NO330118B1 - Nye forbindelser, farmasoytisk sammensetning, anvendelse - Google Patents
Nye forbindelser, farmasoytisk sammensetning, anvendelse Download PDFInfo
- Publication number
- NO330118B1 NO330118B1 NO20045659A NO20045659A NO330118B1 NO 330118 B1 NO330118 B1 NO 330118B1 NO 20045659 A NO20045659 A NO 20045659A NO 20045659 A NO20045659 A NO 20045659A NO 330118 B1 NO330118 B1 NO 330118B1
- Authority
- NO
- Norway
- Prior art keywords
- tetrahydro
- methoxy
- benzazepine
- alkyl
- methyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 217
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- -1 hydroxyC1-6alkyl Chemical group 0.000 claims abstract description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 46
- 239000001257 hydrogen Substances 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 31
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 27
- 239000012453 solvate Substances 0.000 claims abstract description 24
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 23
- 150000002367 halogens Chemical group 0.000 claims abstract description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 18
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000001301 oxygen Substances 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 8
- 125000004429 atom Chemical group 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 7
- 208000028017 Psychotic disease Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 5
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 5
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 230000036506 anxiety Effects 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 208000010877 cognitive disease Diseases 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 201000009032 substance abuse Diseases 0.000 claims description 4
- 231100000736 substance abuse Toxicity 0.000 claims description 4
- 208000011117 substance-related disease Diseases 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- COCPXRGCLUOMPQ-UHFFFAOYSA-N 4-[(8-methoxy-3-methyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)sulfonyl]-n-[(2-methoxyphenyl)methyl]aniline Chemical compound COC1=CC=CC=C1CNC1=CC=C(S(=O)(=O)C=2C(=CC=3CCN(C)CCC=3C=2)OC)C=C1 COCPXRGCLUOMPQ-UHFFFAOYSA-N 0.000 claims description 3
- KJDKDTRDWXCQBE-UHFFFAOYSA-N 6-ethoxy-7-[4-[(4-fluorophenyl)methoxy]phenyl]sulfonyl-1,2,3,4-tetrahydroisoquinoline;hydrochloride Chemical compound Cl.CCOC1=CC=2CCNCC=2C=C1S(=O)(=O)C(C=C1)=CC=C1OCC1=CC=C(F)C=C1 KJDKDTRDWXCQBE-UHFFFAOYSA-N 0.000 claims description 3
- SVXRQILAKMZNDQ-UHFFFAOYSA-N 7-[4-[(4-chlorophenoxy)methyl]phenyl]sulfonyl-8-ethoxy-3-methyl-1,2,4,5-tetrahydro-3-benzazepine Chemical compound CCOC1=CC=2CCN(C)CCC=2C=C1S(=O)(=O)C(C=C1)=CC=C1COC1=CC=C(Cl)C=C1 SVXRQILAKMZNDQ-UHFFFAOYSA-N 0.000 claims description 3
- SEKXUECQSDMHON-UHFFFAOYSA-N 7-[4-[(4-fluorophenoxy)methyl]phenyl]sulfonyl-n,n,3-trimethyl-1,2,4,5-tetrahydro-3-benzazepin-8-amine Chemical compound CN(C)C1=CC=2CCN(C)CCC=2C=C1S(=O)(=O)C(C=C1)=CC=C1COC1=CC=C(F)C=C1 SEKXUECQSDMHON-UHFFFAOYSA-N 0.000 claims description 3
- 208000028698 Cognitive impairment Diseases 0.000 claims description 3
- 108050004812 Dopamine receptor Proteins 0.000 claims description 3
- 102000015554 Dopamine receptor Human genes 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000000142 dyskinetic effect Effects 0.000 claims description 3
- JBVJZWOTVDROBX-UHFFFAOYSA-N n-[[4-[(8-ethoxy-3-methyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)sulfonyl]phenyl]methyl]-2-methoxyaniline Chemical compound CCOC1=CC=2CCN(C)CCC=2C=C1S(=O)(=O)C(C=C1)=CC=C1CNC1=CC=CC=C1OC JBVJZWOTVDROBX-UHFFFAOYSA-N 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 2
- YRIMOYWLZQPOEE-UHFFFAOYSA-N 4-[(8-methoxy-3-methyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)sulfonyl]-n-phenylaniline Chemical compound COC1=CC=2CCN(C)CCC=2C=C1S(=O)(=O)C(C=C1)=CC=C1NC1=CC=CC=C1 YRIMOYWLZQPOEE-UHFFFAOYSA-N 0.000 claims description 2
