JP2014502268A - ヘテロアリールスルホンアミド誘導体、それらの製造およびヒト治療におけるそれらの応用 - Google Patents
ヘテロアリールスルホンアミド誘導体、それらの製造およびヒト治療におけるそれらの応用 Download PDFInfo
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- JP2014502268A JP2014502268A JP2013540331A JP2013540331A JP2014502268A JP 2014502268 A JP2014502268 A JP 2014502268A JP 2013540331 A JP2013540331 A JP 2013540331A JP 2013540331 A JP2013540331 A JP 2013540331A JP 2014502268 A JP2014502268 A JP 2014502268A
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- Prior art keywords
- phenyl
- sulfonamide
- pyridine
- thiazol
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000002360 preparation method Methods 0.000 title claims description 4
- 238000002560 therapeutic procedure Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 81
- 238000000034 method Methods 0.000 claims abstract description 38
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 14
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 13
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 11
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- 102000003734 Voltage-Gated Potassium Channels Human genes 0.000 claims abstract description 10
- 108090000013 Voltage-Gated Potassium Channels Proteins 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical group 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- 229910052717 sulfur Chemical group 0.000 claims abstract description 7
- 239000011593 sulfur Chemical group 0.000 claims abstract description 7
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 3
- 239000011737 fluorine Substances 0.000 claims abstract description 3
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 3
- 125000005493 quinolyl group Chemical group 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract 3
- 239000000460 chlorine Substances 0.000 claims description 68
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- -1 8-quinolyl group Chemical group 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
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- 208000035475 disorder Diseases 0.000 claims description 7
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- 206010028980 Neoplasm Diseases 0.000 claims description 6
- ADXGZLMYJHQLJG-UHFFFAOYSA-N n-[2-[4-(4-methyl-1,3-benzothiazol-2-yl)piperazine-1-carbonyl]phenyl]pyridine-2-sulfonamide Chemical compound N=1C=2C(C)=CC=CC=2SC=1N(CC1)CCN1C(=O)C1=CC=CC=C1NS(=O)(=O)C1=CC=CC=N1 ADXGZLMYJHQLJG-UHFFFAOYSA-N 0.000 claims description 6
- LAEYSTYZGLGKBE-UHFFFAOYSA-N n-[2-[4-(6-chloro-1,3-benzothiazol-2-yl)piperazine-1-carbonyl]phenyl]pyridine-2-sulfonamide;hydrochloride Chemical compound Cl.S1C2=CC(Cl)=CC=C2N=C1N(CC1)CCN1C(=O)C1=CC=CC=C1NS(=O)(=O)C1=CC=CC=N1 LAEYSTYZGLGKBE-UHFFFAOYSA-N 0.000 claims description 6
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 6
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- RMDVJMZBLGSURX-UHFFFAOYSA-N n-[2-[1-(6-bromo-1,3-benzothiazol-2-yl)piperidin-4-yl]oxyphenyl]pyridine-2-sulfonamide Chemical compound S1C2=CC(Br)=CC=C2N=C1N(CC1)CCC1OC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=N1 RMDVJMZBLGSURX-UHFFFAOYSA-N 0.000 claims description 5
- PQUJIYDNCVIJHF-UHFFFAOYSA-N n-[2-[1-(6-methyl-1,3-benzoxazol-2-yl)piperidin-4-yl]oxyphenyl]pyridine-2-sulfonamide Chemical compound O1C2=CC(C)=CC=C2N=C1N(CC1)CCC1OC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=N1 PQUJIYDNCVIJHF-UHFFFAOYSA-N 0.000 claims description 5
- AQQKTRWAWUIXKC-UHFFFAOYSA-N n-[2-[4-(6-bromo-1,3-benzothiazol-2-yl)piperazine-1-carbonyl]phenyl]pyridine-2-sulfonamide Chemical compound S1C2=CC(Br)=CC=C2N=C1N(CC1)CCN1C(=O)C1=CC=CC=C1NS(=O)(=O)C1=CC=CC=N1 AQQKTRWAWUIXKC-UHFFFAOYSA-N 0.000 claims description 5
- CHSGLAMFRYTPKF-UHFFFAOYSA-N n-[2-[4-(6-bromo-1,3-benzothiazol-2-yl)piperazine-1-carbonyl]phenyl]quinoline-8-sulfonamide Chemical compound C1=CN=C2C(S(=O)(=O)NC3=CC=CC=C3C(=O)N3CCN(CC3)C3=NC4=CC=C(C=C4S3)Br)=CC=CC2=C1 CHSGLAMFRYTPKF-UHFFFAOYSA-N 0.000 claims description 5
- XETPZJGILMXLCR-UHFFFAOYSA-N n-[2-[4-(7-chloro-1,3-benzothiazol-2-yl)piperazine-1-carbonyl]phenyl]pyridine-2-sulfonamide Chemical compound S1C=2C(Cl)=CC=CC=2N=C1N(CC1)CCN1C(=O)C1=CC=CC=C1NS(=O)(=O)C1=CC=CC=N1 XETPZJGILMXLCR-UHFFFAOYSA-N 0.000 claims description 5
- UKYIUMLFJHIALD-UHFFFAOYSA-N n-[2-[[1-(4-methoxy-1,3-benzothiazol-2-yl)pyrrolidin-3-yl]methoxy]phenyl]pyridine-2-sulfonamide Chemical compound N=1C=2C(OC)=CC=CC=2SC=1N(C1)CCC1COC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=N1 UKYIUMLFJHIALD-UHFFFAOYSA-N 0.000 claims description 5
- FWKRHEQNUAHZOB-UHFFFAOYSA-N n-[2-[[1-(4-methyl-1,3-benzothiazol-2-yl)pyrrolidin-3-yl]methoxy]phenyl]pyridine-2-sulfonamide Chemical compound N=1C=2C(C)=CC=CC=2SC=1N(C1)CCC1COC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=N1 FWKRHEQNUAHZOB-UHFFFAOYSA-N 0.000 claims description 5
- HQUPVOAZJDPSBO-UHFFFAOYSA-N n-[3-[4-(6-chloro-1,3-benzothiazol-2-yl)piperazine-1-carbonyl]phenyl]-6-methylpyridine-2-sulfonamide Chemical compound CC1=CC=CC(S(=O)(=O)NC=2C=C(C=CC=2)C(=O)N2CCN(CC2)C=2SC3=CC(Cl)=CC=C3N=2)=N1 HQUPVOAZJDPSBO-UHFFFAOYSA-N 0.000 claims description 5
- PRZNECJSFLHDEH-UHFFFAOYSA-N n-[3-[4-(6-chloro-1,3-benzothiazol-2-yl)piperazine-1-carbonyl]phenyl]pyridine-2-sulfonamide Chemical compound S1C2=CC(Cl)=CC=C2N=C1N(CC1)CCN1C(=O)C(C=1)=CC=CC=1NS(=O)(=O)C1=CC=CC=N1 PRZNECJSFLHDEH-UHFFFAOYSA-N 0.000 claims description 5
