 (m, 1H), 7.39 − 7.43 (m, 1H), 7.34 (dt, J = 7.6, 1.1 Hz, 1H), 6.99 (br. s., 1H), 6.61 (d, J = 1.5 Hz, 1H), 4.07 − 4.14 (m, 2H), 3.84 (dd, J = 11.6, 2.8 Hz, 2H), 3.62 (dd, J = 13.6, 9.9 Hz, 2H), 3.48 − 3.56 (m, 4H), 2.35 (s, 3H)
実施例13
tert−ブチル1−({[6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキシラート1−オキシド
1H NMR (DMSO−d6) δ: 10.13 (s, 1H), 8.60 (d, J = 1.5 Hz, 1H), 8.09 (s, 2H), 7.81 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.32 − 7.45 (m, 2H), 7.04 (br. s., 2H), 6.61 (s, 1H), 3.95 − 4.06 (m, 2H), 3.70 − 3.82 (m, 2H), 3.46 − 3.67 (m, 4H), 2.35 (s, 3H), 1.43 (s, 9H
実施例14
6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)−N−(1−オキシド−1λ4,4−チアジナン−1−イリデン)ニコチンアミド
1H NMR (DMSO−d6) δ: 10.13 (s, 1H), 8.59 (d, J = 2.3 Hz, 1H), 8.08 (t, J = 1.8 Hz, 2H), 7.81 (d, J = 1.6 Hz, 1H), 7.74 (ddd, J = 8.4, 1.5, 1.2 Hz, 1H), 7.40 − 7.44 (m, 1H), 7.34 − 7.39 (m, 1H), 7.01 (br. s., 2H), 6.61 (d, J = 1.6 Hz, 1H), 3.68 (dt, J = 13.6, 2.4 Hz, 2H), 3.19 − 3.30 (m, 4H), 2.96 − 3.04 (m, 2H), 2.42 − 2.47 (m, 1H), 2.35 (s, 3H)
実施例15
1−({[6−アミノ−5−({3−[3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
1H NMR (DMSO−d6) δ: 10.13 (s, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.08 − 8.11 (m, 2H), 7.81 (d, J = 1.2 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.40 − 7.44 (m, 1H), 7.34 − 7.39 (m, 1H), 7.03 (br. s., 2H), 6.61 (d, J = 1.5 Hz, 1H), 6.33 (s, 2H), 4.00 − 4.07 (m, 2H), 3.70 − 3.77 (m, 2H), 3.52 − 3.60 (m, 2H), 3.37 − 3.45 (m, 2H), 2.35 (s, 3H)
実施例16
tert−ブチル1−({[6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキシラート1−オキシド
1H NMR (DMSO−d6) δ: 10.46 (s, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 8.02 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.43 − 7.50 (m, 2H), 7.36 − 7.42 (m, 2H), 7.22 − 7.26 (m, 1H), 7.05 (br. s., 2H), 3.97 − 4.01 (m, 2H), 3.73 − 3.79 (m, 2H), 3.61 (br. s., 2H), 3.48 − 3.55 (m, 2H), 2.35 (s, 3H), 1.42 (s, 9H)
実施例17
6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)−N−(1−オキシド−1λ4,4−チアジナン−1−イリデン)ニコチンアミド
1H NMR (DMSO−d6) δ: 10.46 (s, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 8.02 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.48 (dd, J = 6.6, 1.6 Hz, 1H), 7.44 − 7.46 (m, 1H), 7.36 − 7.42 (m, 2H), 7.22 − 7.26 (m, 1H), 7.03 (br. s., 2H), 3.68 (ddd, J = 13.7, 2.5, 2.3 Hz, 2H), 3.21 − 3.31 (m, 4H), 3.01 (ddd, J = 13.6, 9.0, 1.8 Hz, 2H), 2.57 (br. s., 1H), 2.35 (s, 3H)
