JP2021512913A - アルコキシベンゾ五員(六員)複素環式アミン化合物およびその医薬用途 - Google Patents
アルコキシベンゾ五員(六員)複素環式アミン化合物およびその医薬用途 Download PDFInfo
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- JP2021512913A JP2021512913A JP2020542775A JP2020542775A JP2021512913A JP 2021512913 A JP2021512913 A JP 2021512913A JP 2020542775 A JP2020542775 A JP 2020542775A JP 2020542775 A JP2020542775 A JP 2020542775A JP 2021512913 A JP2021512913 A JP 2021512913A
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- alkoxybenzo
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- heterocyclic amine
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- -1 heterocyclic amine compounds Chemical class 0.000 title claims abstract description 59
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 208000008589 Obesity Diseases 0.000 claims abstract description 12
- 235000020824 obesity Nutrition 0.000 claims abstract description 12
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 12
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 8
- 208000010706 fatty liver disease Diseases 0.000 claims abstract description 8
- 231100000240 steatosis hepatitis Toxicity 0.000 claims abstract description 8
- 208000004232 Enteritis Diseases 0.000 claims abstract description 7
- 208000004930 Fatty Liver Diseases 0.000 claims abstract description 7
- 206010019708 Hepatic steatosis Diseases 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 7
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 6
- 230000002265 prevention Effects 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 102000005993 Sphingomyelin synthase Human genes 0.000 claims description 16
- 108020003486 sphingomyelin synthase Proteins 0.000 claims description 16
- 239000003112 inhibitor Substances 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 230000002159 abnormal effect Effects 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 150000003384 small molecules Chemical class 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
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- 239000003937 drug carrier Substances 0.000 claims description 2
- 229960005222 phenazone Drugs 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
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- 150000002632 lipids Chemical class 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
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- 239000005457 ice water Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- IOJPSGHZOLVXLF-UHFFFAOYSA-N 3-(pyridin-3-ylamino)-1,2-benzoxazol-4-ol Chemical compound Oc1cccc2onc(Nc3cccnc3)c12 IOJPSGHZOLVXLF-UHFFFAOYSA-N 0.000 description 5
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- 238000000926 separation method Methods 0.000 description 5
- HGXVRIBRQSFMKB-UHFFFAOYSA-N 4-phenylmethoxy-N-pyridin-3-yl-1,2-benzoxazol-3-amine Chemical compound C(Oc1cccc2onc(Nc3cccnc3)c12)c1ccccc1 HGXVRIBRQSFMKB-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- HZIRBXILQRLFIK-VPZZKNKNSA-N N-{6-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]hexanoyl}sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@H](CO)NC(=O)CCCCCNC1=CC=C([N+]([O-])=O)C2=NON=C12 HZIRBXILQRLFIK-VPZZKNKNSA-N 0.000 description 4
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- 230000002194 synthesizing effect Effects 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
Description
Xは、O、N、S、Cから選択される任意の1つまたは2つであり;
Yは、O、N、S、Cから選択される任意の1つまたは2つであり;
その中、XとYの組み合わせによって以下の構造が得られ:
R1はベンゼン環、複素環またはアシル基から選択され、
ここで、複素環の構造は、以下の構造に限定されない:
R2は、水素、メチル、エチルおよびプロピルから選択される任意の一つ、
R3は、アルコキシ、フェニルシクロメチレンおよび複素環式メチレンから選択され、ここで、ベンジルオキシ、ピリジンメチレン、C1−C8のアルカンまたはC1−C8のアルカンアンモニアを含み。
R3構造は、次の構造に限定されない。
mは0−5である。
1)2−ベンジルオキシ−6−フルオロベンゾニトリル(化合物1)の合成
2)3−アミノ−4−ベンジルオキシベンゾ[d]イソキサゾール(化合物6)の合成
3)3−(ピリジン−3−イルアミノ)−4−ベンジルオキシベンゾ[d]イソキサゾール(化合物8)の合成
4)3−(ピリジン−3−イルアミノ)−4−ヒドロキシベンゾ[d]イソキサゾール(化合物9)の合成
5)2−エチルベンジルブロミド(化合物11)の合成
実施例2:化合物式I−2、I−4〜I−27の合成
式I−2 MS(ESI) (m/z): 370.1(M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.72 (d、 J = 2.7 Hz、 1H)、 8.32 (s、 1H)、 8.18 (dd、 J = 4.7、 1.5 Hz、 1H)、 8.05 (d、 J = 8.4 Hz、 1H)、 7.64 - 7.51 (m、 3H)、 7.38 (dd、 J = 8.4、 4.7 Hz、 1H)、 7.29 (dt、 J = 8.7、 4.3 Hz、 1H)、 7.20 (d、 J = 8.4 Hz、 1H)、 6.90 (d、 J = 8.0 Hz、 1H)、 5.46 (s、 2H).
式I−4 MS(ESI) (m/z): 336.1(M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.67 (d、 J = 2.7 Hz、 1H)、 8.20 (s、 1H)、 8.15 (d、 J = 4.6 Hz、 1H)、 8.00 (d、 J = 8.5 Hz、 1H)、 7.60 (t、 J = 7.6 Hz、 1H)、 7.48 (t、 J = 8.2 Hz、 1H)、 7.35 (td、 J = 9.2、 8.7、 5.6 Hz、 2H)、 7.21 (dt、 J = 15.3、 8.6 Hz、 2H)、 7.12 (d、 J = 8.6 Hz、 1H)、 6.89 (d、 J = 8.1 Hz、 1H)、 5.44 (s、 2H).