- ZQNODSHXXVSTIH-UHFFFAOYSA-N n-[4-[4-(6-chloro-1,3-benzoxazol-2-yl)piperazine-1-carbonyl]phenyl]pyridine-2-sulfonamide Chemical compound O1C2=CC(Cl)=CC=C2N=C1N(CC1)CCN1C(=O)C(C=C1)=CC=C1NS(=O)(=O)C1=CC=CC=N1 ZQNODSHXXVSTIH-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
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- 230000002829 reductive effect Effects 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- MGLBSXFETBFWIT-UHFFFAOYSA-N N1=C(C=CC=C1)S(=O)(=O)NC1(CC=CC=C1)OC1CCNCC1C=1OC2=C(N1)C(=CC=C2)C(C)(C)C Chemical compound N1=C(C=CC=C1)S(=O)(=O)NC1(CC=CC=C1)OC1CCNCC1C=1OC2=C(N1)C(=CC=C2)C(C)(C)C MGLBSXFETBFWIT-UHFFFAOYSA-N 0.000 claims description 4
- HWXWKKJZWGZDJU-UHFFFAOYSA-M [Na+].BrC1=CC=C2N=C(SC2=C1)N1CCN(CC1)C(=O)C1=C([N-]S(=O)(=O)C2=NC=CC=C2)C=CC=C1 Chemical compound [Na+].BrC1=CC=C2N=C(SC2=C1)N1CCN(CC1)C(=O)C1=C([N-]S(=O)(=O)C2=NC=CC=C2)C=CC=C1 HWXWKKJZWGZDJU-UHFFFAOYSA-M 0.000 claims description 4
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- FTCLFVJBYJJMOU-UHFFFAOYSA-N n-[2-[1-(1,3-benzothiazol-2-yl)piperidin-4-yl]oxyphenyl]pyridine-2-sulfonamide Chemical compound C=1C=CC=C(OC2CCN(CC2)C=2SC3=CC=CC=C3N=2)C=1NS(=O)(=O)C1=CC=CC=N1 FTCLFVJBYJJMOU-UHFFFAOYSA-N 0.000 claims description 4
- KGWRAHTZPPVCNC-UHFFFAOYSA-N n-[2-[1-(5-chloro-1,3-benzoxazol-2-yl)piperidin-4-yl]oxyphenyl]pyridine-2-sulfonamide Chemical compound N=1C2=CC(Cl)=CC=C2OC=1N(CC1)CCC1OC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=N1 KGWRAHTZPPVCNC-UHFFFAOYSA-N 0.000 claims description 4
- JHMDXRSCMBWCAH-UHFFFAOYSA-N n-[2-[4-(4-methyl-1,3-benzothiazol-2-yl)-1,4-diazepane-1-carbonyl]phenyl]quinoline-8-sulfonamide Chemical compound N=1C=2C(C)=CC=CC=2SC=1N(CC1)CCCN1C(=O)C1=CC=CC=C1NS(=O)(=O)C1=CC=CC2=CC=CN=C12 JHMDXRSCMBWCAH-UHFFFAOYSA-N 0.000 claims description 4
- PGMZZQSBSZSDSF-UHFFFAOYSA-N n-[2-[4-(6-bromo-1,3-benzothiazol-2-yl)piperazine-1-carbonyl]phenyl]-6-methylpyridine-2-sulfonamide;dihydrochloride Chemical compound Cl.Cl.CC1=CC=CC(S(=O)(=O)NC=2C(=CC=CC=2)C(=O)N2CCN(CC2)C=2SC3=CC(Br)=CC=C3N=2)=N1 PGMZZQSBSZSDSF-UHFFFAOYSA-N 0.000 claims description 4
- BLJDLAIEKBEZBH-UHFFFAOYSA-N n-[2-[4-(6-chloro-1,3-benzoxazol-2-yl)piperazine-1-carbonyl]phenyl]quinoline-8-sulfonamide Chemical compound C1=CN=C2C(S(=O)(=O)NC3=CC=CC=C3C(=O)N3CCN(CC3)C3=NC4=CC=C(C=C4O3)Cl)=CC=CC2=C1 BLJDLAIEKBEZBH-UHFFFAOYSA-N 0.000 claims description 4
- VPQNZNHSRCYEJF-UHFFFAOYSA-N n-[2-[4-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]piperazine-1-carbonyl]phenyl]pyridine-2-sulfonamide Chemical compound N=1C2=CC(C(F)(F)F)=CC=C2SC=1N(CC1)CCN1C(=O)C1=CC=CC=C1NS(=O)(=O)C1=CC=CC=N1 VPQNZNHSRCYEJF-UHFFFAOYSA-N 0.000 claims description 4
- VLPMAOQQURVSNS-UHFFFAOYSA-N n-[2-[4-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]piperazine-1-carbonyl]phenyl]quinoline-8-sulfonamide Chemical compound C1=CN=C2C(S(=O)(=O)NC3=CC=CC=C3C(=O)N3CCN(CC3)C3=NC4=CC=C(C=C4S3)OC(F)(F)F)=CC=CC2=C1 VLPMAOQQURVSNS-UHFFFAOYSA-N 0.000 claims description 4
- VXTMDNUGGBANEZ-UHFFFAOYSA-N n-[2-[[1-(1,3-benzothiazol-2-yl)pyrrolidin-3-yl]methoxy]phenyl]pyridine-2-sulfonamide Chemical compound C=1C=CC=C(OCC2CN(CC2)C=2SC3=CC=CC=C3N=2)C=1NS(=O)(=O)C1=CC=CC=N1 VXTMDNUGGBANEZ-UHFFFAOYSA-N 0.000 claims description 4
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- QZTXJRUCNBJKHI-UHFFFAOYSA-N n-[2-[[1-(6-fluoro-1,3-benzothiazol-2-yl)pyrrolidin-3-yl]methoxy]phenyl]pyridine-2-sulfonamide Chemical compound S1C2=CC(F)=CC=C2N=C1N(C1)CCC1COC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=N1 QZTXJRUCNBJKHI-UHFFFAOYSA-N 0.000 claims description 4
- GHYHGSNORYNIRO-UHFFFAOYSA-N n-[3-[4-(6-chloro-1,3-benzoxazol-2-yl)piperazine-1-carbonyl]phenyl]pyridine-2-sulfonamide Chemical compound O1C2=CC(Cl)=CC=C2N=C1N(CC1)CCN1C(=O)C(C=1)=CC=CC=1NS(=O)(=O)C1=CC=CC=N1 GHYHGSNORYNIRO-UHFFFAOYSA-N 0.000 claims description 4
- TZABFPVQEOIMCQ-UHFFFAOYSA-N n-[4-[4-(6-chloro-1,3-benzothiazol-2-yl)piperazine-1-carbonyl]phenyl]pyridine-2-sulfonamide Chemical compound S1C2=CC(Cl)=CC=C2N=C1N(CC1)CCN1C(=O)C(C=C1)=CC=C1NS(=O)(=O)C1=CC=CC=N1 TZABFPVQEOIMCQ-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
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- GKZUZTODSKKVLP-UHFFFAOYSA-N n-[2-[4-(6-chloro-1,3-benzothiazol-2-yl)piperazine-1-carbonyl]phenyl]quinoline-8-sulfonamide Chemical compound C1=CN=C2C(S(=O)(=O)NC3=CC=CC=C3C(=O)N3CCN(CC3)C3=NC4=CC=C(C=C4S3)Cl)=CC=CC2=C1 GKZUZTODSKKVLP-UHFFFAOYSA-N 0.000 claims description 2
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- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000002780 ion channel assay Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical class NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 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
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 210000005267 prostate cell Anatomy 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000036390 resting membrane potential Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000002948 striated muscle cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HKIGXXRMJFUUKV-UHFFFAOYSA-N tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CO)C1 HKIGXXRMJFUUKV-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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Abstract
