JP2016501846A - 新規のベンゼンスルホンアミドチアゾール化合物 - Google Patents
新規のベンゼンスルホンアミドチアゾール化合物 Download PDFInfo
- Publication number
- JP2016501846A JP2016501846A JP2015541166A JP2015541166A JP2016501846A JP 2016501846 A JP2016501846 A JP 2016501846A JP 2015541166 A JP2015541166 A JP 2015541166A JP 2015541166 A JP2015541166 A JP 2015541166A JP 2016501846 A JP2016501846 A JP 2016501846A
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- compound
- formula
- thiazol
- thiazolyl
- 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
Links
- AJWNYPNPXLNRAO-UHFFFAOYSA-N n-(1,3-thiazol-2-yl)benzenesulfonamide Chemical class C=1C=CC=CC=1S(=O)(=O)NC1=NC=CS1 AJWNYPNPXLNRAO-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 175
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 26
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 201000011510 cancer Diseases 0.000 claims abstract description 17
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 230000000155 isotopic effect Effects 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 201000001441 melanoma Diseases 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 34
- LBSMEKVVMYSTIH-UHFFFAOYSA-N HA15 Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)NC(C=1)=CC=CC=1C1=CSC(NC(C)=O)=N1 LBSMEKVVMYSTIH-UHFFFAOYSA-N 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 32
- -1 CO-alkyl Chemical group 0.000 claims description 23
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 239000000126 substance Substances 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 125000004434 sulfur atom Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000000565 sulfonamide group Chemical group 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- LOLUHAPARKOTKT-UHFFFAOYSA-N n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC1=NC(C=2C=C(NS(=O)(=O)C=3C=CC(Cl)=CC=3)C=CC=2)=CS1 LOLUHAPARKOTKT-UHFFFAOYSA-N 0.000 claims description 4
- MPVDGWYSOHPZCJ-UHFFFAOYSA-N n-[4-[3-[[3-(trifluoromethyl)phenyl]sulfonylamino]phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=C(NS(=O)(=O)C=3C=C(C=CC=3)C(F)(F)F)C=CC=2)=C1 MPVDGWYSOHPZCJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- DBZLWZPPFYISAD-UHFFFAOYSA-N n-[4-[4-[[4-(trifluoromethyl)phenyl]sulfonylamino]phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=CC(NS(=O)(=O)C=3C=CC(=CC=3)C(F)(F)F)=CC=2)=C1 DBZLWZPPFYISAD-UHFFFAOYSA-N 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- YNMUDVMKZOFITQ-UHFFFAOYSA-N 2-chloro-n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]benzamide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC1=CC=CC(C=2N=C(NC(=O)C=3C(=CC=CC=3)Cl)SC=2)=C1 YNMUDVMKZOFITQ-UHFFFAOYSA-N 0.000 claims description 2
- PMZILNHCOJCKBS-UHFFFAOYSA-N 3-chloro-n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]benzamide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC1=CC=CC(C=2N=C(NC(=O)C=3C=C(Cl)C=CC=3)SC=2)=C1 PMZILNHCOJCKBS-UHFFFAOYSA-N 0.000 claims description 2
- BALJKRHJPMTCME-UHFFFAOYSA-N 4-chloro-n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]benzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NC1=NC(C=2C=C(NS(=O)(=O)C=3C=CC(Cl)=CC=3)C=CC=2)=CS1 BALJKRHJPMTCME-UHFFFAOYSA-N 0.000 claims description 2