- TWLOBNIIGJZSCO-UHFFFAOYSA-N 5-methoxy-2-methyl-6-[4-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]sulfonyl-1,3-dihydroisoindole Chemical compound COC1=CC=2CN(C)CC=2C=C1S(=O)(=O)C(C=C1)=CC=C1OCC1=CC=CC(C(F)(F)F)=C1 TWLOBNIIGJZSCO-UHFFFAOYSA-N 0.000 claims description 2
- GBFLXYISFPKKBT-UHFFFAOYSA-N 7-(3-phenylmethoxyphenyl)sulfonyl-2,3,4,5-tetrahydro-1h-3-benzazepine Chemical compound C=1C=C2CCNCCC2=CC=1S(=O)(=O)C(C=1)=CC=CC=1OCC1=CC=CC=C1 GBFLXYISFPKKBT-UHFFFAOYSA-N 0.000 claims description 2
- BRSYMTIKEANUDA-UHFFFAOYSA-N 7-[4-[(3-fluorophenyl)methoxy]phenyl]sulfonyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline Chemical compound COC1=CC=2CCNCC=2C=C1S(=O)(=O)C(C=C1)=CC=C1OCC1=CC=CC(F)=C1 BRSYMTIKEANUDA-UHFFFAOYSA-N 0.000 claims description 2
- GHQFJSFJVANWBE-UHFFFAOYSA-N 7-[4-[(4-chlorophenoxy)methyl]phenyl]sulfonyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline;hydrochloride Chemical compound Cl.COC1=CC=2CCNCC=2C=C1S(=O)(=O)C(C=C1)=CC=C1COC1=CC=C(Cl)C=C1 GHQFJSFJVANWBE-UHFFFAOYSA-N 0.000 claims description 2
- HIBWHHQXUSKNOV-UHFFFAOYSA-N 7-[4-[(4-chlorophenyl)methoxy]phenyl]sulfonyl-8-methoxy-3-methyl-1,2,4,5-tetrahydro-3-benzazepine Chemical compound COC1=CC=2CCN(C)CCC=2C=C1S(=O)(=O)C(C=C1)=CC=C1OCC1=CC=C(Cl)C=C1 HIBWHHQXUSKNOV-UHFFFAOYSA-N 0.000 claims description 2
- QXSWMHVVVHYBMA-UHFFFAOYSA-N 7-[4-[(4-fluorophenyl)methyl]phenyl]sulfonyl-8-methoxy-3-methyl-1,2,4,5-tetrahydro-3-benzazepine Chemical compound COC1=CC=2CCN(C)CCC=2C=C1S(=O)(=O)C(C=C1)=CC=C1CC1=CC=C(F)C=C1 QXSWMHVVVHYBMA-UHFFFAOYSA-N 0.000 claims description 2
- ZYFKSYKCFFNTMF-UHFFFAOYSA-N 8-methoxy-3-methyl-7-(3-phenoxyphenyl)sulfonyl-1,2,4,5-tetrahydro-3-benzazepine Chemical compound COC1=CC=2CCN(C)CCC=2C=C1S(=O)(=O)C(C=1)=CC=CC=1OC1=CC=CC=C1 ZYFKSYKCFFNTMF-UHFFFAOYSA-N 0.000 claims description 2
- GJMUNWIPYJCMGG-UHFFFAOYSA-N 8-methoxy-7-(3-phenoxyphenyl)sulfonyl-2,3,4,5-tetrahydro-1h-3-benzazepine Chemical group COC1=CC=2CCNCCC=2C=C1S(=O)(=O)C(C=1)=CC=CC=1OC1=CC=CC=C1 GJMUNWIPYJCMGG-UHFFFAOYSA-N 0.000 claims description 2
- 208000020925 Bipolar disease Diseases 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- AKULVMIPWCHBEF-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-4-[(8-methoxy-3-methyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)sulfonyl]aniline Chemical compound COC1=CC=2CCN(C)CCC=2C=C1S(=O)(=O)C(C=C1)=CC=C1NCC1=CC=C(F)C=C1 AKULVMIPWCHBEF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- AORPHQUMVNMHPO-UHFFFAOYSA-N n-[(3-methoxyphenyl)methyl]-4-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)sulfonyl]-n-methylaniline Chemical compound COC1=CC=CC(CN(C)C=2C=CC(=CC=2)S(=O)(=O)C=2C(=CC=3CCNCC=3C=2)OC)=C1 AORPHQUMVNMHPO-UHFFFAOYSA-N 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 7
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 7
- 239000000164 antipsychotic agent Substances 0.000 abstract description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract 1
- 229940005529 antipsychotics Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 163
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 127
- 239000000203 mixture Substances 0.000 description 119
- 239000000243 solution Substances 0.000 description 106
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 105
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 91
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 76
- 238000000034 method Methods 0.000 description 64
- 238000005481 NMR spectroscopy Methods 0.000 description 63
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 50
- 235000019439 ethyl acetate Nutrition 0.000 description 45
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- 239000007787 solid Substances 0.000 description 42
