JP5411885B2 - ベンゼンスルホンアミド誘導体およびその医薬組成物 - Google Patents
ベンゼンスルホンアミド誘導体およびその医薬組成物 Download PDFInfo
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- JP5411885B2 JP5411885B2 JP2011056429A JP2011056429A JP5411885B2 JP 5411885 B2 JP5411885 B2 JP 5411885B2 JP 2011056429 A JP2011056429 A JP 2011056429A JP 2011056429 A JP2011056429 A JP 2011056429A JP 5411885 B2 JP5411885 B2 JP 5411885B2
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
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- 238000002512 chemotherapy Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
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- 230000002380 cytological effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
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- 238000003370 dye binding method Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- SVMLUPDEOYWXDG-UHFFFAOYSA-N ethyl 2-[(2-nitrophenyl)hydrazinylidene]propanoate Chemical compound CCOC(=O)C(C)=NNC1=CC=CC=C1[N+]([O-])=O SVMLUPDEOYWXDG-UHFFFAOYSA-N 0.000 description 1
- FNENWZWNOPCZGK-UHFFFAOYSA-N ethyl 2-methyl-3-oxobutanoate Chemical compound CCOC(=O)C(C)C(C)=O FNENWZWNOPCZGK-UHFFFAOYSA-N 0.000 description 1
- GTZAIVBXGPLYGD-UHFFFAOYSA-N ethyl 7-nitro-1h-indole-2-carboxylate Chemical compound C1=CC([N+]([O-])=O)=C2NC(C(=O)OCC)=CC2=C1 GTZAIVBXGPLYGD-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
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- 201000006585 gastric adenocarcinoma Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
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- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
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- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
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- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
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- LXKFODKYRFBZDY-UHFFFAOYSA-N n-(5,8-dimethyl-9h-carbazol-1-yl)-3-(trifluoromethyl)benzenesulfonamide Chemical compound CC1=CC=C(C)C(C2=CC=C3)=C1NC2=C3NS(=O)(=O)C1=CC=CC(C(F)(F)F)=C1 LXKFODKYRFBZDY-UHFFFAOYSA-N 0.000 description 1
- UAPRJVDOAFRVCY-UHFFFAOYSA-N n-(5,8-dimethyl-9h-carbazol-1-yl)-4-methoxy-n-methylbenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C)C1=CC=CC2=C1NC1=C(C)C=CC(C)=C21 UAPRJVDOAFRVCY-UHFFFAOYSA-N 0.000 description 1
- XRFNWYHALJBWAA-UHFFFAOYSA-N n-(5,8-dimethyl-9h-carbazol-1-yl)-4-methoxy-n-propan-2-ylbenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(C)C)C1=CC=CC2=C1NC1=C(C)C=CC(C)=C21 XRFNWYHALJBWAA-UHFFFAOYSA-N 0.000 description 1
- ZFTNRGOHOXUFNG-UHFFFAOYSA-N n-(5,8-dimethyl-9h-carbazol-1-yl)-4-methoxy-n-propylbenzenesulfonamide Chemical compound C=1C=CC(C2=C(C)C=CC(C)=C2N2)=C2C=1N(CCC)S(=O)(=O)C1=CC=C(OC)C=C1 ZFTNRGOHOXUFNG-UHFFFAOYSA-N 0.000 description 1
- KKFHSQWAWAULHU-UHFFFAOYSA-N n-(5,8-dimethyl-9h-carbazol-1-yl)-4-methoxybenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)NC1=CC=CC2=C1NC1=C(C)C=CC(C)=C21 KKFHSQWAWAULHU-UHFFFAOYSA-N 0.000 description 1
- VEDCNEZRWSTSQI-UHFFFAOYSA-N n-(5,8-dimethyl-9h-carbazol-1-yl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=CC=CC2=C1NC1=C(C)C=CC(C)=C21 VEDCNEZRWSTSQI-UHFFFAOYSA-N 0.000 description 1
- NEGHCXHABRVVIR-UHFFFAOYSA-N n-(5,8-dimethyl-9h-carbazol-1-yl)-4-nitrobenzenesulfonamide Chemical compound CC1=CC=C(C)C(C2=CC=C3)=C1NC2=C3NS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 NEGHCXHABRVVIR-UHFFFAOYSA-N 0.000 description 1
- DVEYEQKMLFNJIB-UHFFFAOYSA-N n-(5,8-dimethyl-9h-carbazol-1-yl)-n-ethyl-4-methoxybenzenesulfonamide Chemical compound C=1C=CC(C2=C(C)C=CC(C)=C2N2)=C2C=1N(CC)S(=O)(=O)C1=CC=C(OC)C=C1 DVEYEQKMLFNJIB-UHFFFAOYSA-N 0.000 description 1
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- BEHKKQDANVIHQW-UHFFFAOYSA-N n-(5,8-dimethyl-9h-carbazol-1-yl)benzenesulfonamide Chemical compound CC1=CC=C(C)C(C2=CC=C3)=C1NC2=C3NS(=O)(=O)C1=CC=CC=C1 BEHKKQDANVIHQW-UHFFFAOYSA-N 0.000 description 1
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- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002135 phase contrast microscopy Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940051201 quinoline yellow Drugs 0.000 description 1
- 235000012752 quinoline yellow Nutrition 0.000 description 1
- FZUOVNMHEAPVBW-UHFFFAOYSA-L quinoline yellow ws Chemical compound [Na+].[Na+].O=C1C2=CC=CC=C2C(=O)C1C1=NC2=C(S([O-])(=O)=O)C=C(S(=O)(=O)[O-])C=C2C=C1 FZUOVNMHEAPVBW-UHFFFAOYSA-L 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 231100000338 sulforhodamine B assay Toxicity 0.000 description 1
- 238000003210 sulforhodamine B staining Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 1
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
式中、
R1はH、またはC1-6アルキルであり;
R2およびR3は、それぞれ独立してH、
であるか、または共に結合して
を形成し;
Dは
であり;
R4はH、またはニトロであり;
X、Y、および各R5は、それぞれ独立してH、またはC1-6アルキルであり;
各R6は独立してH、ハロゲン、C1-6アルキル、C1-6アルコキシ、ハロゲン置換C1-6アルキル、ハロゲン置換C1-6アルコキシ、ニトロ、-NR8R9、または-SO2NR10R11であり;
R7はH、またはハロゲンであり;
R8、R9、R10、およびR11は、それぞれ独立してH、またはC1-6アルキルであり;および
i、およびnはそれぞれ独立して0、1、2、または3である。
であってもよく、およびR6はH、ハロゲン、C1-6アルキル、C1-6アルコキシ、ニトロ、-NH2、または-SO2NH2であってもよい。この態様において、好ましくは、R6はH、Cl、メチル、メトキシ、ニトロ、-NH2、または-SO2NH2である。加えて、好ましくは、R2およびR3は、共に結合して
を形成するか;R2およびR3はHであるか;またはR2はHであり、およびR3は
である。
であってもよく、およびR6はH、ハロゲン置換C1-6アルキル、またはハロゲン置換C1-6アルコキシであってもよい。この態様において、好ましくは、R6は-CF3である。加えて、好ましくは、R2およびR3は、共に結合して
を形成する。
であってもよく、およびR6はH、ハロゲン、C1-6アルキル、C1-6アルコキシ、ニトロ、-NH2、または-SO2NH2であってもよい。この態様において、好ましくは、R6はニトロである。加えて、好ましくは、R2およびR3は、共に結合して
を形成するか;またはR2およびR3はHである。
であってもよく、およびR7はH、またはハロゲンであってもよい。この態様において、好ましくは、R1はH、またはメチルであり、およびR7はClである。また、好ましくは、R2およびR3は、共に結合して
を形成する。
1H NMR (200 MHz, CDCl3) δ1.38 (t, J = 7.0 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 4.37 (q, J = 7.2 Hz, 2H, CH2), 6.92 (t, J = 7.2 Hz, ArH, 1H), 7.54 (t, J = 7.2 Hz, 1H, ArH), 8.18 (dd, J = 1.4, 7.2 Hz, 1H, ArH), 8.18 (d, J = 7.2 Hz, 1H, ArH), 13.85 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ10.9, 14.8, 62.0, 116.8, 120.5, 122.6, 130.1, 130.6, 131.1, 131.4, 133.9, 161.2;
MS (EI) m/z 252 (M+1, 100%), 251 (M+, 84%), 136 (M-115, 58%).