実施例18
1−({[6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
1H NMR (DMSO−d6) δ: 10.46 (s, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 8.02 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.48 (dd, J = 6.7, 1.8 Hz, 1H), 7.44 − 7.47 (m, 1H), 7.36 − 7.42 (m, 2H), 7.24 (dd, J = 9.9, 8.7 Hz, 1H), 7.04 (br. s., 2H), 6.32 (s, 2H), 4.00 − 4.06 (m, 2H), 3.71 − 3.76 (m, 2H), 3.57 (dd, J = 13.1, 9.2 Hz, 2H), 3.38 − 3.44 (m, 2H), 2.35 (s, 3H)
実施例19
5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
1H NMR (DMSO−d6) δ: 10.21 (s, 1H), 9.13 (d, J = 2.1 Hz, 1H), 8.94 (d, J = 2.1 Hz, 1H), 8.44 (t, J = 2.1 Hz, 1H), 8.13 (t, J = 1.8 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.78 − 7.81 (m, 1H), 7.40 − 7.43 (m, 1H), 7.34 (dt, J = 7.6, 1.2 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H), 4.16 − 4.20 (m, 2H), 3.96 − 4.00 (m, 2H), 3.91 (dt, J = 14.2, 2.6 Hz, 2H), 3.65 − 3.70 (m, 2H), 2.35 (s, 3H)
調製4
6−アミノ−5−ヨードニコチン酸
1H NMR (DMSO−d6) δ: 12.64 (br. s., 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.25 (d, J = 1.8 Hz, 1H), 6.88 (br. s., 2H)
調製5
6−アミノ−5−ヨード−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
1H NMR (DMSO−d6) δ: 8.57 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 6.78 (br. s., 2H), 4.10 − 4.15 (m, 2H), 3.91 (ddd, J = 12.6, 8.5, 2.1 Hz, 2H), 3.79 − 3.84 (m, 2H), 3.55 − 3.60 (m, 2H)
実施例20
6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
1H NMR (DMSO−d6) δ: 10.13 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.08 − 8.10 (m, 2H), 7.81 (d, J = 1.8 Hz, 1H), 7.72 − 7.75 (m, 1H), 7.41 − 7.43 (m, 1H), 7.35 − 7.39 (m, 1H), 7.04 (br. s., 2H), 6.60 (d, J = 1.5 Hz, 1H), 4.12 − 4.17 (m, 2H), 3.93 (ddd, J = 12.5, 8.7, 2.1 Hz, 2H), 3.82 − 3.86 (m, 2H), 3.56 − 3.61 (m, 2H), 2.35 (s, 3H)
実施例21
6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
1H NMR (DMSO−d6) δ: 10.46 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.44 − 7.49 (m, 2H), 7.36 − 7.42 (m, 2H), 7.24 (dd, J = 9.8, 8.7 Hz, 1H), 7.06 (br. s., 2H), 4.12 − 4.16 (m, 2H), 3.93 (ddd, J = 12.5, 8.7, 1.9 Hz, 2H), 3.81 − 3.86 (m, 2H), 3.56 − 3.61 (m, 2H), 2.35 (s, 3H)
実施例22
6−アミノ−5−({3−{[(2−フルオロ−5−メチルフェニル)アミノ]カルボニル}フェニル)エチニル]−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
