EP1149085A1 - Aminoalkylbenzofurannes faisant office d'agonistes de la serotonine (5-ht(2c)) - Google Patents
Aminoalkylbenzofurannes faisant office d'agonistes de la serotonine (5-ht(2c))Info
- Publication number
- EP1149085A1 EP1149085A1 EP00904438A EP00904438A EP1149085A1 EP 1149085 A1 EP1149085 A1 EP 1149085A1 EP 00904438 A EP00904438 A EP 00904438A EP 00904438 A EP00904438 A EP 00904438A EP 1149085 A1 EP1149085 A1 EP 1149085A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- hydrogen
- mmol
- halo
- aminopropane
- 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- Withdrawn
Links
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 title description 21
- 239000000556 agonist Substances 0.000 title description 7
- 229940076279 serotonin Drugs 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 284
- 239000001257 hydrogen Substances 0.000 claims description 93
- 229910052739 hydrogen Inorganic materials 0.000 claims description 93
- -1 -C(0)NR6R7 Chemical group 0.000 claims description 67
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 150000002431 hydrogen Chemical group 0.000 claims description 50
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 49
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
- 125000005518 carboxamido group Chemical group 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 241000124008 Mammalia Species 0.000 claims description 14
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 230000004913 activation Effects 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 208000008589 Obesity Diseases 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 235000020824 obesity Nutrition 0.000 claims description 6
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 5
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 claims description 5
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 35
- 125000004432 carbon atom Chemical group C* 0.000 claims 10
- 208000020401 Depressive disease Diseases 0.000 claims 1
- 230000000862 serotonergic effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 253
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 175
- 230000002829 reductive effect Effects 0.000 description 167
- 239000000203 mixture Substances 0.000 description 142
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 133
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 123
- 239000011541 reaction mixture Substances 0.000 description 119
- 239000000243 solution Substances 0.000 description 94
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 85
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 84
- 229910001868 water Inorganic materials 0.000 description 81
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 71
- 239000007787 solid Substances 0.000 description 67
- 238000002360 preparation method Methods 0.000 description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- 229920006395 saturated elastomer Polymers 0.000 description 59
- 238000010898 silica gel chromatography Methods 0.000 description 53
- 239000000047 product Substances 0.000 description 48
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 46
- 239000012074 organic phase Substances 0.000 description 46
- 150000001412 amines Chemical class 0.000 description 44
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
- 239000011780 sodium chloride Substances 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 27
- 150000002576 ketones Chemical class 0.000 description 25
- 238000010511 deprotection reaction Methods 0.000 description 24
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 23
- 235000019341 magnesium sulphate Nutrition 0.000 description 23
- 239000003921 oil Substances 0.000 description 23
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 22
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- 238000009472 formulation Methods 0.000 description 21
- 229910052938 sodium sulfate Inorganic materials 0.000 description 21
- 235000011152 sodium sulphate Nutrition 0.000 description 21
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 20
- 239000012071 phase Substances 0.000 description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 17
- 239000008346 aqueous phase Substances 0.000 description 17
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- 239000012299 nitrogen atmosphere Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 239000004615 ingredient Substances 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 125000005843 halogen group Chemical group 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 239000004480 active ingredient Substances 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- TYBMMMOEVBNTDU-UHFFFAOYSA-N 7-bromo-5-fluoro-1-benzofuran Chemical compound FC1=CC(Br)=C2OC=CC2=C1 TYBMMMOEVBNTDU-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 102000005962 receptors Human genes 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 229920002472 Starch Polymers 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000007363 ring formation reaction Methods 0.000 description 10
- 235000019698 starch Nutrition 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 10
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000008107 starch Substances 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- BWHKTKFTQVBHQP-UHFFFAOYSA-N tert-butyl n-[1-(5-fluoro-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)CC1=CC(F)=CC2=C1OC=C2 BWHKTKFTQVBHQP-UHFFFAOYSA-N 0.000 description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000000839 emulsion Substances 0.000 description 8
- 235000013305 food Nutrition 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 7
- RNEOFIVNTNLSEH-UHFFFAOYSA-N 2-bromo-1-benzofuran Chemical compound C1=CC=C2OC(Br)=CC2=C1 RNEOFIVNTNLSEH-UHFFFAOYSA-N 0.000 description 7
- 239000007818 Grignard reagent Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 150000004795 grignard reagents Chemical class 0.000 description 7
- 229920000137 polyphosphoric acid Polymers 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- VQLIJOWSVJKBFP-UHFFFAOYSA-N tert-butyl 2-methylaziridine-1-carboxylate Chemical compound CC1CN1C(=O)OC(C)(C)C VQLIJOWSVJKBFP-UHFFFAOYSA-N 0.000 description 7