1b: 融点 113-114 oC (文献 117-118 oC);
1H NMR (200 MHz, CDCl3) δ1.37 (t, J = 7.0 Hz, 3H, CH3), 2.21 (s, 3H, CH3), 4.33 (q, J = 7.2 Hz, 2H, CH2), 6.96 (dt, J = 1.2, 7.7 Hz, ArH, 1H), 7.58 (t, J = 7.2 Hz, ArH, 1H), 8.00 (d, J = 8.6 Hz, ArH, 1H), 8.15 (dd, J = 1.4, 8.6 Hz, ArH, 1H), 10.91 (s, 1H, NH);
13C NMR (100 MHz, CDCl3) δ11.6, 14.2, 61.6, 116.8, 120.2, 125.7, 132.7, 136.2, 139.2, 140.6, 164.5;
MS (EI) m/z 251 (M+, 100%), 43 (M-208, 63%).
1H NMR (200 MHz, CDCl3) δ1.41 (t, J = 7.2 Hz, 3H, CH3), 4.42 (q, J = 7.2 Hz, 2H, CH2), 7.20 (t, J = 7.9 Hz, 1H, ArH), 7.28 (d, J = 2.1 Hz, 1H, ArH), 7.97 (d, J = 7.8 Hz, 1H, ArH), 8.21 (d, J = 8.0 Hz, 1H, ArH), 10.25 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ14.8, 62.0, 109.7, 120.5, 122.6, 130.0 130.6, 131.1, 131.3, 133.8, 161.1;
MS (EI) m/z 235 (M+1, 100%), 234 (M+, 69%), 189 (M-45, 38%).
1H NMR (200 MHz, DMSO-d6) δ7.35 (t, J = 8.0 Hz, 1H, ArH), 7.40 (d, J = 2.0 Hz, 1H, ArH), 8.22 (d, J = 7.8 Hz, 1H, ArH), 8.27 (dd, J = 0.8, 8.0 Hz , 1H, ArH), 11.16 (s, 1H, NH);
13C NMR (50 MHz, アセトン-d6) δ109.6, 110.0, 120.6, 122.3, 130.1, 131.3, 131.8, 134.0, 161.6;
MS (EI) m/z 206 (M+, 100%), 188 (M-18, 65%), 142 (M-64, 49%), 114 (M-92, 43%).
1H NMR (200 MHz, CDCl3) δ6.63 (dd, J = 2.2, 1.0 Hz, 1H, ArH), 7.08-7.18 (m, 1H, ArH), 7.32 (t, J = 3.0 Hz, 1H, ArH), 7.90 (d, J = 7.8 Hz, 1H, ArH), 8.08 (d, J = 8.1 Hz, 1H, ArH), 9.88 (s, 1H, NH);
13C NMR (50 MHz, アセトン-d6) δ103.7, 118.9, 119.2, 128.4, 129.1, 129.3, 132.9, 133.5;
MS (EI) m/z 162 (M+, 100%), 116 (M-46, 87%), 104 (M-58, 41%), 89 (M-73, 53%).
1H NMR (200 MHz, CDCl3) δ6.41 (d, J = 7.4 Hz, 1H, ArH), 6.54 (dd, J = 2.2, 3.1 Hz, 1H, ArH), 6.86 (t, J = 7.8 Hz, 1H, ArH), 6.90 (s, 1H, NH), 7.24-7.26 (m, 2H, ArH), 7.31-7.32 (m, 1H, ArH), 7.34-7.36 (m, 1H, ArH), 7.50 (d, J = 8.0 Hz, 1H, ArH), 7.54-7.59 (m, 2H, ArH), 9.20 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ103.2, 118.5, 120.2, 120.3, 120.4, 125.8, 127.9, 129.5, 130.6, 132.4, 133.7, 138.3;
MS (EI) m/z 272 (M+, 63%), 131 (M-141, 100%), 104 (M-168, 94%), 77 (M-195, 85%);
HRMS (m/z) for C14H12N2O2S(M+): 計算値 272.0620; 測定値 272.0617. 分析 (C14H12N2O2S): 計算値 C, 61.75; H, 4.44; N, 10.29; 測定値C, 61.48; H, 4.52; N, 10.22.
1H NMR (200 MHz, アセトン-d6) δ2.34 (s, 1H, CH3), 6.47 (dd, J = 3.1, 2.0 Hz, 1H, ArH), 6.73 (dd, J = 7.6, 1.2 Hz , 1H, ArH), 6.84 (dt, J = 7.6, 1.6 Hz, 1H, ArH), 7.26 (dd, J = 4.0, 0.4 Hz, 2H, NH), 7.34-7.41 (m, 2H, ArH), 7.57 (t, J = 1.8 Hz, 1H, ArH), 7.61 (t, J = 1.6 Hz, 1H, ArH), 8.71 (s, 1H, NH), 10.10 (s, 1H, NH);
13C NMR (50 MHz, アセトン-d6) δ21.4, 102.9, 117.7, 119.4, 120.0, 122.3, 126.2, 128.1, 130.2, 131.0, 132.4, 137.7, 144.3;
MS (EI) m/z 286 (M+, 56%), 131 (M-155, 100%), 104 (M-182, 38%).
1H NMR (200 MHz, CDCl3) δ3.7 (s, 3H, CH3), 6.43-6.46 (m, 2H, ArH), 6.72 (s, 1H, ArH), 6.76 (s, 1H, ArH), 6.78 (t, J = 7.6 Hz, 1H, ArH), 7.05 (s, 1H, NH), 7.16 (t, J = 2.6 Hz , 1H, ArH), 7.39 (d, J = 7.4 Hz, 1H, ArH), 7.52 (s, 1H ArH), 7.56 (s, 1H ArH), 9.23 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ56.0, 103.0, 114.6, 118.1, 120.1, 120.5, 125.5, 125.7, 129.8, 123.0, 130.4, 132.1, 163.6;
MS (EI) m/z 302 (M+, 59%), 131 (M-171, 100%), 104 (M-182, 51%).