- 239000000047 product Substances 0.000 description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- 239000012044 organic layer Substances 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- 238000004587 chromatography analysis Methods 0.000 description 29
- 239000000377 silicon dioxide Substances 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 239000012267 brine Substances 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- 239000002585 base Substances 0.000 description 23
- 239000003921 oil Substances 0.000 description 23
- 235000019198 oils Nutrition 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 150000003840 hydrochlorides Chemical class 0.000 description 21
- 238000001816 cooling Methods 0.000 description 17
- 229910000104 sodium hydride Inorganic materials 0.000 description 17
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 16
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 16
- 229910052731 fluorine Inorganic materials 0.000 description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
- 239000012312 sodium hydride Substances 0.000 description 16
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 15
- 229910052801 chlorine Inorganic materials 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 13
- 239000011737 fluorine Substances 0.000 description 13
- 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 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 102000005962 receptors Human genes 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 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
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 11
- 239000012442 inert solvent Substances 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- 238000006722 reduction reaction Methods 0.000 description 10
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 10
- NNLXSIBXDYFUBV-UHFFFAOYSA-N 3-(2,2,2-trifluoroacetyl)-1,2,4,5-tetrahydro-3-benzazepine-7-sulfonyl fluoride Chemical compound C1CN(C(=O)C(F)(F)F)CCC2=CC=C(S(F)(=O)=O)C=C21 NNLXSIBXDYFUBV-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 101100516568 Caenorhabditis elegans nhr-7 gene Proteins 0.000 description 7
- 230000010933 acylation Effects 0.000 description 7
- 238000005917 acylation reaction Methods 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 239000012458 free base Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 238000006485 reductive methylation reaction Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 238000007429 general method Methods 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 239000011698 potassium fluoride Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
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- LYTRBXBDPVDQNA-UHFFFAOYSA-N tert-butyl 8-amino-7-iodo-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC2=CC(N)=C(I)C=C21 LYTRBXBDPVDQNA-UHFFFAOYSA-N 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- LPJUOKRIDZMQSB-UHFFFAOYSA-N tert-butyl-dimethyl-[3-(2,3,4,5-tetrahydro-1h-3-benzazepin-7-ylsulfonyl)phenoxy]silane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(S(=O)(=O)C=2C=C3CCNCCC3=CC=2)=C1 LPJUOKRIDZMQSB-UHFFFAOYSA-N 0.000 description 1
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- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- 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
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- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
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- C07—ORGANIC CHEMISTRY
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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GB0230053A GB0230053D0 (en) | 2002-12-23 | 2002-12-23 | Compounds |
PCT/EP2003/005727 WO2003099786A2 (en) | 2002-05-29 | 2003-05-28 | Aromatic sulfones and their medical use |
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NO20045659L NO20045659L (no) | 2004-12-27 |
