CA1199915A - Carbostyril derivatives, process for producing the same and cardiotonic compositions containing the same - Google Patents
Carbostyril derivatives, process for producing the same and cardiotonic compositions containing the sameInfo
- Publication number
- CA1199915A CA1199915A CA000396327A CA396327A CA1199915A CA 1199915 A CA1199915 A CA 1199915A CA 000396327 A CA000396327 A CA 000396327A CA 396327 A CA396327 A CA 396327A CA 1199915 A CA1199915 A CA 1199915A
- Authority
- CA
- Canada
- Prior art keywords
- group
- lower alkyl
- alkyl group
- phenyl ring
- phenyl
- 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.)
- Expired
Links
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims abstract description 104
- 238000000034 method Methods 0.000 title claims description 127
- 230000003177 cardiotonic effect Effects 0.000 title abstract description 8
- 239000000203 mixture Substances 0.000 title description 43
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 232
- 125000001424 substituent group Chemical group 0.000 claims abstract description 148
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 143
- 125000005843 halogen group Chemical group 0.000 claims abstract description 91
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 85
- 125000005530 alkylenedioxy group Chemical group 0.000 claims abstract description 41
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 38
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 38
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 24
- 125000002252 acyl group Chemical group 0.000 claims abstract description 21
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 16
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 12
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 12
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims abstract description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 7
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims abstract description 7
- 125000004429 atom Chemical group 0.000 claims abstract description 3
- -1 substituted Chemical class 0.000 claims description 536
- 150000001875 compounds Chemical class 0.000 claims description 215
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 136
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 42
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 26
- 239000007858 starting material Substances 0.000 claims description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000003277 amino group Chemical group 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 14
- 125000004423 acyloxy group Chemical group 0.000 claims description 11
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- ZJNIZXCCXHUGPO-UHFFFAOYSA-N 2-oxo-3,4-dihydro-1h-quinoline-6-carboxylic acid;pyrrolidine-2,5-dione Chemical compound O=C1CCC(=O)N1.N1C(=O)CCC2=CC(C(=O)O)=CC=C21 ZJNIZXCCXHUGPO-UHFFFAOYSA-N 0.000 claims description 10
- UKRYUVLBWGYQBY-UHFFFAOYSA-N 6-(piperazine-1-carbonyl)-3,4-dihydro-1h-quinolin-2-one Chemical compound C=1C=C2NC(=O)CCC2=CC=1C(=O)N1CCNCC1 UKRYUVLBWGYQBY-UHFFFAOYSA-N 0.000 claims description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 8
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 claims description 7
- UQYCHNFDTXIQMM-UHFFFAOYSA-N 6-(4-benzylpiperazine-1-carbonyl)-3,4-dihydro-1h-quinolin-2-one Chemical compound C=1C=C2NC(=O)CCC2=CC=1C(=O)N(CC1)CCN1CC1=CC=CC=C1 UQYCHNFDTXIQMM-UHFFFAOYSA-N 0.000 claims description 7
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 6
- YEBPUKCCDDFCBM-UHFFFAOYSA-N 6-(piperazine-1-carbonyl)-1h-quinolin-2-one Chemical compound C=1C=C2NC(=O)C=CC2=CC=1C(=O)N1CCNCC1 YEBPUKCCDDFCBM-UHFFFAOYSA-N 0.000 claims description 4
