JP2006507215A - 過剰増殖性障害の処置に有用なベンゾフランおよびベンゾチオフェン誘導体 - Google Patents
過剰増殖性障害の処置に有用なベンゾフランおよびベンゾチオフェン誘導体 Download PDFInfo
- Publication number
- JP2006507215A JP2006507215A JP2003571267A JP2003571267A JP2006507215A JP 2006507215 A JP2006507215 A JP 2006507215A JP 2003571267 A JP2003571267 A JP 2003571267A JP 2003571267 A JP2003571267 A JP 2003571267A JP 2006507215 A JP2006507215 A JP 2006507215A
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- JP
- Japan
- Prior art keywords
- phenyl
- alkyl
- benzofuran
- optionally substituted
- amino
- 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.)
- Withdrawn
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- 238000011282 treatment Methods 0.000 title claims abstract description 17
- 230000003463 hyperproliferative effect Effects 0.000 title claims abstract description 8
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title abstract description 29
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 129
- 238000000034 method Methods 0.000 claims description 125
- 239000000203 mixture Substances 0.000 claims description 82
- 229910052796 boron Inorganic materials 0.000 claims description 50
- 125000000623 heterocyclic group Chemical group 0.000 claims description 43
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 41
- 229920006395 saturated elastomer Polymers 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 20
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- OUEWJOMEVTXNED-UHFFFAOYSA-N (3-amino-6-pyridin-3-yl-1-benzofuran-2-yl)-(2,4-dichlorophenyl)methanone Chemical compound C=1C=C2C(N)=C(C(=O)C=3C(=CC(Cl)=CC=3)Cl)OC2=CC=1C1=CC=CN=C1 OUEWJOMEVTXNED-UHFFFAOYSA-N 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- DBHZNAMXVFCAMM-UHFFFAOYSA-N [3-amino-6-(2-methyl-1,3-oxazol-4-yl)-1-benzofuran-2-yl]-(2-methoxyphenyl)methanone Chemical compound COC1=CC=CC=C1C(=O)C1=C(N)C2=CC=C(C=3N=C(C)OC=3)C=C2O1 DBHZNAMXVFCAMM-UHFFFAOYSA-N 0.000 claims description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 4
- OSWXORYOERTQAY-UHFFFAOYSA-N [3-amino-6-(2-methylpyridin-3-yl)-1-benzofuran-2-yl]-(2,4-dichlorophenyl)methanone Chemical compound CC1=NC=CC=C1C1=CC=C(C(N)=C(O2)C(=O)C=3C(=CC(Cl)=CC=3)Cl)C2=C1 OSWXORYOERTQAY-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 4
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 claims description 4
- WSLKYYUHGVNXHY-UHFFFAOYSA-N (3-amino-5-fluoro-6-pyridin-3-yl-1-benzofuran-2-yl)-(2,4-dichlorophenyl)methanone Chemical compound FC=1C=C2C(N)=C(C(=O)C=3C(=CC(Cl)=CC=3)Cl)OC2=CC=1C1=CC=CN=C1 WSLKYYUHGVNXHY-UHFFFAOYSA-N 0.000 claims description 3
- BIYYHESSCPEDPN-UHFFFAOYSA-N (3-amino-6-phenyl-1-benzofuran-2-yl)-(2,4-dichlorophenyl)methanone Chemical compound C=1C=C2C(N)=C(C(=O)C=3C(=CC(Cl)=CC=3)Cl)OC2=CC=1C1=CC=CC=C1 BIYYHESSCPEDPN-UHFFFAOYSA-N 0.000 claims description 3
- PQFUOLMSSNVKRX-UHFFFAOYSA-N 3-[3-amino-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl]benzonitrile Chemical compound C=1C=C2C(N)=C(C(=O)C=3C(=CC(Cl)=CC=3)Cl)OC2=CC=1C1=CC=CC(C#N)=C1 PQFUOLMSSNVKRX-UHFFFAOYSA-N 0.000 claims description 3
- KPTCQWWNROKSNL-UHFFFAOYSA-N [3-amino-6-(2-methyl-1,3-thiazol-4-yl)-1-benzofuran-2-yl]-(2,4-dichlorophenyl)methanone Chemical compound S1C(C)=NC(C=2C=C3OC(=C(N)C3=CC=2)C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 KPTCQWWNROKSNL-UHFFFAOYSA-N 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- NJPJRAKQCLNUIM-UHFFFAOYSA-N [3-amino-6-(3-aminophenyl)-1-benzofuran-2-yl]-(2,4-dichlorophenyl)methanone Chemical compound C=1C=C2C(N)=C(C(=O)C=3C(=CC(Cl)=CC=3)Cl)OC2=CC=1C1=CC=CC(N)=C1 NJPJRAKQCLNUIM-UHFFFAOYSA-N 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 6
- FLKRHTSPULOBFM-UHFFFAOYSA-N 2-[3-[3-amino-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl]phenyl]acetamide Chemical compound NC(=O)CC1=CC=CC(C=2C=C3OC(=C(N)C3=CC=2)C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 FLKRHTSPULOBFM-UHFFFAOYSA-N 0.000 claims 1
- IKSPEUNHRGRUMR-UHFFFAOYSA-N 3-[3-amino-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(C=2C=C3OC(=C(N)C3=CC=2)C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 IKSPEUNHRGRUMR-UHFFFAOYSA-N 0.000 claims 1
- WBZHJWSGBJFOTJ-UHFFFAOYSA-N 3-[3-amino-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl]benzenesulfonamide Chemical compound C=1C=C2C(N)=C(C(=O)C=3C(=CC(Cl)=CC=3)Cl)OC2=CC=1C1=CC=CC(S(N)(=O)=O)=C1 WBZHJWSGBJFOTJ-UHFFFAOYSA-N 0.000 claims 1
- QQLWIJDCWYBUHX-UHFFFAOYSA-N 3-[3-amino-2-(2-chloro-4-fluorobenzoyl)-1-benzofuran-6-yl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2C=C3OC(=C(N)C3=CC=2)C(=O)C=2C(=CC(F)=CC=2)Cl)=C1 QQLWIJDCWYBUHX-UHFFFAOYSA-N 0.000 claims 1
- GOWISGPVKCIOQA-UHFFFAOYSA-N 5-[3-amino-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl]pyridine-3-carboxamide Chemical compound NC(=O)C1=CN=CC(C=2C=C3OC(=C(N)C3=CC=2)C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 GOWISGPVKCIOQA-UHFFFAOYSA-N 0.000 claims 1
- ZGHAVJZYGOXINQ-UHFFFAOYSA-N [3-amino-6-(1-methylimidazol-4-yl)-1-benzofuran-2-yl]-(2,4-dichlorophenyl)methanone Chemical compound CN1C=NC(C=2C=C3OC(=C(N)C3=CC=2)C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 ZGHAVJZYGOXINQ-UHFFFAOYSA-N 0.000 claims 1
- JIESZDWWPQVZRI-UHFFFAOYSA-N [3-amino-6-(2-fluoropyridin-3-yl)-1-benzofuran-2-yl]-(2,4-dichlorophenyl)methanone Chemical compound C=1C=C2C(N)=C(C(=O)C=3C(=CC(Cl)=CC=3)Cl)OC2=CC=1C1=CC=CN=C1F JIESZDWWPQVZRI-UHFFFAOYSA-N 0.000 claims 1
- DWWCEPUFYAQRAP-UHFFFAOYSA-N [3-amino-6-(3-fluoro-5-nitrophenyl)-1-benzofuran-2-yl]-(2,4-dichlorophenyl)methanone Chemical compound C=1C=C2C(N)=C(C(=O)C=3C(=CC(Cl)=CC=3)Cl)OC2=CC=1C1=CC(F)=CC([N+]([O-])=O)=C1 DWWCEPUFYAQRAP-UHFFFAOYSA-N 0.000 claims 1
- PZBJOQIJATWMRD-UHFFFAOYSA-N [3-amino-6-(3-methylsulfonylphenyl)-1-benzofuran-2-yl]-(2,4-dichlorophenyl)methanone Chemical compound CS(=O)(=O)C1=CC=CC(C=2C=C3OC(=C(N)C3=CC=2)C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 PZBJOQIJATWMRD-UHFFFAOYSA-N 0.000 claims 1
- QFXBMOQPKUVQLV-UHFFFAOYSA-N [3-amino-6-(3-nitrophenyl)-1-benzofuran-2-yl]-(2,4-dichlorophenyl)methanone Chemical compound C=1C=C2C(N)=C(C(=O)C=3C(=CC(Cl)=CC=3)Cl)OC2=CC=1C1=CC=CC([N+]([O-])=O)=C1 QFXBMOQPKUVQLV-UHFFFAOYSA-N 0.000 claims 1
- QJIYBIVRSKDUST-UHFFFAOYSA-N [3-amino-6-[2-(methylamino)pyridin-3-yl]-1-benzofuran-2-yl]-(2,4-dichlorophenyl)methanone Chemical compound CNC1=NC=CC=C1C1=CC=C(C(N)=C(O2)C(=O)C=3C(=CC(Cl)=CC=3)Cl)C2=C1 QJIYBIVRSKDUST-UHFFFAOYSA-N 0.000 claims 1