- ZNCYXVISFMUXBE-UHFFFAOYSA-N [2-[[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl] acetate Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC(C=2C=C(NS(=O)(=O)C=3C=CC(Cl)=CC=3)C=CC=2)=CS1 ZNCYXVISFMUXBE-UHFFFAOYSA-N 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- NCTOXCWEJGGQBY-UHFFFAOYSA-N n-[3-(2-amino-1,3-thiazol-4-yl)phenyl]-4-chlorobenzenesulfonamide Chemical compound S1C(N)=NC(C=2C=C(NS(=O)(=O)C=3C=CC(Cl)=CC=3)C=CC=2)=C1 NCTOXCWEJGGQBY-UHFFFAOYSA-N 0.000 claims description 2
- KDGBHXZBYIEGAA-UHFFFAOYSA-N n-[4-[3-(benzenesulfonamido)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=C(NS(=O)(=O)C=3C=CC=CC=3)C=CC=2)=C1 KDGBHXZBYIEGAA-UHFFFAOYSA-N 0.000 claims description 2
- IIZLPHOCMKLHOG-UHFFFAOYSA-N n-[4-[3-(methanesulfonamido)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=C(NS(C)(=O)=O)C=CC=2)=C1 IIZLPHOCMKLHOG-UHFFFAOYSA-N 0.000 claims description 2
- SZPPDMWAAXPTQO-UHFFFAOYSA-N n-[4-[3-[(2-nitrophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=C(NS(=O)(=O)C=3C(=CC=CC=3)[N+]([O-])=O)C=CC=2)=C1 SZPPDMWAAXPTQO-UHFFFAOYSA-N 0.000 claims description 2
- PBWWJAJOTZYXSO-UHFFFAOYSA-N n-[4-[3-[(3-nitrophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=C(NS(=O)(=O)C=3C=C(C=CC=3)[N+]([O-])=O)C=CC=2)=C1 PBWWJAJOTZYXSO-UHFFFAOYSA-N 0.000 claims description 2
- KRRGQZPTPYIXMP-UHFFFAOYSA-N n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]-1-hydroxynaphthalene-2-carboxamide Chemical compound C1=CC2=CC=CC=C2C(O)=C1C(=O)NC(SC=1)=NC=1C(C=1)=CC=CC=1NS(=O)(=O)C1=CC=C(Cl)C=C1 KRRGQZPTPYIXMP-UHFFFAOYSA-N 0.000 claims description 2
- LECBLHSWVMNWHW-UHFFFAOYSA-N n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]-2-hydroxybenzamide Chemical compound OC1=CC=CC=C1C(=O)NC1=NC(C=2C=C(NS(=O)(=O)C=3C=CC(Cl)=CC=3)C=CC=2)=CS1 LECBLHSWVMNWHW-UHFFFAOYSA-N 0.000 claims description 2
- SIRXPAKMUHXVAZ-UHFFFAOYSA-N n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)NC1=NC(C=2C=C(NS(=O)(=O)C=3C=CC(Cl)=CC=3)C=CC=2)=CS1 SIRXPAKMUHXVAZ-UHFFFAOYSA-N 0.000 claims description 2
- MJGSOJUOYPETML-UHFFFAOYSA-N n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]-3,4-dimethoxybenzamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=NC(C=2C=C(NS(=O)(=O)C=3C=CC(Cl)=CC=3)C=CC=2)=CS1 MJGSOJUOYPETML-UHFFFAOYSA-N 0.000 claims description 2
- NFFUCMYWYIZITE-UHFFFAOYSA-N n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]-3-hydroxynaphthalene-2-carboxamide Chemical compound OC1=CC2=CC=CC=C2C=C1C(=O)NC(SC=1)=NC=1C(C=1)=CC=CC=1NS(=O)(=O)C1=CC=C(Cl)C=C1 NFFUCMYWYIZITE-UHFFFAOYSA-N 0.000 claims description 2
- PPKVNUBRBYAVFI-UHFFFAOYSA-N n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NC=2SC=C(N=2)C=2C=C(NS(=O)(=O)C=3C=CC(Cl)=CC=3)C=CC=2)=C1 PPKVNUBRBYAVFI-UHFFFAOYSA-N 0.000 claims description 2
- LOOSRNWHJNHIKR-UHFFFAOYSA-N n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]-3-methylbenzamide Chemical compound CC1=CC=CC(C(=O)NC=2SC=C(N=2)C=2C=C(NS(=O)(=O)C=3C=CC(Cl)=CC=3)C=CC=2)=C1 LOOSRNWHJNHIKR-UHFFFAOYSA-N 0.000 claims description 2