- 229960002317 succinimide Drugs 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 15
- ZBRWSODNRGCQMV-UHFFFAOYSA-N 6-[4-(2-phenoxyethyl)piperazine-1-carbonyl]-1h-quinolin-2-one Chemical compound C=1C=C2NC(=O)C=CC2=CC=1C(=O)N(CC1)CCN1CCOC1=CC=CC=C1 ZBRWSODNRGCQMV-UHFFFAOYSA-N 0.000 claims 3
- MXCARJQEMVOHAU-UHFFFAOYSA-N 6-[4-(3-oxo-3-phenylpropyl)piperazine-1-carbonyl]-3,4-dihydro-1h-quinolin-2-one Chemical compound C1CN(C(=O)C=2C=C3CCC(=O)NC3=CC=2)CCN1CCC(=O)C1=CC=CC=C1 MXCARJQEMVOHAU-UHFFFAOYSA-N 0.000 claims 3
- HUUQNWZMQSLPMX-UHFFFAOYSA-N 1-(2-methylpropyl)piperazine Chemical compound CC(C)CN1CCNCC1 HUUQNWZMQSLPMX-UHFFFAOYSA-N 0.000 claims 2
- PTJSLCXRMMGRLY-UHFFFAOYSA-N 1-(2-phenoxyethyl)piperazine Chemical compound C=1C=CC=CC=1OCCN1CCNCC1 PTJSLCXRMMGRLY-UHFFFAOYSA-N 0.000 claims 2
- JXGUHKJKWBEVEP-UHFFFAOYSA-N 6-[4-(2-methylpropyl)piperazine-1-carbonyl]-1h-quinolin-2-one Chemical compound C1CN(CC(C)C)CCN1C(=O)C1=CC=C(NC(=O)C=C2)C2=C1 JXGUHKJKWBEVEP-UHFFFAOYSA-N 0.000 claims 2
- BRTSRAFGNVSHJV-UHFFFAOYSA-N 6-[4-(2-methylpropyl)piperazine-1-carbonyl]-3,4-dihydro-1h-quinolin-2-one Chemical compound C1CN(CC(C)C)CCN1C(=O)C1=CC=C(NC(=O)CC2)C2=C1 BRTSRAFGNVSHJV-UHFFFAOYSA-N 0.000 claims 2
- HIMAPQCWSZVHEJ-UHFFFAOYSA-N 6-[4-(2-phenoxyethyl)piperazine-1-carbonyl]-3,4-dihydro-1h-quinolin-2-one Chemical compound C=1C=C2NC(=O)CCC2=CC=1C(=O)N(CC1)CCN1CCOC1=CC=CC=C1 HIMAPQCWSZVHEJ-UHFFFAOYSA-N 0.000 claims 2
- BTWISIJHDMKQCT-UHFFFAOYSA-N 6-[4-(2-phenylethyl)piperazine-1-carbonyl]-3,4-dihydro-1h-quinolin-2-one Chemical compound C=1C=C2NC(=O)CCC2=CC=1C(=O)N(CC1)CCN1CCC1=CC=CC=C1 BTWISIJHDMKQCT-UHFFFAOYSA-N 0.000 claims 2
- CDRWBUGLZBPPCL-UHFFFAOYSA-N 6-[4-(3-phenylpropyl)piperazine-1-carbonyl]-1h-quinolin-2-one Chemical compound C=1C=C2NC(=O)C=CC2=CC=1C(=O)N(CC1)CCN1CCCC1=CC=CC=C1 CDRWBUGLZBPPCL-UHFFFAOYSA-N 0.000 claims 2
- VCMKKOPAGZSVOM-UHFFFAOYSA-N 6-[4-(4-oxo-4-phenylbutyl)piperazine-1-carbonyl]-3,4-dihydro-1h-quinolin-2-one Chemical compound C1CN(C(=O)C=2C=C3CCC(=O)NC3=CC=2)CCN1CCCC(=O)C1=CC=CC=C1 VCMKKOPAGZSVOM-UHFFFAOYSA-N 0.000 claims 2
- MMPBSPPVURMDBU-UHFFFAOYSA-N 6-[4-[(4-methoxyphenyl)methyl]piperazine-1-carbonyl]-3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC(OC)=CC=C1CN1CCN(C(=O)C=2C=C3CCC(=O)NC3=CC=2)CC1 MMPBSPPVURMDBU-UHFFFAOYSA-N 0.000 claims 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims 2
- LKUAPSRIYZLAAO-UHFFFAOYSA-N 1-(2-phenylethyl)piperazine Chemical compound C1CNCCN1CCC1=CC=CC=C1 LKUAPSRIYZLAAO-UHFFFAOYSA-N 0.000 claims 1
- LOJCUYCKDGYLJH-UHFFFAOYSA-N 1-(3-phenylpropyl)piperazine Chemical compound C=1C=CC=CC=1CCCN1CCNCC1 LOJCUYCKDGYLJH-UHFFFAOYSA-N 0.000 claims 1
- MGLUVVBFISROAH-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]piperazine Chemical compound C1=CC(OC)=CC=C1CN1CCNCC1 MGLUVVBFISROAH-UHFFFAOYSA-N 0.000 claims 1
- GZXSVSMPRXVXNJ-UHFFFAOYSA-N 1-phenyl-3-piperazin-1-ylpropan-1-one Chemical compound C=1C=CC=CC=1C(=O)CCN1CCNCC1 GZXSVSMPRXVXNJ-UHFFFAOYSA-N 0.000 claims 1
- PHTBCTQRJJFKJO-UHFFFAOYSA-N 1-phenyl-4-piperazin-1-ylbutan-1-one Chemical compound C=1C=CC=CC=1C(=O)CCCN1CCNCC1 PHTBCTQRJJFKJO-UHFFFAOYSA-N 0.000 claims 1
- KTJRGPZVSKWRTJ-UHFFFAOYSA-N 3-chloro-1-phenylpropan-1-one Chemical compound ClCCC(=O)C1=CC=CC=C1 KTJRGPZVSKWRTJ-UHFFFAOYSA-N 0.000 claims 1
- 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 claims 1
- GHEFQKHLHFXSBR-UHFFFAOYSA-N 4-chloro-1-phenylbutan-1-one Chemical compound ClCCCC(=O)C1=CC=CC=C1 GHEFQKHLHFXSBR-UHFFFAOYSA-N 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 230000001965 increasing effect Effects 0.000 abstract description 8
- 230000017531 blood circulation Effects 0.000 abstract description 7