1H NMR (DMSO−d6) δ: 10.15 (s, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.27 (s, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.41 (dd, J = 7.3, 1.5 Hz, 1H), 7.18 (dd, J = 10.1, 8.7 Hz, 1H), 7.14 (br. s., 2H), 7.06 − 7.09 (m, 1H), 4.12 − 4.17 (m, 2H), 3.91 − 3.96 (m, 2H), 3.83 (ddd, J = 14.2, 2.6, 2.3 Hz, 2H), 3.57 − 3.62 (m, 2H), 2.31 (s, 3H)
調製6
N−[4−クロロ−3−(トリフルオロメチル)フェニル]−3−ヨードベンズアミド
1H NMR (DMSO−d6) δ: 10.68 (s, 1H), 8.31 − 8.34 (m, 2H), 8.10 (dd, J = 8.8, 2.3 Hz, 1H), 7.96 − 8.00 (m, 2H), 7.73 (d, J = 8.8 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H)
調製7
6−アミノ−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)−5−[(トリメチルシリル)エチニル]ニコチンアミド
実施例23
6−アミノ−5−({3−[(4−クロロ−3−(トリフルオロメチル)フェニル]アミノ}カルボニル)フェニル]エチニル}−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
1H NMR (DMSO−d6) δ: 10.73 (s, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.37 (d, J = 2.6 Hz, 1H), 8.29 (t, J = 1.5 Hz, 1H), 8.11 − 8.15 (m, 2H), 7.95 (dd, J = 16.9, 7.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.15 (br. s., 2H), 4.12 − 4.17 (m, 2H), 3.91 − 3.96 (m, 2H), 3.83 (dt, J = 14.3, 2.7 Hz, 2H), 3.57 − 3.62 (m, 2H)
実施例24
6−アミノ−5−[(3−{[(5‐tert−ブチルイソオキサゾール−3−イル)アミノ]カルボニル}フェニル)エチニル]−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
1H NMR (DMSO−d6) δ: 11.41 (s, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.31 (t, J = 1.6 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.99 (dt, J = 7.9, 1.4 Hz, 1H), 7.91 (dt, J = 7.6, 1.2 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.13 (br. s., 2H), 6.73 (s, 1H), 4.12 − 4.17 (m, 2H), 3.94 (ddd, J = 12.5, 8.7, 2.1 Hz, 2H), 3.81 − 3.85 (m, 2H), 3.57 − 3.62 (m, 2H), 1.33 (s, 9H)
実施例25
6−アミノ−5−[(3−{[(3−メトキシフェニル)アミノ]カルボニル}フェニル)エチニル]−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
1H NMR (DMSO−d6) δ: 10.30 (s, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.26 (t, J = 1.5 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.94 (ddd, J = 7.8, 1.3, 1.2 Hz, 1H), 7.90 (dt, J = 7.6, 1.2 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.47 (t, J = 2.2 Hz, 1H), 7.39 (dd, J = 8.1, 1.0 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.14 (br. s., 2H), 6.70 (dd, J = 8.2, 2.1 Hz, 1H), 4.12 − 4.17 (m, 2H), 3.93 (ddd, J = 12.5, 8.5, 1.9 Hz, 2H), 3.83 (dt, J = 14.3, 2.7 Hz, 2H), 3.76 (s, 3H), 3.57 − 3.62 (m, 2H).