- LQGDSDZKLYNDJC-UHFFFAOYSA-N n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=NC(C=2C=C(NS(=O)(=O)C=3C=CC(Cl)=CC=3)C=CC=2)=CS1 LQGDSDZKLYNDJC-UHFFFAOYSA-N 0.000 claims description 2
- OTCWFINGSKRQLT-UHFFFAOYSA-N n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]-4-nitrobenzamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)NC1=NC(C=2C=C(NS(=O)(=O)C=3C=CC(Cl)=CC=3)C=CC=2)=CS1 OTCWFINGSKRQLT-UHFFFAOYSA-N 0.000 claims description 2
- KMMCNBQRNQCKSO-UHFFFAOYSA-N n-[4-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]benzamide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC1=CC=CC(C=2N=C(NC(=O)C=3C=CC=CC=3)SC=2)=C1 KMMCNBQRNQCKSO-UHFFFAOYSA-N 0.000 claims description 2
- XYFAAKHLERATBS-UHFFFAOYSA-N n-[4-[3-[(4-methylphenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=C(NS(=O)(=O)C=3C=CC(C)=CC=3)C=CC=2)=C1 XYFAAKHLERATBS-UHFFFAOYSA-N 0.000 claims description 2
- AVLYYCNOQITFNG-UHFFFAOYSA-N n-[4-[3-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]phenyl]-1,3-thiazol-2-yl]-2,2-dimethylpropanamide Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)NC(C=1)=CC=CC=1C1=CSC(NC(=O)C(C)(C)C)=N1 AVLYYCNOQITFNG-UHFFFAOYSA-N 0.000 claims description 2
- ZJTHIIOOLALGID-UHFFFAOYSA-N n-[4-[3-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]phenyl]-1,3-thiazol-2-yl]-4-methylbenzamide Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)NC(C=1)=CC=CC=1C(N=1)=CSC=1NC(=O)C1=CC=C(C)C=C1 ZJTHIIOOLALGID-UHFFFAOYSA-N 0.000 claims description 2
- HTKGUSNJOJXLHW-UHFFFAOYSA-N n-[4-[3-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]phenyl]-1,3-thiazol-2-yl]benzamide Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)NC(C=1)=CC=CC=1C(N=1)=CSC=1NC(=O)C1=CC=CC=C1 HTKGUSNJOJXLHW-UHFFFAOYSA-N 0.000 claims description 2
- UVPWBLBGQJNOIK-UHFFFAOYSA-N n-[4-[4-(naphthalen-2-ylsulfonylamino)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=CC(NS(=O)(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=C1 UVPWBLBGQJNOIK-UHFFFAOYSA-N 0.000 claims description 2
- XMDZWAYTBGSROO-UHFFFAOYSA-N n-[4-[4-[(2,4-difluorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=CC(NS(=O)(=O)C=3C(=CC(F)=CC=3)F)=CC=2)=C1 XMDZWAYTBGSROO-UHFFFAOYSA-N 0.000 claims description 2
- CRRAAKQHRZCQOG-UHFFFAOYSA-N n-[4-[4-[(2-fluorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=CC(NS(=O)(=O)C=3C(=CC=CC=3)F)=CC=2)=C1 CRRAAKQHRZCQOG-UHFFFAOYSA-N 0.000 claims description 2
- ITVIWSMUOJFARG-UHFFFAOYSA-N n-[4-[4-[(4-methylphenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=CC(NS(=O)(=O)C=3C=CC(C)=CC=3)=CC=2)=C1 ITVIWSMUOJFARG-UHFFFAOYSA-N 0.000 claims description 2
- TWCDDTFHVUKYGV-UHFFFAOYSA-N n-[4-[4-[[3-(trifluoromethyl)phenyl]sulfonylamino]phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=CC(NS(=O)(=O)C=3C=C(C=CC=3)C(F)(F)F)=CC=2)=C1 TWCDDTFHVUKYGV-UHFFFAOYSA-N 0.000 claims description 2
- RQINYPXAHZTPAK-UHFFFAOYSA-N n-[4-[4-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)NC(C=C1)=CC=C1C1=CSC(NC(C)=O)=N1 RQINYPXAHZTPAK-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001475 halogen functional group Chemical group 0.000 abstract 1