- 230000009090 positive inotropic effect Effects 0.000 abstract description 5
- 230000002107 myocardial effect Effects 0.000 abstract description 4
- 206010003658 Atrial Fibrillation Diseases 0.000 abstract description 3
- 230000008602 contraction Effects 0.000 abstract description 3
- 230000001077 hypotensive effect Effects 0.000 abstract description 3
- 208000012336 Mitral valvular disease Diseases 0.000 abstract description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 abstract 1
- 206010019280 Heart failures Diseases 0.000 abstract 1
- 206010003668 atrial tachycardia Diseases 0.000 abstract 1
- 208000019622 heart disease Diseases 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 184
- 238000002844 melting Methods 0.000 description 147
- 230000008018 melting Effects 0.000 description 147
- 238000006243 chemical reaction Methods 0.000 description 136
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 105
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 87
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- 239000002904 solvent Substances 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 55
- 229960001701 chloroform Drugs 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- 239000011541 reaction mixture Substances 0.000 description 47
- 239000000243 solution Substances 0.000 description 44
- 125000004432 carbon atom Chemical group C* 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 40
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 37
- 150000001412 amines Chemical class 0.000 description 35
- 235000019441 ethanol Nutrition 0.000 description 35
- 239000007864 aqueous solution Substances 0.000 description 32
- 238000004821 distillation Methods 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- 229960000443 hydrochloric acid Drugs 0.000 description 29
- 239000002253 acid Substances 0.000 description 28
- 230000009850 completed effect Effects 0.000 description 28
- 235000011167 hydrochloric acid Nutrition 0.000 description 28
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 26
- 239000003795 chemical substances by application Substances 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 150000007514 bases Chemical class 0.000 description 16
- 238000002347 injection Methods 0.000 description 16
- 239000007924 injection Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- 230000001603 reducing effect Effects 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 229940086542 triethylamine Drugs 0.000 description 12
- 241000282472 Canis lupus familiaris Species 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 238000006722 reduction reaction Methods 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 229920002472 Starch Polymers 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 238000006396 nitration reaction Methods 0.000 description 10
- 230000000144 pharmacologic effect Effects 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- 239000008107 starch Substances 0.000 description 10
- 235000019698 starch Nutrition 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 9
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 150000008065 acid anhydrides Chemical class 0.000 description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
- 239000012452 mother liquor Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000008096 xylene Substances 0.000 description 7
- QNRATNLHPGXHMA-XZHTYLCXSA-N (r)-(6-ethoxyquinolin-4-yl)-[(2s,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]methanol;hydrochloride Chemical compound Cl.C([C@H]([C@H](C1)CC)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OCC)C=C21 QNRATNLHPGXHMA-XZHTYLCXSA-N 0.000 description 6
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 6