生化学的KDRキナーゼアッセイは、10mMのリン酸緩衝食塩水(PBS)(pH7.4)中で1ウエル当たり75μgのpoly−Glu−Tyr(4:1)で一晩被覆した96ウェルマイクロタイタープレート内で行った。被覆プレートは、1ウエル当たり2mLのPBS+0.05% Tween−20(PBS−T)で洗浄し、1%BSAを含むPBSと共に定温放置させてブロックした。次いで、反応開始前に1ウエル当たり2mLのPBS−Tで洗浄した。反応は、キナーゼ緩衝剤(50mMのHepes緩衝剤pH7.4、20mMのMgCl2、0.1mMのMnCl2及び0.2mMのNa3VO4)中で2.7μMのATPを含む100μLの反応体積で行った。試験化合物を、100%DMSO中で再構成し、DMSO最終濃度5%が得られるまで添加した。反応は、200−300ngの精製細胞質内ドメインKDR蛋白質を含むキナーゼ緩衝剤(BPS Bioscience, San Diego, CA)を1ウエル当たり20ul添加して開始した。30℃で15分間インキュベーションした後、反応物をウエル当たり2mLのPBS−Tで洗浄した。PBS−T中で1:10,000に希釈したモノクローナル抗リン酸化チロシン抗体−ペルオキシダーゼ複合体の100μlを30分間ウエルに添加した。1ウエル当たり2mLのPBS−TWEEN−20で洗浄した後、過酸化尿素を含むクエン酸リン酸緩衝液中のo−フェニレンジアミン二塩化水素化物100μl、ペルオキシダーゼの比色基質として7−10分間ウエルに添加した。各々のウエルに100μlの2.5N H2SO4を添加して反応を停止し、492nmにセットしたマイクロプレートELISAリーダーを読み取った。化合物阻害のIC50値は、光学密度(任意単位)対ブランク値を引いた後の化合物濃度の図表から直接計算した。
自動FLIPR(蛍光測定画像解析用プレートリーダー)技術を使用して、蛍光染料で負荷した内皮細胞の細胞内カルシウムレベルの増加を誘発するVEGFの阻害因子をスクリーニングした。HUVEC(ヒト臍帯静脈内皮細胞)を、37℃、5%CO2で一晩、384ウエルフィブロネクチンコートプレート(黒)に播種した。細胞をカルシウム指示薬Fluo−4で37℃、45分間負荷した。細胞を2回(Elx405,Biotek装置)洗浄し、細胞外の染料を除去した。スクリーニングのため、細胞を試験薬と共に、単一濃度(10uM)または0.0001〜10.0uMの濃度で30分間プレインキュベーションし、続いてVEGF165刺激(10ng/mL)を行った。516nmでの蛍光変化を、冷却CCDカメラを使用して全384ウエルで同時に測定した。非刺激試料、刺激試料及び薬物処理試料について最大−最小蛍光レベルを測定することでデータを作成した。試験化合物のIC50値は、阻害剤がない場合はVEGF刺激応答の阻害%から計算した。
生化学的PDGFRβキナーゼアッセイは、10mMのリン酸緩衝食塩水(PBS)(pH 7.4)中で75μgのpoly−Glu−Tyr(4:1)で一晩被覆した96ウェルマイクロタイタープレート内で行った。被覆プレートは、1ウエル当たり2mLのPBS + 0.05% Tween−20(PBS−T)で洗浄し、1%BSAを含むPBSとのインキュベーションによってブロックした後、反応開始前に1ウエル当たり2mLのPBS−Tで洗浄した。反応は、キナーゼ緩衝剤(50mMのHepes緩衝剤pH7.4、20mMのMgCl2、0.1mMのMnCl2及び0.2mMのNa3VO4)中で36μMのATPを含む100μLの反応体積で行った。試験化合物を、100%DMSO中で再構成し、DMSO最終濃度5%が得られるまで添加した。反応は、200−300ngの精製細胞質内ドメインPDGFR−b蛋白質を含むキナーゼ緩衝剤(ミリポア)を1ウエル当たり20ul添加して開始した。30℃で60分間インキュベーションした後、反応物をウエル当たり2mLのPBS−Tで洗浄した。PBS−T中で1:10,000に希釈したモノクローナル抗リン酸化チロシン抗体−ペルオキシダーゼ複合体の100μlを30分間ウエルに添加した。1ウエル当たり2mLのPBS−Tween−20で洗浄した後、過酸化尿素を含むクエン酸リン酸緩衝液中のo−フェニレンジアミン二塩化水素化物100μlを、ペルオキシダーゼの比色基質として7−10分間ウエルに添加した。各々のウエルに100μlの2.5N H2SO4を添加して反応を停止し、492nmにセットしたマイクロプレートELISAリーダーを読み取った。化合物阻害のIC50値は、光学密度(任意単位)対ブランク値を引いた後の化合物濃度の図表から直接計算した。
自動FLIPR(蛍光測定画像解析用プレートリーダー)技術を使用して、蛍光染料で負荷した内皮細胞における細胞内カルシウムレベルのPDGF誘発性増加の阻害についてスクリーニングした。NHDF−Ad(正常ヒト皮膚線維芽細胞、成人:Lonza)を、37℃、5%CO2で一晩、384ウエルフィブロネクチンコートプレート(黒)に播種した。細胞をカルシウム指示薬Fluo−4で37℃、45分間負荷した。細胞を2回(Elx405、Biotek装置)洗浄し、細胞外の染料を除去した。スクリーニングのため、細胞を試験薬と共に、単一濃度(10uM)または0.0001〜10.0uMの濃度で30分間プレインキュベーションし、続いてPDGF−BB刺激(30ng/mL)を行った。516nmでの蛍光変化を、冷却CCDカメラを使用して全384ウエルで同時に測定した。非刺激試料、刺激試料及び薬物処理試料について最大−最小蛍光レベルを測定することでデータを作成した。試験化合物のIC50値は、阻害剤がない場合はPDGF−BB刺激応答の阻害%から計算した。