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical class C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 210000000214 mouth Anatomy 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
- 125000005487 naphthalate group Chemical group 0.000 description 1
- OPECTNGATDYLSS-UHFFFAOYSA-N naphthalene-2-sulfonyl chloride Chemical compound C1=CC=CC2=CC(S(=O)(=O)Cl)=CC=C21 OPECTNGATDYLSS-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229950004864 olamine Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004007 reversed phase HPLC 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
- 230000019491 signal transduction Effects 0.000 description 1
- 201000003708 skin melanoma Diseases 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 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
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960004066 trametinib Drugs 0.000 description 1
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229950000339 xinafoate Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Epidemiology (AREA)
Abstract
Description
R1は、1つの環又は2つの環の縮合環を含むC6−C10アリールを表し、2〜5個の炭素原子はO、S、N及びNR6から選択されるヘテロ原子と置換され、最終的には、R6、ハロ、CN、NO2、CF3、OCF3、COOR6、OCOR6、SO2NR6R7、CONR6R7、NR6R7、NR6COR7、(CH2)p−NR6R7、(CH2)p−OR6及び(CH2)pSR6から選択される5〜11個の置換基で置換され得り、
R2は、SO2R1又はR6であり、
同一である又は異なるR3及びR4は、COR8及びR6から選択され、
R5は、R6、アリール、OR6、SR6、ハロ、CN、NO2、CF3、OCF3、COOR6、SO2NR6R7、CONR6R7、NR6R7又はNHCOR6を表し、
同一である又は異なるR6及びR7は、H又はアルキルを表し、
R8は、H、アルキル、シクロアルキル、アリール、アルキルアリールから選択され、R8においてアリールは1〜4個の同一である又は異なるR5置換基で置換され得るか、又はR8は(CH2)q-NR6R7を表し、
pは0〜6の整数を表し、
qは0〜6の整数を表し、
チアゾリル基は、スルホンアミド基に対してメタ位又はパラ位で6員環と結合され、またチアゾリル基は、硫黄原子に対してα又はβ位で6員環と結合され、
又は、適切な場合に、化学式(1)の化合物の薬学的に許容される塩、及び又は、異性体、互変異性体、溶媒和物、若しくは同位体変種であり、
以下の化合物、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−2−ヒドロキシ−ベンズアミド,
2−(アセチルオキシ)−N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−ベンズアミド,
3−クロロ−N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−ベンズアミド,
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−1−ヒドロキシ−2−ナフタレンカルボキサミド,
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−3−ヒドロキシ−2−ナフタレンカルボキサミド,
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−2−メトキシ−ベンズアミド,
N−[3−(2−アミノ−4−チアゾリル)フェニル]−4−クロロ−ベンゼンスルホンアミド,
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−ベンズアミド,
2−クロロ−N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−ベンズアミド,
4−クロロ−N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−ベンズアミド,
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−3,4−ジメトキシベンズアミド,
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−3−メトキシベンズアミド,
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−4−メトキシベンズアミド,
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−3−メチル−ベンズアミド,
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−4−メチル−ベンズアミド,
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−4−ニトロ−ベンズアミド,
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−4−メチル−ベンズアミド,
は除外される。
R6及びpは上記の定義通りであり、nは1、2、3又は4を表す。
R6及びpは上記の定義通りであり、nは1、2、3又は4を表し、ナフチル基は4級炭素に対して1位、2位又は3位で硫黄原子に付加される。
・R2は、好ましくはH又はSO2R1を表し、R6、ハロ、CN、NO2、CF3、OCF3、COOR6、OCOR6、SO2NR6R7、CONR6R7、NR6R7、NR6COR7、(CH2)p−NR6R7、(CH2)p−OR6及び(CH2)pSR6から選択される1〜4個の、好ましくは1又は2個の置換基で選択的に置換されたフェニル基又はナフチル基であり、好ましい置換基は、R6、ハロ、CF3、NR6R7である。R6とR7とは、H又はメチルを表す。