- VACJTBUWCGCYND-KRWDZBQOSA-N [3-amino-6-[3-[[(2s)-2,3-dihydroxypropyl]amino]phenyl]-1-benzofuran-2-yl]-(2,4-dichlorophenyl)methanone Chemical compound C=1C=C2C(N)=C(C(=O)C=3C(=CC(Cl)=CC=3)Cl)OC2=CC=1C1=CC=CC(NC[C@H](O)CO)=C1 VACJTBUWCGCYND-KRWDZBQOSA-N 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- NPUNSRMMUKWWIW-UHFFFAOYSA-N n-[3-[3-amino-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl]phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC(C=2C=C3OC(=C(N)C3=CC=2)C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 NPUNSRMMUKWWIW-UHFFFAOYSA-N 0.000 claims 1
- XJMNJPQXRWZNLH-UHFFFAOYSA-N n-[3-[3-amino-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl]phenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC(C=2C=C3OC(=C(N)C3=CC=2)C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 XJMNJPQXRWZNLH-UHFFFAOYSA-N 0.000 claims 1
- RCZGDEIAYJLIJV-UHFFFAOYSA-N n-[[3-[3-amino-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl]phenyl]methyl]acetamide Chemical compound CC(=O)NCC1=CC=CC(C=2C=C3OC(=C(N)C3=CC=2)C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 RCZGDEIAYJLIJV-UHFFFAOYSA-N 0.000 claims 1
- QRVHDQOFUQCLKS-UHFFFAOYSA-N n-[[3-[3-amino-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl]phenyl]methyl]methanesulfonamide Chemical compound CS(=O)(=O)NCC1=CC=CC(C=2C=C3OC(=C(N)C3=CC=2)C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 QRVHDQOFUQCLKS-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 265
- 238000002360 preparation method Methods 0.000 description 155
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 122
- 239000000243 solution Substances 0.000 description 97
- 235000019439 ethyl acetate Nutrition 0.000 description 94
- 238000005160 1H NMR spectroscopy Methods 0.000 description 90
- 238000006243 chemical reaction Methods 0.000 description 79
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 76
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 76
- -1 n -propyl Chemical group 0.000 description 73
- 239000007787 solid Substances 0.000 description 69
- 239000011541 reaction mixture Substances 0.000 description 62
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 59
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
- 230000002829 reductive effect Effects 0.000 description 50
- 239000002904 solvent Substances 0.000 description 47
- 239000000047 product Substances 0.000 description 44
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 42
- 239000012044 organic layer Substances 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 229910052786 argon Inorganic materials 0.000 description 38
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 239000002504 physiological saline solution Substances 0.000 description 33
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 32
- 239000007858 starting material Substances 0.000 description 32
- 239000012043 crude product Substances 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000000543 intermediate Substances 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 229910052938 sodium sulfate Inorganic materials 0.000 description 26
- 235000011152 sodium sulphate Nutrition 0.000 description 26
- 239000010410 layer Substances 0.000 description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 23
- 238000000746 purification Methods 0.000 description 23
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- 229910000027 potassium carbonate Inorganic materials 0.000 description 21
- 238000004809 thin layer chromatography Methods 0.000 description 20
- 239000003814 drug Substances 0.000 description 19
- 239000011780 sodium chloride Substances 0.000 description 19
- 235000019441 ethanol Nutrition 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- 239000003826 tablet Substances 0.000 description 17
- 125000004429 atom Chemical group 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 235000019270 ammonium chloride Nutrition 0.000 description 15
- 238000002425 crystallisation Methods 0.000 description 15
- 230000008025 crystallization Effects 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- 238000007429 general method Methods 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 14
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 14
- 239000000872 buffer Substances 0.000 description 14
- 235000014113 dietary fatty acids Nutrition 0.000 description 14
- 239000000194 fatty acid Substances 0.000 description 14
- 229930195729 fatty acid Natural products 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- 229910052763 palladium Inorganic materials 0.000 description 13
- BGSDHEYJKHYYLW-UHFFFAOYSA-N NC1=C(OC2=C1C=CC(=C2)I)C(=O)C2=C(C=C(C=C2)Cl)Cl.B(O)O Chemical compound NC1=C(OC2=C1C=CC(=C2)I)C(=O)C2=C(C=C(C=C2)Cl)Cl.B(O)O BGSDHEYJKHYYLW-UHFFFAOYSA-N 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 12
- 238000000105 evaporative light scattering detection Methods 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 10
- 238000007792 addition Methods 0.000 description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 10
- 125000003118 aryl group Chemical group 0.000 description 10
- 239000002585 base Chemical class 0.000 description 10
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 10
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 10
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 10
- VYWPPRLJNVHPEU-UHFFFAOYSA-N 2-chloro-1-(2,4-dichlorophenyl)ethanone Chemical compound ClCC(=O)C1=CC=C(Cl)C=C1Cl VYWPPRLJNVHPEU-UHFFFAOYSA-N 0.000 description 9
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 hetero ring
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 hetero ring
- C07D333/66—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/74—Naphthothiophenes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
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- C—CHEMISTRY; METALLURGY
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Abstract
Description
本発明の1態様は式(I)
XはOおよびSから選択され、
R1はH、(C1−C6)アルキル、C(O)(C1−C6)アルキルおよびベンゾイルから選択され、
R2は、
OH、CN、NO2、(C1−C6)アルキル、(C1−C6)アルコキシ、ハロ、ハロ(C1−C6)アルキル、ハロ(C1−C6)アルコキシ、C(O)RA、C(O)NRBRB、NRBRB、NH[(C1−C6)アルキル]0−1S(O)2RB、NH[(C1−C6)アルキル]0−1C(O)RAおよびNH[(C1−C6)アルキル]0−1C(O)ORBからそれぞれ独立に選択される1、2もしくは3個の置換基でそれぞれ場合により置換されたフェニルおよびナフチル、
それぞれ、OH、CN、NO2、(C1−C6)アルキル、(C1−C6)アルコキシ、ハロ、ハロ(C1−C6)アルキル、ハロ(C1−C6)アルコキシ、C(O)RA、C(O)NRBRB、NRBRB、NH[(C1−C6)アルキル]0−1S(O)2RB、NH[(C1−C6)アルキル]0−1C(O)RAおよびNH[(C1−C6)アルキル]0−1C(O)ORBから独立に選択される1、2、もしくは3置換基でそれぞれ場合により置換された、6員複素環、5員複素環および縮合2環式複素環から選択される複素環、から選択され、