Description
本発明は、Kvカリウムチャネル、具体的には、チャネルKv1.5、Kv4.3、およびKv11.1の遮断薬としての、ヘテロアリールスルホンアミド誘導体、 それらの製造およびヒト治療におけるそれらの応用に関する。
カリウムチャネルは、ヒトゲノムにおけるイオンチャンネルの最大ファミリーであり、およそ80種の遺伝子が存在する(Tamargo et al., Cardiovasc. Res. 2004, 62: 9-33)。これらのカリウムチャネルは、電位差(Kvチャネル)およびカルシウム(KCaチャネル)により活性化されるチャネル、内向き整流チャネル(Kir)およびtwo−pore型カリウムチャネル(K2p)という3つのサブファミリーに分けられる。サブファミリーはヒト生物体において最も多く発現されるものであり、興奮性細胞(心臓細胞、ニューロン、横紋筋細胞または平滑筋細胞)および非興奮性細胞、例えば、膵臓細胞、前立腺細胞、上皮小体細胞などにおいてほぼ普遍的な分布を示す(総説としては、Gutman G et al., Pharmacol. Rev. 2005, 57:473-508)。
R1は、水素、ハロゲン(F、Cl、Brなど)、トリフルオロメチル、トリフルオロメトキシ、直鎖または分岐鎖C1−C4アルキルおよび直鎖または分岐鎖C1−C4アルコキシからなる群の中から選択される、フェニルコア(芯)Xの1以上の置換基を表し、
nは0、1または2を表し、
Aは酸素または硫黄を表し、
Dは−C(=O)−、−CH2O−、または−O−を表し、
n=1または2であってDが−C(=O)−を表す場合には、Bは窒素を表し、あるいは、n=0であってDが−CH2O−を表す場合またはn=1であってDが−O−を表す場合には、BはCHを表し、
R2は水素、メチル、フッ素もしくは塩素原子、またはメトキシを表し、
HetArは、直鎖もしくは分岐鎖C1−C4アルキル、直鎖もしくは分岐鎖C1−C4アルコキシ、ハロゲン(F、Cl、Brなど)、またはトリフルオロメチルなどの基で場合により置換されていてもよいピリジルもしくはキノリル基を表す)。
を満たすもの
ならびにそれらの薬学的に許容可能な塩である。
R1が、水素、ハロゲン(F、Cl、Brなど)、トリフルオロメチル、トリフルオロメトキシ、直鎖または分岐鎖C1−C4アルキル、およびメトキシからなる群の中から選択される、フェニルコアXの1以上の置換基を表し、
nが1を表し、
Aが酸素または硫黄を表し、
Dが−C(=O)−または−O−を表し、
Dが−C(=O)−を表す場合にはBは窒素を表し、あるいは
Dが−O−を表す場合にはBはCHを表し、
R2が水素を表し、
HetArが、メチルまたはトリフルオロメチルなどの基で置換されていてもよい2−ピリジルまたは8−キノリル基を表し、
かつ、スルホンアミド基(−NH−SO2HetAr)が、とりわけ、フェニルコアY上の、D基が占める位置のオルト位に位置するもの
ならびにそれらの薬学的に許容可能な塩である。
R1が、水素、ハロゲン(F、Cl、Brなど)、トリフルオロメチル、トリフルオロメトキシ、直鎖または分岐鎖C1−C4アルキル、およびメトキシからなる群の中から選択される、フェニル基Xの1以上の置換基を表し、
Aが硫黄を表し、
nが1を表し、
Dが−C(=O)−を表し、
Bが窒素を表し、
R2が水素を表し、
HetArが、メチルまたはトリフルオロメチルなどの基で場合により置換されていてもよい2−ピリジル基を表し、
かつ、スルホンアミド基(−NH−SO2HetAr)がフェニルコアY上の、D基が占める位置のオルト位に位置するもの
ならびにそれらの薬学的に許容可能な塩である。
1)N−(2−(4−(6−フルオロベンゾ[d]オキサゾール−2−イル)ピペラジン−1−カルボニル)フェニル)−5−(トリフルオロメチル)ピリジン−2−スルホンアミド、
2)N−(2−(4−(6−フルオロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
3)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
4)N−(2−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド塩酸塩、
5)N−(2−(4−(4−メチルベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
6)N−(2−(4−(7−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
7)N−(2−(4−(5−(トリフルオロメチル)ベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
8)N−(2−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)−5−(トリフルオロメチル)ピリジン−2−スルホンアミド、
9)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)−6−メチルピリジン−2−スルホンアミド二塩酸塩、
10)N−(3−(4−(6−クロロベンゾ[d]オキサゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
11)N−(3−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
12)N−(3−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)−6−メチルピリジン−2−スルホンアミド、
13)N−(4−(4−(6−フルオロベンゾ[d]オキサゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
14)N−(4−(4−(6−クロロベンゾ[d]オキサゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
15)N−(4−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
16)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)キノリン−8−スルホンアミド、
17)N−(2−(4−(6−クロロベンゾ[d]オキサゾール−2−イル)ピペラジン−1−カルボニル)フェニル)キノリン−8−スルホンアミド、
18)N−(2−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)キノリン−8−スルホンアミド、
19)N−(2−(4−(6−(トリフルオロメトキシ)ベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)キノリン−8−スルホンアミド、
20)N−(2−(4−(4−メチルベンゾ[d]チアゾール−2−イル)−1,4−ジアゼパン−1−カルボニル)フェニル)キノリン−8−スルホンアミド、
21)N−(2−(1−(6−メチルベンゾ[d]オキサゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
22)N−(2−(1−(6−クロロベンゾ[d]オキサゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
23)N−(2−(1−(5−tert−ブチルベンゾ[d]オキサゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
24)N−(2−(1−(5−クロロベンゾ[d]オキサゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
25)N−(2−(1−(ベンゾ[d]チアゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
26)N−(2−(1−(6−クロロベンゾ[d]チアゾール−2−イル)ピペリジン−4−イルオキシ)フェニル−ピリジン−2−スルホンアミド、
27)N−(2−(1−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
28)N−(2−((1−(ベンゾ[d]チアゾール−2−イル)ピロリジン−3−イル)メトキシ)フェニル)ピリジン−2−スルホンアミド、
29)N−(2−((1−(6−フルオロベンゾ[d]チアゾール−2−イル)ピロリジン−3−イル)メトキシ)フェニル)ピリジン−2−スルホンアミド、
30)N−(2−((1−(6−クロロベンゾ[d]チアゾール−2−イル)ピロリジン−3−イル)メトキシ)フェニル)ピリジン−2−スルホンアミド、
31)N−(2−((1−(4−メチルベンゾ[d]チアゾール−2−イル)ピロリジン−3−イル)メトキシ)フェニル)ピリジン−2−スルホンアミド、
32)N−(2−((1−(4−メトキシベンゾ[d]チアゾール−2−イル)ピロリジン−3−イル)メトキシ)フェニル)ピリジン−2−スルホンアミド、
33)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミドリチウム、
34)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミドナトリウム、および
35)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミドカリウム。
本発明の化合物は、下に記載する合成方法を用いることにより、または当業者に公知の合成方法を用いることにより合成することができる。
B=Nの場合の一般式Iで表される化合物のこの合成方法(略図1)は、以下の一連の工程を特徴とする。
B=Nの場合の一般式Iで表される化合物のこの合成方法(略図2)は、以下の一連の工程を特徴とする。
B=CHの場合の一般式Iの化合物のこの合成方法(略図3)は、以下の一連の工程を特徴とする。
中間体1:
a)6−フルオロ−ベンゾオキサゾール−2−チオール(1a)
a)2−クロロ−6−フルオロ−ベンゾチアゾール(2a)
a)6−フルオロ−2−ピペラジン−1−イル−ベンゾオキサゾール(3a)
a)5−トリフルオロメチル−ピリジン−2−スルホニルクロリド(4a)
a)3−(ピリジン−2−スルホンアミド)安息香酸(5a)
(収率:94%)。
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:85−15、Rf=0.36。
(収率:50%)。
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:85−15、Rf=0.37。
a)N−(2−(ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミドトリフルオロアセタート(6a)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:90−10、Rf=0.25。
実施例1:N−(2−(4−(6−フルオロベンゾ[d]オキサゾール−2−イル)ピペラジン−1−カルボニル)フェニル)−5−(トリフルオロメチル)ピリジン−2−スルホンアミド(1)
NMR 1H (CDCl3) ppm: 8.94 (s, 1H), 8.69 (s, 1H), 8.19 (m, 2H), 7.74 (d, 1H), 7.41 (t, 1H), 7.26 (m, 2H), 7.17 (t, 1H), 7.07 (d, 1H), 6.95 (t, 1H), 3.76 (m, 8H).