N−(4−(3−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
5−(ジメチルアミノ)−N−(3−(2−(メチルアミノ)チアゾール−4−イル)フェニル)ナフタレン−1−スルホンアミド、
N−(4−(3−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)−4メチルベンズアミド、
N−(3−(2−アミノチアゾール−4−イル)フェニル)−5−(ジメチルアミノ)ナフタレン−1−スルホンアミド、
N−(4−(3−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)ベンズアミド、
N−(4−(3−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)ピバルアミド、
2−フルオロ−N−(3−(2−(メチルアミノ)チアゾール−4−イル)フェニル)ベンゼンスルホンアミド、
N−(4−(4−(ナフタレン−2−スルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(2−フルオロフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(2,4−ジフルオロフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(3−(トリフルオロメチル)フェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(3−(トリフルオロメチル)フェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(3−(トリフルオロメチル)フェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(4−(トリフルオロメチル)フェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(4−メチルフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(2−ニトロフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(3−ニトロフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(フェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(メチルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(4−メチルフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)−6−アミノ−ヘキサンアミド、
である。
(i)化学式(1)の化合物を所望の酸又は塩基と反応させること、
(ii)化学式(1)の化合物の適切なプリカーサから、酸若しくは塩基に不安定な保護基を除くこと、又は、所望の酸若しくは塩基を用いて、例えばラクトン若しくはラクタムなどの適切な環状プリカーサを開環すること、或いは、
(iii)化学式(1)の化合物の1つの塩を、適切な酸若しくは塩基との反応によって、又は適切なイオン交換カラムを用いて、他の塩に変換すること、
という3つのうちの1つ以上の方法によって調製されてもよい。
(i)化学式(1)の化合物はカルボン酸官能基(−COOH)、そのエステルを含み、例えば化学式(1)の化合物のカルボン酸官能性水素が(C1−C8)アルキルによって置換される化合物、
(ii)化学式(1)の化合物はアルコール官能基(−OH)、そのエーテルを含み、例えば化学式(1)の化合物のアルコール官能性水素が(C1−C6)アルカノイルオキシメチルによって置換される化合物、
(iii)化学式(1)の化合物は第1級又は第2級アミノ官能基、そのアミドを含み、例えば、場合に応じて化学式(1)の化合物の一方又は双方のアミノ官能性水素が(C1−C10)アルカノイルによって置換される化合物、
が含まれる。
(i)メチル基、そのヒドロキシメチル誘導体を含む化学式(1)の化合物、
(ii)アルコキシ基、そのヒドロキシ誘導体を含む化学式(1)の化合物、
(iii)第3級アミノ基、その第2級アミノ誘導体を含む化学式(1)の化合物、
(iv)第2級アミノ基、その第1級アミノ誘導体を含む化学式(1)の化合物、
(v)フェニル部分、そのフェニル誘導体を含む化学式(1)の化合物、
(vi)アミド基、そのカルボン酸誘導体を含む化学式(1)の化合物、
が含まれる。
‐ダカルバジンなどのがん治療に用いられる抗がん剤、
‐フォテムスチンなどのニトロソウレア系アルキル化剤、
‐ベムラフェニブ又はダブラフェニブなどのBRAF阻害剤、
‐トラメチニブなどのMEK阻害剤、
‐抗CTLA4抗体、すなわちイピリムマブ、を含むが、これに限定されない。
‐化学合成及び特性‐
1H及び13C NMRスペクトルは、200又は500のBurker Advance分光計(1Hに対して200又は500MHz、13Cに対して50MHz)で記録された。ケミカルシフトは、テトラメチルシランにおいて百万分率で表される。分裂パターンは、s(1重線)、d(2重線)、t(3重線)、m(多重線)、及びbr(ブロード)として示される。カップリング定数(J値)はヘルツ(Hz)で示される。分析薄層クロマトグラフィー(TLC)はMerck社(VWR)の前被覆されたシリカゲル60F254プレートでおこなわれ、化合物はニンヒドリンテスト及び/又は紫外線光(254nm)下で可視化された。カラムクロマトグラフィーはシリカゲル上でおこなわれた(Merck社、40−63μm)。そして、正モードのエレクトロスプレーイオン化分析(ESI−MS)をBurker Daltonics(Esquire 3000 plus)装置でおこなった。異なるサイズのカラムを用いてウォーターズ社の機器でHPLC分析を記録した。
5−(ジメチルアミノ)−N−(3−(2−(メチルアミノ)チアゾール−4−イル)フェニル)ナフタレン−1−スルホンアミド(Ia1)の調製
<1> 2−ブロモ−1−(3’−ニトロフェニル)エタノン(1a1, R5=H)の調製
<2> 5−(ジメチルアミノ)−N−(3−(2−(メチルアミノ)チアゾール−4−イル)フェニル)ナフタレン−1−スルホンアミド(Ia1/HA19)の調製
<3> 2−N−メチル−4−(3−アミノフェニル)チアゾール(5a4)の調製
<4> 5−(ジメチルアミノ)−N−(3−(2−(メチルアミノ)チアゾール−4−イル)フェニル)ナフタレン−1−スルホンアミド(Ia1)の調製
アミンのスルホン化の通常の方法
<実施例2>