式I−5 MS(ESI) (m/z): 336.1(M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.75 (d、 J = 2.7 Hz、 1H)、 8.34 (s、 1H)、 8.16 (dd、 J = 4.7、 1.5 Hz、 1H)、 8.06 (ddd、 J = 8.4、 3.0、 1.5 Hz、 1H)、 7.48 (d、 J = 8.2 Hz、 1H)、 7.46 - 7.39 (m、 2H)、 7.36 (dd、 J = 8.7、 3.9 Hz、 2H)、 7.12 (d、 J = 8.4 Hz、 2H)、 6.82 (d、 J = 8.0 Hz、 1H)、 5.41 (s、 2H).
式I−6 MS(ESI) (m/z): 336.1(M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.71 (s、 1H)、 8.25 (s、 1H)、 8.14 (d、 J = 4.6 Hz、 1H)、 8.02 (d、 J = 8.4 Hz、 1H)、 7.65 - 7.51 (m、 2H)、 7.43 (t、 J = 8.2 Hz、 1H)、 7.33 (dd、 J = 8.3、 4.7 Hz、 1H)、 7.18 (t、 J = 8.7 Hz、 2H)、 7.08 (d、 J = 8.4 Hz、 1H)、 6.81 (d、 J = 8.1 Hz、 1H)、 5.35 (s、 2H).
式I−7 MS(ESI) (m/z): 336.1(M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.67 (s、 1H)、 8.23 (s、 1H)、 8.15 (s、 1H)、 8.01 (d、 J = 8.4 Hz、 1H)、 7.60 (s、 1H)、 7.49 (q、 J = 8.9、 7.5 Hz、 2H)、 7.34 (s、 3H)、 7.14 (d、 J = 8.4 Hz、 1H)、 6.85 (d、 J = 7.9 Hz、 1H)、 5.46 (s、 2H).
式I−8 MS(ESI) (m/z):352.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.77 (d、 J = 2.6 Hz、 1H)、 8.33 (s、 1H)、 8.21 - 8.14 (m、 1H)、 8.11 - 8.03 (m、 1H)、 7.67 (s、 1H)、 7.48 (dd、 J = 9.4、 7.2 Hz、 2H)、 7.37 (td、 J = 10.2、 8.7、 5.8 Hz、 3H)、 7.13 (d、 J = 8.4 Hz、 1H)、 6.83 (d、 J = 8.0 Hz、 1H)、 5.41 (s、 2H).
式I−9 MS(ESI) (m/z): 352.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.77 (d、 J = 2.7 Hz、 1H)、 8.30 (s、 1H)、 8.19 (d、 J = 4.6 Hz、 1H)、 8.11 - 8.02 (m、 1H)、 7.58 (d、 J = 8.1 Hz、 2H)、 7.45 (dd、 J = 8.1、 6.2 Hz、 3H)、 7.37 (dd、 J = 8.4、 4.7 Hz、 1H)、 7.12 (d、 J = 8.4 Hz、 1H)、 6.83 (d、 J = 8.0 Hz、 1H)、 5.41 (s、 2H).
式I−10 MS(ESI) (m/z): 332.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.54 (s、 1H)、 8.17 - 7.98 (m、 2H)、 7.89 (d、 J = 8.4 Hz、 1H)、 7.34 (d、 J = 8.0 Hz、 2H)、 7.29 - 7.17 (m、 1H)、 7.09 (s、 3H)、 6.99 (d、 J = 8.4 Hz、 1H)、 6.75 (d、 J = 8.0 Hz、 1H)、 5.28 (s、 2H)、 2.24 (s、 3H).
式I−11 MS(ESI) (m/z): 332.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.71 (d、 J = 2.7 Hz、 1H)、 8.28 (s、 1H)、 8.16 (d、 J = 4.6 Hz、 1H)、 8.03 (d、 J = 8.4 Hz、 1H)、 7.46 (t、 J = 8.2 Hz、 1H)、 7.35 (q、 J = 5.3 Hz、 2H)、 7.30 (d、 J = 7.7 Hz、 1H)、 7.25 (t、 J = 7.5 Hz、 1H)、 7.10 (d、 J = 8.1 Hz、 2H)、 6.82 (d、 J = 8.0 Hz、 1H)、 5.35 (s、 2H)、 2.26 (s、 3H).
式I−12 MS(ESI) (m/z): 332.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6)δ 8.73 (s、 1H)、 8.27 (s、 1H)、 8.17 (s、 1H)、 8.05 (d、 J = 8.3 Hz、 1H)、 7.44 (t、 J = 8.2 Hz、 3H)、 7.37 (d、 J = 7.5 Hz、 1H)、 7.17 (d、 J = 7.6 Hz、 2H)、 7.10 (d、 J = 8.4 Hz、 1H)、 6.83 (d、 J = 7.9 Hz、 1H)、 5.36 (s、 2H)、 2.25 (s、 3H).