Claims (27)
- 式Iもしくは式IIの化合物
I
II
またはその薬剤的に許容される塩であって、上式において、
R1は、水素またはNH2であり、
R2は、水素またはNH2であり、
Xは、
であり
Yは、CHまたはNであり、
式Iでは、Ar1は、炭素環式アリール基またはヘテロアリール基であり、前記炭素環式アリール基またはヘテロアリール基は任意選択でハロゲン、トリフルオロメチルまたは低級アルキルで置換されてもよく、
式IIでは、Ar1は、アリール基、すなわち炭素環式アリール基またはヘテロアリール基であり、更に、そのプロドラッグ、薬剤的に許容される塩、ラセミ混合物及びエナンチオマーを含み、
R3は、水素、低級アルキル
であり、
R4は、水素、低級アルキル、(CH2)nCOOR6または(CH2)nCOR7であり、
R5は、水素または低級アルキルであり、
R6は、水素または低級アルキルであり、
R7は、置換アミンであり、
nは0、または1〜6の整数である、前記化合物または塩。 - Xは、−NH−C(O)−である、請求項1記載の化合物。
- Yは、CHである、請求項1記載の化合物。
- 化合物は、式Iであり、Ar1は、フェニル、フラニル及びそれらの置換誘導体からなる基から選択される、請求項1記載の化合物。
- 前記置換誘導体は、低級アルキル及び/またはハロ置換されたフェニル及びフラニルである、請求項4記載の化合物。
- Ar1は、3−メチル−2−フラニル及び2−フルオロ−5−メチルフェニルからなる基から選択される、請求項5記載の化合物。
- R2は、Hである、請求項1記載の化合物。
- R3は、−C(O)N(R4)(R5)である、請求項8記載の化合物。
- 化合物は、式IIであり、前記炭素環式アリールまたはヘテロアリール基は、1つ以上のアルコキシ、ハロゲン、トリハロアルキルまたは低級アルキル基で置換される、請求項1記載の化合物。
- 化合物は、式IIであり、これにおいてAr1はフェニル、オキサゾイル、フラニル及びアルキル、アルキルオキシならびにハロ置換フェニル、オキサゾイル及びフラニルからなる基から選択される、請求項1記載の化合物。
- Ar1は、
3−メチルフラニル
2−フルオロ5−メチルフェニル
4−クロロ5−t−ブチルフェニル
3−メトキシフェニル
5−ブチルオキサゾイル、からなる群から選択される、請求項12記載の化合物。 - 前記化合物は、
tert−ブチル1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキシラート1−オキシド
5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)−N−(1−オキシド−1λ4,4−チアジナン−1−イリデン)ニコチンアミド
1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
エチル3−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)プロパノアート
エチル4−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)ブタノアート
3−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)プロパン酸
4−({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)ブタン酸
N−[3−(3−ヒドロキシピロリジン−1−イル)−3−オキソプロピル]−1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
N−[4−(3−ヒドロキシピロリジン−1−イル)−4−オキソブチル]−1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
N−{4−[(2,3−ジヒドロキシプロピル)アミノ]−4−オキソブチル]−1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
エチル({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)アセタート
({[1−({[5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1−オキシド−1λ4,4−チアジナン−4−イル]カルボニル}アミノ)酢酸
tert−ブチル1−({[6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキシラート1−オキシド
6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル}−N−(1−オキシド−1λ4,4−チアジナン−1−イリデン)ニコチンアミド
1−({[6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