1H NMR (200 MHz, CDCl3) δ6.44 (d, J = 7.4 Hz, 1H, ArH), 6.54 (dd, J = 2.2 , 3.0 Hz , 1H, ArH), 6.84 (t, J = 7.6 Hz, 1H, ArH), 6.96 (s, 1H, NH), 7.34-7.41 (m, 2H, ArH), 7.46-7.55 (m, 2H, ArH), 7.64-7.69 (m, 2H, ArH), 9.28 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ103.2, 118.7, 119.8, 120.2, 120.7, 125.8, 129.3, 129.7, 130.7, 132.3, 136.6, 140.2;
MS (EI) m/z 306 (M+, 25%), 131 (M-171, 90%), 104 (M-182, 100%).
1H NMR (200 MHz, CDCl3) δ6.54 (dd, J = 3.1, 2.1 Hz, 2H, ArH), 6.64 (d, J = 7.4 Hz , 1H, ArH), 6.84 (t, J = 7.7 Hz, 1H, ArH), 7.26-7.28 (m, 2H, ArH, NH), 7.41-7.52 (m, 2H, ArH), 7.58-7.70 (m, 2H, ArH), 7.87 (d, J = 7.9, 1.2 Hz, 1H ArH), 9.06 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ103.3, 118.8, 119.5, 120.1, 121.1, 125.7, 125.8, 130.7, 131.9, 132.6, 133.0, 134.5; MS (EI) m/z 317 (M+, 37%), 206 (M-111, 58%), 131 (M-186, 100%), 104 (M-213, 79%);
HRMS (m/z) for C14H11N3O4S(M+): 計算値 317.0470; 測定値 317.0470. 分析 (C14H11N3O4S): 計算値 C, 52.99; H, 3.49; N, 13.24; 測定値 C, 52.99; H, 3.51; N, 13.07.
1H NMR (200 MHz, CDCl3) δ5.12 (s, 2H, NH2), 8.18 (d, J = 0.6 Hz, 4H, ArH);
13C NMR (50 MHz, CDCl3) δ128.2, 144.9;
MS (EI) m/z 220 (M+, 100%), 156 (M-64, 60%), 76 (M-144, 57%).
実施態様1の化合物4(2.00 g, 12.33 mmol)をイソプロパノール(25 mL)に溶解した後、Fe粉(2.07 g, 37.20 mmol)および、NH4Cl(0.13 g, 2.43 mmol)および水(9 mL)で調製したNH4Cl溶液を添加した。得られた溶液を60℃で1.5時間加熱した後、TLC試験を使用して、反応の完了を確認した。その後、反応溶液中に活性炭を添加し、3分間撹拌した。溶液を濾過し、酢酸エチルを用いて、濾液の容量が150 mLになるまで、残渣を洗浄した。溶液中に、化合物10(3.31 g, 13.3 mmol)およびピリジン(3.00 mL, 33.55 mmol)を連続して添加した。得られた溶液を室温で10時間撹拌した。TLC試験の結果が反応の完了を示した時に、酢酸エチルを添加して反応溶液を250 mLに希釈した。その後、反応溶液を順次、1NのHCl、水、飽和NaHCO3溶液、および塩水で洗浄した。洗浄工程後、有機層の色は弁柄色であった。Na2SO4を加えて脱水し、有機層を濾過および濃縮して、固体を得た。固体をエタノールから再結晶して、針状白色固体である化合物5gを得た(2.13 g, 66%)。
1H NMR (200 MHz, アセトン-d6) δ6.45 (d, J = 4.2 Hz, 1H, ArH), 6.69 (d, J = 7.2 Hz, 1H, ArH), 6.79 (s, 1H, NH), 6.83 (t, J = 7.6 Hz, 1H, ArH), 7.34 (t, J = 2.6 Hz, 1H, ArH), 7.42 (d, J = 7.8 Hz, 1H, ArH), 7.85 (d, J = 8.4 Hz, 2H, ArH), 7.95 (d, J = 8.8 Hz, 2H, ArH), 7.99 (s, 1H, NH), 8.98 (s, 1H, NH), 10.15 (s, 1H, NH);
13C NMR (50 MHz, アセトン-d6) δ102.5, 117.7, 119.6, 121.2, 125.82, 126.0, 127.1, 128.4, 130.7, 140.2, 143.2, 148.3;
MS (EI) m/z 351 (M+, 53%), 131 (M-220, 100%), 104 (M-247, 47%).
1H NMR (200 MHz, CDCl3) δ6.55 (dd, J = 0.8, 2.2 Hz, 1H, ArH), 6.62 (d, J = 7.4 Hz, 1H, ArH), 6.84 (t, J = 7.8 Hz, 1H, ArH), 7.26 (s, 1H, NH), 7.27 (t, J = 3.0 Hz, 1H, ArH), 7.41-7.53 (m, 2H, ArH), 7.58-7.71 (m, 2H, ArH), 7.87 (dd, J = 7.0, 0.8 Hz, 1H,ArH), 9.04 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ103.3, 118.8, 119.4, 120.1, 121.1, 125.7, 125.8, 130.7, 131.9, 132.6, 132.9, 134.5;
MS (EI) m/z 317 (M+, 35%), 131 (M-186, 88%), 104 (M-213, 100%), 77 (M-240, 26%);
HRMS (m/z) for C14H11N3O4S(M+): 計算値 317.0470; 測定値 317.0476. 分析 (C14H11N3O4S): 計算値 C, 52.99; H, 3.49; N, 13.24; 測定値 C, 52.69; H, 3.59; N, 13.13.
1H NMR (200 MHz, アセトン-d6) δ2.52 (s, 3H, CH3), 2.76 (s, 3H, CH3), 6.89 (d, J = 3.6 Hz, 1H, ArH), 7.01-7.08 (m, 3H, ArH), 7.38-7.54 (m, 3H, ArH), 7.73-7.78 (m, 2H, ArH), 7.98 (d, J = 3.8 Hz, 1H, ArH), 8.82 (s, 1H, NH), 9.83 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ17.0, 20.8, 118.3, 118.8, 119.4, 119.8, 121.6, 122.3, 122.6, 127.2, 127.3, 127.9, 129.3, 129.7, 131.2, 136.6, 139.6, 140.3.
1H NMR (400 MHz, CDCl3) δ2.33 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.79 (s, 3H, CH3), 6.71 (d, J = 3.8 Hz, 1H, ArH), 6.92 (d, J = 3.6 Hz, 1H, ArH), 6.97 (t, J = 3.9 Hz, 1H, ArH), 7.01 (s, 1H, NH), 7.15 (t, J = 4.1 Hz, 3H, ArH), 7.59 (d, J = 4.1 Hz, 2H, ArH), 7.98 (d, J = 7.8 Hz, 1H, ArH), 9.07 (s, 1H, NH);
13C NMR (100 MHz, CDCl3) δ16.5, 20.4, 21.5, 117.9, 119.1, 119.214, 121.113, 121.2, 121.3, 121.5, 126.6, 126.6, 127.5, 129.7, 130.7, 134.9, 135.7, 139.1, 144.2;
MS (EI) m/z 364 (M+, 23%), 209 (M-155, 100%), 28 (M-336, 37%);
HRMS (m/z) for C21H20N2O2S(M+): 計算値 364.1245; 測定値 364.1247. 分析 (C21H20N2O2S): 計算値 C, 69.20; H, 5.53; N, 7.69; 測定値 C, 69.23; H, 5.53; N, 7.56.