RAは各々の場合において、独立にH、(C1−C6)アルキル、(C1−C6)アルコキシ、NRBRBもしくは(C1−C6)アルキルであり、ここで前記アルキルは場合によりOH、C(O)RB、ハロ、(C1−C3)アルコキシおよびNRBRBで置換されている、
RBは各々の場合に独立において、H、(C3−C6)シクロアルキルおよび(C1−C6)アルキルであり、ここで前記アルキルは場合によりOH、=O、ハロ、(C1−C6)アルコキシ、NH(C1−C3)アルキル、N[(C1−C3)アルキル]2およびNC(O)(C1−C3)アルキルで置換されており、
そしてここでRBは、それがN原子に結合されている時は各々の場合において(C1−C4)であり、その場合2個の(C1−C4)アルキル基が一緒になって、それらが結合しているN原子と一緒になって飽和環を形成することができ、そして
ここでRBとRBがそれらが結合しているNと一緒に、場合により、利用可能なN原子上で(C1−C6)アルキルで置換されたピペラジニル環もしくはモルホリニル環を形成することができ、ここで前記アルキルがOH、=O、NH2、(C1−C6)アルコキシ、NH(C1−C3)アルキルもしくはN[(C1−C3)アルキル]2で場合により置換されており、
そしてただし、RBがS(O)もしくはS(O)2に結合されている時は、それはHであることはできず、
R3はH、OH、CN、(C1−C3)アルキル、(C1−C3)アルコキシ、ハロ、ハロ(C1−C3)アルキルおよびハロ(C1−C3)アルコキシから選択され、
R4は、
ピペロニル、
Y[ここでYは場合により、=O、N−オキシド、H、CN、NO2、ハロ、ハロ(C1−C6)アルキル、OH、ハロ(C1−C6)アルコキシ、C(O)ORB、C(NH)NRBRB、NRBRB、S(O)0−2RB、S(O)2NRBRB、(C1−C6)アルコキシ(前記アルコキシはOH、NRBRBおよび(C1−C3)アルコキシから選択される1もしくは2個の置換基で場合により置換されている)、NRCRC(ここでRCはRB、C(O)RBおよびS(O)2RBから選択される)、C(O)RD[ここでRDはRA、(C3−C6)シクロアルキル、ZおよびN[(C1−C3)アルキル]Zから選択され、ここでZは各々の場合において、CN、=O、OH、N−オキシド、NO2、ハロ、(C1−C6)アルコキシ、ハロ(C1−C3)アルコキシ、ハロ(C1−C3)アルキル、S(O)2RB、S(O)2NRBRB、NRBRB、C(O)RAおよび(C1−C6)アルキルで場合により独立に置換された複素環であり、ここで前記アルキルはOH、C(O)RB、(C1−C3)アルコキシおよびNRBRBで場合により置換されている]、NRBRE[ここでREはC(O)RA、C(O)RB、S(O)2RB、S(O)2NRBRBおよびC(O)[(C1−C6)アルキル]Zから選択され、ここでZは場合により前記のとおりに置換されている]、(C1−C6)アルキル[ここで前記のアルキルはCN、OH、=O、ハロ、(C1−C6)アルコキシ、C(O)RA、NRBRB、NRCRc、NRBRE,C(NH)NRBRB、S(O)0−2RB、S(O)2NRBRB、C(O)RB、C(O)ORB、Z、C(O)ZおよびC(O)N[(C1−C3)アルキル]Zで場合により置換されており、ここでZが各々の場合において、独立に場合により前記のように置換されている]、
からそれぞれ独立に選択される1、2もしくは3個の置換基で置換された複素環である]、
OH、CN、NO2、ハロ、ハロ(C1−C6)アルキル、ハロ(C1−C6)アルコキシ、C(O)ORB、C(NH)NRBRB、NRBRB、S(O)0−2RB、S(O)2NRBRB、Z、C(O)Z(ここでZは各々の場合において、場合により前記のとおりに置換されている)、(C1−C6)アルコキシ(ここで前記アルコキシがOH、NRBRBおよび(C1−C3)アルコキシから選択される1もしくは2個の置換基で場合により置換されている)、NRCRC(ここでRCはRB、C(O)RBおよびS(O)2RBから選択される)、C(O)RD[ここでRDはRA、(C3−C6)シクロアルキルおよびN[(C1−C3)アルキル]Z(ここでZは場合により、前記の通りに置換されている)から選択される]、NRBRE[ここでREはC(O)RA、C(O)RB、S(O)2RB、S(O)2NRBRBおよびC(O)[(C1−C6)アルキル]Zから選択され、ここでZは場合により前記のとおりに置換されている]、(C1−C6)アルキル[ここで前記アルキルはCN、OH、=O、ハロ、(C1−C6)アルコキシ、C(O)RA、NRBRB、NRBRE、C(NH)NRBRB、S(O)0−2RB、S(O)2NRBRB、C(O)RBC(O)ORB、Z、C(O)ZおよびC(O)N[(C1−C3)アルキル]Zで場合により置換されており、ここでZがそれぞれ場合により独立に前記のとおりに置換されている]、からそれぞれ独立に選択される1、2もしくは3置換基でそれぞれ場合により置換されたフェニルおよびナフチル、
から選択され、
R5およびR6はそれぞれ独立に、H、OH、CN、(C1−C3)アルキル、(C1−C3)アルコキシ、ハロ、ハロ(C1−C3)アルキルおよびハロ(C1−C3)アルコキシから選択される}
の化合物または医薬として許容できるその塩もしくはエステルに関する。
用語「場合により置換された」はそのように修飾された部分が0から、記載されたほぼ最大数の置換基までを有することができることを意味する。いずれかの部分上に2個以上の置換基が存在する時は、各置換基はあらゆる他の置換基と独立に定義され、従って同一でも異なってもよい。
本発明の化合物は概して、商業的に利用可能で、日常的な通常の化学的方法もしくは本明細書に記載の合成法に従って生成可能な出発物質を使用して、当該技術分野で周知の標準方法により、それらに類似の既知の方法により、そして/もしくは以下に開示される方法により調製することができる。本発明の化合物の調製に使用することができる具体的な方法は所望される特定の化合物に左右される。アミンが置換されているか否か、分子上の様々な位置で可能な具体的な置換基の選択等のような因子それぞれが経過される経路に役割を果たす。これらの因子は当業者により容易に認められる。
プロトン(1H)核磁気共鳴(NMR)スペクトルを、基準としてMe4Si(δ0.00)もしくは残留プロトン化溶媒(CHCl3δ7.26;MeOHδ3.30;DMSOδ2.49)のいずれかを使用してGeneral Electric GN−Omega 300(300MHz)分光計で測定した。炭素(13C)NMRスペクトルを、基準として溶媒(CDCl3δ77.0;d3−MeOD;δ49.0;d6−DMSOδ39.5)を使用してGeneral Electric GN−Omega 300(75MHz)分光計により測定した。
以下の略語が本明細書で使用される場合には、それらは以下の意味を有する:
ADDP 1,1’−(アゾジカルボニル)−ジピペリジン
DBU 1,8−ジアザビシクロ[5.4.0]ウンデス−7−エン
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
EA 元素分析
ES 電子スプレー
Et エチル
Et2O ジエチルエーテル
EtOAc 酢酸エチル
GC−MS ガスクロマトグラフィー−質量分析
HEX ヘキサン
LC−MS 液体クロマトグラフィー/質量分析
Me メチル
MeCN アセトニトリル
MeOH メタノール
MPLC 中圧液体クロマトグラフィー
NCS N−クロロスクシンイミド
NMR 核磁気共鳴分光法
Pd(dppf)2Cl2
[1,1−ビス(ジフェニルホスフィノ)−フェロセン]ジクロロ−パ
ラジウム(II)
Ph フェニル
PyBOP ベンゾトリアゾール−1−イル−オキシ−トリス−ピロリジノ−ホスニ
ウム・ヘキサフルオロホスフェート
RT 保持時間(HPLC)
Rf TLC保持因子
rt 室温
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
出発物質および中間体の調製
一般的方法A:2−ハロ−1−アリールケトン(III)
式(III)の化合物は市販であるかもしくは一般的方法Aの反応スキームに示され、かつ1種もしくは複数の以下の実施例中に記載のように調製することができる。
方法A−1
2−ブロモ−1−(2,4,6−トリクロロフェニル)−エタノンの調製
方法A−2a
2−ブロモ−1−(2,5−ジクロロフェニル)−エタノンの調製
実施例3
方法A−2b
2−ブロモ−1−(2−ブロモ−4−フルオロ−フェニル)−エタノンの調製
方法A−3
2−クロロ−1−(4−メチル−3−ピリジニル)エタノン塩酸の調製
段階2:2−クロロ−1−(4−メチル−3−ピリジニル)エタノン塩酸の調製
実施例5
方法A−4
2−クロロ−1−[4−(トリフルオロメチル)−3−ピリジニル)−エタノン塩酸の調製
250 mLの丸底フラスコ中に4−トリフルオロニコチン酸(15.7ミリモル, 1当量)3.0 g(100 mLのTHF中)を入れた。これにトリエチルアミン5.3 mL (3.8 g, 37.7ミリモル, 2.4当量)およびPyBOP9.8 g (18.8 ミリモル, 1.2当量)を添加した。これを室温で10分間撹拌し、ここでメルドラムの酸2.7 g(18.8 ミリモル, 1.2当量)を添加し、反応物を室温で1晩(18時間)撹拌した。
段階2
100 mLのフラスコ中にメチル4−トリフルオロメチルニコチネート1.84 g (9.7 ミリモル, 1当量)(25 mLのCH3COOH 中1 M HCl中) を入れた。次にこれに NCS (9.7 ミリモル, 1 当量) 1.3 gを添加し、反応物を1晩(18時間)撹拌した。
実施例6
方法A−5
1−ベンゾ[1,3]ジオキソール−4−イル−2−ブロモ−エタノンの調製
段階2:中間体1−ベンゾ[1,3]ジオキソール−4−イル−2−ブロモ−エタノンの調製
実施例7
方法A−6
出発物質2−ブロモ−1−[3−(tert−ブチル−ジフェニル−シラニルオキシ)−フェニル]エタノンの調製
段階2:2−ブロモ−1−[3−(tert−ブチル−ジフェニル−シラニルオキシ)フェニル]エタノンの調製
この物質は実施例104の合成;ベンゾフラン−形成段階中に起る脱シリル化において保護形態として使用された。
一般的方法H:中間体(VI)および(VII)の調製
式(I)の本発明の化合物を調製するために使用されるアリールハロゲン化物(VII)、アリールボロン酸もしくはアリールボロネート(VI)(以下のB、C、DおよびGを参照されたい)は市販のものを利用するかもしくは以下の実施例に記載の1種もしくは複数の方法により調製された。以後に記載される方法により調製されるアリールハロゲン化物(VII)はその後、以下に記載の一般的方法B、C−1、D−1およびD−3の出発物質として直接使用されるかもしくは実施例C−2およびD−2の段階1に記載の方法を使用して式(VI)の対応するボロネートに転化されて一般的方法に記載のとおりに使用されることができる。
方法H−1
1−ブロモ−3−メチルスルファニルメチル−ベンゼンの調製
実施例9
方法H−2
アルキルアリールチオエーテルの調製
1−ブロモ−3−イソプロピルスルファニル−ベンゼンの調製
実施例10
方法H−3
1−ブロモ−3−メチルスルホニル−ベンゼンの調製
段階2:1−ブロモ−3−メタンスルホニル−ベンゼンの調製
実施例11
方法H−4
N−(3−ヨード−ベンジル)−メタンスルホンアミドの調製
実施例12
方法H−5
1−(3−ヨード−フェニル)−3−メチル−尿素
実施例13
方法H−6
(R)−3−(3−ブロモ−フェノキシ)−プロパン−1,2−ジオールの調製
実施例14
方法H−7
2−フルオロ−3−ヨード−ピリジンの調製
実施例15
方法H−8
3−ヨード−2−メトキシ−ピリジンの調製
実施例16
方法H−9
(3−ヨード−ピリジン−2−イル)−メチルアミンの調製
実施例17
方法H−10
シクロプロパンカルボン酸(3−ブロモフェニル)アミドの調製
実施例18
方法H−11
3−ブロモ−N−(2−メトキシ−エチル)−ベンゼンスルホンアミドの調製
実施例19
方法H−12
ジエチル−(3−ヨード−ベンジル)−アミンの調製
実施例20
方法H−13
3−ブロモ−N−メチル−ベンズアミドの調製
実施例21
方法H−14
2−(3−ブロモ−フェニル)−アセトアミドの調製
実施例22
方法H−15
2−(3−ブロモ−フェニル)−プロパン−2−オールの調製
一般的方法B:シアノフェノール、シアノチオフェノールの調製および式(I)の化合物への転化
これらの方法において、シアノフェノールもしくはチオフェノール(II)は容易に入手できるフェノールもしくはチオフェノールから調製され、次に一般的方法Bの反応スキームおよび、X=Oである場合の本方法に対する以下の具体的な実施例中に示されるように、(III)と結合されて式(I)の生成物を提供する。
方法B−1
3−アミノ−6−フェニル−1−ベンゾフラン−2−イル)(2、4−ジクロロフェニル)メタノンの調製
段階2:主題化合物3−アミノ−6−フェニル−1−ベンゾフラン−2−イル)(2,4−ジクロロフェニル)メタノンの調製
段階1からの2−シアノ−5−フェニルフェノール(5.71 g, 29.25ミリモル)および2−クロロ−1−(2,4−ジクロロフェニル)エタノン(7.19 g, 32.17 ミリモル, 1.1 当量)の撹拌溶液(50 mLの無水N,N−ジメチルホルムアミド中)に炭酸カリウム(4.85 g, 35.1ミリモル, 1.2 当量)を添加し、橙色の反応混合物を90℃で17時間撹拌した。生成された暗ワイン色の反応物を酢酸エチル(500 mL)および水(300 mL)中に注入した。酢酸エチル層を飽和塩化アンモニウム水溶液、水および生理食塩水で洗浄した。次に有機層を乾燥し(MgSO4)、濾過し、真空蒸発させた。粗生成物を10%酢酸エチル−ヘキサン、次に20%酢酸エチル−ヘキサンで溶離されるシリカゲル上(フラッシュカラムクロマトグラフィー)で精製した。エーテル−ヘキサンからの結晶化により黄色の固体としてベンゾフラン生成物(7.56 g, 67.6%)を与えた。. 1H-NMR (DMSO-d6) δ 8.10 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 3.6 Hz, 1H), 7.74 (d, J = 3.0 Hz, 1 H), 7.71 (m, 2H), 7.62 to 7.53 (m, 5H), 7.47 〜 7.35 (m, 3H); MS LC-MS (MH+ = 382); C21H13Cl2NO2元素分析計算値: 65.99% H 3.43% N 3.66%, 測定値 C 65.70% H 3.40% N 3.72%; 融点 (非補正) 144 〜 146.5 °C.
