AU2006287202B2 - 6-arylalkylamino- 2,3,4,5-tetrahydro-1H-benzo[d]azepines as 5-HT2c receptor agonists - Google Patents
6-arylalkylamino- 2,3,4,5-tetrahydro-1H-benzo[d]azepines as 5-HT2c receptor agonists Download PDFInfo
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- AU2006287202B2 AU2006287202B2 AU2006287202A AU2006287202A AU2006287202B2 AU 2006287202 B2 AU2006287202 B2 AU 2006287202B2 AU 2006287202 A AU2006287202 A AU 2006287202A AU 2006287202 A AU2006287202 A AU 2006287202A AU 2006287202 B2 AU2006287202 B2 AU 2006287202B2
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- Prior art keywords
- alkyl
- optionally substituted
- fluoro substituents
- moiety
- substituents
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- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 title abstract description 16
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 title abstract description 13
- 239000000018 receptor agonist Substances 0.000 title abstract description 7
- 229940044601 receptor agonist Drugs 0.000 title abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims abstract description 208
- -1 6-substituted 2,3,4,5-tetrahydro-lH- benzo[d]azepines Chemical class 0.000 claims abstract description 125
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 13
- 230000036506 anxiety Effects 0.000 claims abstract description 13
- 208000008589 Obesity Diseases 0.000 claims abstract description 12
- 235000020824 obesity Nutrition 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 994
- 125000001153 fluoro group Chemical group F* 0.000 claims description 817
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 166
- 150000001875 compounds Chemical class 0.000 claims description 149
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 140
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 239000001257 hydrogen Substances 0.000 claims description 55
- 150000003839 salts Chemical class 0.000 claims description 52
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 49
- 125000005843 halogen group Chemical group 0.000 claims description 44
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 42
- 125000005605 benzo group Chemical group 0.000 claims description 42
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 39
- 229920006395 saturated elastomer Polymers 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
- 125000004076 pyridyl group Chemical group 0.000 claims description 20
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 20
- 241000124008 Mammalia Species 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- MWVMYAWMFTVYED-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-3-benzazepine Chemical compound C1CNCCC2=CC=CC=C21 MWVMYAWMFTVYED-UHFFFAOYSA-N 0.000 claims description 15
- YGLDQFWPUCURIP-UHFFFAOYSA-N 3h-3-benzazepine Chemical compound C1=CNC=CC2=CC=CC=C21 YGLDQFWPUCURIP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 150000001721 carbon Chemical group 0.000 claims description 10
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims description 3
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 3
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 3
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 3
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 3
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims description 3
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 claims description 3
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 3
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 3
- 208000020401 Depressive disease Diseases 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