MS (-ESI) m/z 548 (M-H-)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.58。
NMR 1H (CDCl3) ppm: 8.65 (d, 1H), 8.58 (s, 1H), 8.03 (d, 1H), 7.89 (t, 1H), 7.77 (d, 1H), 7.50 (m, 1H), 7.39 (m, 3H), 7.12 (m, 3H), 3.62 (m, 8H).
MS (+ESI) m/z 498 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.60。
mp=102℃
NMR 1H (CDCl3) ppm: 8.66 (d, 1H), 8.56 (s, 1H), 8.03 (d, 1H), 7.88 (t, 1H), 7.75 (m, 2H), 7.41 (m, 4H), 7.16 (m, 2H), 3.64 (m, 8H).
MS (+ESI) m/z 558 (MH+)
NMR 1H (DMSO) ppm: 10.70(s, 1H), 8.7(d, 1H), 8.0(m, 1H), 7.8(m, 2H), 7.6(m, 1H), 7.4(d, 1H), 7.3(m, 3H), 7.2(m, 1H), 7.1 (d, 1H), 3.6(m, 8H).
MS(+ESI)m/z 514(MH+ 基準)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.70。
NMR 1H (CDCl3) ppm: 8.65 (m, 2H), 8.03 (d, 1H), 7.87 (t, 1H), 7.79 (d, 1H), 7.48 (d, 1H), 7.41 (m, 2H), 7.20 (d, 1H), 7.14 (m, 2H), 7.04 (t, 1H), 3.63 (m, 8H), 2.56 (s, 3H).
MS (+ESI) m/z 494 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.54。
NMR 1H (CDCl3) ppm: 8.66 (d, 1H), 8.57 (s, 1H), 8.04 (d, 1H), 7.89 (t, 1H), 7.77 (d, 1H), 7.42 (m, 3H), 7.29 (m, 1H), 7.16 (m, 3H), 3.66 (m, 8H).
MS (+ESI) m/z 514 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.66。
NMR 1H (CDCl3) ppm: 8.67 (d, 1H), 8.55 (s, 1H), 8.04 (d, 1H), 7.89 (t, 1H), 7.76 (s, 1H), 7.74 (dd, 2H), 7.41 (m, 3H), 7.21 (d, 1H), 7.14 (t, 1H), 3.68 (m, 8H).
MS (+ESI) m/z 548 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.50。
NMR 1H (CDCl3) ppm: 8.93 (s, 1H), 8.71 (s, 1H), 8.18 (m, 2H), 7.74 (d, 1H), 7.60 (s, 1H), 7.47 (d, 1H), 7.40 (t, 1H), 7.26 (m, 2H), 7.16 (t, 1H), 3.69 (m, 8H).
MS (-ESI) m/z 580 (M-H-)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.73。
mp=180℃
NMR 1H (DMSO-d6) ppm: 10.03 (s, 1H), 8.07 (s, 1H), 7.93 (t, 1H), 7.70 (d, 1H), 7.53 (d, 1H), 7.42 (m, 2H), 7.33 (m, 2H), 7.21 (m, 2H), 3.68 (m, 8H), 2.55 (s, 3H).
MS (+ESI) m/z 572 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−AcOEt:95−5、Rf=0.30。
NMR 1H (DMSO-d6) ppm: 10.76 (s, 1H), 8.73 (d, 1H), 8.08 (t, 1H), 8.00 (d, 1H), 7.67 (t, 1H), 7.60 (s, 1H), 7.32 (m, 2H), 7.22 (m, 3H), 7.08 (d, 1H), 3.63 (m, 6H), 3.34 (m, 2H).
MS (+ESI) m/z 498 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.50。
NMR 1H (DMSO-d6) ppm: 10.77 (s, 1H), 8.73 (d, 1H), 8.09 (t, 1H), 8.00 (d, 1H), 7.94 (d, 1H), 7.67 (m, 1H), 7.46 (d, 1H), 7.32 (m, 2H), 7.22 (m, 2H), 7.09 (d, 1H), 3.66 (m, 6H), 3.34 (m, 2H).
MS (-ESI) m/z 512 (M-H-)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.52。
NMR 1H (DMSO-d6) ppm: 10.71 (s, 1H), 7.95 (m, 2H), 7.79 (d, 1H), 7.52 (d, 1H), 7.46 (d, 1H), 7.32 (m, 2H), 7.23 (m, 2H), 7.09 (d, 1H), 3.62 (m, 6H), 3.38 (m, 2H), 2.52 (s, 3H).
MS (+ESI) m/z 528 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.28。
NMR 1H (DMSO-d6) ppm: 10.87 (s, 1H), 8.72 (d, 1H), 8.06 (m, 2H), 7.67 (m, 1H), 7.44 (d, 1H), 7.33 (d, 1H), 7.27 (m, 3H), 7.21 (d, 1H), 7.02 (t, 1H), 3.61 (m, 8H).
MS (+ESI) m/z 482 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.40。
NMR 1H (DMSO-d6) ppm: 10.89 (s, 1H), 8.70 (d, 1H), 8.04 (m, 2H), 7.62 (m, 2H), 7.29 (m, 3H), 7.18 (m, 3H), 3.62 (m, 8H).
MS (+ESI) m/z 498 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.34。
NMR 1H (DMSO-d6) ppm: 10.87 (s, 1H), 8.73 (d, 1H), 8.07 (m, 2H), 7.93 (d, 1H), 7.65 (t, 1H), 7.44 (d, 1H), 7.32 (m, 3H), 7.21 (d, 2H), 3.60 (m, 8H).
MS (-ESI) m/z 512 (M-H-)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.73。
NMR 1H (CDCl3) ppm: 9.16 (m, 2H), 8.39 (d, 1H), 8.17 (d, 1H), 7.93 (d, 1H), 7.75 (s, 1H), 7.58 (m, 3H), 7.42 (s, 2H), 7.31 (m, 1H), 7.10 (d, 2H), 3.30 (m, 8H).