1H NMR (200 MHz, CDCl3) δ2.54 (s, 3H, CH3), 2.80 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 6.69 (d, J = 7.6 Hz, 1H, ArH), 6.79 (s, 1H, ArH), 6.84 (s, 1H, ArH), 6.90 (s, 1H, NH), 6.96 (dd, J = 7.6, 7.8 Hz, 2H, ArH), 7.14 (d, J = 7.4 Hz, 1H, ArH), 7.60 (t, J = 2.0 Hz, 1H, ArH), 7.63 (t, J = 2.0 Hz, 1H, ArH), 7.99 (d, J = 8.0 Hz, 1H, ArH), 9.09 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ21.0, 24.8, 60.2, 119.0, 122.7, 124.2, 125.0, 125.1, 125.9, 126.1, 130.8, 131.4, 134.4, 135.3, 136.4, 139.5, 144.1, 168.1;
MS (EI) m/z 380 (M+, 55%), 209 (M-171, 100%). 分析 (C21H20N2O3S): 計算値 C, 66.29; H, 5.30; N, 7.36; 測定値 C, 66.05; H, 5.37; N, 7.06.
1H NMR (200 MHz, アセトン-d6) δ2.52 (s, 3H, CH3), 2.77 (s, 3H, CH3), 6.90 (d, J = 7.2 Hz, 1H, ArH), 7.05-7.17 (m, 3H, ArH), 7.46-7.53 (m, 2H, ArH), 7.72 (t, J = 2.1 Hz, 1H, ArH), 7.75 (m, 1H, ArH), 7.89 (dd, J = 7.3 , 1.6 Hz, 1H, ArH), 8.88 (s, 1H, NH), 9.84 (s, 1H, NH);
13C NMR (50 MHz, アセトン-d6) δ16.8, 20.5, 118.5, 120.0, 121.2, 121.5, 121.8, 122.0, 126.7, 127.3, 128.1, 129.8, 131.2, 133.7, 135.6, 139.9, 140.6;
MS (EI) m/z 384 (M+, 27%), 209 (M-175, 100%), 28 (M-356, 60%);
HRMS (m/z) for C20H17ClN2O2S(M+): 計算値 384.0699; 測定値 384.0700. 分析 (C20H17ClN2O2S): 計算値 C, 62.41; H, 4.45; N, 7.28; 測定値 C, 62.42; H, 4.48; N, 7.14.
1H NMR (200 MHz, CDCl3) δ2.55 (s, 3H, CH3), 2.79 (s, 3H, CH3), 6.89 (dd, J = 7.7, 1.0 Hz, 1H, ArH), 6.92-7.03 (m, 2H, ArH), 7.16 (d, J = 7.2 Hz, 1H, ArH), 7.31 (s, 1H, NH), 7.42 (ddd, J = 1.2, 7.4 , 7.9 Hz, 1H, ArH), 7.58 (dd, J = 7.9, 1.4 Hz, 1H, ArH), 7.66 (ddd, J = 1.6, 8.5, 6.9 Hz, 1H, ArH), 7.87 (dd, J = 8.0, 1.2 Hz, 1H, ArH), 8.02 (dd, J = 1.0, 2.8 Hz, 1H, ArH), 8.88 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ17.0, 20.8, 118.3, 118.5, 119.8, 121.6, 121.8, 122.3, 122.9, 125.6, 127.3, 131.2, 131.9, 132.6, 132.9, 134.6, 136.7, 139.5, 148.6, 161.8;
MS (EI) m/z 396 (M+1, 38%), 395 (M+, 12%), 209 (M-186, 100%). 分析 (C20H17N3O4S): 計算値 C, 60.75; H, 4.33; N, 10.63; 測定値 C, 60.46; H, 4.29; N, 10.37.
1H NMR (200 MHz, アセトン-d6) δ2.51 (s, 3H, CH3), 2.74 (s, 3H, CH3), 3.12 (s, 2H, NH2), 6.87 (d, J = 7.0 Hz, 1H, ArH), 7.04-7.17 (m, 3H, ArH), 7.97-8.01 (m, 3H, ArH), 8.24-8.28 (m, 2H, ArH), 9.14 (s, 1H, NH), 9.95 (s, 1H, NH);
13C NMR (50 MHz, アセトン-d6) δ17.0, 20.8, 118.2, 118.4, 119.4, 121.6, 121.9, 122.4, 122.9, 125.6, 127.3, 131.2, 131.9, 132.7, 133.0, 134.5, 136.6, 139.5, 148.6, 161.8.
1H NMR (400 MHz, DMSO-d6) δ2.50 (s, 3H, CH3), 2.69 (s, 3H, CH3), 6.85 (d, J = 7.2 Hz, 1H, ArH), 7.05 (t, J = 8.0 Hz, 1H, ArH), 7.09 (d, J = 7.2 Hz, 1H, ArH), 7.24 (d, J = 7.6 Hz, 1H, ArH), 7.47 (s, 2H, NH2), 7.84 (d, J = 7.6 Hz, 1H, ArH), 7.90 (d, J = 8.0 Hz, 2H, ArH), 7.87 (d, J = 8.0Hz, 2H, ArH), 8.00 (d, J = 8.4 Hz, 2H, ArH), 10.22 (s, 1H, NH), 10.63 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6) δ16.5, 20.3, 116.2, 117.4, 119.5, 120.1, 120.3, 124.8, 126.3, 126.6, 127.9, 129.1, 138.6, 147.7;
MS (EI) m/z 429 (M+, 55%), 209 (M-220, 100%), 28 (M-401, 50%);
HRMS (m/z) for C20H19N3O4S(M+): 計算値 429.0817; 測定値 429.0816. 分析 (C20H19N3O4S): 計算値 C, 55.93; H, 4.46; N, 9.78; 測定値 C, 55.77; H, 4.57; N, 9.64.
1H NMR (200 MHz, アセトン-d6) δ2.53 (s, 3H, CH3), 2.76 (s, 3H, CH3), 6.90 (d, J = 7.2 Hz, 1H, ArH), 7.05-7.14 (m, 2H, ArH), 7.23 (dd, J = 1.2, 3.9 Hz, 1H, ArH), 7.31 (s, 1H, NH), 7.63 (dt, J =1.4, 7.6 Hz, 1H, ArH), 7.76-7.85 (m, 2H, ArH), 7.95 (dt, J = 1.2, 8.2 Hz, 1H, ArH), 8.04 (dd, J = 0.8 , 7.7 Hz, 1H, ArH), 9.10 (s, 1H, NH), 9.96 (s, 1H, NH);
13C NMR (50 MHz, アセトン-d6) δ16.4, 20.2, 118.2, 119.6, 119.8, 121.5, 121.7, 125.3, 126.5, 127.1, 130.8, 131.9, 132.2, 132.6, 135.0, 136.0, 140.0, 148.7;
MS (EI) m/z 395 (M+, 17%), 209 (M-186, 100%);
HRMS (m/z) for C20H17N3O4S(M+): 計算値 395.0940; 測定値 395.0941. 分析 (C20H17N3O4S): 計算値 C, 60.75; H, 4.33; N, 10.63; 測定値 C, 60.66; H, 4.41; N, 10.40.