tert−ブチル1−({[6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキシラート1−オキシド
6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)−N−(1−オキシド−1λ4,4−チアジナン−1−イリデン)ニコチンアミド
1−({[6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)ピリジン−3−イル]カルボニル}イミノ)−1λ4,4−チアジナン−4−カルボキサミド1−オキシド
5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
6−アミノ−5−({3−[(2−フルオロ−5−メチルベンゾイル)アミノ]フェニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−1−イリデン)ニコチンアミド
6−アミノ−5−[{3−[(2−フルオロ−5−メチルフェニル)アミノ]カルボニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
6−アミノ−5−{[3−[{(4−クロロ−3−(トリフルオロメチル)フェニル]アミノ}カルボニル)フェニル]エチニル}−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
6−アミノ−5−[(3−{[(5‐tert−ブチルイソオキサゾール−3−イル)アミノ]カルボニル}フェニル)エチニル]−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
6−アミノ−5−[(3−{[(3−メトキシフェニル)アミノ]カルボニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド
または、それらの薬剤的に許容される塩からなる群から選択される、請求項1記載の化合物。 - 無調節チロシンキナーゼシグナル伝達に関連する疾患の治療方法であって、治療上有効量の請求項1の式Iまたは式IIの化合物を必要とする対象に投与する工程を含む、前記方法。
- 前記疾患は、癌、血管増殖性疾患、線維症及び糸球体間質細胞増殖性疾患及び代謝疾患からなる群から選択される、請求項15記載の方法。
- 前記血管増殖性疾患は、糖尿病網膜症、浸出性加齢黄斑変性症、未熟児網膜症、翼状片、酒さ、関節炎及び再狭窄からなる群から選択される、請求項16記載の方法。
- 前記線維症は、肝硬変及びアテローム性動脈硬化からなる群から選択される、請求項16記載の方法。
- 前記糸球体間質細胞増殖性疾患は、糸球体腎炎、糖尿病ネフロパシー、悪性腎硬化、血栓性微小血管障害症候群、移植拒絶反応及び糸球体症からなる群から選択される、請求項16記載の方法。
- 前記代謝疾患は、乾癬、真正糖尿病、創傷治癒及び神経変性疾患からなる群から選択される、請求項16記載の方法。
- 前記疾患は、眼の疾患である、請求項16記載の方法。
- 前記眼疾患は、翼状片、能動的に炎症を起こした翼状片に関する充血、切除術後の再発性翼状片、切除後の再発性翼状片を回避する予防的治療、視軸に近づく進行性の翼状片、翼状片と関連する慢性の軽度充血、角膜血管新生、血管新生緑内障、虹彩血管新生、慢性アレルギー結膜炎、眼性酒さ、眼瞼結膜炎、再発性上強膜炎、乾性角結膜炎、眼性移植片対宿主病、糖尿病性網膜症、糖尿病黄斑水腫、増殖性糖尿病網膜症、浸出性または新生血管加齢黄斑変性、非浸出性加齢黄斑変性を伴う高リスク眼、網膜静脈閉塞症と関連する血管新生症、次の病的近視、弾性線維偽黄色腫、視神経結晶腔、外傷性脈絡膜破裂、特発性病因、推定眼ヒストプラスマ症症候群及び未熟児網膜症と関連する血管新生症からなる群から選択される、請求項21記載の方法。
- 前記疾患は、日焼け、湿疹、乾癬、接触皮膚炎からなる群から選択される皮膚科兆候である、請求項16記載の方法。
- 5−({3−[{3−メチル−2−フロイル)アミノ]フェニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド、またはその薬剤的に許容される塩である請求項1記載の化合物。
- 6−アミノ−5−({3−[(3−メチル−2−フロイル)アミノ]フェニル}エチニル)−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド、またはその薬剤的に許容される塩である請求項1記載の化合物。
- 6−アミノ−5−[(3−{[(2−フルオロ−5−メチルフェニル)アミノ]カルボニル}フェニル)エチニル]−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド、またはその薬剤的に許容される塩である請求項1記載の化合物。
- 6−アミノ−5−[(3−{[(5−tert−ブチルイソオキサゾール−3−イル)アミノ]カルボニル}フェニル)エチニル]−N−(4−オキシド−1,4λ4−オキサチアン−4−イリデン)ニコチンアミド、またはその薬剤的に許容される塩である請求項1記載の化合物。