MS (+ESI) m/z 608 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.68。
NMR 1H (CDCl3) ppm: 9.15 (m, 2H), 8.40 (d, 1H), 8.20 (d, 1H), 7.96 (d, 1H), 7.57 (m, 3H), 7.31 (m, 3H), 7.18 (d, 1H), 7.10 (d, 2H), 3.30 (m, 8H).
MS (+ESI) m/z 548 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.61。
NMR 1H (CDCl3) ppm: 9.15 (m, 2H), 8.39 (d, 1H), 8.17 (d, 1H), 7.93 (d, 1H), 7.58 (m, 4H), 7.47 (d, 1H), 7.30 (m, 2H), 7.10 (d, 2H), 3.30 (m, 8H).
MS (+ESI) m/z 564 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.76。
NMR 1H (DMSO-d6) ppm: 9.39 (s, 1H), 9.10 (d, 1H), 8.49 (d, 1H), 8.26 (t, 2H), 7.97 (s, 1H), 7.71 (m, 2H), 7.54 (d, 1H), 7.47 (d, 1H), 7.37 (m, 1H), 7.27 (m, 2H), 7.14 (m, 1H), 3.62 (m, 6H), 2.77 (m, 2H).
MS (+ESI) m/z 614 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:95−5、Rf=0.80。
NMR 1H (CDCl3) ppm: 9.13 (m, 1H), 8.86 (m, 1H), 8.62 (d, 1H), 8.41 (m, 1H), 8.20 (m, 1H), 7.98 (m, 1H), 7.55 (m, 2H), 7.47 (m, 1H), 7.28 (m, 1H), 7.12 (m, 1H), 6.99 (m, 2H), 6.85 (m, 1H), 3.71 (m, 4H), 3.51 (m, 2H), 3.20 (m, 2H), 2.47 (s, 3H), 2.09 (m, 2H).
MS (+ESI) m/z 558 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−AcOEt:70−30、Rf=0.43。
NMR 1H (DMSO-d6) ppm: 9.57 (s, 1H), 8.61 (d, 1H), 7.96 (dt, 1H), 7.82 (d, 1H), 7.53 (m, 1H), 7.28 (dd, 1H), 7.24 (s, 1H), 7.18 (d, 1H), 7.1 1 (t, 1H), 6.98 (m, 2H), 6.86 (t, 1H), 4.53 (m, 1H), 3.72 (m, 2H), 3.48 (m, 2H), 2.35 (s, 3H), 1.77 (m, 2H), 1.48 (m, 2H).
MS (+ESI) m/z 465 (MH+)
TLC用シリカゲル60F254プレート(Merck)、石油エーテル−AcOEt:70−30、Rf=0.46。
NMR 1H (DMSO-d6) ppm: 9.58 (s, 1H), 8.63 (d, 1H), 7.98 (dt, 1H), 7.83 (d, 1H), 7.59 (d, 1H), 7.55 (m, 1H), 7.28 (m, 2H), 7.20 (dd, 1H), 7.14 (t, 1H), 6.99 (d, 1H), 6.86 (t, 1H), 4.54 (m, 1H), 3.72 (m, 2H), 3.52 (m, 2H), 1.79 (m, 2H), 1.51 (m, 2H).
MS (+ESI) m/z 485 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:90−10、Rf=0.65。
NMR 1H (DMSO-d6) ppm: 9.57 (s, 1H), 8.63 (m, 1H), 7.97 (dt, 1H), 7.83 (d, 1H), 7.53 (m, 1H), 7.30 (m, 3H), 7.11 (dt, 1H), 7.05 (dd, 1H), 6.99 (d, 1H), 6.85 (dt, 1H), 4.54 (m, 1H), 3.74 (m, 2H), 3.50 (m, 2H), 1.78 (m, 2H), 1.48 (m, 2H), 1.30 (s, 9H).
MS (+ESI) m/z 507 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−AcOEt:70−30、Rf=0.33。
NMR 1H (DMSO-d6) ppm: 9.57 (s, 1H), 8.63 (d, 1H), 7.98 (dt, 1H), 7.83 (d, 1H), 7.55 (m, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 7.29 (dd, 1H), 7.12 (t, 1H), 7.04 (dd, 1H), 6.99 (d, 1H), 6.86 (t, 1H), 4.55 (m, 1H), 3.74 (m, 2H), 3.55 (m, 2H), 1.79 (m, 2H), 1.52 (m, 2H).
MS (+ESI) m/z 485 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−AcOEt:80−20、Rf=0.75。
NMR 1H (DMSO-d6) ppm: 9.59 (s, 1H), 8.62 (d, 1H), 7.97 (dt, 1H), 7.82 (d, 1H), 7.77 (d, 1H), 7.53 (m, 1H), 7.47 (d, 1H), 7.28 (m, 2H), 7.10 (m, 2H), 6.99 (d, 1H), 6.86 (t, 1H), 4.56 (m, 1H), 3.72 (m, 2H), 3.47 (m, 2H), 1.79 (m, 2H), 1.53 (m, 2H).
MS (+ESI) m/z 467 (MH+)
TLC用シリカゲル60F254プレート(Merck)、石油エーテル−AcOEt:60−40、Rf=0.20。
NMR 1H (DMSO-d6)ppm: 9.59 (s, 1H), 8.62 (d, 1H), 7.97 (dt, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.54 (m, 1H), 7.44 (d, 1H), 7.29 (m, 2H), 7.12 (t, 1H), 6.99 (d, 1H), 6.86 (t, 1H), 4.56 (m, 1H), 3.72 (m, 2H), 3.49 (m, 2H), 1.78 (m, 2H), 1.52 (m, 2H).
MS (+ESI) m/z 501 (MH+)
TLC用シリカゲル60F254プレート(Merck)、石油エーテル−AcOEt:60−40、Rf=0.21。
NMR 1H (DMSO-d6) ppm: 9.59 (s, 1H), 8.62 (d, 1H), 8.03 (t, 1H), 7.98 (t, 1H), 7.82 (d, 1H), 7.53 (m, 1H), 7.40 (m, 2H), 7.26 (d, 1H), 7.12 (t, 1H), 6.99 (d, 1H), 6.86 (t, 1H), 4.56 (m, 1H), 3.72 (m, 2H), 3.49 (m, 2H), 1.79 (m, 2H), 1.53 (m, 2H).
MS (+ESI) m/z 545 (MH+)
TLC用シリカゲル60F254プレート(Merck)、CH2Cl2−MeOH:90−10、Rf=0.44。
NMR 1H (DMSO-d6) ppm: 9.62 (s, 1H), 8.73 (d, 1H), 8.03 (dt, 1H), 7.76 (d, 1H), 7.64 (m, 1H), 7.46 (d, 1H), 7.28 (m, 2H), 7.12 (dt, 2H), 7.03 (t, 1H), 6.94 (d, 1H), 6.86 (t, 1H), 3.81 (d, 2H), 3.68 (m, 1H), 3.56 (m, 1H), 3.48 (m, 1H), 3.30 (m, 1H), 2.61 (m, 1H), 2.12 (m, 1H), 1.85 (m, 1H).