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 150000003891 oxalate salts Chemical class 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- QPBWGZMCDWNCMT-UHFFFAOYSA-N 7-[2-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]-1-benzofuran-5-carboxylic acid Chemical compound CC(C)(C)OC(=O)NC(C)CC1=CC(C(O)=O)=CC2=C1OC=C2 QPBWGZMCDWNCMT-UHFFFAOYSA-N 0.000 description 5
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000007903 gelatin capsule Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 238000001038 ionspray mass spectrometry Methods 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 235000006408 oxalic acid Nutrition 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- OFQCQIGMURIECL-UHFFFAOYSA-N 2-[2-(diethylamino)ethyl]-2',6'-dimethylspiro[isoquinoline-4,4'-oxane]-1,3-dione;phosphoric acid Chemical compound OP(O)(O)=O.O=C1N(CCN(CC)CC)C(=O)C2=CC=CC=C2C21CC(C)OC(C)C2 OFQCQIGMURIECL-UHFFFAOYSA-N 0.000 description 4
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 description 4
- MEYRABVEYCFHHB-UHFFFAOYSA-N 2-bromo-4-fluorophenol Chemical compound OC1=CC=C(F)C=C1Br MEYRABVEYCFHHB-UHFFFAOYSA-N 0.000 description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- ASHGTJPOSUFTGB-UHFFFAOYSA-N 3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1 ASHGTJPOSUFTGB-UHFFFAOYSA-N 0.000 description 4
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 4
- NSZGPNKNKQDNPD-UHFFFAOYSA-N 7-bromo-5-(trifluoromethyl)-1-benzofuran Chemical compound FC(F)(F)C1=CC(Br)=C2OC=CC2=C1 NSZGPNKNKQDNPD-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
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- XWNXDMFWSIZDGR-UHFFFAOYSA-N naphthalene-2-sulfonic acid;1-[4-(2-phenylethyl)-1-benzofuran-7-yl]propan-2-amine Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21.C1=2C=COC=2C(CC(N)C)=CC=C1CCC1=CC=CC=C1 XWNXDMFWSIZDGR-UHFFFAOYSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- CZQFHZUOAKLHKM-UHFFFAOYSA-N oxalic acid;1-(4,5,6-trifluoro-1-benzofuran-7-yl)propan-2-amine Chemical compound OC(=O)C(O)=O.CC(N)CC1=C(F)C(F)=C(F)C2=C1OC=C2 CZQFHZUOAKLHKM-UHFFFAOYSA-N 0.000 description 1
- MSRBFBSRKOEFQM-UHFFFAOYSA-N oxalic acid;1-(4,5,6-trimethyl-1-benzofuran-7-yl)propan-2-amine Chemical compound OC(=O)C(O)=O.CC(N)CC1=C(C)C(C)=C(C)C2=C1OC=C2 MSRBFBSRKOEFQM-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- WURFKUQACINBSI-UHFFFAOYSA-M ozonide Chemical compound [O]O[O-] WURFKUQACINBSI-UHFFFAOYSA-M 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- OTYPIDNRISCWQY-UHFFFAOYSA-L palladium(2+);tris(2-methylphenyl)phosphane;dichloride Chemical compound Cl[Pd]Cl.CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C.CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C OTYPIDNRISCWQY-UHFFFAOYSA-L 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
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- 239000008188 pellet Substances 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940100595 phenylacetaldehyde Drugs 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 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
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000010149 post-hoc-test Methods 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- DPRNGVMETFECFP-UHFFFAOYSA-M potassium;7-bromo-5-nitro-1-benzofuran-2-carboxylate Chemical compound [K+].[O-][N+](=O)C1=CC(Br)=C2OC(C(=O)[O-])=CC2=C1 DPRNGVMETFECFP-UHFFFAOYSA-M 0.000 description 1
- AXWFEPHNMJJUAG-UHFFFAOYSA-M potassium;7-bromo-5-nitro-1-benzofuran;7-bromo-5-nitro-1-benzofuran-2-carboxylate Chemical compound [K+].[O-][N+](=O)C1=CC(Br)=C2OC=CC2=C1.[O-][N+](=O)C1=CC(Br)=C2OC(C(=O)[O-])=CC2=C1 AXWFEPHNMJJUAG-UHFFFAOYSA-M 0.000 description 1
- VLYFRFHWUBBLRR-UHFFFAOYSA-L potassium;sodium;carbonate Chemical compound [Na+].[K+].[O-]C([O-])=O VLYFRFHWUBBLRR-UHFFFAOYSA-L 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229940048084 pyrophosphate Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 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
- 239000012056 semi-solid material Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KNFKTVCUMBVFCZ-UHFFFAOYSA-N tert-butyl 1-(1-benzofuran-2-ylmethyl)cyclopropane-1-carboxylate Chemical compound C=1C2=CC=CC=C2OC=1CC1(C(=O)OC(C)(C)C)CC1 KNFKTVCUMBVFCZ-UHFFFAOYSA-N 0.000 description 1
- OSWULUXZFOQIRU-UHFFFAOYSA-N tert-butyl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)CN OSWULUXZFOQIRU-UHFFFAOYSA-N 0.000 description 1
- ADRAFURXTAHZNO-MTAIBDRRSA-N tert-butyl N-[(2R)-1-[5-(trifluoromethyl)-1-benzofuran-7-yl]propan-2-yl]carbamate (2R)-1-[5-(trifluoromethyl)-1-benzofuran-7-yl]propan-2-amine hydrochloride Chemical compound C(C)(C)(C)OC(=O)N[C@@H](CC1=CC(=CC=2C=COC21)C(F)(F)F)C.Cl.FC(C=2C=C(C1=C(C=CO1)C2)C[C@@H](C)N)(F)F ADRAFURXTAHZNO-MTAIBDRRSA-N 0.000 description 1
- ANDYBORFHSOPRA-UHFFFAOYSA-N tert-butyl N-[1-(1-benzofuran-2-yl)-2-methylcyclopropyl]carbamate Chemical compound C(C)(C)(C)OC(=O)NC1(C(C1)C)C=1OC2=C(C1)C=CC=C2 ANDYBORFHSOPRA-UHFFFAOYSA-N 0.000 description 1
- UAKAZPLWZBVBCN-UHFFFAOYSA-N tert-butyl N-[1-(2,3-dichloro-5-fluoro-2,3-dihydro-1-benzofuran-7-yl)propan-2-yl]carbamate 1-(3-chloro-5-fluoro-1-benzofuran-7-yl)propan-2-amine hydrochloride Chemical compound C(C)(C)(C)OC(=O)NC(CC1=CC(=CC=2C(C(OC21)Cl)Cl)F)C.Cl.ClC2=COC1=C2C=C(C=C1CC(C)N)F UAKAZPLWZBVBCN-UHFFFAOYSA-N 0.000 description 1
- BWHKTKFTQVBHQP-SNVBAGLBSA-N tert-butyl n-[(2r)-1-(5-fluoro-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C)CC1=CC(F)=CC2=C1OC=C2 BWHKTKFTQVBHQP-SNVBAGLBSA-N 0.000 description 1
- OQZJRTYLLKZQKF-SNVBAGLBSA-N tert-butyl n-[(2r)-1-[5-(trifluoromethyl)-1-benzofuran-7-yl]propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C)CC1=CC(C(F)(F)F)=CC2=C1OC=C2 OQZJRTYLLKZQKF-SNVBAGLBSA-N 0.000 description 1
- PDAFIZPRSXHMCO-ZCFIWIBFSA-N tert-butyl n-[(2r)-1-hydroxypropan-2-yl]carbamate Chemical compound OC[C@@H](C)NC(=O)OC(C)(C)C PDAFIZPRSXHMCO-ZCFIWIBFSA-N 0.000 description 1
- OSWKHPPWABHWDE-VIFPVBQESA-N tert-butyl n-[(2s)-1-(2-bromo-5-fluoro-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C)CC1=CC(F)=CC2=C1OC(Br)=C2 OSWKHPPWABHWDE-VIFPVBQESA-N 0.000 description 1
- ZNBRXRSORNMLIZ-UHFFFAOYSA-N tert-butyl n-[1-(1-benzofuran-2-carbonyl)cyclopropyl]carbamate Chemical compound C=1C2=CC=CC=C2OC=1C(=O)C1(NC(=O)OC(C)(C)C)CC1 ZNBRXRSORNMLIZ-UHFFFAOYSA-N 0.000 description 1