式I−13 MS(ESI) (m/z): 386.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.66 (d、 J = 2.8 Hz、 1H)、 8.19 (s、 1H)、 8.15 (d、 J = 4.6 Hz、 1H)、 8.08 - 7.95 (m、 1H)、 7.79 (d、 J = 7.9 Hz、 2H)、 7.69 (t、 J = 7.7 Hz、 1H)、 7.52 (dt、 J = 29.6、 7.9 Hz、 2H)、 7.34 (dd、 J = 8.5、 4.7 Hz、 1H)、 7.15 (d、 J = 8.4 Hz、 1H)、 6.76 (d、 J = 8.0 Hz、 1H)、 5.55 (s、 2H).
式I−14 MS(ESI) (m/z): 386.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.73 (d、 J = 2.7 Hz、 1H)、 8.37 (s、 1H)、 8.19 - 8.12 (m、 1H)、 8.08 - 8.01 (m、 1H)、 7.97 (s、 1H)、 7.82 (d、 J = 7.6 Hz、 1H)、 7.66 (d、 J = 7.9 Hz、 1H)、 7.60 (t、 J = 7.7 Hz、 1H)、 7.48 (t、 J = 8.3 Hz、 1H)、 7.34 (dd、 J = 8.4、 4.7 Hz、 1H)、 7.12 (d、 J = 8.5 Hz、 1H)、 6.85 (d、 J = 8.1 Hz、 1H)、 5.48 (s、 2H).
式I−15 MS(ESI) (m/z): 386.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.79 (d、 J = 2.7 Hz、 1H)、 8.40 (s、 1H)、 8.17 (d、 J = 4.7 Hz、 1H)、 8.08 (d、 J = 8.5 Hz、 1H)、 7.74 (s、 4H)、 7.46 (t、 J = 8.2 Hz、 1H)、 7.36 (dd、 J = 8.4、 4.8 Hz、 1H)、 7.12 (d、 J = 8.5 Hz、 1H)、 6.79 (d、 J = 8.1 Hz、 1H)、 5.52 (s、 2H).
式I−16 MS(ESI) (m/z): 348.0 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.66 (d、 J = 2.7 Hz、 1H)、 8.18 (d、 J = 7.1 Hz、 2H)、 8.01 (d、 J = 8.0 Hz、 1H)、 7.53 - 7.43 (m、 2H)、 7.39 - 7.30 (m、 2H)、 7.10 (dd、 J = 19.3、 8.3 Hz、 2H)、 6.94 (t、 J = 7.3 Hz、 1H)、 6.85 (d、 J = 8.0 Hz、 1H)、 5.38 (s、 2H)、 3.81 (s、 3H).
式I−17 MS(ESI) (m/z): 348.0 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.74 (d、 J = 2.7 Hz、 1H)、 8.31 (s、 1H)、 8.17 (d、 J = 4.7 Hz、 1H)、 8.06 (d、 J = 8.1 Hz、 1H)、 7.46 (t、 J = 8.2 Hz、 1H)、 7.40 - 7.32 (m、 1H)、 7.28 (t、 J = 7.9 Hz、 1H)、 7.11 (dd、 J = 14.6、 6.4 Hz、 3H)、 6.85 (t、 J = 8.9 Hz、 2H)、 5.37 (s、 2H)、 3.69 (s、 3H).
式I−18 MS(ESI) (m/z): 348.0 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.71 (d、 J = 2.7 Hz、 1H)、 8.22 (s、 1H)、 8.17 (d、 J = 4.7 Hz、 1H)、 8.07 - 8.01 (m、 1H)、 7.47 (dd、 J = 12.7、 8.1 Hz、 3H)、 7.36 (dd、 J = 8.4、 4.7 Hz、 1H)、 7.09 (d、 J = 8.4 Hz、 1H)、 6.92 (d、 J = 8.3 Hz、 2H)、 6.87 (d、 J = 8.0 Hz、 1H)、 5.32 (s、 2H)、 3.70 (s、 3H).
式I−19 MS(ESI) (m/z): 402.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.68 (d、 J = 2.7 Hz、 1H)、 8.21 (s、 1H)、 8.17 (d、 J = 4.7 Hz、 1H)、 8.02 (d、 J = 7.9 Hz、 1H)、 7.73 (d、 J = 7.6 Hz、 1H)、 7.55 - 7.47 (m、 2H)、 7.44 (d、 J = 7.6 Hz、 2H)、 7.36 (dd、 J = 8.4、 4.8 Hz、 1H)、 7.16 (d、 J = 8.4 Hz、 1H)、 6.85 (d、 J = 8.0 Hz、 1H)、 5.48 (s、 2H).
式I−20 MS(ESI) (m/z): 402.0 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.75 (d、 J = 2.8 Hz、 1H)、 8.33 (s、 1H)、 8.17 (d、 J = 4.6 Hz、 1H)、 8.09 - 8.01 (m、 1H)、 7.57 (d、 J = 10.4 Hz、 2H)、 7.50 (dt、 J = 12.3、 8.1 Hz、 2H)、 7.39 - 7.27 (m、 2H)、 7.13 (d、 J = 8.4 Hz、 1H)、 6.86 (d、 J = 8.0 Hz、 1H)、 5.45 (s、 2H).