1H NMR (200 MHz, CDCl3) δ6.78 (d, J = 7.9 Hz, 1H, ArH), 7.24-7.38 (m, 4H, ArH), 7.57-7.70 (m, 3H, ArH), 8.00 ( d, J = 8.0 Hz, 2H, ArH), 8.33 (d, J = 8.1 Hz, 2H, ArH), 9.81 (s, 1H, NH);
13C NMR (50 MHz, アセトン-d6) δ104.1, 115.5, 122.0, 123.3, 124.9, 125.2, 126.4, 129.4, 129.7, 129.8, 131.7, 138.6, 139.3, 143.2, 148.7, 157.1;
MS (EI) m/z 455 (M+, 44%), 280 (M-175, 85 %), 234 (M-221, 66%), 130 (M-325, 52%);
HRMS (m/z) for C20H14ClN5O4S(M+): 計算値 455.0455; 測定値 455.0424. 分析 (C20H14ClN5O4S): 計算値 C ,52.69; H, 3.10; N, 15.36; 測定値 C, 52.44; H, 3.17; N, 15.08.
1H NMR (200 MHz, CDCl3) δ2,30 (s, 3H, CH3), 6.82 (d, J = 8.0 Hz, 1H, ArH), 7.14 (d, J = 8.0 Hz, 2H, ArH), 7.40-7.34 (m, 2H, ArH), 7.42-7.55( m, 3H, ArH), 7.60 (d, J = 8.0 Hz, 1H, ArH), 7.64 (s, 1H, ArH), 7.68 (s, 1H, ArH), 7.83 (s, 1H, NH), 7.93 (t, J = 1.4 Hz, 1H, ArH), 7.96 (t, J = 1.8 Hz, 1H, ArH), 9.65 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ22.0, 104.0, 116.9, 121.2, 122.8, 123.0, 123.5, 127.8, 128.8, 129.48, 130.3, 130.9, 132.4, 135.2, 143.8, 145.0, 153.8;
MS (EI) m/z 390 (M+, 58%), 235 (M-155, 100 %), 28 (M-362, 86%).
1H NMR (200 MHz, CDCl3) δ6.70 (d, J= 8.0 Hz, 1H, ArH), 7.34 (d, J = 8.6 Hz, 3H, ArH), 7.34-7.50 (m, 5H, ArH, NH), 7.62 (d, J = 8.2 Hz, 3H, ArH), 7.94 (d, J = 8.6 Hz, 2H, ArH), 9.42 (s, 1H, NH);
13C NMR (50 MHz, CDCl3) δ103.2, 119.5, 120.8, 121.0, 121.3, 121.5, 126.3, 126.8, 127.6, 129.3, 130.7, 133.2, 139.4, 140.1, 145.1, 154.7;
MS (EI) m/z 410 (M+, 33%), 235 (M-175, 100 %), 130 (M-280, 48%), 111 (M-299, 55%);
HRMS (m/z) for C20H15ClN4O2S(M+): 計算値 410.0604; 測定値 410.0607.
ESI (M-H+) 439.1;
1H NMR (200 Hz, DMSO-d6)δ2.07 (s, 3H, CH3), 2.68 (s, 3H, CH3), 3.43 (s, 3H, OCH3), 3.62 (s, 6H, OCH3), 6.82 (d, J = 7.2 Hz, 1H, ArH), 6.95 (s, 2H, ArH), 7.00-7.15 (m, 2H, ArH), 7.37 (d, J = 7.6 Hz, 1H, ArH), 7.87 (d, J = 7.6 Hz, 1H, ArH), 7.72 (s, 1H, NH), 10.51 (s, 1H, NH);
13C NMR (50 Hz, DMSO-d6)δ16.37, 20.07, 55.99, 59.87, 104.24, 117.27, 118.38, 119.12, 119.31, 120.32, 120.56, 121.15, 124.77, 126.15, 129.82, 132.85, 133.96, 138.45, 140.67, 152.50.
分析 (C23H24N2O5S): 計算値 C, 62.71; H, 5.49; N, 6.36; S, 7.28; 測定値 C, 62.75; H, 5.69; N, 6.59; S, 7.10.
ESI (M-H+) 417.1;
1H NMR (400 Hz, DMSO-d6)δ2.43 (s, 3H, CH3), 2.66 (s, 3H, CH3), 6.82 (d, J = 7.2 Hz, 1H, ArH), 7.05-7.11 (m, 2H, ArH), 7.27 (d, J = 7.6 Hz, 1H, ArH), 7.62 (t, J = 8.0 Hz, 1H, ArH), 7.86 (t, J = 7.6 Hz, 2H, ArH), 7.92 (d, J = 8.0 Hz, 1H, ArH), 8.13 (s, 1H, ArH), 9.97 (s, 1H, ArH), 10.50 (s, 1H, NH);
13C NMR (100 Hz, DMSO-d6)δ16.28, 19.98, 111.40, 118.71, 119.07, 119.73, 120.18, 120.32, 120.60, 121.88, 123.39, 123.43, 123.47, 124.59, 124.96, 126.20, 129.49, 129.60, 129.64, 129.77, 129.82, 130.56, 130.80, 132.99, 138.56, 140.52.
分析 (C21H17F3N2O2S): 計算値 C, 60.28; H, 4.10; N, 6.69; F, 13.62; S, 7.66; 測定値 C, 75.89; H, 5.88; N, 12.76.
ESI (M-H+) 389.0;
1H NMR (400 Hz, DMSO-d6)δ2.71 (s, 3H, CH3), 6.86 (d, J = 7.2 Hz, 1H, ArH), 7.07-7.16 (m, 3H, ArH), 7.31 (d, J = 8.0 Hz, 1H, ArH), 7.37 (d, J = 4.0 Hz, 1H, ArH), 10.20 (s, 1H, NH), 10.57 (s, 1H, NH);
13C NMR (100 Hz, DMSO-d6)δ16.49, 20.05, 117.51, 117.84, 119.14, 119.61, 120.37, 120.40, 120.64, 124.99, 126.24, 127.87, 129.83, 132.63, 132.71, 135.32, 138.08, 138.60. 分析 (C18H15ClN2O2S2): 計算値 C, 55.31; H, 3.87; N, 7.17; S, 16.41; 測定値 C, 55.37; H, 3.60; N, 7.45; S, 16.27.
ESI (M-H+) 588.1;
1H NMR (400 Hz, DMSO-d6)δ2.43 (s, 3H, CH3), 2.71 (s, 3H, CH3), 6.07 (d, J = 8.8 Hz, 1H, ArH), 6.89 (d, J = 7.2 Hz, 1H, ArH), 7.09 (d, J = 7.2 Hz, 1H, ArH), 7.14 (t, J = 8.0 Hz, 1H, ArH), 7.28 (d, J = 7.6 Hz, 1H, ArH), 7.59 (dd, J = 8.8 Hz, 2.4 Hz, 1H, ArH), 7.89 (s, 2H, ArH), 7.95 (d, J = 8.0 Hz, 1H, ArH), 8.41 (d, J = 2.4 Hz, 1H, ArH), 9.96 (s, 1H, NH), 10.56 (s, 1H, NH);
13C NMR (100 Hz, DMSO-d6)δ16.49, 20.07, 113.74, 117.58, 119.35, 119.70, 120.43, 120.50, 120.84, 122.06, 124.14, 125.05, 126.42, 126.60, 128.35, 128.66, 129.97, 133.94, 138.62, 139.25, 143.13, 138.05, 155.27.