- DUFYYKGNRAMGNG-UHFFFAOYSA-N 2-oxo-3,4-dihydro-1h-quinoline-6-carboxylic acid Chemical compound N1C(=O)CCC2=CC(C(=O)O)=CC=C21 DUFYYKGNRAMGNG-UHFFFAOYSA-N 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
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- 230000037396 body weight Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- YZYDPPZYDIRSJT-UHFFFAOYSA-K boron phosphate Chemical compound [B+3].[O-]P([O-])([O-])=O YZYDPPZYDIRSJT-UHFFFAOYSA-K 0.000 description 1
- 229910000149 boron phosphate Inorganic materials 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
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- 238000000576 coating method Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
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- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- IUBJENFETVFDPK-UHFFFAOYSA-N ethyl 2-[4-(2-oxo-3,4-dihydro-1h-quinoline-6-carbonyl)piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1C(=O)C1=CC=C(NC(=O)CC2)C2=C1 IUBJENFETVFDPK-UHFFFAOYSA-N 0.000 description 1
- JAWWTWOBVZYGPI-UHFFFAOYSA-N ethyl 2-oxo-3,4-dihydro-1h-quinoline-6-carboxylate Chemical compound N1C(=O)CCC2=CC(C(=O)OCC)=CC=C21 JAWWTWOBVZYGPI-UHFFFAOYSA-N 0.000 description 1
- AYYNUGSDPRDVCH-UHFFFAOYSA-N ethyl 3,4-dimethoxybenzoate Chemical compound CCOC(=O)C1=CC=C(OC)C(OC)=C1 AYYNUGSDPRDVCH-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
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- 210000003191 femoral vein Anatomy 0.000 description 1
- 229940032958 ferric phosphate Drugs 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
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- 239000000945 filler Substances 0.000 description 1
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- 235000003599 food sweetener Nutrition 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
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- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
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- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- 125000001145 hydrido group Chemical group *[H] 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 1
- WBJZTOZJJYAKHQ-UHFFFAOYSA-K iron(3+) phosphate Chemical compound [Fe+3].[O-]P([O-])([O-])=O WBJZTOZJJYAKHQ-UHFFFAOYSA-K 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 229910000399 iron(III) phosphate Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
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- 210000005240 left ventricle Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
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- 229910001463 metal phosphate Inorganic materials 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- QQHNGZNHRRLNKI-UHFFFAOYSA-N methyl carbonobromidate Chemical compound COC(Br)=O QQHNGZNHRRLNKI-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
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- SMBBZHGTZJNSRQ-UHFFFAOYSA-N n'-(6,6-dichlorohexyl)methanediimine Chemical compound ClC(Cl)CCCCCN=C=N SMBBZHGTZJNSRQ-UHFFFAOYSA-N 0.000 description 1
- ZSBYTZDMNFXERF-UHFFFAOYSA-N n,n-bis(2-chloroethyl)-2-oxo-3,4-dihydro-1h-quinoline-6-carboxamide Chemical compound N1C(=O)CCC2=CC(C(=O)N(CCCl)CCCl)=CC=C21 ZSBYTZDMNFXERF-UHFFFAOYSA-N 0.000 description 1
- GUZWPGHACVQJLA-UHFFFAOYSA-N n,n-bis(2-hydroxyethyl)-2-oxo-3,4-dihydro-1h-quinoline-6-carboxamide Chemical compound N1C(=O)CCC2=CC(C(=O)N(CCO)CCO)=CC=C21 GUZWPGHACVQJLA-UHFFFAOYSA-N 0.000 description 1
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 1
- HBUKVRTZBZARFA-UHFFFAOYSA-N n-[4-[3-[4-(2-oxo-3,4-dihydro-1h-quinoline-6-carbonyl)piperazin-1-yl]propanoyl]phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1C(=O)CCN1CCN(C(=O)C=2C=C3CCC(=O)NC3=CC=2)CC1 HBUKVRTZBZARFA-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