- FJWDUGIORIZLHF-UHFFFAOYSA-N tert-butyl n-[1-(2,3-dichloro-5-fluoro-2,3-dihydro-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)CC1=CC(F)=CC2=C1OC(Cl)C2Cl FJWDUGIORIZLHF-UHFFFAOYSA-N 0.000 description 1
- OSWKHPPWABHWDE-UHFFFAOYSA-N tert-butyl n-[1-(2-bromo-5-fluoro-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)CC1=CC(F)=CC2=C1OC(Br)=C2 OSWKHPPWABHWDE-UHFFFAOYSA-N 0.000 description 1
- VIPZJTSYBDVMJS-UHFFFAOYSA-N tert-butyl n-[1-(2-chloro-5-fluoro-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)CC1=CC(F)=CC2=C1OC(Cl)=C2 VIPZJTSYBDVMJS-UHFFFAOYSA-N 0.000 description 1
- UQBDPZNGNBOTGB-UHFFFAOYSA-N tert-butyl n-[1-(2-chloro-5-fluoro-1-benzofuran-7-yl)propan-2-yl]carbamate;1-(2-chloro-5-fluoro-1-benzofuran-7-yl)propan-2-amine;hydrochloride Chemical compound Cl.CC(N)CC1=CC(F)=CC2=C1OC(Cl)=C2.CC(C)(C)OC(=O)NC(C)CC1=CC(F)=CC2=C1OC(Cl)=C2 UQBDPZNGNBOTGB-UHFFFAOYSA-N 0.000 description 1
- ASNNUSVFNYVVOQ-UHFFFAOYSA-N tert-butyl n-[1-(3-cyano-5-fluoro-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)CC1=CC(F)=CC2=C1OC=C2C#N ASNNUSVFNYVVOQ-UHFFFAOYSA-N 0.000 description 1
- PDEZTJQKLPWUBT-UHFFFAOYSA-N tert-butyl n-[1-(5-acetamido-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)CC1=CC(NC(C)=O)=CC2=C1OC=C2 PDEZTJQKLPWUBT-UHFFFAOYSA-N 0.000 description 1
- HHAGSQLIGPRIDU-UHFFFAOYSA-N tert-butyl n-[1-(5-fluoro-1-benzofuran-7-yl)propan-2-yl]carbamate;1-(5-fluoro-1-benzofuran-7-yl)propan-2-amine;hydrochloride Chemical compound Cl.CC(N)CC1=CC(F)=CC2=C1OC=C2.CC(C)(C)OC(=O)NC(C)CC1=CC(F)=CC2=C1OC=C2 HHAGSQLIGPRIDU-UHFFFAOYSA-N 0.000 description 1
- DVHGKGWQVXHXPP-UHFFFAOYSA-N tert-butyl n-[1-(5-fluoro-2-formyl-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)CC1=CC(F)=CC2=C1OC(C=O)=C2 DVHGKGWQVXHXPP-UHFFFAOYSA-N 0.000 description 1
- UTKCAXFJNWZQJD-UHFFFAOYSA-N tert-butyl n-[1-(5-fluoro-2-trimethylsilyl-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)CC1=CC(F)=CC2=C1OC([Si](C)(C)C)=C2 UTKCAXFJNWZQJD-UHFFFAOYSA-N 0.000 description 1
- JWSRQYWNIOCUNB-UHFFFAOYSA-N tert-butyl n-[1-(5-methoxy-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound COC1=CC(CC(C)NC(=O)OC(C)(C)C)=C2OC=CC2=C1 JWSRQYWNIOCUNB-UHFFFAOYSA-N 0.000 description 1
- DRJBZGHSQHHKFT-UHFFFAOYSA-N tert-butyl n-[1-(5-nitro-1-benzofuran-7-yl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)CC1=CC([N+]([O-])=O)=CC2=C1OC=C2 DRJBZGHSQHHKFT-UHFFFAOYSA-N 0.000 description 1
- HIDCCMLCMGFSHI-UHFFFAOYSA-N tert-butyl n-[1-[1-benzofuran-2-yl(hydroxy)methyl]cyclopropyl]carbamate Chemical compound C=1C2=CC=CC=C2OC=1C(O)C1(NC(=O)OC(C)(C)C)CC1 HIDCCMLCMGFSHI-UHFFFAOYSA-N 0.000 description 1
- HMDUVXIDDBSMIF-UHFFFAOYSA-N tert-butyl n-[1-[5-(methylamino)-1-benzofuran-7-yl]propan-2-yl]carbamate Chemical compound CNC1=CC(CC(C)NC(=O)OC(C)(C)C)=C2OC=CC2=C1 HMDUVXIDDBSMIF-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 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
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 1
Classifications
-
- 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
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
Definitions
- the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has a rich pharmacology arising from a heterogeneous population of at least seven receptor classes.
- the serotonin 5-HT2 class is further subdivided into at least three subtypes, designated 5-HT2a' 5_HT 2b' and 5-HT2 c .
- the 5-H 2c receptor has been isolated and characterized (Julius, et al . , U.S. Patent No. 4,985,352), and transgenic mice lacking the 5-HT2 c receptor have been reported to exhibit seizures and an eating disorder resulting in increased consumption of food (Julius, et al . , U.S. Patent No. 5,698,766).
- Compounds selective for the 5-HT2 c receptor would provide useful therapies for the treatment of seizure and eating disorders without the side effects associated with current therapies.
- the present invention provides aminoalkylbenzofurans of Formula I :
- A is -CHR 13 - or a bond
- R is hydrogen, halo, cyano, -C(0)NR ⁇ R 7 , C ⁇ _-C6 alkyl, C1-C4 alkoxycarbonyl , carboxy, or phenyl optionally substituted with one or two substituents selected from the group consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;
- R! is hydrogen, halo, cyano, carboxamido, formyl, trimethylsilyl, trifluoromethyl, pentafluoroethyl, or C ⁇ _-Cg alkyl ;
- R 2 and R 3 are independently hydrogen, halo, amino, nitro, C . -C4 alkoxy, cyano, carboxamido, -C(0)NR8R9,
- R 4 and R 4 ' are independently hydrogen, C1-C4 alkyl, or benzyl; or R 4 and R 4 ' together with the carbon atom to which they are attached form a cyclopropyl moiety;
- R5 is hydrogen, C ⁇ _-C alkyl, or benzyl;
- R 5 ' is hydrogen, or R ⁇ and R5 ' together with the carbon atom to which they are attached form a cyclopropyl moiety;
- R6 and R 7 are independently hydrogen or C1-C4 alkyl;
- R8 is hydrogen or C ⁇ _-C4 alkyl;
- R9 is C ⁇ _-Cg alkyl where the alkyl chain is optionally substituted with a substituent selected from the group consisting of carboxy, phenyl, or pyridyl, said phenyl or pyridyl substituent optionally substituted with one or two substituents selected from the group consisting of halo, C ⁇ _- C4 alkyl, or C1-C4 alkoxy;
- R!0 is hydrogen or C1-C4 alkyl
- R 11 is C1-C4 alkyl or C1-C4 acyl
- R 12 is hydrogen, halo, or C1-C4 alkyl; R!3 i s hydrogen, C1-C4 alkyl, or benzyl; R!4 i s hydrogen, C ⁇ _-C4 alkyl, or phenyl optionally substituted with a substituent selected from the group consisting of halo, C ⁇ -CA alkyl, and C1-C4 alkoxy; or pharmaceutically acceptable acid addition salts thereof .
- This invention also provides a pharmaceutical formulation which comprises, in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of Formula I .
- the present invention provides a method for increasing activation of the 5-HT2C receptor in mammals by administering to a mammal in need of such activation a pharmaceutically effective amount of a compound of Formula I.
- a further embodiment of this invention is a method for increasing activation of the 5-HT2C receptor for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are depression, obesity, bulimia, premenstrual syndrome or late luteal phase syndrome, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, anxiety, seizure disorders, and mutism. Any of these methods employ a compound of Formula I .