分析 (C26H18Cl3N3O5S): 計算値 C, 52.85; H, 3.07; N, 7.11; S, 5.43; 測定値 C, 53.10; H, 3.27; N, 7.36; S, 5.68.
ESI (M-H+) 328.8;
1H NMR (400 Hz, DMSO-d6)δ2.54 (s, 3H, CH3), 2.74 (s, 3H, CH3), 6.89 (d, J = 7.2 Hz, 1H, ArH), 6.97 (d, J = 7.2 Hz, 1H, ArH), 7.08-7.16 (m, 2H), 7.29 (d, J = 7.7 Hz, 2H, ArH), 7.51 (d, J = 8.3 Hz, 2H, ArH), 7.60 (d, J = 7.7 Hz, 1H, ArH), 7.82 (d, J = 7.84 Hz, 1H, ArH), 8.53 (s, 1H, NH), 8.82 (s, 1H, NH), 10.65 (s, 1H, NH);
13C NMR (100 Hz, DMSO-d6)δ16.81, 20.16, 117.04, 117.64, 118.31, 119.10, 120.44, 120.99, 121.79, 123.51, 124.81, 125.92, 128.79, 129.65, 131.89, 138.81, 139.92, 153.07. 分析 (C21H19N3O・0.125C2H5OH): 計算値 C, 76.15; H, 5.94; N, 12.54; 測定値 C, 75.89; H, 5.88; N, 12.76.
ESI (M-H+) 358.9;
1H NMR (200 Hz, DMSO-d6)δ2.54 (s, 3H, CH3), 2.74 (s, 3H, CH3), 3.71 (s, 3H, CH3), 6.80-6.91 (m, 3H), 7.07-7.16 (m, 2H), 7.42 (d, J = 8.8 Hz, 2H, ArH), 7.60 (d, J = 7.0 Hz, 1H, ArH), 7.80 (d, J = 7.4 Hz, 1H, ArH), 8.50 (s, 1H, NH), 8.72 (s, 1H, NH), 10.68 (s, 1H, NH);
13C NMR (50 Hz, DMSO-d6)δ16.85, 20.21, 55.18, 114.02, 116.73, 116.79, 117.65, 119.14, 120.13, 120.45, 121.01, 123.83, 124.78, 125.91, 129.67, 131.68, 132.97, 138.81, 153.26, 154.46, 221.88.
分析 (C22H21N3O2・0.125C2H5OH): 計算値 C, 73.18; H, 6.00; N, 11.51; 測定値 C, 72.98; H, 5.92; N, 11.94.
ESI (M-H+) 365.1;
1H NMR (200 Hz, アセトン-d6)δ2.60 (s, 3H, CH3), 2.80 (s, 3H, CH3), 3.29 (s, 3H, CH3), 3.91 (s, 3H, CH3), 6.64 (d, J = 7.8 Hz, 1H, ArH), 6.92 (d, J = 7.2 Hz, 1H, ArH), 7.03-7.18 (m, 4H, ArH), 7.59 (d, J = 8.8 Hz, 2H, ArH), 8.10 (d, J = 8.0 Hz, 1H, ArH), 10.23 (s, 1H, NH);
13C NMR (50 Hz, アセトン-d6)δ17.14, 20.65, 39.86, 56.15, 114.92, 118.87, 119.58, 119.58, 121.68, 122.82, 122.90, 126.85, 126.90, 126.97, 127.50, 129.57, 131.09, 131.14, 139.22, 140.21, 164.21.
分析 (C22H22N2O3S): 計算値 C, 66.98; H, 5.62; N, 7.10; 測定値 C, 75.89; H, 5.88; N, 12.76.
ESI (M-H+) 431.1;
1H NMR (200 Hz, DMSO-d6)δ2.57 (s, 3H, CH3), 2.73 (s, 3H, CH3), 3.33 (s, 3H, CH3), 6.59 (d, J = 7.8 Hz, 1H, ArH), 6.87(d, J = 7.3 Hz, 1H, ArH), 7.59 (t, J = 7.8 Hz, 1H, ArH), 7.11 (d, J = 7.3 Hz, 1H, ArH), 7.70-8.13 (m, 5H, ArH), 11.12 (s, 1H, NH);
13C NMR (50 Hz, DMSO-d6)δ17.27, 20.27, 118.22, 118.55, 120.57, 120.68, 122.46, 122.53, 124.42, 124.57, 125.69, 126.76, 129.74, 130.98, 131.86, 137.83, 138.23, 139.13. 分析 (C22H19FN2O2S): 計算値 C, 61.10; H, 4.43; N, 6.48; S, 7.41; 測定値 C, 61.39; H, 4.49; N, 6.97; S, 7.42.
ESI (M-H+) 407.1;
1H NMR (400 Hz, DMSO-d6)δ0.97 (t, J = 6.8 Hz, 3H, CH3), 2.58 (s, 3H, CH3), 2.73 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 6.56 (d, J = 7.6 Hz, 1H, ArH), 6.87 (d, J = 7.2 Hz, 1H, ArH), 7.01 (t, J = 7.6 Hz, 1H, ArH), 7.06-7.11 (m, 3H, ArH), 7.58 (d, J = 8.8 Hz, 2H, ArH), 8.04 (d, J = 7.6 Hz, 1H, ArH), 10.91 (s, 1H, NH);
13C NMR (100 Hz, DMSO-d6)δ 13.21, 17.33, 20.22, 46.06, 55.67, 114.24, 118.09, 118.47, 120.49, 120.56, 122.06, 122.39, 123.28, 125.26, 126.57, 129.62, 129.83, 139.01, 139.42, 162.60.
分析 (C23H24N2O3S): 計算値 C, 67.62; H, 5.92; N, 6.86; 測定値 C, 67.40; H, 6.18; N, 6.55.
ESI (M-H+) 421.1;
1H NMR (400 Hz, DMSO-d6)δ0.79 (t, J = 7.4 Hz, 3H, CH3), 2.58 (s, 3H, CH3), 2.73 (s, 3H, CH3), 3.35 (s, 2H, CH2), 3.81 (s, 3H, OCH3), 6.60 (d, J = 7.6 Hz, 1H, ArH), 6.87 (d, J = 7.3 Hz, 1H, ArH), 7.01 (t, J = 7.7 Hz, 1H, ArH), 7.09-7.11 (m, 3H, ArH), 7.57 (d, J = 8.8 Hz, 2H, ArH), 8.04 (d, J = 7.8 Hz, 1H, ArH), 10.76 (s, 1H, NH);
13C NMR (100 Hz, DMSO-d6)δ 11.07, 17.28, 20.21, 21.12, 52.89, 55.64, 114.21, 118.06, 118.51, 120.52, 120.56, 121.99, 122.89, 123.35, 125.33, 126.58, 129.60, 129.69, 129.85, 138.97, 139.05, 162.60.