NO330118B1 true NO330118B1 (no) | 2011-02-21 |
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JP (1) | JP4268126B2 (ja) |
KR (1) | KR20050013196A (ja) |
AR (1) | AR040126A1 (ja) |
AT (1) | ATE354566T1 (ja) |
AU (1) | AU2003232846B9 (ja) |
BR (1) | BR0311315A (ja) |
CA (1) | CA2486962A1 (ja) |
CY (1) | CY1107053T1 (ja) |
DE (1) | DE60311986T2 (ja) |
DK (1) | DK1511727T3 (ja) |
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IL (1) | IL165330A0 (ja) |
IS (1) | IS2482B (ja) |
MX (1) | MXPA04011945A (ja) |
MY (1) | MY133587A (ja) |
NO (1) | NO330118B1 (ja) |
NZ (1) | NZ536694A (ja) |
PL (1) | PL374081A1 (ja) |
PT (1) | PT1511727E (ja) |
RU (1) | RU2327690C2 (ja) |
SI (1) | SI1511727T1 (ja) |
TW (1) | TWI281914B (ja) |
WO (1) | WO2003099786A2 (ja) |
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TWI281914B (en) | 2002-05-29 | 2007-06-01 | Glaxo Group Ltd | Compounds |
US7217732B2 (en) * | 2002-06-19 | 2007-05-15 | Schering Corporation | Cannabinoid receptor agonists |
GB0319235D0 (en) * | 2003-08-15 | 2003-09-17 | Glaxo Group Ltd | Novel compounds |
GB0327737D0 (en) * | 2003-11-28 | 2003-12-31 | Glaxo Group Ltd | Novel compounds |
GB0327738D0 (en) * | 2003-11-28 | 2003-12-31 | Glaxo Group Ltd | Novel compound |
GB0327741D0 (en) * | 2003-11-28 | 2003-12-31 | Glaxo Group Ltd | Novel compounds |
GB0327740D0 (en) * | 2003-11-28 | 2003-12-31 | Glaxo Group Ltd | Novel compounds |
GB0505437D0 (en) * | 2005-03-17 | 2005-04-20 | Merck Sharp & Dohme | Therapeutic agents |
GB0505725D0 (en) * | 2005-03-19 | 2005-04-27 | Merck Sharp & Dohme | Therapeutic agents |
JP5415067B2 (ja) * | 2005-03-31 | 2014-02-12 | アミリン・ファーマシューティカルズ,リミテッド・ライアビリティ・カンパニー | 肥満および摂食障害の制御、防止および治療のための組成物および方法 |
GB0510599D0 (en) * | 2005-05-24 | 2005-06-29 | Glaxo Group Ltd | Novel compounds |
GB0603087D0 (en) * | 2006-02-15 | 2006-03-29 | Glaxo Group Ltd | Novel use |
US20070293475A1 (en) * | 2006-06-20 | 2007-12-20 | Alcon Manufacturing Ltd. | Aryl and heteroaryl tetrahydrobenzazepine derivatives and their use for treating glaucoma |
ES2705101T3 (es) * | 2008-11-06 | 2019-03-21 | Ventirx Pharmaceuticals Inc | Métodos de síntesis de derivados de benzazepinas |
CA2970502A1 (en) * | 2014-12-12 | 2016-06-16 | The Schepens Eye Research Institute, Inc. | Gdnf induction for the treatment of retinal disorders |
US11124497B1 (en) | 2020-04-17 | 2021-09-21 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
US11174231B1 (en) | 2020-06-09 | 2021-11-16 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
US11351149B2 (en) | 2020-09-03 | 2022-06-07 | Pfizer Inc. | Nitrile-containing antiviral compounds |
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JPH01503233A (ja) | 1986-10-28 | 1989-11-02 | スミス・クライン・アンド・フレンチ・ラボラトリース・リミテッド | 製薬活性化合物 |
DE3869446D1 (de) * | 1987-03-10 | 1992-04-30 | Lion Corp | Desodorierungsmittel. |
EP0285287A3 (en) | 1987-03-23 | 1990-08-16 | Smithkline Beecham Corporation | 3-benzazepine compounds for use in treating gastrointestinal motility disorders |
GB8717374D0 (en) | 1987-07-22 | 1987-08-26 | Smith Kline French Lab | Pharmaceutically active compounds |
US5032604A (en) | 1989-12-08 | 1991-07-16 | Merck & Co., Inc. | Class III antiarrhythmic agents |
GB9127041D0 (en) | 1991-12-20 | 1992-02-19 | Fujisawa Pharmaceutical Co | New use |
GB9212308D0 (en) | 1992-06-10 | 1992-07-22 | Ici Plc | Therapeutic compositions |
US5707987A (en) | 1994-02-25 | 1998-01-13 | Banyu Pharmaceutical Co., Ltd. | Carbapenem derivatives |
US5684195A (en) | 1994-07-14 | 1997-11-04 | G. D. Searle & Co. | Method of preparing sulfmonamides from sulfones |
ATE288444T1 (de) | 1995-05-29 | 2005-02-15 | Pfizer | Dipeptide, die die ausschüttung von wachstumshormonen stimulieren |
DE19548785A1 (de) | 1995-12-27 | 1997-07-03 | Basf Ag | Saure Polyazofarbstoffe |