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- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
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- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 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
- 239000002244 precipitate Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 229940005657 pyrophosphoric acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate 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
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 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
- 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
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000001680 trimethoxyphenyl group Chemical group 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22437/81 | 1981-02-17 | ||
| JP56022437A JPS57136517A (en) | 1981-02-17 | 1981-02-17 | Cardiotonic |
| JP56057732A JPS57171974A (en) | 1981-04-15 | 1981-04-15 | Carbostyril derivative |
| JP57732/81 | 1981-04-15 | ||
| JP12714581A JPS5829766A (ja) | 1981-08-12 | 1981-08-12 | カルボスチリル誘導体 |
| JP127145/81 | 1981-08-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1199915A true CA1199915A (en) | 1986-01-28 |
Family
ID=27283844
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000396327A Expired CA1199915A (en) | 1981-02-17 | 1982-02-16 | Carbostyril derivatives, process for producing the same and cardiotonic compositions containing the same |
Country Status (21)
| Country | Link |
|---|---|
| US (3) | US4487772A (en, 2012) |
| KR (1) | KR860001337B1 (en, 2012) |
| AT (1) | AT386198B (en, 2012) |
| AU (1) | AU530264B2 (en, 2012) |
| BE (1) | BE892148A (en, 2012) |
| CA (1) | CA1199915A (en, 2012) |
| CH (1) | CH651827A5 (en, 2012) |
| DE (1) | DE3204892A1 (en, 2012) |
| DK (1) | DK152287C (en, 2012) |
| ES (2) | ES509693A0 (en, 2012) |
| FI (1) | FI77852C (en, 2012) |
| FR (1) | FR2512818B1 (en, 2012) |
| GB (1) | GB2094789B (en, 2012) |
| IT (1) | IT1157002B (en, 2012) |
| MX (1) | MX156153A (en, 2012) |
| NL (1) | NL8200593A (en, 2012) |
| NO (1) | NO159446C (en, 2012) |
| PH (1) | PH18085A (en, 2012) |
| PT (1) | PT74440B (en, 2012) |
| SE (1) | SE445348B (en, 2012) |
| SU (1) | SU1331426A3 (en, 2012) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PH17194A (en) * | 1980-03-06 | 1984-06-19 | Otsuka Pharma Co Ltd | Novel carbostyril derivatives,and pharmaceutical composition containing the same |
| FI77852C (fi) * | 1981-02-17 | 1989-05-10 | Otsuka Pharma Co Ltd | Foerfarande foer framstaellning av nya, saosom hjaertmediciner anvaendbara substituerade amid- och (maettad heterocykel)karbonylkarbostyrilderivat. |
| AU532361B2 (en) * | 1981-09-01 | 1983-09-29 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
| US4578381A (en) * | 1982-07-05 | 1986-03-25 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
| US4845100A (en) * | 1985-04-12 | 1989-07-04 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives and salts thereof, processes for preparing the same and cardiotonic composition containing the same |
| US4921862A (en) * | 1986-05-29 | 1990-05-01 | Syntex (U.S.A.) Inc. | Carbostyril derivatives as combined thromboxane synthetase and cyclic-amp phosphodiesterase inhibitors |
| US4792561A (en) * | 1986-05-29 | 1988-12-20 | Syntex (U.S.A.) Inc. | Carbostyril derivatives as combined thromboxane synthetase and cyclic-AMP phosphodiesterase inhibitors |
| DK397387A (da) * | 1986-07-31 | 1988-02-01 | Otsuka Pharma Co Ltd | Carbostyrilderivater og salte deraf samt fremgangsmaade til fremstilling af saadanne forbindelser |