分析 (C24H26N2O3S): 計算値 C, 68.22; H, 6.20; N, 6.63; S, 7.59; 測定値 C, 68.43; H, 6.05; N, 6.66; S, 7.26.
ESI (M-H+) 421.1;
1H NMR (400 Hz, アセトン-d6)δ1.12 (t, J = 6.6 Hz, 6H, CH3), 2.56 (s, 3H, CH3), 2.81 (s, 3H, CH3), 2.85 (s, 2H, CH2), 3.87 (s, 3H, OCH3), 4.78 (m, 1H, CH), 6.79 (d, J = 7.6 Hz, 1H, ArH), 6.92 (d, J = 7.3 Hz, 1H, ArH), 7.03-7.15 (m, 4H, ArH), 7.66 (d, J = 8.9 Hz, 2H, ArH), 8.18 (d, J = 7.9 Hz, 1H, ArH), 10.02 (s, 1H, NH);
13C NMR (100 Hz, アセトン-d6)δ17.15, 20.64, 21.86, 22.20, 23.32, 53.17, 56.09, 114.83, 118.77, 119.18, 120.27, 121.74, 122.06, 123.69, 126.90, 127.49, 128.51, 130.73, 131.08, 133.77, 140.06, 141.98, 163.87. 分析 (C24H26N2O3S): 計算値 C, 68.22; H, 6.20; N, 6.63; S, 7.59; 測定値 C, 68.12; H, 6.43; N, 6.45; S, 7.25.
ESI (M-H+) 211.0;
1H NMR (400 Hz, DMSO-d6)δ7.27-7.37 (m, 2H, ArH), 7.51 (t, J = 7.2 Hz, 1H, ArH), 7.75 (d, J = 8.0 Hz, 1H, ArH), 8.23 (d, J = 7.6 Hz, 1H, ArH), 8.30 (d, J = 7.7 Hz, 1H, ArH), 8.60 (d, J = 7.2 Hz, 1H, ArH), 12.16 (s, 1H, NH);
13C NMR (100 Hz, DMSO-d6)δ112.64, 118.36, 120.65, 120.70, 121.53, 121.72, 127.14, 127.35, 128.08, 131.70, 132.93, 140.68.
分析 (C12H8N2O2): 計算値 C, 67.92; H, 3.80; N, 13.20; 測定値 C, 67.94; H, 3.95; N, 13.21.
ESI (M-H+) 351.0;
1H NMR (400 Hz, DMSO-d6)δ3.74 (s, 3H, OCH3), 6.90-7.02 (m, 4H, ArH), 7.14 (t, J = 7.2 Hz, 1H, ArH), 7.38 (t, J = 7.6 Hz, 1H, ArH), 7.57 (d, J = 8.0 Hz, 1H, ArH), 7.67 (d, J = 8.8 Hz, 1H, ArH), 7.88 (d, J = 7.6 Hz, 1H, ArH), 8.05 (d, J = 7.6 Hz, 1H, ArH), 9.80 (s, 1H, NH), 10.94 (s, 1H, NH);
13C NMR (100 Hz, DMSO-d6)δ55.58, 111.50, 114.22, 117.77, 118.64, 118.88, 119.91, 120.20, 121.00, 122.27, 123.99, 125.85, 129.12, 131.14, 134.59, 139.49, 162.40.
分析 (C19H16N2O3S): 計算値 C, 64.76; H, 4.58; N, 7.95; S, 9.10; 測定値 C, 64.79; H, 4.75; N, 7.88; S, 8.47.
ESI (M-H+) 389.0;
1H NMR (400 Hz, DMSO-d6)δ6.75 (d, J = 7.6 Hz, 1H, ArH), 6.96 (t, J = 7.7 Hz, 1H, ArH), 7.14 (t, J = 7.5 Hz, 1H, ArH), 7.38 (t, J = 7.7 Hz, 1H, ArH), 7.54 (d, J = 8.1 Hz, 1H, ArH), 7.74 (d, J = 7.7 Hz, 1H, ArH), 7.94-7.79 (m, 4H, ArH), 8.06 (d, J = 7.7 Hz, 1H, ArH), 10.08 (s, 1H, NH), 11.02 (s, 1H, NH);
13C NMR (100 Hz, DMSO-d6)δ111.51, 118.61, 118.93, 119.02, 119.82, 120.32, 121.49, 122.22, 123.60, 124.30, 124.73, 126.07, 129.66, 129.89, 130.79, 131.01, 135.65, 139.69, 140.62.
分析 (C19H13F3N2O2S): 計算値 C, 58.46; H, 3.36; N, 7.18; F, 14.60; S, 8.21; 測定値 C, 72.98; H, 5.92; N, 11.94.
本発明のベンゼンスルホンアミド誘導体の予備細胞毒性分析において、ヒト膀胱癌TSGH細胞、ヒト肝芽腫HepG2細胞、ヒト直腸結腸腺癌HT-29細胞、ヒト鼻咽頭癌KB細胞、ヒト胃腺癌AGS細胞、ヒト乳癌MCF-7細胞、肺癌A549細胞、およびヒト前立腺癌PC-3細胞を使用し、腫瘍細胞に対する阻害活性を評価した。
全ての細胞系は、10%ウシ胎仔血清を加えたRPMI 1640中、5% CO2を含有する37℃の加湿室中で保持した。その後、全ての細胞系を化合物で72時間処理し、続いて0.4 mg/mLのMTTと共に37℃で2時間インキュベートした。培地を除去し、DMSOを添加してMTTの沈殿を溶解した。サーモマックス・マイクロプレート・リーダー(Thermomax microplate reader)(モレキュラー・デバイス(Molecular Devices)、米国カリフォルニア州、サニーベール)を用いて、540 nmで吸光度を測定することにより、細胞増殖を定量し、本発明のベンゼンスルホンアミド誘導体のIC50値を計算した。
全ての細胞系は、96穴マイクロタイタープレートにおいて、10%ウシ胎仔血清を加えたRPMI 1640中、5% CO2を含有する37℃の加湿室中で保持した。24時間後、一部の穴の細胞系を、10%トリクロロ酢酸(TCA)でその場で固定して、薬物添加時点(T0)の測定結果を示した。その後、他のウェルの細胞系を、本発明のベンゼンスルホンアミド誘導体と共にさらに48時間インキュベートし、10% TCAでその場で固定して、反応を停止した時間(Tx)での測定結果を示した。プレートをPBSでリンスし、空気乾燥した後、0.4%スルホローダミンB溶液(1%酢酸中の対容量重量)を各ウェルに添加し、プレートを室温で10分間インキュベートした。1%酢酸で結合していないスルホローダミンBを除去し、プレートを空気乾燥した。続いて、スルホローダミンBと結合した細胞を10 mMトリス塩基(トリズマ(Trizma);シグマ)で可溶化した。サーモマックス・マイクロプレート・リーダー(Thermomax microplate reader)(モレキュラー・デバイス(Molecular Devices)、米国カリフォルニア州、サニーベール)を用いて、515 nmで吸光度を測定することにより、細胞増殖を定量した。検出した吸光度より、本発明のベンゼンスルホンアミド誘導体の半数阻害濃度(GI50)を得た。
肺癌A549細胞(BCRC 60074; BCRC)を、10%ウシ胎仔血清を加えたRPMI 1640中、5% CO2を含有する37℃の加湿室中で保持した。全ての細胞系を毎週2世代成長させた。