N−(4−(3−5−ナフタレン−2−スルホンアミド)フェニル)チアゾール−2yl)アセトアミド(Ia2/HA26)の調製
<1> 2−ブロモ−1−(3’−ニトロフェニル)エタノン(1a1、R5=H)の調製
該化合物は実施例1と同様の手順で調製された。
<3> N−(4−(3’−アミノフェニル)チアゾール−2−イル)アセトアミド(5a1、R5=H、R3、R4=H、Ac)の調製
(4a1、R5=H、R3、R4=H、Ac)(2.2g、8.35mmol)とパラジウム活性炭素(10%)とを含む0℃の混合物に、1:1のジクロロメタン・メタノール(35mL)混合物に含まれたNaBH4(5当量、1.58g、41.75mmol)を添加し、反応混合物を5時間撹拌した。セライトパッドを用いて濾過した後、濾過物を減圧下で濃縮し、粗物質をシリカゲルカラム(99:1〜95:5、CH2Cl2−MeOH)で精製して白色固体としての純粋化合物(5a1)を得た。産生量974 mg (50%); Rf=0.25 (cyclohexane /EtOAc: 1/1); SM (ESI) m/z= 256 [M+Na]+; 1H NMR (DMSO d6, 200 MHz): δ 2.13 (s, 3H,CH3), 5.12 (s, 2H, NH2), 6.50 (dt, 1H, J = 6.44 Hz, J =2.4 Hz, H4’), 7.03 (m, 2H, H6’ and H5’), 7.34(s, 1H, H5), 7.93 (s, 1H, H2’), 12.22 (s, 1H, NH); 13CNMR (DMSO-d6 , 50 MHz): δ 22.4 (CH3), 106.8 (CAr), 111.2 (CAr), 113.5 (CAr), 129.1 (CAr), 134.8 (CAr), 148.8 (CAr), 149.5 (CAr), 157.5 (CAr), 162.2 (CAr), 168.5 (Ccarbonyl)
<4> N−(4−(3−5−ナフタレン−2−スルホンアミド)フェニル)チアゾール−2イル)アセトアミド(Ia2/HA26)の調製
<実施例3>
N−(4−(3’−(2’’’−フルオロフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド(Ia3/HA 25)の調製
<実施例4>
N−(4−(3−(3−(トリフルオロメチルフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド(Ia4)の調製
<実施例5>
N−(4−(4’−(2’’, 4’’−ジフルオロフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド(Ib1)の調製
<1> 2−N−アセチルアミノ−4−(4−ニトロフェニル)チアゾール(4b1)の調製
<2> 2−N−アセチルアミノ−4−(4−アミノフェニル)チアゾール(5b1)の調製
<3> Ib1の調製
<実施例6>
N−(4−(4−(4(トリフルオロメチル)フェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド(Ib2)の調製
<実施例7>
さらなる中間物の調製
<7.1.> 4−(3’−ニトロフェニル)−2−アミノチアゾール(4a2、R5=H、R3=R4=H)の調製
<7.2.> N−(4−(3’−ニトロフェニル)チアゾール−2−イル)ベンズアミド(4a3、R5=H、R3=R4=H)の調製
<7.3.> N−(4−(3’−アミノフェニル)チアゾール−2−イル)ベンズアミド(5a2、R5=H、R3、R4=H、Ac)の調製
下記の化合物は、上記記載の化合物と同様の手順を用いて調製された。
本発明の化合物の抗がん作用
−材料と方法−
〔効力及び効能評価のための実験プロトコル〕
〔細胞の培養〕
新生児の包皮から取得された正常なヒトメラノサイト(NHM)を、2%FCS、ウシ脳下垂体抽出物(10μg/ml)、PMA(8nM)、bFGF(1ng/ml)、インスリン(5μg/ml)、ヒドロコルチゾン(0.5μg/ml)、フォルスコリン(10μM)、ゲンタマイシン(20μg/ml)、ペニシリン/ストレプトマイシン/アムホテリシンB(100U/ml)(Invitrogen)で補完したMCDB153(Sigma社)内において、5%CO2のもと37℃で増殖させた。
細胞を6ウェルプレートに播種し(60000細胞/ウェル)、枯渇させ、提示された時間で化合物と共にインキュベートした。そして細胞を200μlのHyQTase(Thermo)の存在下で剥離し、2mlのRPMI 1640 Glutamax(Gibco)を細胞溶液に添加した。10μlのこの溶液を、10μlの0.4%トリパンブルーで1分間染色し、Malassezチャンバーでカウントした。
TRIS−HCl(pH7.5、50mM)、NaCl(15mM)、Triton X−100(1%)、並びにプロテアーゼ及びホスファターゼ阻害剤を含むFisher緩衝剤内においてタンパク質を抽出した。短時間で、細胞溶解物(30μg)をSDS−PAGEにより分離し、PVDF膜(Millipore、モルスアイム、フランス)に移し、そして所定の抗体に曝露した。タンパク質はAmersham(アーリントンハイツ、イリノイ州、アメリカ合衆国)のECLシステムで可視化された。表されるウェスタンブロッティングは少なくとも3つの独立した実験を示す。
BALB/C・nu/nu胸腺欠損マウス(Harlan)を用いた。該動物は生後6週間で体重は20〜25gであった。マウスは12時間毎の周期の動物のC3Mに収容された。動物は水と飼料を適宜与えられた。マウスを最初に1週間馴化させ、そしてA375細胞(200μlのPBSに250万細胞)を右側と左側に皮下注射した。処置はがん細胞注射の8日後に始められた(腫瘍が見えるようになったとき)。種々の化合物を、ラブラフィル(90%)(Gattefosse)、Tween80(1%)及びN,N−ジメチルアセトアミド(9%)の混合物に希釈した。0.7mg/日のPLX4032、SR44(HA15)、SR47(HA32)、SR50(JG25)又は対照のラブラフィルの混合物で腹腔内に毎日処置を受けた6匹のマウスからなる5つのグループを定義した。腫瘍の大きさは、カリパスを用いて週に3回測定された。
<1> HA15は黒色腫細胞及びその他のがん細胞型の細胞生存性を抑止する。
本願明細書にわたって、様々な参考文献において本発明に関する最先端の技術が記載される。これら参考文献の開示は本開示に参考として組み込まれる。
Claims (16)
- 化学式(1)の化合物であり、
同一である又は異なるQ1〜Q5はCR6を表し、
R1は、1つの環又は2つの環の縮合環を含むC6−C10アリールを表し、2〜5個の炭素原子はO、S、N及びNR6から選択されるヘテロ原子と置換され、最終的には、R6、ハロ、CN、NO2、CF3、OCF3、COOR6、OCOR6、SO2NR6R7、CONR6R7、NR6R7、NR6COR7、(CH2)p−NR6R7、(CH2)p−OR6及び(CH2)pSR6から選択される5〜11個の置換基で置換され、