- This invention also provides the use of a compound of Formula I for the manufacture of a medicament for the treatment of obesity. Additionally, this invention provides a pharmaceutical formulation adapted for the treatment of obesity containing a compound of Formula I. Furthermore, this invention includes a method for the treatment of obesity which comprises administering an effective amount of a compound of Formula I .
- alkyl includes such groups as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, and the like.
- alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
- acyl includes such groups as formyl, acetyl, propionyl, b tyryl, 2-methylpropionyl, and the like.
- halo includes fluoro, chloro, bromo and iodo.
- the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since some of the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature.
- Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
- organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
- Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogenphosphate, metaphosphate, pyro-phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1 , 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxy- benzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,
- variable A is -CHR 13 - anc : R13 i s other than hydrogen
- R 4 ' and R 4 are not the same
- the compounds of the invention exist, are formulated, and are used as single enantiomers or diastereomers
- the present invention also contemplates the compounds of the invention existing in racemic form and as mixtures of the individual enantiomers and diastereomers .
- the methods and formulations of the invention also contemplate the use and formulation of the compounds of the invention in their racemic form and as mixtures of the individual enantiomers and diastereomers.
- the individual enantiomers and diastereomers may be prepared by chiral chromatography of the racemic or enantiomerically or diastereomerically enriched free amine, or fractional crystallization of salts prepared from racemic or enantiomerically or diastereomerically enriched free amine and a chiral acid.
- the free amine may be reacted with a chiral auxiliary and the enantiomers or diastereomers separated by chromatography followed by removal of the chiral auxiliary to regenerate the free amine.
- separation of enantiomers or diastereomers may be performed at any convenient point in the synthesis of the compounds of the invention.
- the compounds of the invention may also be prepared by the use of chiral syntheses.
- A is a bond; ab) A is attached at the 4-position of the benzofuran ring; ac) A is attached at the 5-position of the benzofuran ring; ad) A is attached at the 6-position of the benzofuran ring; ae) A is attached at the 7-position of the benzofuran ring; af) R is hydrogen; ag) R is halo; ah) R is cyano; ai) R is -C(0)NR 6 R 7 ; aj ) R is C ⁇ -Cg alkyl; ak) R is C .
- R is carboxy; am) R is phenyl optionally substituted with one or two substituents selected from the group consisting of halo, C1-C alkyl, and C1-C4 alkoxy; an) R 1 is hydrogen; ao) R! is halo; ap) R! is cyano; aq) R!
- R 1 is carboxamido; ar) R 1 is trifluoromethyl; as) R 1 is C1-C4 alkyl; at) R2 is hydrogen; au) R 2 is halo; av) R 2 is fluoro; aw) R 2 is amino; ax) R 2 is C1-C4 alkoxy; ay) R 2 is C ⁇ _-C4 alkyl optionally substituted with a substituent selected from the group consisting of C ⁇ _-C4 alkoxy, hydroxy, phenoxy, and phenyl; az) R 2 is -C(0)NR 8 R 9 ; ba) R 2 is -NR 10 -* 11 ; bb) R 2 is trifluoromethyl; be) R3 is hydrogen; bd) R 3 is halo; be) R3 is fluoro; bf) R 3 is trifluoromethyl ; bg) R 3 is C ⁇ _-C4 alkyl optionally substituted with a substituent selected from
- the present invention also provides a method for increasing activation of the 5-HT2C receptor in mammals by administering to a mammal in need of such activation a pharmaceutically effective amount of a compound of Formula I.
- the preferred mammal is human.
- variable A is a bond
- variables R, R 1 , R 2 , R 3 , R 4 . R4 ' r anc ; R 5 are as previously defined:
- the bromobenzofuran is coupled with an appropriate enol acetate in the presence of palladium( II) chloride, tri (o- tolyl)phosphine, and tributyl tin methoxide to provide the corresponding ketone.
- This ketone is then reductively aminated under standard conditions, such as treatment of the ketone with ammonium acetate and sodium cyanoborohydride in the presence of acid, to provide the primary amines of the present invention.
- the bromobenzofuran may be treated with magnesium to prepare the corresponding Grignard reagent. This compound is then reacted with copper (I) bromide followed by an appropriate N-protected aziridine to provide the corresponding N-protected amine. Deprotection of the amine then provides the compounds of the present invention.
- protecting groups which may be conveniently removed. Commonly the protecting group employed is the tert-butoxycarbonyl group, which is then removed by treatment with acid, typically hydrochloric acid.
- variable A is -CHR13- are prepared as described in the following scheme where * variables R, R- 1 -, R 2 , R 3 , R 4 , R ⁇ R ⁇ 2 , and R ⁇ 3 are a s previously defined:
- the bromobenzofuran is coupled with an appropriate allylic alcohol in the presence of palladium(II) acetate and an appropriate triarylphosphine such as triphenylphosphine or tri (o-tolyl)phosphine to provide the corresponding ketone.
- This ketone is then reductively aminated under standard conditions to provide the compounds of the present invention.
- R 4 ' moiety may be introduced by reacting the ketone prepared above with an appropriate alkylating agent under standard conditions .
- the requisite benzofuran intermediates are either commercially available or may be prepared from an appropriately substituted phenol by methods well known in the art as illustrated in the following scheme where variables R , R 3 , and R ⁇ - 2 are as previously defined:
- Bases useful for this reaction include hydride sources, such as sodium or potassium hydride, or carbonates, such as sodium or potassium carbonate.
- the phenoxide solution is then reacted with a chloro- or bromoacetaldehyde which is protected as a cyclic or dialkyl acetal .
- Bromoacetaldehyde diethyl acetal is particularly useful for this reaction.
- the phenoxyacetaldehyde acetal prepared by this procedure is reacted with a source of acid in a suitable solvent to provide the desired benzofuran.
- Suitable solvents include aromatic solvents such as toluene, xylene, benzene, and halobenzenes such as chlorobenzene .
- Suitable acids include concentrated sulfuric acid, polyphosphoric acid, and acidic resins such as Amberlyst 15TM.
- the phenoxide solution is treated with an allyl bromide or allyl chloride to provide, after standard isolation and purification procedures, the corresponding allyl ether.
- This purified ether is heated at a temperature sufficient to effect an ortho-Claisen rearrangement to provide the corresponding o-allylphenol. It is critical that the allyl ether employed in this rearrangement is substantially free of residual dimethyl- formamide.
- the rearrangement can provide a mixture of two isomeric products. These isomers may be separated at this stage or later in the synthetic sequence as is convenient or desired.
- the separation may be effected by chromatography, distilla-tion, or crystallization.
- the o-allylphenol is then treated with an excess of ozone in an appropriate solvent, dichloromethane and methanol are useful solvents for this step.
- the reaction mixture is then purged of ozone and the ozonide is treated under reducing conditions, typically by treatment with triphenylphosphine or dimethyl- sulfide, to provide the corresponding phenylacetaldehyde .
- triphenylphosphine or dimethyl- sulfide to provide the corresponding phenylacetaldehyde .
- a solution of this equilibrium mixture in a suitable solvent, such as toluene is treated with a catalytic amount of an appropriate acid, such as sulfuric acid, to provide the desired benzofuran.
