NZ243326A - Benzodiazepine, benzazepine; benzothiazepine and benzoxazepine derivatives; pharmaceutical compositions - Google Patents

Info

Publication number

NZ243326A

NZ243326A NZ243326A NZ24332692A NZ243326A NZ 243326 A NZ243326 A NZ 243326A NZ 243326 A NZ243326 A NZ 243326A NZ 24332692 A NZ24332692 A NZ 24332692A NZ 243326 A NZ243326 A NZ 243326A

Authority

NZ

New Zealand

Prior art keywords

amino

oxo

tetrahydro

mmol

phenyl

Prior art date

1991-06-28

Links

• Espacenet
• Global Dossier
• Discuss

• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
• 229940049706 benzodiazepine Drugs 0.000 title claims description 14
• DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 title description 2
• SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 title description 2
• FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical compound S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 title 1
• ZCXLTWVZYXBHJS-UHFFFAOYSA-N 1,2-benzoxazepine Chemical class O1N=CC=CC2=CC=CC=C12 ZCXLTWVZYXBHJS-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 330
• 125000001424 substituent group Chemical group 0.000 claims abstract description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
• 208000010110 spontaneous platelet aggregation Diseases 0.000 claims abstract description 15
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 13
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 12
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 12
• 229920006395 saturated elastomer Polymers 0.000 claims abstract description 11
• 150000003839 salts Chemical class 0.000 claims abstract description 8
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 6
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 5
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 112
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 102
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 90
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 64
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
• -1 5-tetrazolyl Chemical group 0.000 claims description 57
• 229910052739 hydrogen Inorganic materials 0.000 claims description 18
• 150000001413 amino acids Chemical class 0.000 claims description 16
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
• 125000003118 aryl group Chemical group 0.000 claims description 12
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 10
• 239000003814 drug Substances 0.000 claims description 8
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 230000005764 inhibitory process Effects 0.000 claims description 6
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 5
• 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 5
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 125000002950 monocyclic group Chemical group 0.000 claims description 4
• 125000001624 naphthyl group Chemical group 0.000 claims description 4
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 3
• 125000005843 halogen group Chemical group 0.000 claims description 3
• 208000028867 ischemia Diseases 0.000 claims description 3
• 125000006362 methylene amino carbonyl group Chemical group [H]N(C([*:2])=O)C([H])([H])[*:1] 0.000 claims description 3
• 208000010125 myocardial infarction Diseases 0.000 claims description 3
• 230000001052 transient effect Effects 0.000 claims description 3
• 125000000304 alkynyl group Chemical group 0.000 claims description 2
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
• 125000006360 carbonyl amino methylene group Chemical group [H]N(C([*:1])=O)C([H])([H])[*:2] 0.000 claims description 2
• ZDGGJQMSELMHLK-UHFFFAOYSA-N m-Trifluoromethylhippuric acid Chemical compound OC(=O)CNC(=O)C1=CC=CC(C(F)(F)F)=C1 ZDGGJQMSELMHLK-UHFFFAOYSA-N 0.000 claims description 2
• 230000004048 modification Effects 0.000 claims description 2
• 238000012986 modification Methods 0.000 claims description 2
• 235000019260 propionic acid Nutrition 0.000 claims description 2
• 238000000034 method Methods 0.000 abstract description 40
• 230000002401 inhibitory effect Effects 0.000 abstract description 7
• 230000000694 effects Effects 0.000 abstract description 6
• 230000002378 acidificating effect Effects 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 355
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 292
• 239000000243 solution Substances 0.000 description 180
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 175
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 158
• 239000000203 mixture Substances 0.000 description 155
• 235000019439 ethyl acetate Nutrition 0.000 description 142
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 114
• 229910001868 water Inorganic materials 0.000 description 106
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 95
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 85
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 82
• 239000007787 solid Substances 0.000 description 82
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• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
• 239000000741 silica gel Substances 0.000 description 70
• 229910002027 silica gel Inorganic materials 0.000 description 70
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 69
• 238000006243 chemical reaction Methods 0.000 description 66
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 64
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 59
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 52
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 49
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
• 239000000047 product Substances 0.000 description 43
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 42
• 238000002360 preparation method Methods 0.000 description 40
• 229960000583 acetic acid Drugs 0.000 description 37
• 239000000706 filtrate Substances 0.000 description 37
• 238000004809 thin layer chromatography Methods 0.000 description 37
• 238000005481 NMR spectroscopy Methods 0.000 description 36
• 239000002904 solvent Substances 0.000 description 36
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 34
• 238000003818 flash chromatography Methods 0.000 description 34
• 239000011541 reaction mixture Substances 0.000 description 33
• 229910052786 argon Inorganic materials 0.000 description 32
• 239000003054 catalyst Substances 0.000 description 32
• 108090000765 processed proteins & peptides Proteins 0.000 description 32
• 230000002829 reductive effect Effects 0.000 description 31
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
• 238000003756 stirring Methods 0.000 description 28
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 26
• 238000010992 reflux Methods 0.000 description 25
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
• 239000012267 brine Substances 0.000 description 23
• 238000001914 filtration Methods 0.000 description 23
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
• 239000002253 acid Substances 0.000 description 21
• 238000001704 evaporation Methods 0.000 description 21
• 230000008020 evaporation Effects 0.000 description 21
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
• 239000003921 oil Substances 0.000 description 20
• 235000019198 oils Nutrition 0.000 description 20
• 239000000284 extract Substances 0.000 description 19
• 238000004128 high performance liquid chromatography Methods 0.000 description 19
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 19
• 101001068640 Nicotiana tabacum Basic form of pathogenesis-related protein 1 Proteins 0.000 description 18
• 229940024606 amino acid Drugs 0.000 description 17
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
• 239000003527 fibrinolytic agent Substances 0.000 description 16
• 239000001257 hydrogen Substances 0.000 description 16
• 239000000463 material Substances 0.000 description 16
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• 238000000746 purification Methods 0.000 description 16
• 239000000725 suspension Substances 0.000 description 16
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
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• BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 14
• 239000003153 chemical reaction reagent Substances 0.000 description 14
• 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 14
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
• 239000005457 ice water Substances 0.000 description 13
• 238000005160 1H NMR spectroscopy Methods 0.000 description 12
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 12
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 12
• 229910052938 sodium sulfate Inorganic materials 0.000 description 12
• 235000011152 sodium sulphate Nutrition 0.000 description 12
• 238000001035 drying Methods 0.000 description 11
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 10
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 10
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• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
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• 229960000187 tissue plasminogen activator Drugs 0.000 description 9
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
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