方法B−2a
[3−アミノ−6−(2−メチル−オキサゾール−4−イル)−ベンゾフラン−2−イル]−(2−メトキシ−フェニル)−メタノンの調製
段階2:中間体3−(2−メチル−オキサゾール−4−イル)−フェノールの調製
段階3:中間体2−ヒドロキシ−4−(2−メチル−オキサゾール−4−イル)−ベンズアルデヒドの調製
段階4:中間体2−ヒドロキシ−4−(2−メチル−オキサゾール−4−イル)−ベンゾニトリルの調製
段階5:[3−アミノ−6−(2−メチル−オキサゾール−4−イル)−ベンゾフラン−2−イル]−(2−メトキシ−フェニル)−メタノンの調製
実施例25
方法B−2b
[3−アミノ−6−(2−メチル−チアゾール−4−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンの調製
段階2:中間体3−(2−メチル−チアゾール−4−イル)−フェノールの調製
段階3:中間体2−ヒドロキシ−4−(2−メチル−チアゾール−4−イル)−ベンズアルデヒドの調製
段階4:
中間体2−ヒドロキシ−4−(2−メチル−オキサゾール−4−イル)−ベンゾニトリルの調製に記載のものと同様な方法を使用した。2段階の全収率は83%であった。1H-NMR (CH3OH-d4) δ 7.75 (s, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.48 (d, J=1.6 Hz 1H), 7.42 (dd, J=8.2 Hz, 1.6 Hz, 1H), 2.75 (s, 3H). MS LC-MS MH+=217.2; Rf = 0.18, 30% EtOAc-HEX.
段階5:2[3−アミノ−6−(2−メチル−チアゾール−4−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンの調製
実施例26
方法B−2c
[3−アミノ−6−(1−メチル−1H−ピラゾール−3−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンの調製
段階2:中間体2−ヒドロキシ−4−(1−メチル−1H−ピラゾール−3−イル)−ベンゾニトリルの調製
段階3:[3−アミノ−6−(1−メチル−1H−ピラゾール−3−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンの調製
方法B−3
(3−アミノ−6−ピリジン−3−イル−ベンゾフラン−2−イル)−(2−メトキシ−フェニル)−メタノンの調製
段階2:出発物質:2−ヒドロキシ−4−(ピリジン−3−イル)ベンゾニトリルの調製
段階3:主題化合物:(3−アミノ−6−ピリジン−3−イル−ベンゾフラン−2−イル)−(2−メトキシ−フェニル)−メタノンの調製
実施例28
方法B−4
N−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−ピリジン−1−イル}−ピロピオンアミドの調製
段階2:N−(3’−ベンジルオキシ−4’−シアノ−ビフェニル−3−イル)−N−プロピオニル−プロピオンアミドの調製
段階3:N−(4’−シアノ−3’−ヒドロキシ−ビフェニル−3−イル)−N−プロピオニル−プロピオンアミドの調製
段階4:主題化合物:N−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−フェニル}−N−プロピオニル−ピロピオンアミドの調製
段階5:N−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−ピリジン−1−イル}−ピロピオンアミドの調製
実施例29
[3−アミノ−6(4−メチル−チオフェン−3−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンにより代表される方法B−5
段階2:[3−アミノ−6(4−メチル−チオフェン−3−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンの調製
表1に示した更なる化合物は容易に入手できるそして/もしくはその合成が本明細書に教示されている適当な出発物質を選択し、そして前記の方法Aおよび/もしくはBの方法または当該技術分野で周知の他の標準的化学方法を使用して前記のように調製された。
*以下はLCMS条件である:HPLC -電子スプレー質量スペクトル(HPLC ES-MS)は2基のGilson 306ポンプ、Gilson 215 Autosampler、Gilsonダイオードアレー検出計、a YMC Pro C-18 カラム (2 x 23 mm, 120 A)を備えたGilson HPLC システムおよびz-スプレー電子スプレーイオン化を伴なうMicromass LCZ シングル4極質量分析計を使用して得た。スペクトルは2秒間120〜1000amuからスキャンした。ELSD (蒸発光線散乱検出計) のデータもアナログチャンネルとして獲得した。勾配溶離は 1.5 mL/分における、 0.02% TFAを含む水中2% アセトニトリルとしてのバッファーAおよび0.02% TFA を含むアセトニトリル中2%水としてのバッファー Bを使用した。試料は以下のように溶離した: 0.5 分間90% A〜 3.5 分間95% B の勾配を使用し、0.5 分間 95% B で維持し、次にカラムを0.1 分間最初の状態の復帰させた。総実施時間は 4.8 分であった
**comm は市販を意味する。
以下の一般的方法Cの反応スキームには式(IV)および(V)の中間体を経過する式(I)の化合物の調製の一般的に適用できる方法が具体的に示される。室温から100℃の間の温度でDMF、MeCNのような溶媒中で塩基性条件下における(例えば、炭酸セシウム、炭酸カリウム、炭酸ナトリウム、DBU)適当に置換された2−シアノ−5−ヨード−フェノール(II)および1−アリール−2−ハロエタノン(III)の縮合が6−ヨード−ベンゾフラン(IV)を与える。(IV)とアリールボロン酸もしくはボロネート(VI)間のパラジウム媒介カプリング反応が所望の化合物を与える。あるいはまた、6−ヨード−ベンゾフラン(IV)をボロネート(V)に転化させ、次にそれを使用してアリールハロゲン化物(VII)とのパラジウム媒介カプリングにより所望の化合物を調製した。
方法C−1a
[3−アミノ−6−(3−ピリジニル)−1−ベンゾフラン−2−イル](2,4−ジクロロフェニル)メタノンの調製
段階 2: 中間体(3−アミノ−6−ヨード−1−ベンゾフラン−2−イル)(2,4−ジクロロフェニル)メタノンの調製
段階3:主題化合物:[3−アミノ−6−(3−ピリジニル)−1−ベンゾフラン−2−イル](2,4−ジクロロフェニル)メタノンの調製
実施例45a
方法C−1b
(3−アミノ−5−フルオロ−6−ピリジン−3−イル−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノンの調製
段階2:出発物質:5−フルオロ−2−ヒドロキシ−4−ヨードベンゾニトリルの調製
段階3:出発物質:3−アミノ−6−ヨード−1−ベンゾフラン−2−イル)(2,4−ジクロロフェニル)メタノンの調製
段階4:主題化合物:(3−アミノ−5−フルオロ−6−ピリジン−3−イル−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノンの調製
[3−アミノ−6−(2−メチル−フェニル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンの調製
実施例46
方法C−2
[3−アミノ−6−(2−メチル−3−ピリジニル)−1−ベンゾフラン−2−イル](2,4−ジクロロフェニル)メタノンの調製
段階2:主題化合物:[3−アミノ−6−(2−メチル−3−ピリジニル)−1−ベンゾフラン−2−イル](2,4−ジクロロフェニル)メタノンの調製
*以下はLCMS条件である:HPLC -電子スプレー質量スペクトル(HPLC ES-MS)は2基のGilson 306ポンプ、Gilson 215 Autosampler、Gilsonダイオードアレー検出計、a YMC Pro C-18 カラム (2 x 23 mm, 120 A)を備えたGilson HPLC システムおよびz-スプレー電子スプレーイオン化を伴なうMicromass LCZ シングル4極質量分析計を使用して得た。スペクトルは2秒間120〜1000amuからスキャンした。ELSD (蒸発光線散乱検出計) のデータもアナログチャンネルとして獲得した。勾配溶離は 1.5 mL/分における、 0.02% TFAを含む水中2% アセトニトリルとしてのバッファーAおよび0.02% TFA を含むアセトニトリル中2%水としてのバッファー Bを使用した。試料は以下のように溶離した: 0.5 分間90% A〜 3.5 分間95% B の勾配を使用し、0.5 分間 95% B で維持し、次にカラムを0.1 分間最初の状態の復帰させた。総実施時間は 4.8 分であった
**comm は市販を意味する。
式(I)の化合物の調製の代替方法が一般的方法D−1およびD−2の反応スキームおよび下記の一般的方法D−3の反応スキームに示される。
段階2:中間体:4−ブロモ−2−ヒドロキシ−ベンゾニトリルの調製
段階3:(3−アミノ−6−ブロモ−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノンの調製
実施例147
(3−アミノ−6−ブロモ−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノンとアリールボロン酸もしくはボロネート間のパラジウム媒介カプリング
(3−アミノ−6−ヨード−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノン(IV)の代わりに(3−アミノ−6−ブロモ−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノン(VIII)を使用することを除いて、実施例C−1段階3に記載のものと全く同一の方法を使用した。実施例D−3段階2にも同様な反応が認められる。
実施例148
[3−アミノ−6−(3−エチル−フェニル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンの調製