- benzofurans substituted in the 2- and/or 3-position may be prepared by modification of the chemistry described in Synthetic Scheme III.
- the phenol may be alkylated with a suitable haloketone and then cyclized to provide a substituted benzofuran.
- the benzofuran moiety may be substituted in the 2- or 3-position at any convenient point in the synthesis of the compounds of the present invention by methods known to those skilled in the art .
- benzofurans may also be prepared from an appropriately substituted phenol as illustrated in the following scheme where variables R , R 3 , and R ⁇ 2 are as previously defined:
- a mixture of an appropriate phenol and hexamethylenetetra- mine are treated with an appropriate acid, such as trifluoroacetic acid, to provide upon aqueous workup the corresponding o-formylphenol .
- This o-formylphenol is then treated with (bromomethyl) triphenylphosphonium bromide followed by an appropriate base such as potassium tert- butoxide to provide the desired benzofuran.
- bromobenzofuran is treated with either magnesium metal to provide the corresponding Grignard reagent, or with an alkyllithium at low temperature to effect halogen metal exchange. Either of these reagents is then reacted with an appropriate reagent, for example dimethyIformamide, to provide the corresponding formylbenzofuran.
- This formylbenzofuran is reduced under standard hydride reducing conditions, for example sodium borohydride in ethanol, to provide the corresponding alcohol.
- the alcohol is then converted to the corresponding nitrile by either converting first to the corresponding halide and displacing with a source of cyanide anion, or by directly converting the alcohol to the nitrile by reaction with trimethylsilylchloride and sodium cyanide in a mixture of dimethylformamide and acetonitrile in the presence of catalytic sodium iodide as described by dans et al . (Journal of Organic Chemistry, 46, 2985 (1981)).
- the requisite nitrile may also be prepared beginning with an appropriate benzofurylacetate ester, such as ethyl benzofurylacetate.
- the benzofurylacetate ester is reacted with formamide in the presence of an appropriate base, such as sodium methoxide, to prepare the corresponding benzofur- ylacetamide.
- This acetamide is then dehydrated to provide the desired nitrile by reaction with an appropriate dehydrating agent, such as trifluoroacetic anhydride in the presence of pyridine as described by Campagna, et al . (Tetrahedron Letters, 1813 (1977)).
- the cyclopropyl moiety is introduced by reacting this nitrile with 1,2-dibromoethane and aqueous sodium hydroxide in the presence of a phase-transfer catalyst such as benzyltriethylammoniu chloride under the conditions described by Sychkova and Shabarov (Zh. Org . Khim. , 16, 2086 (1980) ) .
- a phase-transfer catalyst such as benzyltriethylammoniu chloride under the conditions described by Sychkova and Shabarov (Zh. Org . Khim. , 16, 2086 (1980) ) .
- Reduction of the corresponding cyclopropylamide with an appropriate hydride reducing agent, for example lithium aluminum hydride or borane dimethylsulfide complex, provides the compound of the present invention.
- benzofurylacetate ester may be reacted with 1,2-dibromoethane in the presence of an excess of an appropriate base, such as lithium diisopropylamide, to provide the corresponding ester of 1-benzofuryl-l-carboxycy- clopropane.
- an appropriate base such as lithium diisopropylamide
- the resulting tert- butyl ester is subjected to standard Curtius rearrangement conditions to provide the corresponding N-tert- butoxycarbonyl 1-amino-l- (benzofuryl) methylcyclopropane .
- This compound is deprotected by treatment with acid to provide the compounds of the present invention. If necessary or desired, the starting aldehyde may be reduced to the corresponding alcohol and then converted to the corresponding bromomethylbenzofuran.
- This reagent is then reacted with 1-1ert-butoxycarbony1eyelopropy11ithium essentially as described by Haener, to provide 1-tert- butoxycarbonyl-1- (benzofuryl) methylcyclopropane which is then subjected to the Curtius rearrangement/deprotection sequence described supra to provide the compounds of the present invention.
- the starting bromobenzofuran may be reacted with magnesium metal under standard conditions to prepare the corresponding Grignard reagent, benzof rylmag- nesium bromide.
- This Grignard reagent is then reacted with the Weinreb amide, N-methyl N-methoxy 1- (tert-butoxycarbon- ylamino) cyclopropane-1-carboxamide, to provide 1- ( tert- butoxycarbonylamino) -1- (benzofurylcarbonyl ) cyclopropane.
- This ketone is then reduced under standard conditions, typically with sodium borohydride in methanol or ethanol, to provide 1- (tert-butoxycarbonylamino) -1- (benzofuryl (hydroxy- methyl) ) cyclopropane.
- This alcohol is then converted to the corresponding acetate and reduced to the corresponding methylene by treatment with samarium iodide as previously described.
- the requisite Weinreb amide, N-methyl N-methoxy 1- ( tert-butoxycarbonylamino) cyclo- propane-1-carboxamide may be prepared from the commercially available 1-amino-l-carboxycyclopropane by standard methods well known in the art.
- alkoxy groups may be cleaved to provide the corresponding phenols, and primary amines may be diazotized and displaced to provide the corresponding halogenated compounds .
- the following Preparations and Examples are illustrative of methods useful for the synthesis of the compounds of the present invention.
- This oil was subjected to silica gel chromatography, eluting with a gradient system of hexane containing from 0- 30% ethyl acetate. Fractions containing the fastest eluting compound were combined and concentrated under reduced pressure to provide 18.1 gm (28%) of 2-bromo-5-methoxyphenol as a clear liquid.
- the aqueous phase was extracted with three 100 mL portions of diethyl ether.
- the organic phases were combined and extracted well with 5 N sodium hydroxide.
- These basic aqueous extracts were combined and cooled in an ice/water bath.
- the pH of this aqueous solution was adjusted to about 1 with 5 N hydrochloric acid and then extracted with three 100 mL portions of diethyl ether.
- These ether extracts were combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
- the resulting residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 10% ethyl acetate.
- reaction mixture was stirred at 0°C for about one hour.
- the reaction mixture was washed twice with 200 mL portions of water, once with 200 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
- the residue was subjected to silica gel chromatography, eluting with 1:1 hexane : ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure.
- the reaction mixture was concentrated under reduced pressure and the residue dissolved in water. This aqueous solution was washed with ethyl acetate and the organic phase discarded. The remaining aqueous phase was made acidic by the addition of aqueous potassium hydrogen sulfate. The aqueous phase was again extracted with ethyl acetate. This organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from a mixture of chloroform and hexane to provide 0.300 gm (92%) of the title compound as a white crystalline solid in two crops.
- Preparation XXIV 3 isopropy1-5-fluoro-7-bromobenzofuran Beginning with 4-methylpent-2-en-l-yl 2-bromo-4- fluorophenyl ether, the title compound was prepared essentially as described in Preparation XX.
- Preparation XXV 3 4-dimethyl-5-fluoro-7-bromobenzofuran Beginning with but-2-en-l-yl 2-bromo-4-fluoro-5- methylphenyl ether, the title compound was prepared essentially as described in Preparation XX.