式I−21 MS(ESI) (m/z): 402.0 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.76 (d、 J = 2.7 Hz、 1H)、 8.31 (s、 1H)、 8.18 (d、 J = 4.6 Hz、 1H)、 8.05 (d、 J = 8.5 Hz、 1H)、 7.67 (d、 J = 8.3 Hz、 2H)、 7.48 (t、 J = 8.2 Hz、 1H)、 7.38 (d、 J = 8.1 Hz、 3H)、 7.12 (d、 J = 8.4 Hz、 1H)、 6.84 (d、 J = 7.9 Hz、 1H)、 5.44 (s、 2H).
式I−22 MS(ESI) (m/z): 343.1 (M+H)+.1H NMR (400 MHz、 DMSO−d6) δ 8.71 (d、 J = 2.6 Hz、 1H)、 8.17 (d、 J = 4.7 Hz、 2H)、 8.04 (ddd、 J = 8.3、 2.8、 1.4 Hz、 1H)、 7.96 - 7.88 (m、 1H)、 7.83 (d、 J = 7.8 Hz、 1H)、 7.79 - 7.71 (m、 1H)、 7.61 - 7.47 (m、 2H)、 7.36 (dd、 J = 8.4、 4.7 Hz、 1H)、 7.17 (d、 J = 8.4 Hz、 1H)、 6.95 (d、 J = 8.0 Hz、 1H)、 5.60 (s、 2H).
式I−23 MS(ESI) (m/z): 343.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.74 (s、 1H)、 8.33 (s、 1H)、 8.14 (d、 J = 4.6 Hz、 1H)、 8.04 (d、 J = 5.3 Hz、 2H)、 7.85 (d、 J = 7.9 Hz、 1H)、 7.76 (d、 J = 7.6 Hz、 1H)、 7.58 (d、 J = 7.7 Hz、 1H)、 7.45 (t、 J = 8.2 Hz、 1H)、 7.39 - 7.29 (m、 1H)、 7.11 (d、 J = 8.4 Hz、 1H)、 6.80 (d、 J = 8.0 Hz、 1H)、 5.42 (s、 2H).
式I−24 MS(ESI) (m/z): 343.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.78 (s、 1H)、 8.37 (s、 1H)、 8.21 - 8.10 (m、 1H)、 8.06 (d、 J = 8.4 Hz、 1H)、 7.83 (d、 J = 7.8 Hz、 2H)、 7.69 (d、 J = 7.9 Hz、 2H)、 7.44 (t、 J = 8.2 Hz、 1H)、 7.35 (t、 J = 6.7 Hz、 1H)、 7.11 (d、 J = 8.4 Hz、 1H)、 6.76 (d、 J = 8.0 Hz、 1H)、 5.49 (s、 2H).
式I−25 MS(ESI) (m/z): 346.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.27 (d、 J = 2.7 Hz、 1H)、 8.11 (d、 J = 4.6 Hz、 1H)、 7.79 (d、 J = 5.5 Hz、 2H)、 7.56 (t、 J = 8.2 Hz、 1H)、 7.29 (dd、 J = 8.5、 4.7 Hz、 1H)、 7.16 (dd、 J = 7.8、 5.8 Hz、 2H)、 7.08 (d、 J = 7.5 Hz、 2H)、 7.01 (d、 J = 8.0 Hz、 1H)、 5.34 (s、 2H)、 2.36 (s、 6H).
式I−26 MS(ESI) (m/z): 386.0 (M+H)+.1H NMR (400 MHz、 DMSO−d6) δ 8.46 (d、 J = 2.7 Hz、 1H)、 8.15 (d、 J = 4.7 Hz、 1H)、 7.94 (s、 1H)、 7.89 (d、 J = 9.5 Hz、 1H)、 7.60 (d、 J = 7.6 Hz、 3H)、 7.50 (dd、 J = 8.9、 7.2 Hz、 1H)、 7.34 (dd、 J = 8.4、 4.6 Hz、 1H)、 7.23 (d、 J = 8.4 Hz、 1H)、 7.13 (d、 J = 8.0 Hz、 1H)、 5.54 (s、 2H).
式I−27 MS(ESI) (m/z): 354.1 (M+H)+. 1H NMR (400 MHz、 DMSO−d6) δ 8.60 (s、 1H)、 8.19 (d、 J = 4.3 Hz、 1H)、 8.11 (s、 1H)、 7.97 (d、 J = 8.2 Hz、 1H)、 7.66 - 7.48 (m、 2H)、 7.37 (dd、 J = 8.3、 4.4 Hz、 1H)、 7.26 - 7.14 (m、 3H)、 7.07 (d、 J = 7.9 Hz、 1H)、 5.49 (s、 2H).