段階2:[3−アミノ−6−(3−エチル−フェニル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンの調製
実施例149
N−{3−[2−(2,4−ジクロロ−ベンゾイル)−3−メチルアミノ−ベンゾフラン−6−イル]−フェニル}−アセトアミドの調製
段階2:N−{3−[2−(2,4−ジクロロ−ベンゾイル)−3−メチルアミノ−ベンゾフラン−6−イル]−フェニル}−アセトアミドの調製
表3の他の化合物を、容易に入手できそして/もしくはその合成が本明細書に教示されている適当な出発物質を選択し、そして前記の方法もしくは当該技術分野で周知の標準の化学的方法を使用することにより前記と同様な方法で調製することができる。
*以下はLCMS条件である:HPLC -電子スプレー質量スペクトル(HPLC ES-MS)は2基のGilson 306ポンプ、Gilson 215 Autosampler、Gilsonダイオードアレー検出計、a YMC Pro C-18 カラム (2 x 23 mm, 120 A)を備えたGilson HPLC システムおよびz-スプレー電子スプレーイオン化を伴なうMicromass LCZ シングル4極質量分析計を使用して得た。スペクトルは2秒間120〜1000amuからスキャンした。ELSD (蒸発光線散乱検出計) のデータもアナログチャンネルとして獲得した。勾配溶離は 1.5 mL/分における、 0.02% TFAを含む水中2% アセトニトリルとしてのバッファーAおよび0.02% TFA を含むアセトニトリル中2%水としてのバッファー Bを使用した。試料は以下のように溶離した: 0.5 分間90% A〜 3.5 分間95% B の勾配を使用し、0.5 分間 95% B で維持し、次にカラムを0.1 分間最初の状態の復帰させた。総実施時間は 4.8 分であった
**comm は市販を意味する。
下記の一般的反応スキームに具体的に示した方法E−1〜E−4はR4置換基が窒素原子によりベンゾフラン核に結合されている本発明の実施例を調製するために使用された手段であった。実施例E−1〜E−4は適当に置換された2−シアノフェノール(中間体XIもしくはXIII)を調製するための様々な方法を表わす。室温から100℃の間の温度でDMF,MeCNのような溶媒中で塩基性条件下で(例えば、炭酸セシウム、炭酸カリウム、炭酸ナトリウム、DBU)の(XI)もしくは(XIII)の1−アリール−2−ハロエタノン(III)との縮合により式(I)をもつ所望の生成物を与える。
3−[3−アミノ−2−(2,4−ジクロロベンゾイル)−1−ベンゾフラン−6−イル]−1,3−オキサゾリジン−2−オンの調製
段階2:出発物質:2−(ベンジルオキシ)−4−(2−オキソ−1,3−オキサゾリジン−3−イル)ベンゾニトリルの調製
段階3:2−ヒドロキシ−4−(2−オキソ−1,3−オキサゾリジン−3−イル)−ベンゾニトリルの調製
段階4:3−[3−アミノ−2−(2,4−ジクロロベンゾイル)−1−ベンゾフラン−6−イル]−1,3−オキサゾリジン−2−オンの調製
実施例177
(3−アミノ−6−モルホリン−4−イル−ベンゾフラン−2−イル)−(2,4−ジクロロフェニル)−メタノンの調製
段階2:2−ヒドロキシ−4−(モルホリン−4−イル)−ベンゾニトリルの調製
段階3:(3−アミノ−6−モルホリン−4−イル−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノンの調製
実施例178
(3−アミノ−6−ピロル−1−イル−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノンの調製
段階2:主題化合物:(3−アミノ−6−ピロル−1−イル−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノンの調製
実施例179
(3−アミノ−6−イミダゾール−1−イル−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノンの調製
段階2:出発物質:2−ヒドロキシ−4−(イミダゾール−1−イル)ベンゾニトリルの調製
段階3:主題化合物:(3−アミノ−6−イミダゾール−1−イル−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノンの調製
表4の他の化合物を、容易に入手でき、そして/もしくはその合成が本明細書に教示されている適当な出発物質を選択し、そして前記のもしくは当該技術分野で周知の他の標準の化学的方法を使用して前記と同様な方法で調製することができる。
*以下はLCMS条件である:HPLC -電子スプレー質量スペクトル(HPLC ES-MS)は2基のGilson 306ポンプ、Gilson 215 Autosampler、Gilsonダイオードアレー検出計、a YMC Pro C-18 カラム (2 x 23 mm, 120 A)を備えたGilson HPLC システムおよびz-スプレー電子スプレーイオン化を伴なうMicromass LCZ シングル4極質量分析計を使用して得た。スペクトルは2秒間120〜1000amuからスキャンした。ELSD (蒸発光線散乱検出計) のデータもアナログチャンネルとして獲得した。勾配溶離は 1.5 mL/分における、 0.02% TFAを含む水中2% アセトニトリルとしてのバッファーAおよび0.02% TFA を含むアセトニトリル中2%水としてのバッファー Bを使用した。試料は以下のように溶離した: 0.5 分間90% A〜 3.5 分間95% B の勾配を使用し、0.5 分間 95% B で維持し、次にカラムを0.1 分間最初の状態の復帰させた。総実施時間は 4.8 分であった
**comm は市販を意味する。
式(I)の他の化合物への式Iの化合物(前記の方法により調製された)の更なる誘導のために使用される様々な方法を下記の実施例に記載する。
実施例195
N−[2−(2,4−ジクロロ−ベンゾイル)−6−フェニル−ベンゾフラン−3−イル]−アセトアミドの調製
実施例196
N−[6−(3−シアノ−フェニル)−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−3−イル]−アセトアミドの調製
実施例197
3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−ベンズアミドの調製
実施例198
N−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−フェニル}−2−メトキシアセトアミドの調製
実施例199
2−アミノ−N−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−フェニル}アセトアミドの調製
実施例200
{3−アミノ−6−[3−((R)−2,3−ジヒドロキシ−プロピルアミノ)−フェニル]−ベンゾフラン−2−イル}−(2,4−ジクロロ−フェニル)−メタノンの調製
実施例201
(3−アミノ−6−ピリジン−3−イル−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノンの調製
実施例202
1−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−ピペリジン−1−イル}−3−ジエチルアミノ−プロパン−1−オンの調製
実施例203
[3−アミノ−6−(1−イソプロピル−ピペリジン−3−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンの調製
実施例204
[3−アミノ−6−(1−ブチル−ピペリジン−3−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンの調製
実施例205
2−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−フェニル}−アセトアミジン・トリフルオロ酢酸の調製
実施例206
3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−N,N−ジメチル−ベンズアミジンの調製
実施例207
[3−アミノ−6−(3−メチルアミノ−フェニル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノンの調製
実施例208
(3−アミノ−6−ピリジン−3−イル−ベンゾフラン−2−イル)−(2,4−ジクロロフェニル)メタノン・塩酸の調製
表5の他の化合物を、容易に入手でき、そして/もしくはその合成が本明細書に教示されている適当な出発物質を使用し、そして前記の方法もしくは当該技術分野で周知の他の基準化学的方法を使用して、実施例195のF−1〜208のF−9に対し、前記のものに類似の方法で調製した。
*以下はLCMS条件である:HPLC -電子スプレー質量スペクトル(HPLC ES-MS)は2基のGilson 306ポンプ、Gilson 215 Autosampler、Gilsonダイオードアレー検出計、a YMC Pro C-18 カラム (2 x 23 mm, 120 A)を備えたGilson HPLC システムおよびz-スプレー電子スプレーイオン化を伴なうMicromass LCZ シングル4極質量分析計を使用して得た。スペクトルは2秒間120〜1000amuからスキャンした。ELSD (蒸発光線散乱検出計) のデータもアナログチャンネルとして獲得した。勾配溶離は 1.5 mL/分における、 0.02% TFAを含む水中2% アセトニトリルとしてのバッファーAおよび0.02% TFA を含むアセトニトリル中2%水としてのバッファー Bを使用した。試料は以下のように溶離した: 0.5 分間90% A〜 3.5 分間95% B の勾配を使用し、0.5 分間 95% B で維持し、次にカラムを0.1 分間最初の状態の復帰させた。総実施時間は 4.8 分であった
**comm は市販を意味する。
本発明におけるベンゾチオフェンの調製を以下の一般的スキームに示し、具体的には実施例221の調製に記載する。
[3−アミノ−6−(3−ピリジニル)−1−ベンゾチオフェン−2−イル](2,4−ジクロロフェニル)メタノンの調製
段階2:S−(2−シアノ−5−ヨード−フェニル)−ジメチルチオ−カルバミン酸の調製