- MUTBQNLDPSOWDQ-UHFFFAOYSA-N 1-[4-[[(7-chloro-2,3,4,5-tetrahydro-1h-3-benzazepin-6-yl)amino]methyl]phenyl]-2-(2,2,2-trifluoroethylsulfanyl)ethanone Chemical compound C1=CC(C(=O)CSCC(F)(F)F)=CC=C1CNC1=C(Cl)C=CC2=C1CCNCC2 MUTBQNLDPSOWDQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- YETZEGOZUAGHLY-UHFFFAOYSA-N n-[4-[[(7-chloro-2,3,4,5-tetrahydro-1h-3-benzazepin-6-yl)amino]methyl]phenyl]-2-methylcyclopropane-1-carboxamide Chemical compound CC1CC1C(=O)NC(C=C1)=CC=C1CNC1=C(Cl)C=CC2=C1CCNCC2 YETZEGOZUAGHLY-UHFFFAOYSA-N 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- AUHPYCJOFPGMJP-UHFFFAOYSA-N 4-[5-[[(7-chloro-2,3,4,5-tetrahydro-1h-3-benzazepin-6-yl)amino]methyl]pyridin-2-yl]-n-(cyclopropylmethyl)-1,3-thiazol-2-amine Chemical compound ClC1=CC=C2CCNCCC2=C1NCC(C=N1)=CC=C1C(N=1)=CSC=1NCC1CC1 AUHPYCJOFPGMJP-UHFFFAOYSA-N 0.000 claims 1
- GNVNZGPIFWRVDF-UHFFFAOYSA-N 7-chloro-n-(2-cyclopentyloxy-1-pyridin-3-ylethyl)-2,3,4,5-tetrahydro-1h-3-benzazepin-6-amine Chemical compound ClC1=CC=C2CCNCCC2=C1NC(C=1C=NC=CC=1)COC1CCCC1 GNVNZGPIFWRVDF-UHFFFAOYSA-N 0.000 claims 1
- JQPIRMVVDKGKOI-UHFFFAOYSA-N 7-chloro-n-[[4-(n-ethoxy-c-methylcarbonimidoyl)phenyl]methyl]-2,3,4,5-tetrahydro-1h-3-benzazepin-6-amine Chemical compound C1=CC(C(C)=NOCC)=CC=C1CNC1=C(Cl)C=CC2=C1CCNCC2 JQPIRMVVDKGKOI-UHFFFAOYSA-N 0.000 claims 1
- FKLIFPLWWCEIBW-UHFFFAOYSA-N 7-chloro-n-[[4-(n-methoxy-c-methylcarbonimidoyl)phenyl]methyl]-2,3,4,5-tetrahydro-1h-3-benzazepin-6-amine Chemical compound C1=CC(C(C)=NOC)=CC=C1CNC1=C(Cl)C=CC2=C1CCNCC2 FKLIFPLWWCEIBW-UHFFFAOYSA-N 0.000 claims 1
- OHBFUXADWNWFJJ-UHFFFAOYSA-N 7-chloro-n-[[4-[c-methyl-n-(2-methylpropoxy)carbonimidoyl]phenyl]methyl]-2,3,4,5-tetrahydro-1h-3-benzazepin-6-amine Chemical compound C1=CC(C(C)=NOCC(C)C)=CC=C1CNC1=C(Cl)C=CC2=C1CCNCC2 OHBFUXADWNWFJJ-UHFFFAOYSA-N 0.000 claims 1
- WGTHUEXKTMBYGI-UHFFFAOYSA-N n-[4-[[(7-chloro-2,3,4,5-tetrahydro-1h-3-benzazepin-6-yl)amino]methyl]phenyl]-2,2-dimethylpropanamide Chemical compound C1=CC(NC(=O)C(C)(C)C)=CC=C1CNC1=C(Cl)C=CC2=C1CCNCC2 WGTHUEXKTMBYGI-UHFFFAOYSA-N 0.000 claims 1
- 125000001113 thiadiazolyl group Chemical group 0.000 claims 1
- 125000003884 phenylalkyl group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 267
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 250
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 250
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 228
- 239000000203 mixture Substances 0.000 description 168
- 239000012141 concentrate Substances 0.000 description 133
- 235000008504 concentrate Nutrition 0.000 description 133
- 239000000243 solution Substances 0.000 description 127
- 235000019439 ethyl acetate Nutrition 0.000 description 124
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 118
- 238000003756 stirring Methods 0.000 description 118
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 115
- 239000000284 extract Substances 0.000 description 106
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 88
- 238000004587 chromatography analysis Methods 0.000 description 88
- 239000000543 intermediate Substances 0.000 description 82
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 80
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 75
- 239000000741 silica gel Substances 0.000 description 74
- 229910002027 silica gel Inorganic materials 0.000 description 74
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- 238000002360 preparation method Methods 0.000 description 69
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 66
- 239000007787 solid Substances 0.000 description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 58
- 239000011734 sodium Substances 0.000 description 56
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
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- 239000010410 layer Substances 0.000 description 43
- 238000000034 method Methods 0.000 description 43
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- 239000011541 reaction mixture Substances 0.000 description 40
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 38
- 150000001412 amines Chemical class 0.000 description 36
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- 239000002904 solvent Substances 0.000 description 33