1日目に、ヒト線維芽細胞と共培養したHUVEC(ヒト臍帯静脈内皮細胞)を最適化した培地中でインキュベートし、5% CO2を含有する37℃の加湿室中で保持した。1日後、陽性対照として、培地に組み換えヒトVEGF(25 ng/mL)を加え、陰性対照として、スラミン(2 M)と組み合わせたヒトVEGF(25 ng/mL)を用いた。細胞を、GM119を含まないか含む(0.1、1または10μM)VEGF(25 ng/mL)で刺激した。3、6および8日目に培地を交換した。11日目に、抗ヒトCD31抗体(クラボウ、東京、日本)により、臍帯静脈内皮細胞のチューブ様構造が観察され、チューブ様構造の領域を分析した。
G418の選択下で蛍ルシフェラーゼ遺伝子を安定して発現するネズミ乳癌細胞系4T1-Luc細胞を、10%ウシ胎仔血清を加えたRPMI中で培養した。細胞を、5% CO2を含有する空気中、37℃で保持し、週に2回継代培養した。
4T1-Luc細胞をGM119で処理した後、位相差顕微鏡を用いて4T1-Luc細胞の細胞形態を観察した。6穴プレートにカバーグラスを置き、各ウェルに50,000個の腫瘍細胞を播種した。腫瘍細胞を10%ウシ胎仔血清を加えた培地中で成長させた後、0、0.01、0.1、1または10μMのGM119で48時間処理した。細胞をギムザ染色液(ギムザ粉0.38 g、メタノール15%、およびグリセロール5%)で染色した。細胞を洗浄、乾燥およびシールした後、位相差顕微鏡で細胞の画像を撮影した。
4T1-Luc細胞をGM119(0、0.01、0.1、1または10μM)で36時間処理した後、遠心分離により細胞を回収した。その後、回収した細胞を氷上、超音波で15秒間破壊した。遠心分離後、細胞溶解物の上層を回収して、細胞抽出物を得た。タンパク質濃度をブラッドフォード色素結合法(バイオラド(BioRad)、米国)で分析した。25μgの細胞抽出物をSDS-PAGEで分離し、移動させ、抗体である抗p53、抗p-p53、および抗アクチンを用いて可視化した。
GM119(25 mg/kg)を、4T1-Luc細胞を短時間移植したマウスに適用した後、それにタキソール(10 mg/kg)を適用して、GM119の4T1-Luc細胞に対する効果を観察した。
Claims (18)
- 以下の式(I)で表される、ベンゼンスルホンアミド誘導体:
式中、
R1はH、またはC1-6アルキルであり;
R 2 はH,およびR 3 は、
であるか、または共に結合して
を形成し;
Dは
であり;
R4はH、またはニトロであり;
X、Y、および各R5はそれぞれ独立して C1-6アルキルであり;
各R6は独立してH、ハロゲン、C1-6アルキル、C1-6アルコキシ、ハロゲン置換C1-6アルキル、ハロゲン置換C1-6アルコキシ、ニトロ、-NR8R9、または-SO2NR10R11であり;
R7はH、またはハロゲンであり;
R8、R9、R10、およびR11は、それぞれ独立してH、またはC1-6アルキルであり;
iは、0.1、または2であり;および
nは、0、1、2、または3である。 - 請求項1に記載のベンゼンスルホンアミド誘導体であって、 R8、およびR9 がHである、ベンゼンスルホンアミド誘導体。
- 請求項1に記載のベンゼンスルホンアミド誘導体であって、R10、およびR11がHである、ベンゼンスルホンアミド誘導体。
- 請求項4に記載のベンゼンスルホンアミド誘導体であって、式中、R6がH、Cl、メチル、メトキシ、ニトロ、-NH2、または-SO2NH2である、ベンゼンスルホンアミド誘導体。
- 請求項7に記載のベンゼンスルホンアミド誘導体であって、R6が-CF3である、ベンゼンスルホンアミド誘導体。
- 請求項10に記載のベンゼンスルホンアミド誘導体であって、R6がニトロである、ベンゼンスルホンアミド誘導体。
- 請求項13に記載のベンゼンスルホンアミド誘導体であって、R1がH、またはメチルであり、およびR7がClである、ベンゼンスルホンアミド誘導体。
- 請求項1に記載のベンゼンスルホンアミド誘導体であって、ベンゼンスルホンアミド誘導体が細胞周期阻害剤として使用される、ベンゼンスルホンアミド誘導体。
- 請求項1に記載のベンゼンスルホンアミド誘導体であって、ベンゼンスルホンアミド誘導体が、胃癌細胞、結腸癌細胞、および鼻咽頭癌細胞の成長を阻害する、ベンゼンスルホンアミド誘導体。
- 細胞周期阻害剤として使用される医薬組成物であって、以下の式(I)で表されるベンゼンスルホンアミド誘導体の有効量を含む、医薬組成物:
式中、
R1はH、またはC1-6アルキルであり;
R 2 はH,およびR 3 は
であるか、または共に結合して
を形成し;
Dは
であり;
R4はH、またはニトロであり;
X、Y、および各R5はそれぞれ独立して C 1-6 アルキルであり;
各R6は独立してH、ハロゲン、C1-6アルキル、C1-6アルコキシ、ハロゲン置換C1-6アルキル、ハロゲン置換C1-6アルコキシ、ニトロ、-NR8R9、または-SO2NR10R11であり;
R7はH、またはハロゲンであり;
R8、R9、R10、およびR11は、それぞれ独立してH、またはC1-6アルキルであり;
iは、0,1、または2であり、および
nは、0、1,2、または3である。
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TW099107557A TWI410408B (zh) | 2010-03-16 | 2010-03-16 | 苯磺醯胺衍生物及其醫藥組合物 |
TW099107557 | 2010-03-16 |
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EP (1) | EP2366687B1 (ja) |
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US5834462A (en) * | 1993-07-26 | 1998-11-10 | Eisai Co., Ltd. | Tricyclic heterocyclic sulfonamide and sulfonic ester derivatives |
JP3690825B2 (ja) * | 1993-07-26 | 2005-08-31 | エーザイ株式会社 | 三環式ヘテロ環含有スルホンアミドおよびスルホン酸エステル誘導体 |
NZ273073A (en) * | 1993-09-10 | 1996-09-25 | Eisai Co Ltd | Bicyclic heterocyclic sulphonamide and sulphonic acid ester derivatives and pharmaceutical compositions thereof |
JP3545461B2 (ja) * | 1993-09-10 | 2004-07-21 | エーザイ株式会社 | 二環式ヘテロ環含有スルホンアミド誘導体 |
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EP2366687A2 (en) | 2011-09-21 |
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JP2011190261A (ja) | 2011-09-29 |
TW201132626A (en) | 2011-10-01 |
TWI410408B (zh) | 2013-10-01 |
US8173693B2 (en) | 2012-05-08 |
KR20110104449A (ko) | 2011-09-22 |
EP2366687A3 (en) | 2011-12-14 |
US20110230651A1 (en) | 2011-09-22 |
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