段階3:2−シアノ−5−ヨードチオフェノールの調製
段階4:中間体2−[(2’,4’−ジクロロフェニル)カルボニル]−3−アミノ]−6−ヨード−ベンゾチオフェンの調製
段階5:主題化合物:[3−アミノ−6−(3−ピリジニル)−1−ベンゾチオフェン−2−イル](2,4−ジクロロ−フェニル)メタノンの調製
表6に見られる他の化合物は、容易に入手できるそして/もしくはその合成が本明細書に記載されている適当な出発物質を選択し、かつ前記の方法もしくは当該技術分野で周知の他の標準化学方法を使用することにより前記と類似の方法を調製した。
*以下はLCMS条件である:HPLC -電子スプレー質量スペクトル(HPLC ES-MS)は2基のGilson 306ポンプ、Gilson 215 Autosampler、Gilsonダイオードアレー検出計、a YMC Pro C-18 カラム (2 x 23 mm, 120 A)を備えたGilson HPLC システムおよびz-スプレー電子スプレーイオン化を伴なうMicromass LCZ シングル4極質量分析計を使用して得た。スペクトルは2秒間120〜1000amuからスキャンした。ELSD (蒸発光線散乱検出計) のデータもアナログチャンネルとして獲得した。勾配溶離は 1.5 mL/分における、 0.02% TFAを含む水中2% アセトニトリルとしてのバッファーAおよび0.02% TFA を含むアセトニトリル中2%水としてのバッファー Bを使用した。試料は以下のように溶離した: 0.5 分間90% A〜 3.5 分間95% B の勾配を使用し、0.5 分間 95% B で維持し、次にカラムを0.1 分間最初の状態の復帰させた。総実施時間は 4.8 分であった
**comm は市販を意味する。
式Iの化合物はそれが医薬として許容できる組成物として調製される時に本明細書に更に説明される症状(conditions)を処置するための本方法に有用である。医薬として許容できる組成物は医薬として許容できる担体と混合した式Iの化合物である。医薬として許容できる担体は、担体に起因するあらゆる副作用が有効成分の有益な効果を損なわないように有効成分の有効な活性と協調する濃度で患者に対し比較的無毒で無害のあらゆる担体である。
酸性化剤(例えばそれらに限定はされないが、酢酸、クエン酸、フマル酸、塩酸、硝酸が含まれる)、
アルカリ性化剤(例えばそれらに限定はされないが、アンモニア溶液、炭酸アンモニウム、ジエタノールアミン、モノエタノールアミン、水酸化カリウム、硼酸ナトリウム、炭酸ナトリウム、水酸化ナトリウム、トリエタノールアミン、トロールアミンが含まれる)、
吸着剤(例えばそれらの限定はされないが、粉末セルロールおよび活性炭が含まれる)、
エアゾール噴射剤(例えばそれらに限定はされないが、二酸化炭素、CCl2F2、F2ClC−CClF2およびCClF3が含まれる)、
空気置換剤(例えばそれらに限定はされないが、窒素およびアルゴンが含まれる)、
抗カビ保存剤(例えばそれらに限定はされないが、安息香酸、ブチルパラベン、エチルパラベン、メチルパラベン、プロピルパラベン、安息香酸ナトリウムが含まれる)、
抗微生物保存剤(例えばそれらに限定はされないが、塩化ベンズアルコニウム、塩化ベンズエトニウム、ベンジルアルコール、塩化セチルピリジニウム、クロロブタノール、フェノール、フェニルエチルアルコール、硝酸フェニル水銀およびチメロサールが含まれる)、
抗酸化剤(例えばそれらに限定はされないが、アスコルビン酸、アスコルビルパルミテート、ブチル化ヒドロキシアニソール、ブチル化ヒドロキシトルエン、次亜リン酸、モノチオグリセロール、プロピルガレート、アスコルビン酸ナトリウム、亜硫酸水素ナトリウム、ナトリウムホルムアルデヒドスルホキシレート、ナトリウムメタビスルファイトが含まれる)、
結合物質(例えばそれらに限定はされないが、ブロックポリマー、天然および合成ゴム、ポリアクリレート、ポリウレタン、シリコーン、ポリシロキサンおよびスチレン−ブタジエンコポリマーが含まれる)、
緩衝剤(例えばそれらに限定はされないが、カリウムメタホスフェート、二カリウムホスフェート、酢酸ナトリウム、無水クエン酸ナトリウムおよび二水和クエン酸ナトリウムが含まれる)、
担体(例えばそれらに限定はされないが、アカシアシロップ、芳香シロップ、芳香エリキシル、チェリーシロップ、ココアシロップ、オレンジシロップ、シロップ、コーン油、鉱油、落花生油、ゴマ油、静菌性塩化ナトリウム注射および注射用静菌水が含まれる)、
キレート化剤(例えばそれらに限定はされないが、エデト酸二ナトリウムおよびエデト酸が含まれる)、
着色剤(例えばそれらに限定はされないが、FD&CレッドNo.3、FD&CレッドNo.20、FD&CイエローNo.6、FD&CブルーNo.2、D&CグリーンNo.5、D&CオレンジNo.5、D&CレッドNo.8、カラメルおよび酸化第2鉄赤が含まれる)、
清澄剤(例えばそれらに限定はされないが、ベントナイトが含まれる)、
乳化剤(例えばそれらに限定はされないが、アカシア、セトマクロゴール、セチルアルコール、グリセリルモノステアレート、レシチン、ソルビタンモノオレエート、ポリオキシエチレン50モノステアレートが含まれる)、
カプセル封入剤(例えばそれらに限定はされないが、ゼラチンおよびセルロースアセテートフタレートが含まれる)、
香料剤(例えばそれらに限定はされないが、アニス油、シナモン油、ココア、メントール、オレンジ油、ペパーミント油およびバニリンが含まれる)、
保湿剤(例えばそれらに限定はされないが、グリセロール、プロピレングリコールおよびソルビトールが含まれる)、
研磨剤(例えばそれらに限定はされないが、鉱油およびグリセリンが含まれる)、
油(例えばそれらに限定はされないが、ラッカセイ油、鉱油、オリーブ油、ピーナツ油、ゴマ油および植物油が含まれる)、
軟膏基剤(例えばそれらに限定はされないが、ラノリン、親水性軟膏、ポリエチレングリコール軟膏、ペトロラタム、親水性ペトロラタム、白色軟膏、黄色軟膏およびローズ水軟膏が含まれる)、
透過性促進剤(経皮配達)(例えばそれらに限定はされないが、モノヒドロキシもしくはポリヒドロキシアルコール、1価−もしくは多価アルコール、飽和もしくは不飽和脂肪アルコール、飽和もしくは不飽和脂肪エステル、飽和もしくは不飽和ジカルボン酸、必須油、ホスファチジル誘導体、セファリン、テルペン、アミド、エーテル、ケトンおよび尿素が含まれる)、
可塑化剤(例えばそれらに限定はされないが、ジエチルフタレートおよびグリセロールが含まれる)、
溶媒(例えばそれらに限定はされないが、エタノール、コーン油、綿実油、グリセロール、イソプロパノール、鉱油、オレイン酸、ピーナツ油、精製水、注射用水、注射用滅菌水および潅注用滅菌水が含まれる)、
硬化剤(例えばそれらに限定はされないが、セチルアルコ−ル、セチルエステルワックス、微細結晶ワックス、パラフィン、ステアリルアルコール、白色ワックスおよび黄色ワックスが含まれる)、
座薬基剤(例えばそれらに限定はされないが、ココアバターおよびポリエチレングリコール(混合物)が含まれる)、
界面活性剤(例えばそれらに限定はされないが、ベンズアルコニウムクロリド、ノノキシノール10、オキシトキシノール9、ポリソルベート80、ナトリウムラウリルスルフェートおよびソルビタンモノパルミテートが含まれる)、
懸濁剤(例えばそれらに限定はされないが、寒天、ベントナイト、カーボマー、カルボキシメチルセルロースナトリウム、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カオリン、メチルセルロース、トラガカントおよびビーガムが含まれる)、
甘味剤(例えばそれらに限定はされないが、アスパルテーム、デキストロース、グリセロール、マニトール、プロピレングリコール、サッカリンナトリウム、ソルビトールおよび蔗糖が含まれる)、
錠剤付着抑制剤(例えばそれらに限定はされないが、マグネシウムステアレートおよびタルクが含まれる)、
錠剤結合剤(例えばそれらに限定はされないが、アカシア、アルギン酸、カルボキシメチルセルロースナトリウム、圧縮性(compressible)糖、エチルセルロース、ゼラチン、液体ブドウ糖、メチルセルロース、非架橋ポリビニルピロリドンおよび前以てゼラチン化したデンプンが含まれる)、
錠剤およびカプセル希釈剤(例えばそれらに限定はされないが、二塩基性リン酸カルシウム、カオリン、乳糖、マニトール、微細結晶セルロース、粉砕セルロース、沈殿炭酸カルシウム、炭酸ナトリウム、リン酸ナトリウム、ソルビトールおよびデンプンが含まれる)、
打錠剤(例えばそれらに限定はされないが、液体ブドウ糖、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、エチルセルロース、セルロースアセテートフタレートおよびセラックが含まれる)、
打錠賦形剤(例えばそれらに限定はされないが、二塩基性リン酸カルシウムが含まれる)、
錠剤崩壊剤(例えばそれらに限定はされないが、アルギン酸、カルボキシメチルセルロースカルシウム、微細結晶セルロース、ポラクリリンカリウム、架橋ポリビニルピロリドン、アルギン酸ナトリウム、ナトリウムデンプングリコレートおよびデンプンが含まれる)、
直打用滑沢剤(例えばそれらに限定はされないが、コロイド状シリカ、コーンスターチおよびタルクが含まれる)、
滑沢剤(例えばそれらに限定はされないが、カルシウムステアレート、マグネシウムステアレート、鉱油、ステアリン酸および亜鉛ステアレートが含まれる)、
錠剤/カプセル遮光剤(例えばそれらに限定はされないが、二酸化チタンが含まれる)、
錠剤−光沢剤(例えばそれらに限定はされないが、カルナバワックスおよび白色ワックスが含まれる)、
増粘剤(例えばそれらに限定はされないが、蜜蝋、セチルアルコールおよびパラフィンが含まれる)、
等張性付与剤(tonicity agents)(例えば、それらに限定はされないが、デキストロースおよび塩化ナトリウムが含まれる)、
粘度増加剤(例えばそれらに限定はされないが、アルギン酸、ベントナイト、カーボマー、カルボキシメチルセルロースナトリウム、メチルセルロース、ポリビニルピロリドン、アルギン酸ナトリウムおよびトラガカントが含まれる)、並びに
加湿剤(例えばそれらに限定はされないが、ヘプタデカエチレンオキシセタノール、レシチン、ソルビトールモノオレエート、ポリオキシエチレンソルビトールモノオレエートおよびポリオキシエチレンステアレートが含まれる)。