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
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- 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 24
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 22
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- 239000002002 slurry Substances 0.000 description 22
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 19
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- 150000001649 bromium compounds Chemical class 0.000 description 17
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- 229910021529 ammonia Inorganic materials 0.000 description 16
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- 125000001309 chloro group Chemical group Cl* 0.000 description 13
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
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- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 10
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- 239000007858 starting material Substances 0.000 description 10
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- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 150000002431 hydrogen Chemical group 0.000 description 9
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 9
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- ATHCJQPVIPYTCU-UHFFFAOYSA-N tert-butyl n-[(4-cyanophenyl)methyl]-n-cyclohexylcarbamate Chemical compound C1CCCCC1N(C(=O)OC(C)(C)C)CC1=CC=C(C#N)C=C1 ATHCJQPVIPYTCU-UHFFFAOYSA-N 0.000 description 1
- OYQLYCDWNIHZAZ-UHFFFAOYSA-N tert-butyl n-[(4-cyanophenyl)methyl]-n-propan-2-ylcarbamate Chemical compound CC(C)(C)OC(=O)N(C(C)C)CC1=CC=C(C#N)C=C1 OYQLYCDWNIHZAZ-UHFFFAOYSA-N 0.000 description 1
- BBSVDLXXIGIELL-UHFFFAOYSA-N tert-butyl n-[(6-chloropyridin-2-yl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=CC(Cl)=N1 BBSVDLXXIGIELL-UHFFFAOYSA-N 0.000 description 1
- VJMBHARIHIDJMC-UHFFFAOYSA-N tert-butyl n-[(6-cyanopyridin-3-yl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=C(C#N)N=C1 VJMBHARIHIDJMC-UHFFFAOYSA-N 0.000 description 1
- BQSORYXVEAERPG-UHFFFAOYSA-N tert-butyl n-[[4-(2,2-dimethylpropanoylamino)phenyl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=C(NC(=O)C(C)(C)C)C=C1 BQSORYXVEAERPG-UHFFFAOYSA-N 0.000 description 1
- NBUPDWAGGHPOQP-UHFFFAOYSA-N tert-butyl n-[[4-(aminomethyl)phenyl]methyl]-n-(2-methylpropyl)carbamate Chemical compound CC(C)(C)OC(=O)N(CC(C)C)CC1=CC=C(CN)C=C1 NBUPDWAGGHPOQP-UHFFFAOYSA-N 0.000 description 1
- WFNSSRRDVGELTD-UHFFFAOYSA-N tert-butyl n-[[4-(aminomethyl)phenyl]methyl]-n-cyclohexylcarbamate Chemical compound C1CCCCC1N(C(=O)OC(C)(C)C)CC1=CC=C(CN)C=C1 WFNSSRRDVGELTD-UHFFFAOYSA-N 0.000 description 1
- YXPDQDTXJVDZTE-UHFFFAOYSA-N tert-butyl n-[[4-(aminomethyl)phenyl]methyl]-n-propan-2-ylcarbamate Chemical compound CC(C)(C)OC(=O)N(C(C)C)CC1=CC=C(CN)C=C1 YXPDQDTXJVDZTE-UHFFFAOYSA-N 0.000 description 1
- ZECMDFWXHVHCFO-UHFFFAOYSA-N tert-butyl n-[[4-[(2,2,3,3-tetramethylcyclopropanecarbonyl)amino]phenyl]methyl]carbamate Chemical compound C1=CC(CNC(=O)OC(C)(C)C)=CC=C1NC(=O)C1C(C)(C)C1(C)C ZECMDFWXHVHCFO-UHFFFAOYSA-N 0.000 description 1
- XURFWVWKWXAFOM-UHFFFAOYSA-N tert-butyl n-[[6-(aminomethyl)pyridin-3-yl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=C(CN)N=C1 XURFWVWKWXAFOM-UHFFFAOYSA-N 0.000 description 1
- LPDDROMUEKWJKX-UHFFFAOYSA-N tert-butyl n-[[6-(piperidin-1-ylmethyl)pyridin-3-yl]methyl]carbamate Chemical compound N1=CC(CNC(=O)OC(C)(C)C)=CC=C1CN1CCCCC1 LPDDROMUEKWJKX-UHFFFAOYSA-N 0.000 description 1
- YFHIBQUEYWTQQR-PKNBQFBNSA-N tert-butyl n-[[6-[(e)-2-cyclohexylethenyl]pyridin-3-yl]methyl]carbamate Chemical compound N1=CC(CNC(=O)OC(C)(C)C)=CC=C1\C=C\C1CCCCC1 YFHIBQUEYWTQQR-PKNBQFBNSA-N 0.000 description 1
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 1
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000006250 trifluoro ethyl amino group Chemical group [H]N(*)C([H])([H])C(F)(F)F 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- 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