- the resulting mixture was cooled to 0°C and was then treated with 15 mL 20% aqueous sodium thiosulfate.
- the resulting slurry was stirred for about 1 hour and then the phases separated.
- the organic phase was washed sequentially with 3 x 20 mL 20% aqueous sodium thiosulfate followed by 3 x 20 mL saturated aqueous sodium chloride.
- 3-bromo-4-fluorophenyl allyl ether was placed in a sealed tube and was deoxygenated by bubbling nitrogen through the liquid. The tube was sealed and then heated at 230°C for 3 hours. After cooling to room temperature, the mixture is subjected to silica gel chromatography, eluting with 8:1 hexane: diethyl ether. The faster eluting product isomer was 2-allyl-4-fluoro-5-bromophenol . The slower eluting isomer was 2-allyl-3-bromo-4-fluorophenol . The isomers were isolated in a ratio of 3:2 respectively.
- reaction mixture was stirred without cooling for two hours.
- the reaction mixture was then diluted with 500 mL water and the resulting solid collected by filtration.
- the solid was washed with water until the wash was neutral (pH about 7) .
- the solid was dried under reduced pressure and was then subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0-2% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 57 gm (62%) 2-hydroxy-3-bromo-5-fluoro- 6-chlorobenzaldehyde .
- the reaction mixture was diluted with 700 mL of hexane and the resulting precipitate removed by filtration.
- the recovered solid was slurried in 300 mL hexane and filtered 4 times.
- the combined filtrates were washed with 2 x 500 mL water followed by 500 mL saturated aqueous sodium chloride.
- the remaining organics were dried over sodium sulfate and concentrated under reduced pressure to provide a residual solid.
- This solid was slurried and filtered with 4 x 300 mL diethyl ether to remove triphenylphosphine oxide.
- the filtrate was separated and the organic phase was extracted with two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride. The remaining organic phase was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane containing 20% ethyl acetate. This solid was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0-20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from hexane to provide 13.5 gm (56%) of the desired compound.
- This ketone was converted to 0.082 gm (32%) of l-(7- fluorobenzofur-5-yl) -2-aminopropane essentially as described in Example 1. This amine was converted to the hydrochloride salt to provide the title compound.
- reaction mixture was diluted with 200 mL ethyl acetate, washed sequentially with 100 mL of water and 100 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was slurried in diethyl ether and filtered, providing 0.14 gm (60%) of the desired compound in two crops .
- reaction mixture was then stirred for 3 hours at which point 0.03 mL (0.77 mMol) ammonium hydroxide were added. After stirring about 20 hours at room temperature the reaction mixture was concentrated under reduced pressure. The residue was diluted with 300 mL ethyl acetate and washed with sequentially with 100 mL 2 N sodium hydroxide, 200 mL saturated aqueous ammonium chloride, 100 mL water, and 100 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 1:1 hexane: ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.055 gm (28%) of the desired compound.
- the reaction mixture was partitioned between 300 mL ethyl acetate and 300 mL water. The phases were separated and the aqueous phase was extracted twice with 200 mL ethyl acetate. The organic phases were combined and washed sequentially with two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.38 gm (69%) of the desired compound as a yellow solid.
- reaction mixture was quenched by addition of 2 mL saturated aqueous ammonium chloride and was then allowed to warm to room temperature.
- EXAMPLE 29 1- ( 5-fluorobenzofur-7-yl ) -3-aminobutane hydrochloride Nitrogen was bubbled through a mixture of 1.0 gm (4.65 mMol) 5-fluoro-7-bromobenzofuran, 0.61 mL (6.98 mMol) 3- buten-2-ol, 0.057 gm (0.186 mMol) tri (o-tolyl) phosphine, and 0.47 gm (5.58 mMol) sodium bicarbonate in 35 mL N- methylpyrrolidinone for 10 minutes.
- N-tert-butoxycarbonyl 1- (5- [N' -tert-butoxycarbonyl j amino- benzofur-7-yl) -2-aminopropane
- the reaction mixture was diluted with 25 mL ethyl acetate and stirred vigorously. The organic phase was decanted off and the process was repeated. The combined organic extracts were combined and concentrated under reduced pressure. The residual oily solid was subjected to flash silica gel chromatography eluting with dichloromethane containing 4% methanol . Fractions containing the desired product were combined and concentrated under reduced pressure to provide a yellow oil. The oil was dissolved in diethyl ether and the solution was then concentrated under reduced pressure to provide 0.121 gm (78%) of the desired compound as an off- white foam.
- reaction mixture was then allowed to stir at room temperature for about 18 hours at which point it was heated at reflux for 9 hours followed by about 18 hours at room temperature.
- To this mixture were then added 0.5 mL 50% aqueous sodium hydroxide and 2 mL dioxane and the resulting mixture was stirred at room temperature for about 18 hours.
- the reaction mixture was then partitioned between 2 mL of water and 25 mL diethyl ether. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure.
- the residual oil was subjected to flash silica gel chromatography, eluting with hexane containing 30% ethyl acetate. Fractions containing the desired product were combined and concentrated under reduced pressure to provide 0.042 gm (60%) of the desired compound as a colorless oil.
- EXAMPLE 38 1- (5-hydroxybenzofur-7-yl) -2-aminopropane hydrochloride A mixture of 0.73 gm (2.38 mMol) N-tert-butoxycarbonyl 1- ( 5-methoxybenzofur-7-yl) -2-aminopropane and 3.30 gm (28.52 mMol) pyridine hydrochloride were heated at 170°C in a sealed tube for 15 hours . The mixture was cooled and the residue was dissolved in dichloromethane containing 10% methanol and 1% ammonium hydroxide. The solution was concentrated under reduced pressure and the pyridine remaining in the residue was removed azeotropically by diluting the residue with water and concentrating three times.
- reaction mixture was allowed to warm to room temperature and was then stirred at room temperature for 30 minutes.
- the reaction mixture was diluted with 20 volumes of ethyl acetate and was washed sequentially with IN hydrochloric acid, water, and saturated aqueous sodium chloride. The remaining organics were concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane containing 30% ethyl acetate. Fractions containing the desired product were combined and concentrated under reduced pressure to provide 0.894 gm (80%) of the desired compound.
- reaction mixture was then diluted with ethyl acetate and the resulting solution washed sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride.
- the remaining organic phase was concentrated under reduced pressure and the residue subjected to flash silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.723 gm (62%) of the desired compound.
- This ketone was converted to 0.38 gm (75%) of l-(5- (methoxycarbonyl) benzofur-7-yl) -2-aminopropane essentially as described in Example 1. This amine was converted to the oxalate salt to provide the title compound.
- reaction mixture was then washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure.
- the residue was subjected to silica gel chromatography, eluting with dichloromethane containing 1% methanol saturated with ammonia. Fractions containing the desired product were combined and concentrated under reduced pressure to provide 0.164 gm (70%) of the desired compound as a white solid.