滅菌IV溶液:本発明の望ましい化合物の5mg/mL溶液を滅菌注射用水を使用して生成し、必要に応じてpHを調節する。溶液は投与用に滅菌5%デキストロースで1〜2mg/mLに希釈されて、60分間にわたりIV注入物として投与される。
IV投与のための凍結乾燥粉末:滅菌調製物は(i)凍結乾燥粉末として本発明の所望の化合物100〜1000mg、(ii)32〜327mg/mLのクエン酸ナトリウム、および(iii)300〜3000mgのデキストラン40、により調製することができる。調製物を10〜20mg/mLの濃度に、滅菌注射用生理食塩水もしくはデキストロース5%で再構成し、それを更に生理食塩水もしくはデキストロース5%で0.2〜0.4mg/mLに希釈し、15〜60分間にわたり、IVボラスもしくはIV注入のいずれかにより投与される。
筋肉内用懸濁物:以下の溶液もしくは懸濁物を筋肉内注射用に調製することができる:
本発明の所望の水不溶性化合物50mg/mL
ナトリウムカルボキシメチルセルロース5mg/mL
TWEEN80を4mg/mL
塩化ナトリウム9mg/mL
ベンジルアルコール9mg/mL
硬殻カプセル:多数の単位カプセルは、それぞれ粉末有効成分100mg、乳糖150mg、セルロース50mgおよびマグネシウムステアレート6mgを標準の2片の硬いゼラチンカプセルに充填することにより調製される。
軟らかいゼラチンカプセル:大豆油、綿実油もしくはオリーブ油のような消化性油中の有効成分の混合物を調製し、溶融ゼラチン中への正の置き換えポンプにより注入して、有効成分100mgを含む軟らかいゼラチンカプセルを形成する。カプセルを洗浄し、乾燥する。有効成分をポリエチレングリコール、グリセリンおよびソルビトールの混合物中に溶解して水混和性医薬混合物を調製することができる。
錠剤:多数の錠剤を、投与単位が有効成分100mg、コロイド状二酸化ケイ素0.2mg、マグネシウムステアレート5mg、微細結晶セルロース275mg、デンプン11mgおよび乳糖98.8mgであるように、通常の方法により調製する。おししさを増し、優美性および安定性を改善し、もしくは吸収を遅らせるために適当な水性および非水性コティングを適用することができる。
即時放出錠/カプセル:これらは通常のおよび新規の方法により製造される固体経口投与形態である。これらの単位は医薬の即時溶解および配達のために水なしで経口摂取される。有効成分を糖、ゼラチン、ペクチンおよび甘味剤のような成分を含む液体中に混合する。これらの液体が凍結乾燥および固体状態抽出法により固形の錠剤もしくはカプレットに固化される。薬剤配合物を、粘弾性および熱可塑性糖およびポリマーもしくは発泡性成分とともに圧縮して、水の必要なしに即時の放出を意図された多孔質マトリックスを生成することができる。
本明細書に記載の化合物および組成物は過剰増殖性障害を処置もしくは予防するために使用することができる。所望の薬理学的効果を達成するために、それを必要とする患者に有効量の本発明の化合物もしくは組成物を投与することができる。本発明の目的のための患者は本明細書に更に記載される具体的な障害の処置(予防的処置を含む)の必要な、ヒトを含む哺乳動物である。医薬的に有効量の化合物もしくは組成物は処置されている具体的な過剰増殖性障害に対して所望の結果をもたらすもしくはそれに影響を与える量である。
本発明の化合物を試験するために使用された付着性腫瘍細胞増殖性アッセイはPromegaにより開発されたCell Titre-Gloと呼ばれる読みだし(readout)を伴なう(Cunningham, BA "A Growing Issue: Cell Proliferation Assays. Modern kits ease quantification of cell growth(細胞増殖アッセイ。現代のキットは細胞成長の定量化を容易にする)" The Scientist 2001, 15(13), 26, およびCrouch, SP et al., "The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity(細胞増殖および細胞毒性の指標としてのATP生体発光の使用)" Journal of Immunological Methods 1993, 160, 81-88)。
中の癌の化学療法剤投与計画上に挙げられた化合物、例えば、アスパラギナーゼ、ブレオマイシン、カルボプラチン、カルムスチン、クロラムブシル、シスプラチン、コラスパーゼ、シクロホスファミド、シタラビン、ダカルバジン、ダクチノマイシン、ダウノルビシン、ドキソルビシン(アドリアマイシン)、エピルビシン、エトポシド、5−フルオロウラシル、ヘキサメチルメラミン、ヒドロキシ尿素、イフォスファミド、イリノテカン、ロイコボリン、ロムスチン、メクロレサミン(mechlorethamine)、6−メルカプトプリン、メスナ、メトトレキセート、マイトマイシンC、ミトキサントロン、プレドニソロン、プレドニソン、プロカルバジン、ラロキシフェン、ストレプトゾシン、タモキシフェン、チオグアニン、トポテカン、ビンブラスチン、ビンクリスチンおよびビンデシンが含まれる。
Claims (26)
- 式I
XはOおよびSから選択され、
R1はH、(C1−C6)アルキル、C(O)(C1−C6)アルキルおよびベンゾイルから選択され、
R2は、
OH、CN、NO2、(C1−C6)アルキル、(C1−C6)アルコキシ、ハロ、ハロ(C1−C6)アルキル、ハロ(C1−C6)アルコキシ、C(O)RA、C(O)NRBRB、NRBRB、NH[(C1−C6)アルキル]0−1S(O)2RB、NH[(C1−C6)アルキル]0−1C(O)RAおよびNH[(C1−C6)アルキル]0−1C(O)ORBからそれぞれ独立に選択される1、2もしくは3個の置換基でそれぞれ場合により置換されたフェニルおよびナフチル、
それぞれの複素環がOH、CN、NO2、(C1−C6)アルキル、(C1−C6)アルコキシ、ハロ、ハロ(C1−C6)アルキル、ハロ(C1−C6)アルコキシ、C(O)RA、C(O)NRBRB、NRBRB、NH[(C1−C6)アルキル]0−1S(O)2RB、NH[(C1−C6)アルキル]0−1C(O)RAおよびNH[(C1−C6)アルキル]0−1C(O)ORBからそれぞれ独立に選択される1、2もしくは3個の置換基で場合により置換された6員複素環、5員複素環および縮合2環式複素環から選択される複素環、
から選択され、
RAは各々の場合において、独立にH、(C1−C6)アルキル、(C1−C6)アルコキシ、NRBRBもしくは(C1−C6)アルキルであり、ここで前記アルキルは場合によりOH、C(O)RB、ハロ、(C1−C3)アルコキシおよびNRBRBで置換されており、
RBは各々の場合において独立に、H、(C3−C6)シクロアルキルおよび(C1−C6)アルキルであり、ここで前記アルキルは場合によりOH、=O、ハロ、(C1−C6)アルコキシ、NH(C1−C3)アルキル、N[(C1−C3)アルキル]2およびNC(O)(C1−C3)アルキルで置換されており、
そしてここでRBがN原子に結合されている時、各々の場合においてRBは(C1−C4)アルキルであり、その場合2つの(C1−C4)アルキル基が一緒に、それらが結合しているN原子と一緒になって飽和環を形成することができ、そして
ここでRBとRBはそれらが結合しているNと一緒に、場合により、利用可能なN原子上で(C1−C6)アルキルで置換されたピペラジニル環もしくはモルホリニル環を形成することができ、ここで前記アルキルはOH、=O、NH2、(C1−C6)アルコキシ、NH(C1−C3)アルキルもしくはN[(C1−C3)アルキル]2で場合により置換されており、
そしてただし、RBがS(O)もしくはS(O)2に結合されている時は、それはHであることはできず、
R3はH、OH、CN、(C1−C3)アルキル、(C1−C3)アルコキシ、ハロ、ハロ(C1−C3)アルキルおよびハロ(C1−C3)アルコキシから選択され、
R4は、
ピペロニル、
Y[ここでYは、=O、N−オキシド、H、CN、NO2、ハロ、ハロ(C1−C6)アルキル、OH、ハロ(C1−C6)アルコキシ、C(O)ORB、C(NH)NRBRB、NRBRB、S(O)0−2RB、S(O)2NRBRB、(C1−C6)アルコキシ(前記アルコキシはOH、NRBRBおよび(C1−C3)アルコキシから選択される1もしくは2個の置換基で場合により置換されている)、NRCRC(ここでRCはRB、C(O)RBおよびS(O)2RBから選択される)、C(O)RD[ここでRDはRA、(C3−C6)シクロアルキル、ZおよびN[(C1−C3)アルキル]Zから選択され、ここでZは各々の場合において、CN、=O、OH、N−オキシド、NO2、ハロ、(C1−C6)アルコキシ、ハロ(C1−C3)アルコキシ、ハロ(C1−C3)アルキル、S(O)2RB、S(O)2NRBRB、NRBRB、C(O)RAおよび(C1−C6)アルキルで場合により独立に置換された複素環であり、ここで前記アルキルはOH、C(O)RB、(C1−C3)アルコキシおよびNRBRBで場合により置換されている]、NRBRE[ここでREはC(O)RA、C(O)RB、S(O)2RB、S(O)2NRBRBおよびC(O)[(C1−C6)アルキル]Zから選択され、ここでZは場合により前記のとおりに置換されている]、(C1−C6)アルキル[ここで前記アルキルはCN、OH、=O、ハロ、(C1−C6)アルコキシ、C(O)RA、NRBRB、NRCRc、NRBRE,C(NH)NRBRB、S(O)0−2RB、S(O)2NRBRB、C(O)RB、C(O)ORB、Z、C(O)ZおよびC(O)N[(C1−C3)アルキル]Zで場合により置換されており、ここでZは各々の場合において、独立に場合により前記のように置換されている]、
からそれぞれ独立に選択される1、2もしくは3個の置換基で場合により置換された複素環である]、