-
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| US60/731,081 | 2005-10-28 | ||
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| WO2007028132A2 (en) * | 2005-09-01 | 2007-03-08 | Eli Lilly And Company | 6-N-LINKED HETEROCYCLE-SUBSTITUTED 2,3,4,5-TETRAHYDRO-1H-BENZO[d]AZEPINES AS 5-HT2C RECEPTOR AGONISTS |
| EP2727585A1 (en) | 2006-05-16 | 2014-05-07 | Takeda Pharmaceutical Company Limited | In-vivo screening method |
| WO2007140213A1 (en) | 2006-05-26 | 2007-12-06 | Forest Laboratories Holdings Limited | Pyridoazepine derivatives |
| US20100266504A1 (en) | 2007-11-15 | 2010-10-21 | Takahiro Matsumoto | Condensed pyridine derivative and use thereof |
| JP5216912B2 (ja) | 2008-04-29 | 2013-06-19 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ccr1受容体拮抗薬としてのインダゾール化合物 |
| EP2297112B1 (en) | 2008-05-06 | 2013-04-03 | Boehringer Ingelheim International GmbH | Pyrazole compounds as ccr1 antagonists |
| MX2011002951A (es) | 2008-09-26 | 2011-04-26 | Boehringer Ingelheim Int | Compuestos de azaindazol como antagonistas del receptor de ccr1. |
| MX2012004644A (es) | 2009-10-21 | 2012-05-08 | Boehringer Ingelheim Int | Compuestos de indazol y pirazolopiridina como antagonistas del receptor de ccr1. |
| WO2011056440A1 (en) | 2009-10-27 | 2011-05-12 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds as ccr1 receptor antagonists |
| JP2013512954A (ja) * | 2009-12-08 | 2013-04-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 置換インダゾール及びアザインダゾール化合物の生成に有効な中間体の合成方法 |
| WO2011137109A1 (en) | 2010-04-30 | 2011-11-03 | Boehringer Ingelheim International Gmbh | Azaindazole amide compounds as ccr1 receptor antagonists |
| 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 |
| EP2655371B1 (en) | 2010-12-23 | 2015-02-25 | Boehringer Ingelheim International GmbH | Pyrazolopiperidine compounds as ccr1 receptor antagonists |
| JP6440625B2 (ja) | 2012-11-14 | 2018-12-19 | ザ・ジョンズ・ホプキンス・ユニバーシティー | 精神分裂病を処置するための方法および組成物 |
| WO2015066344A1 (en) | 2013-11-01 | 2015-05-07 | Arena Pharmaceuticals, Inc. | 5-ht2c receptor agonists and compositions and methods of use |
| SG11201610975RA (en) * | 2014-07-03 | 2017-01-27 | Celgene Quanticel Res Inc | Inhibitors of lysine specific demethylase-1 |
| CN105622511B (zh) * | 2014-11-03 | 2018-01-23 | 北京瑞都医药科技有限公司 | 一种减肥药物及其制备方法 |
| CN109071440A (zh) * | 2016-05-13 | 2018-12-21 | 日产化学株式会社 | 2-乙酰基吡啶化合物的制造方法 |
| US20210052600A1 (en) | 2017-12-27 | 2021-02-25 | Takeda Pharmaceutical Company Limited | Therapeutic agents for stress urinary incontinence and incotinence of feces |
| AU2020416203A1 (en) * | 2020-01-03 | 2022-06-16 | Blue Oak Pharmaceuticals, Inc. | Compounds and compositions for treating CNS disorders |
| CN114163426B (zh) * | 2020-09-10 | 2024-03-19 | 上海爱博医药科技有限公司 | 苯并含氧杂环类化合物及其医药应用 |
| GB202101734D0 (en) | 2021-02-08 | 2021-03-24 | Cerevance Inc | Novel Compounds |
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| WO2005082859A1 (en) * | 2004-02-25 | 2005-09-09 | Eli Lilly And Company | 6-substituted 2,3,4,5-tetrahydro-1h-benzo[d]azepines as 5-ht2c receptor agonists |
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| US4265890A (en) * | 1978-07-07 | 1981-05-05 | Smithkline Corporation | 6-Phenyl thio- and 6-cyclohexyl thio-2,3,4,5-tetrahydro-1H-3-benzazepines |
| US5023252A (en) | 1985-12-04 | 1991-06-11 | Conrex Pharmaceutical Corporation | Transdermal and trans-membrane delivery of drugs |
| EP0285287A3 (en) | 1987-03-23 | 1990-08-16 | Smithkline Beecham Corporation | 3-benzazepine compounds for use in treating gastrointestinal motility disorders |
| US4985352A (en) * | 1988-02-29 | 1991-01-15 | The Trustees Of Columbia University In The City Of New York | DNA encoding serotonin 1C (5HT1c) receptor, isolated 5HT1c receptor, mammalian cells expressing same and uses thereof |
| US5011472A (en) | 1988-09-06 | 1991-04-30 | Brown University Research Foundation | Implantable delivery system for biological factors |