MS (+ESI) m/z 467 (MH+)
TLC用シリカゲル60F254プレート(Merck)、AcOEt、Rf=0.55。
NMR 1H (DMSO-d6) ppm: 9.61 (s, 1H), 8.72 (d, 1H), 8.03 (t, 1H), 7.84 (d, 1H), 7.71 (d, 1H), 7.63 (m, 1H), 7.45 (m, 1H), 7.26 (d, 1H), 7.12 (m, 2H), 6.94 (d, 1H), 6.86 (t, 1H), 3.83 (d, 2H), 3.67 (m, 1H), 3.53 (m, 1H), 3.48 (m, 1H), 3.30 (m, 1H), 2.62 (m, 1H), 2.09 (m, 1H), 1.85 (m, 1H).
MS (+ESI) m/z 485 (MH+)
TLC用シリカゲル60F254プレート(Merck)、石油エーテル−AcOEt:50−50、Rf=0.23。
NMR 1H (DMSO-d6) ppm: 9.61 (s, 1H), 8.72 (d, 1H), 8.03 (dt, 1H), 7.91 (d, 1H), 7.84 (d, 1H), 7.63 (m, 1H), 7.43 (d, 1H), 7.28 (m, 2H), 7.10 (t, 1H), 6.94 (d, 1H), 6.86 (t, 1H), 4.03 (d, 2H), 3.66 (m, 1H), 3.53 (m, 2H), 3.30 (m, 1H), 2.61 (m, 1H), 2.11 (m, 1H), 1.84 (m, 1H).
MS (+ESI) m/z 501 (MH+)
TLC用シリカゲル60F254プレート(Merck)、石油エーテル−AcOEt:50−50、Rf=0.36。
NMR 1H (DMSO-d6) ppm: 9.61 (s, 1H), 8.74 (d, 1H), 8.04 (t, 1H), 7.84 (d, 1H), 7.63 (m, 1H), 7.57 (d, 1H), 7.28 (d, 1H), 7.10 (m, 2H), 6.94 (m, 2H), 6.86 (t, 1H), 3.84 (d, 2H), 3.72 (m, 1H), 3.58 (m, 1H), 3.52 (m, 1H), 3.30 (m, 1H), 2.63 (m, 1H), 2.5 (s, 3H), 2.10 (m, 1H), 1.80 (m, 1H).
MS (+ESI) m/z 481 (MH+)
TLC用シリカゲル60F254プレート(Merck)、石油エーテル−AcOEt:50−50、Rf=0.63。
NMR 1H (DMSO-d6) ppm: 9.61 (s, 1H), 8.76 (d, 1H), 8.05 (t, 1H), 7.84 (d, 1H), 7.63 (m, 1H), 7.34 (d, 1H), 7.28 (d, 1H), 7.10 (t, 1H), 7.00 (t, 1H), 6.94 (d, 1H), 6.89 (m, 2H), 3.86 (s, 3H), 3.82 (d, 2H), 3.67 (m, 1H), 3.50 (m, 2H), 3.27 (m, 1H), 2.63 (m, 1H), 2.10 (m, 1H), 1.83 (m, 1H).
MS (+ESI) m/z 497 (MH+)
mp=122.42℃
NMR 1H (DMSO-d6) ppm: 8.48 (d, 1H), 8.03 (s, 1H), 7.81 (d, 2H), 7.38 (m 2H), 7.38 (m, 1H), 7.18 (d, 1H), 6.86 (m, 2H), 6.46 (t, 1H), 4.02 (m, 2H), 3.78 (m, 1H), 3.44 (m, 4H), 3.14 (m, 1H).
MS (+ESI) m/z 558 (MH+)
mp=330℃
NMR 1H (DMSO-d6) ppm: 8.48 (d, 1H), 8.03 (s, 1H), 7.82 (m, 2H), 7.39 (m 2H), 7.34 (m, 1H), 7.17 (d, 1H), 6.86 (m, 2H), 6.46 (t, 1H), 4.01 (m, 2H), 3.78 (m, 1H), 3.46 (m, 4H), 3.14 (m, 1H).
MS (+ESI) m/z 558 (MH+)
mp=201℃
NMR 1H (DMSO-d6) ppm: 8.49 (d, 1H), 8.03 (s, 1H), 7.82 (m, 2H), 7.39 (m 2H), 7.34 (m, 1H), 7.18 (d, 1H), 6.87 (m, 2H), 6.46 (t, 1H), 4.00 (m, 2H), 3.78 (m, 1H), 3.42 (m, 4H), 3.14 (m, 1H).
MS (+ESI) m/z 558 (MH+)
カリウムチャネルKv1.5に関する前記化合物の薬理学的評価を、96ウェルプレートと、タリウムイオン測定によるFLIPR技術を用いて行った。Kv1.5チャネルのヒトアイソフォームで安定的にトランスフェクトされたHEK293細胞を、実験の24時間前に96ウェルプレート(次の培養培地:DMEM、10%SVF、ペニシリン/ストレプトマイシン、選択用抗生物質としてG418、にポリリジンが塗布されている)に播種する(15 106細胞/プレート、200μl/ウェル)。
DEAD アゾジカルボン酸ジエチル
DMAP Ν,Ν−4−ジメチルアミノピリジン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
DPO (2−イソプロピル−5−メチル−シクロヘキシル)ジフェニルホスフィンオキシド
ESI エレクトロスプレーイオン化
HPLC 高速液体クロマトグラフィー
mp 融点
MS 質量スペクトル
NMR 核磁気共鳴
Rf 移動率
Temp. 温度
TFA トリフルオロ酢酸
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
Claims (13)
- 下記一般式Iで表される化合物またはその一つの薬学的に許容可能な塩:
R1は、水素、F、Cl、またはBrなどのハロゲン、トリフルオロメチル、トリフルオロメトキシ、直鎖または分岐鎖C1−C4アルキル、および直鎖または分岐鎖C1−C4アルコキシからなる群の中から選択される、フェニルコアXの1以上の置換基を表し、
nは0、1、または2を表し、
Aは酸素または硫黄を表し、
Dは−C(=O)−、−CH2O−、または−O−を表し、
n=1または2であって、Dが−C(=O)−を表す場合には、Bは窒素を表し、あるは、n=0であってDが−CH2O−を表す場合またはn=1であってDが−O−を表す場合には、BはCHを表し、
R2は水素、メチル、フッ素、もしくは塩素原子、またはメトキシを表し、
HetArは、直鎖もしくは分岐鎖C1−C4アルキル、直鎖もしくは分岐鎖C1−C4アルコキシ、F、Cl、もしくはBrなどのハロゲン、またはトリフルオロメチルなどの基で置換されていてもよいピリジルもしくはキノリル基を表す)。 - R1が、水素、F、Cl、またはBrなどのハロゲン、トリフルオロメチル、トリフルオロメトキシ、直鎖または分岐鎖C1−C4アルキル、およびメトキシからなる群の中から選択される、フェニルコアの1以上の置換基を表し、
nが1を表し、
Aが酸素または硫黄を表し、
Dが−C(=O)−または−O−を表し、
Dが−C(=O)−を表す場合にはBが窒素を表し、あるいは
Dが−O−を表す場合にはBがCHを表し、
R2が水素を表し、
HetArが、メチルまたはトリフルオロメチルなどの基で置換されていてもよい2−ピリジルまたは8−キノリル基を表す、請求項1および請求項2のいずれかに記載の一般式Iの化合物、またはその一つの薬学的に許容可能な塩。 - R1が、水素、F、Cl、もしくはBrなどのハロゲン、トリフルオロメチル、トリフルオロメトキシ、直鎖もしくは分岐鎖C1−C4アルキル、またはメトキシなどのフェニルコアの1以上の置換基を表し、
Aが硫黄を表し、
nが1を表し、
Dが−C(=O)−を表し、
Bが窒素を表し、
R2が水素を表し、ならびに
HetArが、メチルまたはトリフルオロメチルなどの基で置換されていてもよい2−ピリジル基を表す、請求項1〜3のいずれか一項に記載の一般式Iの化合物、またはその一つの薬学的に許容可能な塩。 - 1)N−(2−(4−(6−フルオロベンゾ[d]オキサゾール−2−イル)ピペラジン−1−カルボニル)フェニル)−5−(トリフルオロメチル)ピリジン−2−スルホンアミド、
2)N−(2−(4−(6−フルオロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
3)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
4)N−(2−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド塩酸塩、
5)N−(2−(4−(4−メチルベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
6)N−(2−(4−(7−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
7)N−(2−(4−(5−(トリフルオロメチル)ベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
8)N−(2−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)−5−(トリフルオロメチル)ピリジン−2−スルホンアミド、
9)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)−6−メチルピリジン−2−スルホンアミド二塩酸塩、