実施例3:3−(ピリジン−3−イルアミノ)−4−(2−トリフルオロメトキシ−5−クロロベンジルオキシ)−ベンゾ[d]イソキサゾール(式I−3)の合成
1)2−トリフルオロメトキシ−5−クロロベンズアルデヒド(化合物13)の合成
2)2−トリフルオロメトキシ−5−クロロベンジルアルコール(化合物14)の合成
3)3−(ピリジン−3−イルアミノ)−4−(2−トリフルオロメトキシ−5−クロロベンジルオキシ)−ベンゾ[d]イソキサゾール−4−(2−トリフルオロメトキシ−5−クロロベンジルオキシの合成)(式I−3)
実施例4:3−(メチル(ピリジン−3−イル)アミノ)−4−(2、6−ジフルオロベンジルオキシ)ベンゾ[d]イソキサゾール(式I−28)の合成
実施例5:3−(ピリジン−3−イルアミノ)−4−ベンジルオキシ−1H−インダゾール(式I−29)の合成
1)4−ベンジルオキシ−1H−インダゾール−3−アミン(16)の合成
2)2−(4−ベンジルオキシ−1H−3−インダゾリル)−イソインドリン−1、3−ジオン(17)の合成
2)2−(1−タートブトキシカルボニル−4−ベンジルオキシ−1H−3−インダゾリル)−イソインドリン−1、3−ジオン(18)の合成
3)1−タートブトキシカルボニル−4−ベンジルオキシ−1H−インダゾール−3−アミン(19)の合成
4)1−タートブトキシカルボニル−3−(ピリジン−3−イルアミノ)−4−ベンジルオキシ−1H−インダゾール(20)の合成
5)3−(ピリジン−3−イルアミノ)−4−ベンジルオキシ−1H−インダゾール(式I−29)の合成
実施例6:1−メチル−3−(ピリジン−3−イルアミノ)−4−ベンジルオキシ−1H−インダゾール(式I−30)の合成
1)2−(1−メチル−4−ベンジルオキシ−1H−3−インダゾリル)−イソインドリン−1、3−ジオン(21)の合成
2)1−メチル−3−(ピリジン−3−イルアミノ)−4−ベンジルオキシ−1H−インダゾール(式I−30)の合成
実施例7:3−(ピリジン−3−イルアミノ)−4−ベンジルオキシ−ベンゾ[d]イソチアゾール(式I−31)の合成
1)4−ベンジルオキシベンゾ[d]イソチアゾール−3−アミン(23)の合成
2)3−(ピリジン−3−イルアミノ)−4−ベンジルオキシ−ベンゾ[d]イソチアゾール(式I−31)の合成
実施例8:1−(ピリジン−3−イルアミノ)−8−ベンジルオキシイソキノリン(式I−32)の合成
1)8−ベンジルオキシイソキノリン(25)の合成
2)8−ベンジルオキシイソキノリン−2−窒素酸化物(26)の合成
3)1−クロロ−8−ベンジルオキシイソキノリン(27)の合成
実施例9:4−(2−クロロ−5−フルオロベンジルオキシ)−3−(ピリミジン−5−イルアミノ)ベンゾ[d]イソキサゾール(式I−33)の合成
1)2−(2−クロロ−5−フルオロベンジルオキシ)−6−フルオロベンゾニトリル(化合物27)の合成
2)3−アミノ−4−(2−クロロ−5−フルオロベンジルオキシ)ベンゾ[d]イソキサゾール(30)の合成
3)4−(2−クロロ−5−フルオロベンジルオキシ)−3−(ピリミジン−5−イルアミノ)ベンゾ[d]イソキサゾール(式I−33)の合成
1)3−(2−クロロアセトアミド)−4−(2−クロロ−5−フルオロベンジルオキシ)ベンゾ[d]イソキサゾール(化合物33)の合成
2)4−(2−クロロ−5−フルオロベンジルオキシ)−3−(2−(N、N−ジメチル)アセトアミド)ベンゾ[d]イソキサゾール(式I−34)の合成
実施例11:I−35〜I−38の合成
式I−35 MS(ESI)(m/z):406.1(M+H)+.1H NMR(400 MHz、DMSO−d6)δ 10.18(s、1H)、7.71-7.52(m、3H)、7.39-7.28(m、1H)、7.24(d、J=8.4 Hz、1H)、7.02(d、J=8.1 Hz、1H)、5.29(s、2H)、3.00(s、2H)、2.11(q、J=7.2 Hz、4H)、0.74(t、J=7.2 Hz、6H).
式I−36 MS(ESI)(m/z):404.1(M+H)+.1H NMR(400 MHz、DMSO−d6)δ 10.10(s、1H)、7.57−7.51(m、3H)、7.25(q、J=8.6 Hz、2H)、6.92(d、J=8.0 Hz、1H)、5.30(s、2H)、3.16(s、2H)、2.38(s、4H)、1.47(s、4H).
式I−37 MS(ESI)(m/z):418(M+H)+.1H NMR(400 MHz、DMSO−d6)δ 10.11(s、1H)、7.61-7.53(m、2H)、7.53-7.46(m、1H)、7.33-7.20(m、2H)、6.92(d、J=8.1 Hz、1H)、5.37(s、2H)、3.02(s、2H)、2.29(s、4H)、1.37-1.20(m、6H).
式I−38 MS(ESI)(m/z):420(M+H)+.1H NMR(400 MHz、DMSO−d6)δ 10.08(s、1H)、7.62-7.44(m、3H)、7.24(d、J=8.5 Hz、2H)、6.88(d、J=7.8 Hz、1H)、5.33(s、2H)、3.37(s、4H)、3.04(s、2H)、2.30(s、4H).