R2は、SO2R1又はR6であり、
同一である又は異なるR3及びR4は、COR8及びR6から選択され、
R5は、R6、アリール、OR6、SR6、ハロ、CN、NO2、CF3、OCF3、COOR6、SO2NR6R7、CONR6R7、NR6R7又はNHCOR6を表し、
同一である又は異なるR6及びR7は、H又はアルキルを表し、
R8は、H、アルキル、シクロアルキル、アリール、アルキルアリールから選択され、R8におけるアリールは同一である又は異なる1〜4個のR5置換基で置換されるか、又はR8は−(CH2)q−NR6R7を表し、
pは0〜6の整数を表し、
qは0〜6の整数を表し、
チアゾリル基は、スルホンアミド基に対してメタ位又はパラ位で6員環と結合され、硫黄原子に対してα位又はβ位で6員環と結合され、
又は、適切な場合に、前記化学式(1)の化合物の薬学的に許容される塩、及び又は、異性体、互変異性体、溶媒和物、若しくは同位体変種であり、
以下の化合物、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−2−ヒドロキシ−ベンズアミド、
2−(アセチルオキシ)−N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−ベンズアミド、
3−クロロ−N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−ベンズアミド、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−1−ヒドロキシ−2−ナフタレンカルボキサミド、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−3−ヒドロキシ−2−ナフタレンカルボキサミド、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−2−メトキシ−ベンズアミド、
N−[3−(2−アミノ−4−チアゾリル)フェニル]−4−クロロ−ベンゼンスルホンアミド、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−ベンズアミド、
2−クロロ−N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−ベンズアミド、
4−クロロ−N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−ベンズアミド、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−3,4−ジメトキシベンズアミド、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−3−メトキシベンズアミド、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−4−メトキシベンズアミド、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−3−メチル−ベンズアミド、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−4−メチル−ベンズアミド、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−4−ニトロ−ベンズアミド、
N−[4−[3−[[(4−クロロフェニル)スルホニル]アミノ]フェニル]−2−チアゾリル]−4−メチル−ベンズアミド、
は除外される、化合物。 - 化学式(2)で表され、
Q1〜Q5、R2、R3及びR4は請求項1の定義通りであり、R9は、R6、ハロ、CN、NO2、CF3、OCF3、COOR6、OCOR6、SO2NR6R7、CONR6R7、NR6R7、NR6COR7、(CH2)p−NR6R7、(CH2)p−OR6又は(CH2)pSR6を表し、
R6は請求項1の定義通りであり、nは1、2、3又は4を表し、pは0〜6の整数を表す、請求項1に記載の化合物。 - 化学式(3)で表され、
Q1〜Q5、R2、R3及びR4は請求項1の定義通りであり、R9は、R6、ハロ、CN、NO2、CF3、OCF3、COOR6、OCOR6、SO2NR6R7、CONR6R7、NR6R7、NR6COR7、(CH2)p−NR6R7、(CH2)p−OR6又は(CH2)pSR6を表し、
R6は請求項1の定義通りであり、nは1、2、3又は4を表し、pは0、1、2、3、4、5又は6を表し、ナフチル基は4級炭素に対して1位、2位又は3位で硫黄原子に付加される、請求項1に記載の化合物。 - R2はH又はSO2R1を表し、R1は、R6、ハロ、CN、NO2、CF3、OCF3、COOR6、OCOR6、SO2NR6R7、CONR6R7、NR6R7、NR6COR7、(CH2)p−NR6R7、(CH2)p−OR6及び(CH2)pSR6から選択される1〜4個の、好ましくは1又は2個の置換基で選択的に置換されるフェニル基又はナフチル基であり、
R6とpとは請求項1の定義通りである、請求項1〜3のいずれか1項に記載の化合物。 - R3はHを表し、R4はH、アルキル、CO−アルキル、アリールを表し、アリールは、R6、ハロ、CN、NO2、CF3、OCF3、COOR6、OCOR6、SO2NR6R7、CONR6R7、NR6R7、NR6COR7、(CH2)p−NR6R7、(CH2)p−OR6及び(CH2)pSR6から選択される1個以上の置換基を含み、
R6、R7及びpは請求項1の定義通りである、請求項1〜4のいずれか1項に記載の化合物。 - R6はH又はアルキルであり、
R9は、R6、ハロ、CN、NO2、CF3、OCF3、COOR6、OCOR6、SO2NR6R7、CONR6R7、NR6R7、NR6COR7、(CH2)p−NR6R7、(CH2)p−OR6又は(CH2)pSR6であり、
同一である又は異なるR6及びR7はH又はアルキルであり、pは0、1、2、3、4,5又は6である、請求項1〜5のいずれか1項に記載の化合物。 - 前記チアゾリル基は、前記スルホンアミド基に対してメタ位である、請求項1〜6のいずれか1項に記載の化合物。
- 前記チアゾリル基は、前記硫黄原子に対してβ位で6員芳香環と結合される、請求項1〜7のいずれか1項に記載の化合物。
- qは5を表し、
R8は−(CH2)5−NH2を表す、請求項1〜8のいずれか1項に記載の化合物。 - N−(4−(3−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
5−(ジメチルアミノ)−N−(3−(2−(メチルアミノ)チアゾール−4−イル)フェニル)ナフタレン−1−スルホンアミド、
N−(4−(3−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)−4−メチルベンズアミド、
N−(3−(2−アミノチアゾール−4−イル)フェニル)−5−(ジメチルアミノ) ナフタレン−1−スルホンアミド、