10)N−(3−(4−(6−クロロベンゾ[d]オキサゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
11)N−(3−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
12)N−(3−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)−6−メチルピリジン−2−スルホンアミド、
13)N−(4−(4−(6−フルオロベンゾ[d]オキサゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
14)N−(4−(4−(6−クロロベンゾ[d]オキサゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
15)N−(4−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミド、
16)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)キノリン−8−スルホンアミド、
17)N−(2−(4−(6−クロロベンゾ[d]オキサゾール−2−イル)ピペラジン−1−カルボニル)フェニル)キノリン−8−スルホンアミド、
18)N−(2−(4−(6−クロロベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)キノリン−8−スルホンアミド、
19)N−(2−(4−(6−(トリフルオロメトキシ)ベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)キノリン−8−スルホンアミド、
20)N−(2−(4−(4−メチルベンゾ[d]チアゾール−2−イル)−1,4−ジアゼパン−1−カルボニル)フェニル)キノリン−8−スルホンアミド、
21)N−(2−(1−(6−メチルベンゾ[d]オキサゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
22)N−(2−(1−(6−クロロベンゾ[d]オキサゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
23)N−(2−(1−(5−tert−ブチルベンゾ[d]オキサゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
24)N−(2−(1−(5−クロロベンゾ[d]オキサゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
25)N−(2−(1−(ベンゾ[d]チアゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
26)N−(2−(1−(6−クロロベンゾ[d]チアゾール−2−イル)ピペリジン−4−イルオキシ)フェニル−ピリジン−2−スルホンアミド、
27)N−(2−(1−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペリジン−4−イルオキシ)フェニル)ピリジン−2−スルホンアミド、
28)N−(2−((1−(ベンゾ[d]チアゾール−2−イル)ピロリジン−3−イル)メトキシ)フェニル)ピリジン−2−スルホンアミド、
29)N−(2−((1−(6−フルオロベンゾ[d]チアゾール−2−イル)ピロリジン−3−イル)メトキシ)フェニル)ピリジン−2−スルホンアミド、
30)N−(2−((1−(6−クロロベンゾ[d]チアゾール−2−イル)ピロリジン−3−イル)メトキシ)フェニル)ピリジン−2−スルホンアミド、
31)N−(2−((1−(4−メチルベンゾ[d]チアゾール−2−イル)ピロリジン−3−イル)メトキシ)フェニル)ピリジン−2−スルホンアミド、
32)N−(2−((1−(4−メトキシベンゾ[d]チアゾール−2−イル)ピロリジン−3−イル)メトキシ)フェニル)ピリジン−2−スルホンアミド、
33)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミドリチウム、
34)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミドナトリウム、および
35)N−(2−(4−(6−ブロモベンゾ[d]チアゾール−2−イル)ピペラジン−1−カルボニル)フェニル)ピリジン−2−スルホンアミドカリウム
から選択される、請求項1〜4のいずれか一項に記載の一般式Iの化合物。 - 請求項1〜5のいずれか一項に記載の一般式Iで表される化合物(式中、B=N)の製造方法であって、下記の一連の工程を含む、方法:
(a1)下記一般式II:
で表される化合物と、下記式XV:
で表されるイサト酸無水物誘導体とを、ジメチルアミノピリジンなどの塩基の存在下で縮合させ、下記式III:
で表される中間体を得る工程、
(a2)式IIIの中間体と、下記一般式IV:
で表されるスルホニルクロリドとを、ピリジンなどの塩基の存在下で縮合させ、式Iで表される化合物を得る工程、および
(a3)任意に、前の工程(a2)で得られた式Iで表される化合物を、薬学的に許容可能な塩基または酸の存在下で塩形成させ、式Iで表される化合物の薬学的に許容可能な塩を得る工程。 - 請求項1〜5のいずれか一項に記載の一般式Iで表される化合物(式中、B=N)の製造方法であって、下記の一連の工程を含む、方法:
(b1)下記一般式V:
で表される化合物と、請求項7で定義される一般式IVのスルホニルクロリドとを、ピリジンなどの塩基の存在下で縮合させ、下記式VI:
で表される化合物を得る工程、
(b2)式VIの化合物を、とりわけ、炭酸カリウムなどの塩基の存在下で鹸化させ、下記式VII:
で表される化合物を得る工程、
(b3)式VIIの化合物と、請求項6に記載の式IIの化合物とをカップリングさせ、式Iで表される化合物を得る工程、および
(b4)任意に、前の工程(b3)で得られた式Iで表される化合物を、薬学的に許容可能な塩基または酸の存在下で塩形成させ、式Iで表される化合物の薬学的に許容可能な塩を得る工程。 - 請求項1〜5のいずれか一項に記載の一般式Iで表される化合物(式中、B=CH)の製造方法であって、下の連続的工程を含む、方法:
(c1)下記一般式VIII:
で表される化合物と、下記一般式IX:
で表される化合物とを縮合させ、下記式X:
で表される化合物を得る工程、
(c2)式Xで表される化合物を還元させ、下記式XI:
で表される化合物を得る工程、
(c3)式XIで表される化合物と、請求項6に記載の一般式IVのスルホニルクロリドとを、ピリジンなどの塩基の存在下でカップリングさせ、下記式XII:
で表される化合物を得る工程、
(c4)式XIIの化合物のアミド基を加水分解させ、下記式XIII:
で表される化合物を得る工程、
(c5)式XIIIの化合物と、下記式XIV:
で表される化合物とをカップリングさせ、式Iで表される化合物を得る工程、ならびに
(c6)任意に、前の工程(c5)で得られた式Iで表される化合物を、薬学的に許容可能な塩基または酸の存在下で塩形成させ、式Iで表される化合物の薬学的に許容可能な塩を得る工程。 - 医薬として使用するための、請求項1〜5のいずれか一項に記載の一般式Iの化合物。
- Kvカリウムチャネル、より詳細には、チャネルKv1.5、Kv4.3、またはKv11.1の遮断薬として使用するための、請求項1〜5のいずれか一項に記載の一般式Iの化合物。
- Kvカリウムチャネル、より詳細には、チャネルKv1.5、Kv4.3、またはKv11.1の遮断薬を必要とする疾患の治療および/または予防を目的とした医薬として使用するための、請求項9に記載の化合物。
- 心房細動、心耳および/または心室の心拍障害、細胞周期および/または細胞増殖および/または再生の機能が損なわれている病状、例えば、癌または慢性炎症などの治療および/または予防を目的とした医薬として使用するための、請求項9に記載の化合物。
- 請求項1〜5のいずれか一項に記載の一般式Iで表される化合物を、少なくとも一つの薬学的に許容可能な賦形剤とともに含む、医薬組成物。
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Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
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SG10201403696UA (en) | 2009-06-29 | 2014-10-30 | Agios Pharmaceuticals Inc | Therapeutic compounds and compositions |
SI2704721T1 (en) * | 2011-05-03 | 2018-08-31 | Agios Pharmaceuticals, Inc. | ACTIVATORS PIANO KINASE FOR USE IN THERAPY |
JP6267112B2 (ja) | 2011-05-03 | 2018-01-24 | アジオス ファーマシューティカルズ, インコーポレイテッド | ピルビン酸キナーゼアクチベーターの使用方法 |
WO2014139144A1 (en) | 2013-03-15 | 2014-09-18 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
EP3057945A1 (en) * | 2013-10-17 | 2016-08-24 | Basf Se | Process for preparing substituted isatoic acid anhydride compounds and derivatives thereof |