- EXAMPLE 48 1- (N' - [1- (pyridin-4-yl) eth-2-yl] 5-carboxamidobenzofur-7- yl) -2-aminopropane dihydrochloride Beginning with N-tert-butoxycarbonyl 5-carboxybenzofur- 7-yl) -2-aminopropane and 4- (2-ethylamino) pyridine, the title compound was prepared essentially as described in EXAMPLE 46.
- EXAMPLE 49 1- (N* - [carboxymethyl] 5-carboxamidobenzofur-7-yl) -2- aminopropane trifluoroacetate Beginning with N-tert-butoxycarbonyl 5-carboxybenzofur- 7-yl) -2-aminopropane and glycine tert-butyl ester hydrochloride, the title compound was prepared essentially as described in EXAMPLE 46.
- This ketone was converted to 1- (4-trifluoromethylbenzo- fur-7-yl) -2-aminopropane essentially as described in Example 1. This amine was converted to the hydrochloride salt to provide 0.13 gm (39%) of the title compound.
- This ketone was converted to 1- (4-chloro-5-fluoro- benzofur-7-yl) -2-aminopropane essentially as described in Example 1.
- This amine was converted to the hydrochloride salt to provide 0.080 gm (49%) of the title compound as a white solid.
- EXAMPLE 68 1- (3-isopropyl-5-fluorobenzofur-7-yl) -2-aminopropane oxalate Beginning with 3-isopropyl-5-fluoro-7-bromobenzofuran, the title compound was prepared essentially as described in EXAMPLE 1.
- EXAMPLE 74 2- (5-fluorobenzofur-7-yl) -1-aminobutane oxalate Beginning with 5-fluoro-7-bromobenzofuran, 2- (5- fluorobenzofur-7-yl) -1-aminobutane was prepared essentially as described in EXAMPLE 39. This amine was treated with oxalic acid to provide the title compound.
- reaction mixture was quenched by the addition of 0.13 mL (2.13 mMol) iodomethane.
- the reaction mixture was allowed to warm to room temperature and was diluted with ethyl acetate. This mixture was then washed sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The remaining organics were concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.16 gm (90%) of the desired compound.
- EXAMPLE 90 1- (3-pentyl-5-fluorobenzofur-7-yl) -2-aminopropane oxalate Beginning with 3-pentyl-5-fluoro-7-bromobenzofuran, the title compound was prepared essentially as described in EXAMPLE 1.
- EXAMPLE 92 1- (5-fluoro-6-methylbenzofur-7-yl) -2-aminopropane Beginning with 5-fluoro-6-methyl-7-bromobenzofuran, the title compound was prepared essentially as described in EXAMPLE 1.
- Membrane Preparation AV12 cells stably transfected with the human 5-HT2 c receptors were grown in suspension and harvested by centrifugation, resuspended in 50 mM tris-HCl, pH 7.4, and frozen at -70°C. On the day of assay, an aliquot of cells was thawed, resuspended in 40 mL of 50 mM tris-HCl, pH 7.4, and centrifuged at 39,800 x g for 10 minutes at 4°C . The resulting pellet was resuspended, incubated at 37°C for 10 minutes to remove endogenous serotonin, then centrifuged twice more.
- Nonlinear regression analysis was performed on the concentration response curves using a four parameter logistic equation described by DeLean (DeLean, et al . , Molecular Pharmacology, 21, 5-16 (1982)). IC50 values were converted to K-j_ values using the Cheng-Prusoff equation (Cheng, et al . , Biochem. Pharmacol., 22, 3099-3108 (1973)). Representative compounds of the present invention were found to have affinity for the 5-HT2 c receptor as measured essentially by the procedure described supra .
- the 5-HT2c receptor is functionally coupled to a G- protein. Agonist activation of G-protein-coupled receptors results in the release of GDP from the -subunit of the G- protein and the subsequent binding of GTP . The binding of the stable analog [35s]-GTP ⁇ S is an indicator of this receptor's activation.
- Representative compounds of the present invention were tested in the [35s]-GTP ⁇ S assay and were found to be agonists of the 5-HT2 c receptor.
- Representative compounds of the present invention were tested in the feeding assay and were found to reduce food consumed by fasting rats.
- compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient.
- These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal .
- Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
- Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g. , REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
- the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
- a carrier which can be in the form of a capsule, sachet, paper or other container.
- the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
- the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols
- ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
- excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
- the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
- compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art .
- the compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
- the active compounds are generally effective over a wide dosage range.
- dosages per day normally fall within the range of about 0.01 to about 30 mg/kg.
- the range of about 0.1 to about 15 mg/kg/day, in single or divided dose is especially preferred.
- the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
- dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
- Hard gelatin capsules containing the following ingredients are prepared:
- Quantity Ingredient (mg/capsule)
- the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
- a tablet formula is prepared using the ingredients below:
- Quantity Ingredient (mg/tablet)
- the components are blended and compressed to form tablets, each weighing 240 mg.
- a dry powder inhaler formulation is prepared containing the following components:
- Tablets each containing 30 mg of active ingredient, are prepared as follows:
- Quantity Ingredient (mg/tablet)
- the active ingredient, starch and cellulose are passed through a No . 20 mesh U.S. sieve and mixed thoroughly.
- the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
- the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
- the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No . 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
- Capsules each containing 40 mg of medicament are made as follows :
- Quantity Ingredient (mg/capsule)
- the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No . 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
- Suppositories each containing 25 mg of active ingredient are made as follows:
- Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
- the medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
- the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
- Capsules each containing 15 mg of medicament, are made as follows:
- the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
- An intravenous formulation may be prepared as follows :
- a topical formulation may be prepared as follows:
- Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
- the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90°C.
- the solution is cooled to about 50-55°C and the medicament is slowly admixed.
- the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
- transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
- the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g. , U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
- patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
- the type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s) , and the state of the patient .