実施例12:3−(ピリジン−3−イルアミノ)−4−((2−フェニルピリジン−4−イル)メトキシ)−ベンゾ[d]イソキサゾール(式I−39)の合成
1)2−フェニルイソニコチンアルデヒド(化合物34)の合成
2)(2−フェニルピリジン−4−イル)メタノール(化合物35)の合成
3)3−(ピリジン−3−イルアミノ)−4−((2−フェニルピリジン−4−イル)メトキシ)−ベンゾ[d]イソキサゾール(式I−39)の合成
実施例13:4−(3−((3−(ピリジン−3−イルアミノ)ベンゾ[d]イソキサゾール−4−イル)オキシ)プロピル)ピペリジン−1−カルボン酸tert−ブチルエステル( 式I−40)合成
1)4−(3−((メチルスルホニル)オキシ)プロピル)ピペリジン−1−カルボン酸tert−ブチルエステル(化合物38)の合成
実施例14:化合物I−2の塩酸塩の調製
0.60 g(1.63 mmol、1.0 eq)の化合物1−2を10 mLの乾燥酢酸エチルに溶解し、1.44 mL(1.8 mmol、1.1 eq)のHCl(g)を上記の溶液に氷水浴条件下で滴下する。酢酸エチル溶液(c=1.25 mol/L)、10分間の反応後に吸引ろ過し、乾燥して、0.53gの白色粉末状固体を80%の収率で得る。
実験器具と材料
1.エレクトリックヒートサモスタッチク水浴(上海一恒科技有限公司)
2.渦混合器(上海精科実業有限公司XW−80A)
3.高速遠心機(Eppendorf 5804R)
4.HPLC Agilent 1100 (Agilent Technologies、 Palo Alto、 CA、 USA)、四次ポンプ、真空脱気、FLD蛍光検出器。
5.HPLCクロマトグラフィーカラムCOSMOSIL 5C18−MS−II(4.6mm I.D.×250 mm)。
6.DMPCはSanta Cruz (USA)から購入、エタノールで溶解し、濃度は40 mMである。
C6−NBD−Ceramide(6−((N−(7−ニトロベンズ−2−オキサ−1、3−ジアゾル−4−イル)アミノ)ヘキサノイル)−スフィングシン)はSanta Cruz (USA)から購入、DMSOで溶解し、濃度は1.16 mMである。
8.使用された有機溶媒はすべて上海国薬試薬公司から購入したものである。メタノールはHPLC級で、水はMilli−Qポンプで濾過し、脱イオン化し、0.22 μm膜で濾過した超純水である。その他の生物サプライは国産公司から購入した。
9.テスト化合物溶液を製法;それぞれのテスト化合物1〜2 mgをアキュレイト量り、まずに適当な量のDMSOを加え、3 mM的貯蔵溶液をアキュレイト生成した。一定の体積のテスト化合物のDMSO貯蔵溶液を取って、適当な体積のDMSOを加え、テスト化合物はほしい濃度の溶液に希釈した。
0.03 μL SMS2純粋酵素DDM溶液(総タンパク質含有量1.5μg/μL)、1μL試験化合物のDMSO溶液またはブランクDMSO溶液、79.7 μL DDMバッファーを1.5 mLエッペンドルフチューブに追加、ボルテックス30秒間、室温で5分間放置する。次に、1 μLのDMPCエタノール溶液(40 mM)と1 μLのC6−NBD−セラミドDMSO(1.16 mM)を含む20 μLのDDMバッファーを追加する。30秒間ボルテックスした後37℃で水浴下で0.5時間インキュベートする。取り除き、200 μLの無水エタノールを加え、30秒間ボルテックスする。混合液200 μLを取り出し、4℃で保存して高速液体クロマトグラフィー分析を行う。
上記のSMS2阻害活性検出法を参考にして、対応する操作にはSMS2純粋酵素の代わりにSMS1純粋酵素を使用する。
試験化合物6 mM DMSO貯蔵溶液を勾配希釈し、五つの濃度段階の溶液を調製し、それぞれ1 μLを実施例15の最初のステップの試験システムに加え、サンプルを実施例15の最初のステップの方法に従って調製した。五つの異なる濃度での化合物のAsm値は、高速液体クロマトグラフィーによって決定され(化合物D2はポジティブコントロール)、五つの異なる濃度での抑制率が計算およびフィッティングされ、各化合物が3グループ並行して半数抑制濃度(IC50)を測定した。化合物式I−1からI−38のSMS2の半数抑制濃度(IC50)とSMS1の単一濃度(50 μM)の抑制率およびいくつかの化合物のSMS1の半数抑制濃度(IC50)を表1に示す。
スフィンゴミエリン合成酵素2の半数抑制濃度(IC50)の測定と同様の操作により、対応する濃度で実験を行うことができる。
Claims (8)
- 式(I)の構造で表されるアルコキシベンゾ五員(六員)複素環式アミン化合物またはその薬学的に許容される塩:
式の中、
Xは、O、N、S、Cから選択される任意の1つまたは2つであり;
Yは、O、N、S、Cから選択される任意の1つまたは2つであり;
その中、XとYの組み合わせによって以下の構造が得られ:
ここで、R4はメチルまたは水素、エチルであり、
R1はベンゼン環、複素環またはアシル基から選択され、
ここで、複素環の構造は
であり、アシル構造は
であり、
R2は、水素、メチル、エチルおよびプロピルから選択される任意の一つ、
R3は、アルコキシ、フェニルシクロメチレンおよび複素環式メチレンから選択され、ここで、ベンジルオキシ、ピリジンメチレン、C1−C8のアルカンまたはC1−C8のアルカンアンモニアを含み、
R3構造は、
であり、Rはo−F、m−F、p−F、o−Cl、m−Cl、p−Cl、o−Me、m−Me、p−Me、o−CF3、m−CF3、p−CF3、o−OCF3、m−OCF3、p−OCF3、o−OMe、m−OMe、p−OMe、o−CN、m−CN、p−CN、o−Etまたはフェニル基から選択される1つまたは2つの置換基であり、
mは0−5である。 - 前記薬学的に許容される塩は、塩酸塩、臭化水素酸塩、酒石酸塩、メタンスルホン酸塩であることを特徴とする、請求項1または2に記載の式(I)の構造で表されるアルコキシベンゾ五員(六員)複素環式アミン化合物またはその薬学的に許容される塩。
- 請求項1〜3のいずれか一項に記載の式(I)の構造によって表されるアルコキシベンゾ五員(六員)複素環式アミン化合物またはその薬学的に許容される塩と、医学的に許容される担体とからなる医薬組成物。
- 請求項1〜4のいずれか一項に記載の式(I)の構造によって表されるアルコキシベンゾ五員(六員)複素環式アミン化合物、その薬学的に許容される塩、およびそれらの医学的に許容される担体とからなる医薬組成物が、スフィンゴミエリンシンターゼ小分子阻害剤の調製における使用。