WO2015095111A1 (en) * | 2013-12-18 | 2015-06-25 | Merck Sharp & Dohme Corp. | Diazepane orexin receptor antagonists |
CN104292179A (zh) * | 2014-10-19 | 2015-01-21 | 湖南华腾制药有限公司 | 一种2-氯苯并[d]恶唑-5-甲醛的制备方法 |
FR3029112A1 (fr) * | 2014-12-02 | 2016-06-03 | Pf Medicament | Dispersion solide a base de derives d'heteroarylsulfonamides a usage pharmaceutique |
AU2016276951B2 (en) | 2015-06-11 | 2020-10-08 | Agios Pharmaceuticals, Inc. | Methods of using pyruvate kinase activators |
EP3601273B1 (en) * | 2017-03-24 | 2021-12-01 | Genentech, Inc. | 4-piperidin-n-(pyrimidin-4-yl)chroman-7-sulfonamide derivatives as sodium channel inhibitors |
CN107556266B (zh) * | 2017-09-12 | 2021-04-23 | 华南农业大学 | 一种2-巯基-4-取代-6-氟苯并噻唑及其制法、应用 |
AR116898A1 (es) * | 2018-10-30 | 2021-06-23 | H Lundbeck As | DERIVADOS DE ARILSULFONILPIRROLCARBOXAMIDA COMO ACTIVADORES DE CANALES DE POTASIO Kv3 |
CN113200934B (zh) * | 2021-05-18 | 2022-05-31 | 郑州大学 | 含苯并吗啉酮-联苯骨架化合物及其制备方法和应用 |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006130986A1 (en) * | 2005-06-09 | 2006-12-14 | Merck Frosst Canada Ltd. | Azacyclohexane derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase |
EP1939189A1 (en) * | 2005-08-26 | 2008-07-02 | Shionogi & Co., Ltd. | Derivative having ppar agonistic activity |
WO2009055357A1 (en) * | 2007-10-25 | 2009-04-30 | Boehringer Ingelheim International Gmbh | Diazepane compounds which modulate the cb2 receptor |
WO2009149508A1 (en) * | 2008-06-13 | 2009-12-17 | Bionomics Limited | Novel potassium channel blockers and uses thereof |
WO2010111948A1 (zh) * | 2009-03-31 | 2010-10-07 | 中国药科大学 | 芳甲胺类化合物、其制备方法及其医药用途 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5149700A (en) * | 1990-05-30 | 1992-09-22 | American Home Products Corporation | Substituted arylsulfonamides and benzamides |
DE10128331A1 (de) * | 2001-06-12 | 2002-12-19 | Aventis Pharma Gmbh | Anthranilsäureamide mit Heteroarylsulfonyl-Seitenkette, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltende pharmazeutische Zubereitungen |
PL1828154T3 (pl) * | 2004-12-09 | 2009-10-30 | Hoffmann La Roche | Pochodne fenylopiperazynometanonu |
GB0815781D0 (en) * | 2008-08-29 | 2008-10-08 | Xention Ltd | Novel potassium channel blockers |
WO2010130638A1 (en) * | 2009-05-14 | 2010-11-18 | Evotec Ag | Sulfonamide compounds, pharmaceutical compositions and uses thereof |
SG10201403696UA (en) * | 2009-06-29 | 2014-10-30 | Agios Pharmaceuticals Inc | Therapeutic compounds and compositions |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006130986A1 (en) * | 2005-06-09 | 2006-12-14 | Merck Frosst Canada Ltd. | Azacyclohexane derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase |
EP1939189A1 (en) * | 2005-08-26 | 2008-07-02 | Shionogi & Co., Ltd. | Derivative having ppar agonistic activity |
WO2009055357A1 (en) * | 2007-10-25 | 2009-04-30 | Boehringer Ingelheim International Gmbh | Diazepane compounds which modulate the cb2 receptor |
WO2009149508A1 (en) * | 2008-06-13 | 2009-12-17 | Bionomics Limited | Novel potassium channel blockers and uses thereof |
WO2010111948A1 (zh) * | 2009-03-31 | 2010-10-07 | 中国药科大学 | 芳甲胺类化合物、其制备方法及其医药用途 |
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Publication number | Publication date |
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BR112013012615A2 (pt) | 2016-09-06 |
TW201225951A (en) | 2012-07-01 |
JP5837085B2 (ja) | 2015-12-24 |
IL226495A0 (en) | 2013-07-31 |
EP2643318A1 (en) | 2013-10-02 |
KR20130119943A (ko) | 2013-11-01 |
AR083903A1 (es) | 2013-04-10 |
AU2011333772A1 (en) | 2013-06-06 |
NZ610700A (en) | 2014-12-24 |
RU2013126251A (ru) | 2014-12-27 |
MY168283A (en) | 2018-10-19 |
KR101838326B1 (ko) | 2018-03-13 |
CA2817531A1 (en) | 2012-05-31 |
US9156834B2 (en) | 2015-10-13 |
US20140357624A1 (en) | 2014-12-04 |
HK1187345A1 (en) | 2014-04-04 |
CN103209980A (zh) | 2013-07-17 |
TWI576106B (zh) | 2017-04-01 |
MX2013005734A (es) | 2013-08-01 |
FR2967674B1 (fr) | 2012-12-14 |
WO2012069503A1 (en) | 2012-05-31 |
US20130172326A1 (en) | 2013-07-04 |
MX352396B (es) | 2017-11-22 |
RU2582995C2 (ru) | 2016-04-27 |
US8846930B2 (en) | 2014-09-30 |
MA34658B1 (fr) | 2013-11-02 |
UA109295C2 (uk) | 2015-08-10 |
IL226495A (en) | 2017-06-29 |
FR2967674A1 (fr) | 2012-05-25 |
AU2011333772B2 (en) | 2016-08-18 |
CN103209980B (zh) | 2015-06-03 |
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