OH、CN、NO2、ハロ、ハロ(C1−C6)アルキル、ハロ(C1−C6)アルコキシ、C(O)ORB、C(NH)NRBRB、NRBRB、S(O)0−2RB、S(O)2NRBRB、Z、C(O)Z(ここでZは各々の場合において、場合により前記のとおりに置換されている)、(C1−C6)アルコキシ(ここで前記アルコキシはOH、NRBRBおよび(C1−C3)アルコキシから選択される1もしくは2個の置換基で場合により置換されている)、NRCRC(ここでRCはRB、C(O)RBおよびS(O)2RBから選択される)、C(O)RD[ここでRDはRA、(C3−C6)シクロアルキルおよびN[(C1−C3)アルキル]Zから選択され、ここでZは場合により前記のとおりに置換されている]、NRBRE[ここでREはC(O)RA、C(O)RB、S(O)2RB、S(O)2NRBRBおよびC(O)[(C1−C6)アルキル]Zから選択され、ここでZは場合により前記のとおりに置換されている]、(C1−C6)アルキル[ここで前記アルキルはCN、OH、=O、ハロ、(C1−C6)アルコキシ、C(O)RA、NRBRB、NRBRE、C(NH)NRBRB、S(O)0−2RB、S(O)2NRBRB、C(O)RBC(O)ORB、Z、C(O)ZおよびC(O)N[(C1−C3)アルキル]Zで場合により置換されており、ここでZは各々の場合において、場合により独立に前記のとおりに置換されている]、からそれぞれ独立に選択される1、2もしくは3個の置換基でそれぞれ場合により置換されたフェニルおよびナフチル、
から選択され、
R5およびR6はそれぞれ独立に、H、OH、CN、(C1−C3)アルキル、(C1−C3)アルコキシ、ハロ、ハロ(C1−C3)アルキルおよびハロ(C1−C3)アルコキシから選択される}
の化合物または医薬として許容できるその塩もしくはエステル。 - XがOである請求項1の化合物。
- XがSである請求項1の化合物。
- R2がそれぞれ、場合により置換されているフェニル、6員複素環および5員複素環から選択される、請求項2の化合物。
- R4がそれぞれ場合により置換されているYおよびフェニルから選択される請求項2の化合物。
- R2がそれぞれ場合により置換されたフェニル、6員複素環および5員複素環から選択され、かつR4がそれぞれ場合により置換されたYおよびフェニルから選択される請求項2の化合物。
- R4がフェニルおよびYから選択され、ここでYは5員複素環およびピリジンから選択され、ここで各環状部分が場合により置換されている請求項5の化合物。
- R2およびR4がそれぞれ独立に場合により1もしくは2個の置換基で置換され、かつR3、R5およびR6がそれぞれ独立にH、OH、Cl、F、CN、CH3、OCH3、CF3およびOCF3から選択される請求項6の化合物。
- R1がHおよび(C1−C6)アルキルから選択される請求項8の化合物。
- R2がそれぞれ場合により置換されているフェニル、6員複素環および5員複素環から選択される請求項3の化合物。
- R4がそれぞれ場合により置換されたYおよびフェニルから選択される請求項3の化合物。
- R2がそれぞれ場合に置換されたフェニル、6員複素環および5員複素環から選択され、かつR4がそれぞれ場合により置換されたYおよびフェニルから選択される請求項3の化合物。
- R4が、環部分がそれぞれ場合により置換された、フェニルおよびYから選択され、ここでYが5員複素環およびピリジンから選択される請求項11の化合物。
- R2およびR4がそれぞれ独立に場合により1もしくは2個の置換基で置換され、かつR3、R5およびR6がそれぞれ独立にH、OH、Cl、F、CN、CH3、OCH3、CF3およびOCF3から選択される請求項12の化合物。
- R1がHおよび(C1−C6)アルキルから選択される請求項14の化合物。
- (3−アミノ−6−フェニル−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノン、
(3−アミノ−6−ピリジン−3−イル−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノン、
[3−アミノ−6−(3−ニトロ−フェニル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノン、
[3−アミノ−6−(3−アミノ−フェニル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノン、
3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−ベンゾニトリル、
N−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−フェニル}−メタンスルホンアミド、
N−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−フェニル}−アセトアミド、
[3−アミノ−6−(2−メチル−ピリジン−3−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノン、
5−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−ニコチンアミド、
3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−ベンゼンスルホンアミド、
(3−アミノ−5−フルオロ−6−ピリジン−3−イル−ベンゾフラン−2−イル)−(2,4−ジクロロ−フェニル)−メタノン、
{3−アミノ−6−[3−((S)−2,3−ジヒドロキシ−プロピルアミノ)−フェニル]−ベンゾフラン−2−イル}−(2,4−ジクロロ−フェニル)−メタノン、
3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−N−メチル−ベンズアミド、
[3−アミノ−6−(1−メチル−1H−イミダゾール−4−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノン、
3−[3−アミノ−2−(2−クロロ−4−フルオロ−ベンゾイル)−ベンゾフラン−6−イル]−ベンズアミド、
2−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−フェニル}−アセトアミド、
[3−アミノ−6−(2−メチル−チアゾール−4−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノン、
N−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−ベンジル}−メタンスルホンアミド、
N−{3−[3−アミノ−2−(2,4−ジクロロ−ベンゾイル)−ベンゾフラン−6−イル]−ベンジル}−アセトアミド、
[3−アミノ−6−(2−メチル−オキサゾール−4−イル)−ベンゾフラン−2−イル]−(2−メトキシ−フェニル)−メタノン、
[3−アミノ−6−(3−フルオロ−5−ニトロ−フェニル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノン、
[3−アミノ−6−(3−メタンスルホニル−フェニル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノン、
[3−アミノ−6−(2−フルオロ−ピリジン−3−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノン、および
[3−アミノ−6−(2−メチルアミノ−ピリジン−3−イル)−ベンゾフラン−2−イル]−(2,4−ジクロロ−フェニル)−メタノン、
から選択される化合物。 - 式Iの化合物を含んで成る組成物。
- XがOである請求項17記載の組成物。
- XがSである請求項17記載の組成物。
- R2がそれぞれ場合により置換されたフェニル、6員複素環および5員複素環から選択され、かつR4がそれぞれ場合により置換されたYおよびフェニルから選択される請求項18記載の組成物。
- R2がそれぞれ場合により置換されたフェニル、6員複素環および5員複素環から選択され、かつR4がそれぞれ場合により置換されたYおよびフェニルから選択される請求項19記載の組成物。
- 過剰増殖性障害の処置若しくは予防を要する患者に対する有効量の式Iの化合物の投与を含んで成る、過剰増殖性障害を処置もしくは予防する方法。
- XがOである請求項22記載の方法。
- XがSである請求項22記載の方法。
- R2がそれぞれ場合により置換されたフェニル、6員複素環および5員複素環から選択され、かつR4がそれぞれ場合により置換されたYおよびフェニルから選択される請求項23記載の方法。
- R2がそれぞれ場合により置換されたフェニル、6員複素環および5員複素環から選択され、かつR4がそれぞれ場合により置換されたYおよびフェニルから選択される請求項24記載の組成物。
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JP2007501796A (ja) * | 2003-08-07 | 2007-02-01 | バイエル・フアーマシユーチカルズ・コーポレーシヨン | 過剰増殖性障害の処置に有用なベンゾフラン誘導体 |
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Cited By (5)
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JP2007501796A (ja) * | 2003-08-07 | 2007-02-01 | バイエル・フアーマシユーチカルズ・コーポレーシヨン | 過剰増殖性障害の処置に有用なベンゾフラン誘導体 |
JP4709757B2 (ja) * | 2003-08-07 | 2011-06-22 | ニツポネツクス・インコーポレーテツド | 過剰増殖性障害の処置に有用なベンゾフラン誘導体 |
JP2010521466A (ja) * | 2007-03-12 | 2010-06-24 | ネクター セラピューティックス | オリゴマー−オピオイドアゴニスト複合体 |
WO2012011314A1 (ja) | 2010-07-22 | 2012-01-26 | 扶桑薬品工業株式会社 | ベンゾフラノン化合物およびそれを含む医薬組成物 |
US8563743B2 (en) | 2010-07-22 | 2013-10-22 | Fuso Pharmaceutical Industries, Ltd. | Benzofuranone compound and pharmaceutical composition containing same |
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