- 前記アルコキシベンゾ五員(六員)複素環式アミン化合物がさらに溶剤化合物を含み、ここで、溶剤が水、エタノールまたはメタノールであることを特徴とする、請求項1または2に記載の式(I)の構造によって表されるアルコキシベンゾ五員(六員)複素環式アミン化合物またはその薬学的に許容される塩。
- 請求項1〜5のいずれか一項に記載の式(I)の構造で表されるアルコキシベンゾ五員(六員)複素環式アミン化合物、その薬学的に許容される塩、およびそれらの医学的に許容される単体とからなる医薬組成物が、スフィンゴミエリンレベルの異常な増加によって引き起こされる疾患の予防および治療のための医薬品における使用。
- 前記スフィンゴミエリンレベルの異常な増加により引き起こされる疾患が、アテローム性動脈硬化症、II型糖尿病、脂肪肝または肥満およびそれらのメタボリックシンドローム、ならびに腸炎を含む炎症性疾患を含む、請求項7記載の使用。
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SG11202003463XA (en) | 2017-10-18 | 2020-05-28 | Jubilant Epipad LLC | Imidazo-pyridine compounds as pad inhibitors |
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MX2020005363A (es) | 2017-11-24 | 2020-10-01 | Jubilant Episcribe Llc | Compuestos heterociclicos como inhibidores de prmt5. |
CN110117278B (zh) | 2018-02-07 | 2022-07-19 | 石家庄以岭药业股份有限公司 | 烷氧基苯并五元(六元)杂环胺类化合物及其药物用途 |
EP3765453A1 (en) | 2018-03-13 | 2021-01-20 | Jubilant Prodel LLC | Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation |
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Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11506728A (ja) * | 1995-06-06 | 1999-06-15 | ヘキスト・マリオン・ルセル・インコーポレイテツド | 抗精神病剤としてのピリジンイミニル−1,2−ベンゾイソオキサゾール類及び−ベンゾイソチアゾール類 |
JP2005530711A (ja) * | 2002-03-11 | 2005-10-13 | アベンティス・ファーマ・ソシエテ・アノニム | アミノインダゾール誘導体、その製造方法、医薬としての該方法の中間体の使用および該誘導体を含む医薬組成物 |
JP2007523937A (ja) * | 2004-02-27 | 2007-08-23 | エフ.ホフマン−ラ ロシュ アーゲー | インダゾール誘導体およびそれを含む医薬組成物 |
WO2008089310A2 (en) * | 2007-01-18 | 2008-07-24 | Lexicon Pharmaceuticals, Inc. | Delta 5 desaturase inhibitors for the treatment of obesity |
WO2008089307A2 (en) * | 2007-01-18 | 2008-07-24 | Lexicon Pharmaceuticals, Inc. | Delta 5 desaturase inhibitors for the treatment of pain, inflammation and cancer |
JP2008543956A (ja) * | 2005-06-28 | 2008-12-04 | サノフィ−アベンティス | Rho−キナーゼの阻害剤としてのイソキノリン誘導体 |
JP2010111624A (ja) * | 2008-11-06 | 2010-05-20 | Shionogi & Co Ltd | Ttk阻害作用を有するインダゾール誘導体 |
JP2011502958A (ja) * | 2007-06-19 | 2011-01-27 | 武田薬品工業株式会社 | グルコキナーゼ活性化インダゾール化合物 |
CN101993382A (zh) * | 2009-08-21 | 2011-03-30 | 复旦大学 | 芳香胺类衍生物或其类似物及其应用 |
JP2017529333A (ja) * | 2014-08-24 | 2017-10-05 | フダン ユニバーシティ | 2−アルコキシベンゾイル芳香族アミン化合物及びその薬物の用途 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3755332A (en) * | 1971-07-01 | 1973-08-28 | Ciba Geigy Corp | Substituted 4 indazolaminoquinolines |
US5668154A (en) * | 1995-06-06 | 1997-09-16 | Hoechst Marion Roussel Inc. | Pyridiniminyl-1,2-benzisoxazoles and -benzisothiazoles |
GB9914486D0 (en) * | 1999-06-21 | 1999-08-18 | Smithkline Beecham Plc | Medicaments |
WO2008090048A2 (en) * | 2007-01-26 | 2008-07-31 | Basf Se | 3-amino-1,2-benzisothiazole compounds for combating animal pest ii |
EP1647549A1 (en) * | 2004-10-14 | 2006-04-19 | Laboratoire Theramex | Indazoles, benzisoxazoles and benzisothiazoles as estrogenic agents |