| GB8709448D0 (en) * | 1987-04-21 | 1987-05-28 | Pfizer Ltd | Heterobicyclic quinoline derivatives |
| US5227381A (en) * | 1988-05-02 | 1993-07-13 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivative |
| DE3818830A1 (de) * | 1988-06-03 | 1989-12-14 | Boehringer Mannheim Gmbh | Bicyclische carboxamide, verfahren zu ihrer herstellung, deren vorstufen, und diese verbindungen enthaltende arzneimittel |
| JP2686887B2 (ja) * | 1992-08-11 | 1997-12-08 | キッセイ薬品工業株式会社 | ピペリジノ−３，４−ジヒドロカルボスチリル誘導体 |
| JPH06239858A (ja) * | 1993-02-16 | 1994-08-30 | Otsuka Pharmaceut Co Ltd | 末梢血管拡張剤 |
| CN1052224C (zh) * | 1993-04-07 | 2000-05-10 | 大塚制药株式会社 | 哌啶衍生物、含有它的外周血管舒张剂及其应用 |
| ES2128629T3 (es) * | 1994-10-31 | 1999-05-16 | Merck Patent Gmbh | Derivados de bencilpiperidina con afinidad elevada a puntos de enlace de receptores de aminoacidos. |
| US6589954B1 (en) * | 1998-05-22 | 2003-07-08 | Scios, Inc. | Compounds and methods to treat cardiac failure and other disorders |
| US6340685B1 (en) * | 1998-05-22 | 2002-01-22 | Scios, Inc. | Compounds and methods to treat cardiac failure and other disorders |
| US6867209B1 (en) | 1998-05-22 | 2005-03-15 | Scios, Inc. | Indole-type derivatives as inhibitors of p38 kinase |
| US6448257B1 (en) | 1998-05-22 | 2002-09-10 | Scios, Inc. | Compounds and methods to treat cardiac failure and other disorders |
| IL146309A (en) | 1999-05-21 | 2008-03-20 | Scios Inc | Derivatives of the indole type and pharmaceutical preparations containing them as inhibitors of kinase p38 |
| WO2004014389A1 (en) * | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | 3,4-dihydroquinolin-2-one, 5,6-fused oxazin-3-one, and 5,6-fused thiazin-3-one derivatives as matrix metalloproteinase inhibitors |
| CN1890225A (zh) * | 2003-12-10 | 2007-01-03 | 詹森药业有限公司 | 作为多聚(adp－核糖)聚合酶抑制剂的被取代的6－环己基烷基取代的2－喹啉酮和2－喹喔啉酮 |
| MY142362A (en) * | 2004-01-29 | 2010-11-30 | Otsuka Pharma Co Ltd | Pharmaceutical composition for promoting angiogenesis |
| EP2021340B1 (en) | 2006-04-21 | 2014-07-23 | The Government Of The United States, As Represented by The Secretary Of Health And Human Services | Beta-amyloid pet imaging agents |
| WO2010021681A2 (en) * | 2008-08-18 | 2010-02-25 | Combinatorx (Singapore) Pte. Ltd. | Compositions and methods for treatment of viral diseases |
| AU2010266018B2 (en) | 2009-06-25 | 2014-01-09 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
| EP2566329B1 (en) | 2010-05-04 | 2020-09-09 | Alkermes Pharma Ireland Limited | Process for synthesizing oxidized lactam compounds |
| WO2011163594A2 (en) | 2010-06-24 | 2011-12-29 | Alkermes, Inc. | Prodrugs of nh-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives |
| JP7269948B2 (ja) * | 2017-11-28 | 2023-05-09 | エフ． ホフマン－ラ ロシュ アーゲー | 新規複素環式化合物 |
| WO2019134985A1 (en) | 2018-01-08 | 2019-07-11 | F. Hoffmann-La Roche Ag | Octahydropyrido[1,2-alpha]pyrazines as magl inhibitors |
| CN109651285B (zh) * | 2019-01-30 | 2020-06-30 | 苏州大学 | 多溴代苯并[1,3]噁嗪衍生物的合成方法 |
| CA3190277A1 (en) | 2020-09-03 | 2022-03-10 | Joerg Benz | Heterocyclic compounds |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2997474A (en) * | 1959-10-12 | 1961-08-22 | Paul A J Janssen | 1-aryl-omega-(4-arylpiperazine) alkanols |
| US3555030A (en) * | 1964-11-25 | 1971-01-12 | Smith Kline French Lab | Muscle relaxant and analgesic compositions |
| US4115569A (en) * | 1971-11-19 | 1978-09-19 | Hoechst Aktiengesellschaft | Cyclic diamine derivatives |
| US4256890A (en) * | 1972-09-14 | 1981-03-17 | Otsukapharmaceutical Co., Ltd. | 3,4-Dihydrocarbostyril derivatives and process for producing the same |
| IT998326B (it) * | 1973-08-06 | 1976-01-20 | Montedison Spa | Derivati degli acidi chinolin 8 carbossilici ad attivita antiparas sitaria |