N−(4−(3−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)ベンズアミド、
N−(4−(3−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)ピバルアミド、
2−フルオロ−N−(3−(2−(メチルアミノ)チアゾール−4−イル)フェニル)ベンゼンスルホンアミド、
N−(4−(4−(ナフタレン−2−スルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(2−フルオロフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(2,4−ジフルオロフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(3−(トリフルオロメチル)フェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(3−(トリフルオロメチル)フェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(3−(トリフルオロメチル)フェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(4−(トリフルオロメチル)フェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(4−メチルフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(2−ニトロフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(3−ニトロフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(フェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(メチルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(4−(4−メチルフェニルスルホンアミド)フェニル)チアゾール−2−イル)アセトアミド、
N−(4−(3−(5−(ジメチルアミノ)ナフタレン−1−スルホンアミド)フェニル)チアゾール−2−イル)−5−アミノ−バレルアミド、
から選択される、請求項1に記載の化合物。 - 化学式(1)の化合物であり、
同一である又は異なるQ1〜Q5はCR6を表し、
R1は、1つの環又は2つの環の縮合環を含むC6−C10アリールを表し、2〜5個の炭素原子はO、S及びNR6から選択されるヘテロ原子で置換され、最終的には、R6、ハロ、CN、NO2、CF3、OCF3、COOR6、OCOR6、SO2NR6R7、CONR6R7、NR6R7、NR6COR7、(CH2)p−NR6R7、(CH2)p−OR6及び(CH2)pSR6から選択される5〜11個の置換基で置換され、
R2は、SO2R1又はR6であり、
同一である又は異なるR3及びR4は、COR8及びR6から選択され、
R5は、R6、アリール、OR6、SR6、ハロ、CN、NO2、CF3、OCF3、COOR6、SO2NR6R7、CONR6R7、NR6R7又はNHCOR6を表し、
同一である又は異なるR6及びR7は、H又はアルキルを表し、
R8は、H、アルキル、シクロアルキル、アリール、アルキルアリールから選択され、R8におけるアリールは同一である又は異なる1〜4個のR5置換基で置換されるか、又はR8は−(CH2)q−NR6R7を表し、pは0〜6の整数を表し、qは0〜6の整数を表し、
チアゾリル基は、スルホンアミド基に対してメタ位又はパラ位で6員環と結合され、S原子に対してα位又はβ位で6員環と結合され、
又は、適切な場合に、前記化学式(1)の化合物の薬学的に許容される塩、及び又は、異性体、互変異性体、溶媒和物、若しくは同位体変種である、がんの処置における使用のための化合物。 - 化学式(1)の化合物を調製するための方法であり、
a. 化学式1’aの化合物を適切な溶媒に含まれた臭素化剤で臭素化し、
Q1、Q2、Q3、Q5及びR5は請求項1の定義通りである、ステップと、
b. 前記ステップaで取得された化合物2’aをハンチュ反応の条件で化学式3aの化合物と反応させ、
Q1、Q2、Q3、Q5及びR5は請求項1の定義通りであり、
R3及びR4は請求項1の定義通りである、ステップと、
c. 前記ステップbで取得された化学式4’aの化合物を、不活性溶媒内において還元条件のもと水素源と反応させ、
Q1、Q2、Q3、Q5、R3、R4及びR5は請求項1の定義通りである、ステップと、
d. 前記ステップcで取得された化学式5’aの化合物を適切な溶媒内において化学式6aの化合物と反応させ、
Q1、Q2、Q3、Q5、R3、R4及びR5は請求項1の定義通りであり、
R1は請求項1の定義通りである、ステップと、
e. 前記ステップdで取得された化学式I’aの化合物を、化学式(1)の化合物を取得するため、塩基の存在下において化学式R2Xの化合物と反応させ、
Q1、Q2、Q3、Q5、R1、R3、R4及びR5は請求項1の定義通りであり、
R2は請求項1の定義通りであり、Xはハロゲン原子である、ステップと、
f. 取得された化学式(1)の化合物を分離するステップとを含む、方法。 - 化学式(1)の化合物を調製するための方法であり、
a. 化学式1’cの化合物を、不活性溶媒内において化学式1eの化合物と反応させ、
Q1、Q2、Q3、Q5は請求項1の定義通りであり、Xは脱離基を表し、
R3、R4及びR5は請求項1の定義通りであり、EはSnBu3、B(OH)2及びHから選択される、ステップと、
b. 前記ステップaで取得された化学式2’cの化合物を、不活性溶媒内において還元条件のもと水素源と反応させ、
Q1、Q2、Q3、Q5、R3、R4及びR5は請求項1の定義通りである、ステップと、
c. 前記ステップbで取得された化学式3’cの化合物を、非プロトン溶媒内において化学式6a化合物と反応させ、
Q1、Q2、Q3、Q5、R3、R4及びR5は請求項1の定義通りであり、
R1は請求項1の定義通りである、ステップと、
d. 前記ステップcで取得された化学式I’cの化合物を、塩基の存在下において化学式R2Xの化合物と反応させ、
Q1、Q2、Q3、Q5、R1、R3、R4及びR5は請求項1の定義通りであり、
R2は請求項1の定義通りであり、Xはハロゲン原子である、ステップと、
e. 取得された化学式(1)の化合物を分離するステップとを含む、方法。 - 請求項1〜13のいずれか1項に記載の化合物と薬学的に許容される担体とを含む医薬組成物。
- 動物又はヒトのがん病態を処置するための医薬組成物であり、請求項14の組成物の治療有効量を前記がん病態を有する前記動物又はヒトに投与するステップを含む、医薬組成物。
- 前記がんは黒色腫である、請求項15に記載の医薬組成物。
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