WO2006046552A1 (ja) * | 2004-10-27 | 2006-05-04 | Toyama Chemical Co., Ltd. | 新規な含窒素複素環化合物およびその塩 |
AU2006218403A1 (en) * | 2005-03-03 | 2006-09-08 | Sirtris Pharmaceuticals, Inc. | Fused heterocyclic compounds and their use as sirtuin modulators |
EP1856099A2 (en) * | 2005-03-03 | 2007-11-21 | Sirtris Pharmaceuticals, Inc. | Acridine and quinoline derivatives as sirtuin modulators |
DE102005026194A1 (de) * | 2005-06-06 | 2006-12-07 | Grünenthal GmbH | Substituierte N-Benzo[d]isoxazol-3-yl-amin-Derivate und deren Verwendung zur Herstellung von Arzneimitteln |
JP2010519204A (ja) * | 2007-02-16 | 2010-06-03 | アムジエン・インコーポレーテツド | 窒素含有複素環ケトン類およびそれらのc−Met阻害薬としての使用 |
JP6661192B2 (ja) | 2016-01-19 | 2020-03-11 | 国立大学法人北海道大学 | Sms2阻害活性を有するセラミド誘導体 |
CN110117278B (zh) | 2018-02-07 | 2022-07-19 | 石家庄以岭药业股份有限公司 | 烷氧基苯并五元(六元)杂环胺类化合物及其药物用途 |
-
2018
- 2018-02-07 CN CN201810124854.9A patent/CN110117278B/zh active Active
-
2019
- 2019-01-21 US US16/967,118 patent/US11396504B2/en active Active
- 2019-01-21 JP JP2020542775A patent/JP7475049B2/ja active Active
- 2019-01-21 WO PCT/CN2019/072468 patent/WO2019154047A1/zh unknown
- 2019-01-21 EP EP19751009.2A patent/EP3750890A4/en active Pending
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11506728A (ja) * | 1995-06-06 | 1999-06-15 | ヘキスト・マリオン・ルセル・インコーポレイテツド | 抗精神病剤としてのピリジンイミニル−1,2−ベンゾイソオキサゾール類及び−ベンゾイソチアゾール類 |
JP2005530711A (ja) * | 2002-03-11 | 2005-10-13 | アベンティス・ファーマ・ソシエテ・アノニム | アミノインダゾール誘導体、その製造方法、医薬としての該方法の中間体の使用および該誘導体を含む医薬組成物 |
JP2007523937A (ja) * | 2004-02-27 | 2007-08-23 | エフ.ホフマン−ラ ロシュ アーゲー | インダゾール誘導体およびそれを含む医薬組成物 |
JP2008543956A (ja) * | 2005-06-28 | 2008-12-04 | サノフィ−アベンティス | Rho−キナーゼの阻害剤としてのイソキノリン誘導体 |
WO2008089310A2 (en) * | 2007-01-18 | 2008-07-24 | Lexicon Pharmaceuticals, Inc. | Delta 5 desaturase inhibitors for the treatment of obesity |
WO2008089307A2 (en) * | 2007-01-18 | 2008-07-24 | Lexicon Pharmaceuticals, Inc. | Delta 5 desaturase inhibitors for the treatment of pain, inflammation and cancer |
JP2011502958A (ja) * | 2007-06-19 | 2011-01-27 | 武田薬品工業株式会社 | グルコキナーゼ活性化インダゾール化合物 |
JP2010111624A (ja) * | 2008-11-06 | 2010-05-20 | Shionogi & Co Ltd | Ttk阻害作用を有するインダゾール誘導体 |
CN101993382A (zh) * | 2009-08-21 | 2011-03-30 | 复旦大学 | 芳香胺类衍生物或其类似物及其应用 |
JP2017529333A (ja) * | 2014-08-24 | 2017-10-05 | フダン ユニバーシティ | 2−アルコキシベンゾイル芳香族アミン化合物及びその薬物の用途 |
Non-Patent Citations (4)
Title |
---|
"CAS Registry No.2186218-29-9", DATABASE REGISTRY [ONLINE], JPN7022004516, 7 March 2018 (2018-03-07), ISSN: 0004882033 * |
DENG, XIAODONG ET AL., EUR.J.MED.CHEM., vol. 73, JPN6022039982, 2014, pages 1 - 7, ISSN: 0004882036 * |
MO, MINGGUANG ET AL., J.MED.CHEM., vol. 61, JPN6022039984, 2018, pages 8241 - 8254, ISSN: 0004882034 * |
QI, XIANG-YU ET AL., BIOORG.MED.CHEM.LETT., vol. 27, JPN6022039983, 2017, pages 3511 - 3515, ISSN: 0004882035 * |
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