US6046210A (en) | 1996-05-11 | 2000-04-04 | Smithkline Beecham P.L.C. | Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors |
ES2154470T3 (es) | 1996-08-14 | 2001-04-01 | Smithkline Beecham Plc | Derivados de tetrahidroisoquinolina y su uso farmaceutico. |
DE19638486A1 (de) | 1996-09-20 | 1998-03-26 | Basf Ag | Hetaroylderivate |
DE19638484A1 (de) | 1996-09-20 | 1998-03-26 | Basf Ag | Hetaroylderivate |
EP0986540B1 (en) | 1997-04-22 | 2005-02-16 | Euro-Celtique S.A. | The use of carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones as sodium channel blockers |
GB9708805D0 (en) | 1997-05-01 | 1997-06-25 | Smithkline Beecham Plc | Compounds |
EP0937723A1 (de) | 1998-02-18 | 1999-08-25 | Roche Diagnostics GmbH | Neue Sulfonamide, Verfahren zu ihrer Herstellung sowie diese enthaltende Arzneimittel |
GB9804734D0 (en) | 1998-03-05 | 1998-04-29 | Pfizer Ltd | Compounds |
US6344486B1 (en) | 1998-04-03 | 2002-02-05 | 3-Dimensional Pharmaceuticals, Inc. | Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors |
WO2000021959A1 (en) | 1998-10-09 | 2000-04-20 | Janssen Pharmaceutica N.V. | 4,5-dihydro-isoxazole derivatives and their pharmaceutical use |
AR022229A1 (es) | 1999-01-12 | 2002-09-04 | Abbott Gmbh & Co Kg | Compuestos de triazol, composicion farmaceutica que los comprende y uso de los mismos para preparar dicha composicion |
CN1349498A (zh) | 1999-03-03 | 2002-05-15 | 宝洁公司 | 含有链烯基和炔基的金属蛋白酶抑制剂 |
EP1183235A2 (en) | 1999-05-24 | 2002-03-06 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
US6531478B2 (en) | 2000-02-24 | 2003-03-11 | Cheryl P. Kordik | Amino pyrazole derivatives useful for the treatment of obesity and other disorders |
AU2001259592B2 (en) | 2000-05-11 | 2005-02-24 | Bristol-Myers Squibb Co. | Tetrahydroisoquinoline analogs useful as growth hormone secretagogues |
US6416458B1 (en) * | 2000-07-12 | 2002-07-09 | Therion Research Inc. | Therapeutic flexible magnetic sheet and method |
WO2002021951A1 (en) | 2000-09-14 | 2002-03-21 | Edmund Gene Butts | Curling garment brush retainer |
DE10053799A1 (de) | 2000-10-30 | 2002-05-08 | Bayer Ag | Verwendung von Tetrahydroisochinolinsulfonamiden |
US7429579B2 (en) * | 2000-11-14 | 2008-09-30 | Smithkline Beecham, Plc | Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents) |
WO2002046164A1 (en) | 2000-12-07 | 2002-06-13 | Astrazeneca Ab | Therapeutic compounds |
GB0111186D0 (en) | 2001-05-08 | 2001-06-27 | Smithkline Beecham Plc | Novel compounds |
EP1456178A1 (en) | 2001-12-21 | 2004-09-15 | Smithkline Beecham Plc | 7-sulfonyl-3-benzazepine derivatives as modulators of the dopamine receptor and their use for the treatment of cns disorders |
TW200306843A (en) | 2002-02-13 | 2003-12-01 | Glaxo Group Ltd | Novel compounds |
AU2003218660A1 (en) | 2002-02-13 | 2003-09-04 | Glaxo Group Limited | Benzenesulfonamide derivatives and their use as dopamine d3 and d2 receptor liga ds |
BR0307557A (pt) | 2002-02-13 | 2005-01-04 | Glaxo Group Ltd | Derivados benzenosulfonamida como agentes antipsicóticos |
GB0210762D0 (en) | 2002-05-10 | 2002-06-19 | Glaxo Group Ltd | Compounds |
GB0212399D0 (en) | 2002-05-29 | 2002-07-10 | Glaxo Group Ltd | Compounds |
TWI281914B (en) | 2002-05-29 | 2007-06-01 | Glaxo Group Ltd | Compounds |
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- 2003-05-28 BR BR0311315-9A patent/BR0311315A/pt not_active Application Discontinuation
- 2003-05-28 RU RU2004138588/04A patent/RU2327690C2/ru not_active IP Right Cessation
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- 2003-05-28 SI SI200330757T patent/SI1511727T1/sl unknown
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- 2003-05-28 CA CA002486962A patent/CA2486962A1/en not_active Abandoned
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- 2003-05-28 WO PCT/EP2003/005727 patent/WO2003099786A2/en active IP Right Grant
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