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- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
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Abstract
La présente invention concerne des aminoalkylbenzofurannes sérotoninergiques de formule (I), dans laquelle R, R?1, R2, R3, R4, R4', R5, R5' et R12¿ sont tels que définis dans le mémoire descriptif.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11738599P | 1999-01-27 | 1999-01-27 | |
US117385P | 1999-01-27 | ||
PCT/US2000/001342 WO2000044737A1 (fr) | 1999-01-27 | 2000-01-19 | Aminoalkylbenzofurannes faisant office d'agonistes de la serotonine (5-ht(2c)) |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1149085A1 true EP1149085A1 (fr) | 2001-10-31 |
Family
ID=22372628
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00904438A Withdrawn EP1149085A1 (fr) | 1999-01-27 | 2000-01-19 | Aminoalkylbenzofurannes faisant office d'agonistes de la serotonine (5-ht(2c)) |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1149085A1 (fr) |
JP (1) | JP2002535396A (fr) |
AU (1) | AU2619800A (fr) |
CA (1) | CA2361516A1 (fr) |
WO (1) | WO2000044737A1 (fr) |
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SE0004245D0 (sv) | 2000-11-20 | 2000-11-20 | Pharmacia Ab | Novel compounds and their use |
CA2449899C (fr) | 2000-11-20 | 2010-04-06 | Biovitrum Ab | Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2 |
AU2002346671B2 (en) * | 2001-12-14 | 2005-08-11 | Alcon, Inc. | Aminoalkyl-benzofuran-5-OL compounds for the treatment of glaucoma |
CN100484933C (zh) | 2002-06-19 | 2009-05-06 | 比奥维特罗姆股份公开公司 | 新的吡嗪化合物及其在制备用于治疗与5-羟色胺相关的疾病的药物中的用途 |
BR0314419A (pt) * | 2002-08-30 | 2005-07-19 | Alcon Inc | Compostos de 5-croman-5-il-etilamina substituìdos, seu uso e composição farmacêutica incluindo-o |
US7078419B2 (en) | 2003-03-10 | 2006-07-18 | Boehringer Ingelheim Pharmaceuticals, Inc. | Cytokine inhibitors |
CL2004000826A1 (es) | 2003-04-25 | 2005-03-04 | Pfizer | Uso de un agonista para el receptor 5-ht2c para preparar un medicamento util en el tratamiento de la incontinencia urinaria provocada por estres, con la condicion de que el agonista no sea 1-[6-cloro-5-(trifluorometil)-2-piridinil]piperazina (org-129 |
US20050261347A1 (en) * | 2003-10-24 | 2005-11-24 | Wyeth | Dihydrobenzofuranyl alkanamine derivatives and methods for using same |
US7435837B2 (en) * | 2003-10-24 | 2008-10-14 | Wyeth | Dihydrobenzofuranyl alkanamine derivatives and methods for using same |
WO2006000902A1 (fr) * | 2004-06-25 | 2006-01-05 | Pfizer Products Inc. | Composes dihydrobenzofurane et leurs utilisations |
EP2248524A3 (fr) | 2004-08-25 | 2011-03-09 | Takeda Pharmaceutical Company Limited | Agents preventifs/remedes pour l'incontinence de stress et procede de selecetion de ceux-ci |
WO2006103511A1 (fr) | 2005-03-31 | 2006-10-05 | Pfizer Products Inc. | Derives de cyclopentapyridine et de tetrahydroquinoline |
CN101175740A (zh) * | 2005-04-22 | 2008-05-07 | 惠氏公司 | 二氢苯并呋喃衍生物和其用途 |
JP2008538581A (ja) * | 2005-04-22 | 2008-10-30 | ワイス | {[(2r)−7−(2,6−ジクロロフェニル)−5−フルオロ−2,3−ジヒドロ−1−ベンゾフラン−2−イル]メチル}アミン塩酸塩の結晶形態 |
CN101203218A (zh) * | 2005-04-22 | 2008-06-18 | 惠氏公司 | 苯并呋喃基链烷胺衍生物和其作为5-ht2c激动剂的用途 |
CA2629962A1 (fr) * | 2005-11-30 | 2007-06-07 | F. Hoffmann-La Roche Ag | 3-amino-1-arylpropyl indoles et indoles a substitution azo |
EP2742936A1 (fr) | 2006-05-16 | 2014-06-18 | Takeda Pharmaceutical Company Limited | Composé hétérocyclique condensé et son utilisation |
EP2789338A3 (fr) | 2007-11-15 | 2015-01-14 | Takeda Pharmaceutical Company Limited | Dérivé de pyridine condensé et son utilisation |
KR101062376B1 (ko) | 2008-04-10 | 2011-09-06 | 한국화학연구원 | 신규 인돌 카르복실산 비스피리딜 카르복사마이드 유도체,이의 제조방법 및 이를 유효성분으로 함유하는 조성물 |
JPWO2011071136A1 (ja) | 2009-12-11 | 2013-04-22 | アステラス製薬株式会社 | 線維筋痛症治療剤 |
US20130267500A1 (en) | 2010-09-01 | 2013-10-10 | Arena Pharmaceuticals, Inc. | 5-ht2c receptor agonists in the treatment of disorders ameliorated by reduction of norepinephrine level |
WO2015066344A1 (fr) | 2013-11-01 | 2015-05-07 | Arena Pharmaceuticals, Inc. | Agonistes du récepteur 5-ht2c et compositions et procédés d'utilisation |
CN104529962B (zh) * | 2014-12-22 | 2016-08-17 | 中科院广州化学有限公司 | 一种2-烷氨基-3-氰基苯并呋喃类化合物及制备方法 |
EP3733204A4 (fr) | 2017-12-27 | 2021-09-15 | Takeda Pharmaceutical Company Limited | Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale |
CN110317129A (zh) * | 2019-05-30 | 2019-10-11 | 杭州迈世腾药物科技有限公司 | 2-溴-5-甲氧基苯酚的合成方法 |
CN110684000B (zh) * | 2019-10-18 | 2021-08-31 | 上海皓元医药股份有限公司 | 苯并呋喃衍生物的制备方法 |
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US4414986A (en) | 1982-01-29 | 1983-11-15 | Medtronic, Inc. | Biomedical stimulation lead |
US5433729A (en) | 1991-04-12 | 1995-07-18 | Incontrol, Inc. | Atrial defibrillator, lead systems, and method |
DE69307873T2 (de) | 1992-04-10 | 1997-08-07 | Cardiorhythm | Herzkatheter zur messung eines bezugspotentials |
SE9203732D0 (sv) | 1992-12-11 | 1992-12-11 | Siemens Elema Ab | Elektrodsystem foer defibrillator |
CN1129443A (zh) * | 1993-06-14 | 1996-08-21 | 美国辉瑞有限公司 | 仲胺用作治糖尿病和治肥胖病药物 |
US5423772A (en) | 1993-08-13 | 1995-06-13 | Daig Corporation | Coronary sinus catheter |
US5476498A (en) | 1994-08-15 | 1995-12-19 | Incontrol, Inc. | Coronary sinus channel lead and method |
GB9517559D0 (en) * | 1995-08-26 | 1995-10-25 | Smithkline Beecham Plc | Novel compounds |
US5683445A (en) | 1996-04-29 | 1997-11-04 | Swoyer; John M. | Medical electrical lead |
CN1228775A (zh) * | 1996-05-14 | 1999-09-15 | 葛兰素集团有限公司 | 作为时间生物学药物的苯并呋喃和苯并吡喃 |
-
2000
- 2000-01-19 JP JP2000595993A patent/JP2002535396A/ja not_active Withdrawn
- 2000-01-19 WO PCT/US2000/001342 patent/WO2000044737A1/fr active Application Filing
- 2000-01-19 CA CA002361516A patent/CA2361516A1/fr not_active Abandoned
- 2000-01-19 EP EP00904438A patent/EP1149085A1/fr not_active Withdrawn
- 2000-01-19 AU AU26198/00A patent/AU2619800A/en not_active Abandoned
Non-Patent Citations (1)
Title |
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See references of WO0044737A1 * |
Also Published As
Publication number | Publication date |
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CA2361516A1 (fr) | 2000-08-03 |
WO2000044737A1 (fr) | 2000-08-03 |
AU2619800A (en) | 2000-08-18 |
JP2002535396A (ja) | 2002-10-22 |
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