| GB9116824D0 (en) | 1991-08-05 | 1991-09-18 | Smithkline Beecham Corp | Chemical compounds |
| US5639748A (en) * | 1991-08-05 | 1997-06-17 | Smithkline Beecham Corporation | 6,9-disubstituted benzazepines having α-adrenoceptor blocking activity |
| WO1993004866A1 (fr) | 1991-09-11 | 1993-03-18 | Canon Kabushiki Kaisha | Element de nettoyage ameliore pour tete de jet d'encre et dispositif a jet d'encre equipe d'un tel element de nettoyage |
| GB9119467D0 (en) | 1991-09-12 | 1991-10-23 | Smithkline Beecham Corp | Chemical compounds |
| US5698766A (en) * | 1995-04-05 | 1997-12-16 | The Regents Of The University Of California | Transgenic animal model for testing drugs for treating eating disorders and epilepsy |
| EP1213017A3 (en) | 2000-12-05 | 2003-11-12 | Akzo Nobel N.V. | Use of a 5-HT2C receptor agonist for the treatment of hot flushes |
| JPWO2002074746A1 (ja) * | 2001-03-16 | 2004-07-08 | 山之内製薬株式会社 | ベンゾアゼピン誘導体 |
| DE60206762T2 (de) | 2001-07-13 | 2006-07-13 | Pharmacia & Upjohn Co. Llc, Kalamazoo | Hexahydroazepino(4,5-g)indole und -indoline als 5-ht rezeptor-liganden |
| CA2468010A1 (en) | 2001-11-28 | 2003-06-05 | Pharmacia & Upjohn Company | Benzazepine derivatives and their use as 5-ht ligands |
| US6953787B2 (en) | 2002-04-12 | 2005-10-11 | Arena Pharmaceuticals, Inc. | 5HT2C receptor modulators |
| JP4782003B2 (ja) | 2003-06-17 | 2011-09-28 | アリーナ ファーマシューティカルズ, インコーポレイテッド | 5ht2cレセプター関連疾患の処置に有用なベンズアゼピン誘導体 |
| DK2332921T3 (en) | 2003-06-17 | 2016-05-09 | Arena Pharm Inc | 8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3benzazepine hydrochloride |
| TW200510324A (en) | 2003-08-11 | 2005-03-16 | Lilly Co Eli | 6-(2,2,2-trifluoroethylamino)-7-chiloro-2, 3, 4, 5-tetrahydro-1h-benzo[d]azepine as a 5-ht2c receptor agonist |
| US20070275949A1 (en) | 2003-10-22 | 2007-11-29 | Arena Pharmaceuticals, Inc. | Benzazepine Derivatives and Methods of Prophylaxis or Treatment of 5Ht2C Receptor Associated Diseases |
| WO2005042491A1 (en) * | 2003-10-22 | 2005-05-12 | Arena Pharmaceuticals, Inc. | Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases |
| RS50996B (sr) | 2004-12-21 | 2010-10-31 | Arena Pharmaceuticals Inc. | Kristalni oblici (r)-8-hloro-1-metil-2,3,4,5-tetrahidro-1h-benzazepin hlorhidrat |
| KR101519441B1 (ko) | 2004-12-23 | 2015-05-12 | 아레나 파마슈티칼스, 인크. | 5ht2c 수용체 조정물질 조성물 및 그의 사용 방법 |
| BRPI0615033A2 (pt) * | 2005-09-01 | 2011-04-26 | Lilly Co Eli | composto, composição farmacêutica, e, uso de um composto |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005082859A1 (en) * | 2004-02-25 | 2005-09-09 | Eli Lilly And Company | 6-substituted 2,3,4,5-tetrahydro-1h-benzo[d]azepines as 5-ht2c receptor agonists |
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| AU2006287202A8 (en) | 2008-03-13 |
| JP5155864B2 (ja) | 2013-03-06 |
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| AU2006287202A1 (en) | 2007-03-08 |
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| PT1924561E (pt) | 2013-01-16 |
| US20080269196A1 (en) | 2008-10-30 |
| WO2007028083A2 (en) | 2007-03-08 |
| EP1924561A2 (en) | 2008-05-28 |
| ES2397400T3 (es) | 2013-03-06 |
| BRPI0615048A2 (pt) | 2010-03-30 |
| CA2619448C (en) | 2013-08-13 |
| EP1924561B1 (en) | 2012-11-14 |
| CN101258131A (zh) | 2008-09-03 |
| DK1924561T3 (da) | 2012-12-10 |
| SI1924561T1 (sl) | 2013-02-28 |
| WO2007028083A3 (en) | 2007-05-18 |
| US20110269745A1 (en) | 2011-11-03 |
| CN101258131B (zh) | 2013-07-24 |
| JP2009507034A (ja) | 2009-02-19 |
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Free format text: IN VOL 22, NO 8, PAGE(S) 865 UNDER THE HEADING PCT APPLICATIONS THAT HAVE ENTERED THE NATIONAL PHASE -NAME INDEX UNDER THE NAME ELI LILLY AND COMPANY, APPLICATION NO. 2006287202, UNDER INID (54), CORRECT THE TITLE TO 6-ARYLALKYLAMINO2,3,4,5-TETRAHYDRO-1H-BENZO¢D!AZEPINES AS 5-HT2C RECEPTOR AGONISTS. |
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