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PCT/US2014/069601 WO2015089220A1 (en) | 2013-12-12 | 2014-12-10 | Substituted nicotinamide derivatives as kinase inhibitors |
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US20110300416A1 (en) | 2010-06-03 | 2011-12-08 | Bertness Kevin I | Battery pack maintenance for electric vehicle |
US10046649B2 (en) | 2012-06-28 | 2018-08-14 | Midtronics, Inc. | Hybrid and electric vehicle battery pack maintenance device |
US11740294B2 (en) | 2010-06-03 | 2023-08-29 | Midtronics, Inc. | High use battery pack maintenance |
US10429449B2 (en) | 2011-11-10 | 2019-10-01 | Midtronics, Inc. | Battery pack tester |
US11325479B2 (en) | 2012-06-28 | 2022-05-10 | Midtronics, Inc. | Hybrid and electric vehicle battery maintenance device |
US10843574B2 (en) | 2013-12-12 | 2020-11-24 | Midtronics, Inc. | Calibration and programming of in-vehicle battery sensors |
US10473555B2 (en) | 2014-07-14 | 2019-11-12 | Midtronics, Inc. | Automotive maintenance system |
WO2016123075A1 (en) | 2015-01-26 | 2016-08-04 | Midtronics, Inc. | Alternator tester |
US10608353B2 (en) | 2016-06-28 | 2020-03-31 | Midtronics, Inc. | Battery clamp |
US11054480B2 (en) | 2016-10-25 | 2021-07-06 | Midtronics, Inc. | Electrical load for electronic battery tester and electronic battery tester including such electrical load |
CN108456163A (zh) | 2017-02-20 | 2018-08-28 | 中国科学院上海药物研究所 | 含邻氨基杂芳环炔基的化合物及其制备方法和用途 |
US11513160B2 (en) | 2018-11-29 | 2022-11-29 | Midtronics, Inc. | Vehicle battery maintenance device |
CN111662227B (zh) * | 2019-03-06 | 2022-07-05 | 中国科学院上海药物研究所 | 邻氨基吡啶炔类化合物及其制备方法和用途 |
US11566972B2 (en) | 2019-07-31 | 2023-01-31 | Midtronics, Inc. | Tire tread gauge using visual indicator |
US11545839B2 (en) | 2019-11-05 | 2023-01-03 | Midtronics, Inc. | System for charging a series of connected batteries |
US11668779B2 (en) | 2019-11-11 | 2023-06-06 | Midtronics, Inc. | Hybrid and electric vehicle battery pack maintenance device |
US11474153B2 (en) | 2019-11-12 | 2022-10-18 | Midtronics, Inc. | Battery pack maintenance system |
US11973202B2 (en) | 2019-12-31 | 2024-04-30 | Midtronics, Inc. | Intelligent module interface for battery maintenance device |
US11486930B2 (en) | 2020-01-23 | 2022-11-01 | Midtronics, Inc. | Electronic battery tester with battery clamp storage holsters |
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