| US4026897A (en) * | 1974-01-31 | 1977-05-31 | Otsuka Pharmaceutical Company | 5-[1-Hydroxy-2-(substituted-amino)]alkyl-8-hydroxycarbostyril derivatives |
| US4022784A (en) * | 1974-01-31 | 1977-05-10 | Otsuka Pharmaceutical Company Limited | 5-[1-Hydroxy-2-(substituted-amino)]alkyl-8-substituted-carbostyril and -3,4-dihydrocarbostyril derivatives |
| US4145542A (en) * | 1974-06-13 | 1979-03-20 | Otsuka Pharmaceutical Co., Ltd. | 5- 1-Hydroxy-2-(heterocyclic-amino)!alkyl-8-hydroxy-3,4-dihydrocarbostyril derivatives |
| FI59246C (fi) * | 1974-06-24 | 1981-07-10 | Otsuka Pharma Co Ltd | Foerfarande foer framstaellning av benscykloamidderivat anvaendbara vid trombos- och emboliterapin |
| JPS51118771A (en) * | 1975-04-09 | 1976-10-18 | Otsuka Pharmaceut Co Ltd | Method for preparing carbostyryl derivatives |
| US3994900A (en) * | 1976-01-23 | 1976-11-30 | E. R. Squibb & Sons, Inc. | 6-(Or 8)-[[(substituted amino)alkyl]oxy(or thio)]-3,4-dihydro-4-phenyl-2(1H)-quinolinones |
| US4210753A (en) * | 1976-03-17 | 1980-07-01 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril compounds |
| GB1589871A (en) * | 1976-07-19 | 1981-05-20 | Conder Group Serv Ltd | Tank construction |
| JPS609713B2 (ja) * | 1976-10-08 | 1985-03-12 | 大塚製薬株式会社 | カルボスチリル誘導体 |
| IE46852B1 (en) * | 1977-06-10 | 1983-10-05 | Otsuka Pharma Co Ltd | Novel carbostyril derivatives |
| JPS5416478A (en) * | 1977-07-08 | 1979-02-07 | Otsuka Pharmaceut Co Ltd | 3,4-dihydrocarbostyril herivative |
| DE2928583A1 (de) * | 1979-07-14 | 1981-01-29 | Thomae Gmbh Dr K | Verfahren zur herstellung von carbostyrilderivaten |
| PH17194A (en) * | 1980-03-06 | 1984-06-19 | Otsuka Pharma Co Ltd | Novel carbostyril derivatives,and pharmaceutical composition containing the same |
| FI77852C (fi) * | 1981-02-17 | 1989-05-10 | Otsuka Pharma Co Ltd | Foerfarande foer framstaellning av nya, saosom hjaertmediciner anvaendbara substituerade amid- och (maettad heterocykel)karbonylkarbostyrilderivat. |
-
1982
- 1982-02-03 FI FI820338A patent/FI77852C/fi not_active IP Right Cessation
- 1982-02-12 DE DE19823204892 patent/DE3204892A1/de active Granted
- 1982-02-15 BE BE0/207321A patent/BE892148A/fr not_active IP Right Cessation
- 1982-02-15 MX MX8210261A patent/MX156153A/es unknown
- 1982-02-15 PH PH26870A patent/PH18085A/en unknown
- 1982-02-15 SU SU823394100A patent/SU1331426A3/ru active
- 1982-02-16 SE SE8200916A patent/SE445348B/sv not_active IP Right Cessation
- 1982-02-16 FR FR8202479A patent/FR2512818B1/fr not_active Expired
- 1982-02-16 US US06/348,709 patent/US4487772A/en not_active Expired - Lifetime
- 1982-02-16 NL NL8200593A patent/NL8200593A/nl not_active Application Discontinuation
- 1982-02-16 PT PT74440A patent/PT74440B/pt not_active IP Right Cessation
- 1982-02-16 NO NO820479A patent/NO159446C/no unknown
- 1982-02-16 AT AT0059582A patent/AT386198B/de not_active IP Right Cessation
- 1982-02-16 CA CA000396327A patent/CA1199915A/en not_active Expired
- 1982-02-16 DK DK066582A patent/DK152287C/da active
- 1982-02-16 AU AU80528/82A patent/AU530264B2/en not_active Ceased
- 1982-02-16 KR KR8200668A patent/KR860001337B1/ko not_active Expired
- 1982-02-17 IT IT67177/82A patent/IT1157002B/it active
- 1982-02-17 ES ES509693A patent/ES509693A0/es active Granted
- 1982-02-17 GB GB8204581A patent/GB2094789B/en not_active Expired
- 1982-02-17 CH CH996/82A patent/CH651827A5/de not_active IP Right Cessation
- 1982-12-16 ES ES518303A patent/ES518303A0/es active Granted
-
1983
- 1983-08-22 US US06/525,812 patent/US4454130A/en not_active Expired - Lifetime
- 1983-08-22 US US06/525,284 patent/US4468402A/en not_active Expired - Lifetime
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |