DE69503753T2 - Tetracyclische derivate, verfahren zu ihrer herstellung und ihre verwendung - Google Patents
Tetracyclische derivate, verfahren zu ihrer herstellung und ihre verwendungInfo
- Publication number
- DE69503753T2 DE69503753T2 DE69503753T DE69503753T DE69503753T2 DE 69503753 T2 DE69503753 T2 DE 69503753T2 DE 69503753 T DE69503753 T DE 69503753T DE 69503753 T DE69503753 T DE 69503753T DE 69503753 T2 DE69503753 T2 DE 69503753T2
- Authority
- DE
- Germany
- Prior art keywords
- indole
- pyrido
- cis
- dione
- hexahydro
- 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 - Lifetime
Links
- 238000000034 method Methods 0.000 title claims description 193
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 153
- FFCZQVKVWGGQFB-UHFFFAOYSA-N 9h-pyrido[3,4-b]indole-1,4-dione Chemical compound N1C2=CC=CC=C2C2=C1C(=O)N=CC2=O FFCZQVKVWGGQFB-UHFFFAOYSA-N 0.000 claims description 100
- 239000000203 mixture Substances 0.000 claims description 54
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 36
- -1 halo-C1−6alkyl Chemical group 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 230000002829 reductive effect Effects 0.000 claims description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 12
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical class COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 150000001555 benzenes Chemical class 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 6
- 208000010412 Glaucoma Diseases 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 6
- 206010020772 Hypertension Diseases 0.000 claims description 6
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 6
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 6
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 6
- 201000009961 allergic asthma Diseases 0.000 claims description 6
- 201000010105 allergic rhinitis Diseases 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 210000004204 blood vessel Anatomy 0.000 claims description 6
- 206010006451 bronchitis Diseases 0.000 claims description 6
- 208000023819 chronic asthma Diseases 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 201000006370 kidney failure Diseases 0.000 claims description 6
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 6
- 229930192474 thiophene Natural products 0.000 claims description 6
- 208000019553 vascular disease Diseases 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 230000008991 intestinal motility Effects 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 229910003827 NRaRb Inorganic materials 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 229910052757 nitrogen Chemical group 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims description 4
- 229910052701 rubidium Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- TXELQQBHZDWVMC-DYESRHJHSA-N (6r,12ar)-6-(3-chloro-4-methoxy-phenyl)-2-methyl-6,7,12,12a-tetrahydro-3h-pyrazino[1,2-b]$b-carboline-1,4-quinone Chemical compound C1=C(Cl)C(OC)=CC=C1[C@@H]1C(NC=2C3=CC=CC=2)=C3C[C@H]2N1C(=O)CN(C)C2=O TXELQQBHZDWVMC-DYESRHJHSA-N 0.000 claims description 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 239000011593 sulfur Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- PWUCUSITNKSTMS-CJFMBICVSA-N (6r,12ar)-6-(1,3-benzodioxol-5-yl)-2-cyclopentyl-6,7,12,12a-tetrahydro-3h-pyrazino[1,2-b]$b-carboline-1,4-quinone Chemical compound N1([C@@H](C2=C(C3=CC=CC=C3N2)C[C@@H]1C1=O)C=2C=C3OCOC3=CC=2)C(=O)CN1C1CCCC1 PWUCUSITNKSTMS-CJFMBICVSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical class 0.000 claims description 2
- XHDLVMPUSXRZOS-FOIQADDNSA-N nortadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H]3C(=O)NCC(N23)=O)=C1 XHDLVMPUSXRZOS-FOIQADDNSA-N 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 7
- 206010002388 Angina unstable Diseases 0.000 claims 2
- 201000001068 Prinzmetal angina Diseases 0.000 claims 2
- 208000007718 Stable Angina Diseases 0.000 claims 2
- 208000007814 Unstable Angina Diseases 0.000 claims 2
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 2
- 150000003577 thiophenes Chemical group 0.000 claims 2
- 230000010243 gut motility Effects 0.000 claims 1
- 238000007614 solvation Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 276
- 239000000543 intermediate Substances 0.000 description 177
- 239000013078 crystal Substances 0.000 description 162
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 151
- 238000004458 analytical method Methods 0.000 description 118
- 238000001953 recrystallisation Methods 0.000 description 109
- 239000000047 product Substances 0.000 description 93
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 91
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 91
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
- 239000000243 solution Substances 0.000 description 54
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 52
- 239000007787 solid Substances 0.000 description 49
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- KCUNTYMNJVXYKZ-JTQLQIEISA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 KCUNTYMNJVXYKZ-JTQLQIEISA-N 0.000 description 34
- 239000002904 solvent Substances 0.000 description 34
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 25
- 239000013067 intermediate product Substances 0.000 description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000007832 Na2SO4 Substances 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- 238000001704 evaporation Methods 0.000 description 21
- 230000008020 evaporation Effects 0.000 description 21
- 229910052938 sodium sulfate Inorganic materials 0.000 description 21
- 235000011152 sodium sulphate Nutrition 0.000 description 21
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 239000004480 active ingredient Substances 0.000 description 16
- 238000003818 flash chromatography Methods 0.000 description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000003826 tablet Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 12
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- DABYEOZXRSTEGL-NSHDSACASA-N ethyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@H](N)C(=O)OCC)=CNC2=C1 DABYEOZXRSTEGL-NSHDSACASA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- DABYEOZXRSTEGL-UHFFFAOYSA-N racemic tryptophan ethyl ester Natural products C1=CC=C2C(CC(N)C(=O)OCC)=CNC2=C1 DABYEOZXRSTEGL-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 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 7
- 239000002775 capsule Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 6
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 229940081310 piperonal Drugs 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 5
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 5
- 229940068968 polysorbate 80 Drugs 0.000 description 5
- 229920000053 polysorbate 80 Polymers 0.000 description 5
- 239000012047 saturated solution Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 206010002383 Angina Pectoris Diseases 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 208000003782 Raynaud disease Diseases 0.000 description 4
- 208000012322 Raynaud phenomenon Diseases 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- 208000002551 irritable bowel syndrome Diseases 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000001665 trituration Methods 0.000 description 4
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 description 3
- 102000002723 Atrial Natriuretic Factor Human genes 0.000 description 3
- 101800001288 Atrial natriuretic factor Proteins 0.000 description 3
- 101800001890 Atrial natriuretic peptide Proteins 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
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- 125000004175 fluorobenzyl group Chemical group 0.000 description 1
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- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
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- 125000006277 halobenzyl group Chemical group 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- RERZNCLIYCABFS-UHFFFAOYSA-N harmaline Chemical compound C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IIRDTKBZINWQAW-UHFFFAOYSA-N hexaethylene glycol Chemical class OCCOCCOCCOCCOCCOCCO IIRDTKBZINWQAW-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- XNFNGGQRDXFYMM-UHFFFAOYSA-N hydron;methyl 2-amino-3-(1h-indol-3-yl)propanoate;chloride Chemical compound [Cl-].C1=CC=C2C(CC([NH3+])C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-UHFFFAOYSA-N 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
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- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- OVWYEQOVUDKZNU-UHFFFAOYSA-N m-tolualdehyde Chemical compound CC1=CC=CC(C=O)=C1 OVWYEQOVUDKZNU-UHFFFAOYSA-N 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 229940057948 magnesium stearate Drugs 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229940087646 methanolamine Drugs 0.000 description 1
- COQGJODYTGQIQG-OLACKDHBSA-N methyl (1r,3r)-1-(1,3-benzodioxol-5-yl)-2-(2-chloropropanoyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2C(=O)C(C)Cl)C(=O)OC)=C1 COQGJODYTGQIQG-OLACKDHBSA-N 0.000 description 1
- CEKZLEXKVZHVSL-IEBWSBKVSA-N methyl (1r,3r)-1-(2,3-dihydro-1-benzofuran-5-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2OCCC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2)C(=O)OC)=C1 CEKZLEXKVZHVSL-IEBWSBKVSA-N 0.000 description 1
- XPDHGPCPXNTVIF-WOJBJXKFSA-N methyl (1r,3r)-1-(2,3-dihydro-1h-inden-5-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2CCCC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2)C(=O)OC)=C1 XPDHGPCPXNTVIF-WOJBJXKFSA-N 0.000 description 1
- YCXGMYSYRWHDRT-SJLPKXTDSA-N methyl (1r,3r)-1-(3-chloro-4-methoxyphenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2)C(=O)OC)=CC=C(OC)C(Cl)=C1 YCXGMYSYRWHDRT-SJLPKXTDSA-N 0.000 description 1
- YCCPHMBIMIJBPW-QZTJIDSGSA-N methyl (1r,3r)-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2)C(=O)OC)=CC=C(OC)C=C1 YCCPHMBIMIJBPW-QZTJIDSGSA-N 0.000 description 1
- NQDBWALBJVPWQF-GRKNLSHJSA-N methyl (1r,3r)-1-[3,4-bis(phenylmethoxy)phenyl]-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=1C=CC=CC=1COC1=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2)C(=O)OC)=CC=C1OCC1=CC=CC=C1 NQDBWALBJVPWQF-GRKNLSHJSA-N 0.000 description 1
- LIPVUDSNGRJSQE-QAPCUYQASA-N methyl (1s,3r)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2OCOC2=CC([C@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2)C(=O)OC)=C1 LIPVUDSNGRJSQE-QAPCUYQASA-N 0.000 description 1
- XPDHGPCPXNTVIF-UXHICEINSA-N methyl (1s,3r)-1-(2,3-dihydro-1h-inden-5-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2CCCC2=CC([C@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2)C(=O)OC)=C1 XPDHGPCPXNTVIF-UXHICEINSA-N 0.000 description 1
- NQDBWALBJVPWQF-MVSFAKPFSA-N methyl (1s,3r)-1-[3,4-bis(phenylmethoxy)phenyl]-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=1C=CC=CC=1COC1=CC([C@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2)C(=O)OC)=CC=C1OCC1=CC=CC=C1 NQDBWALBJVPWQF-MVSFAKPFSA-N 0.000 description 1
- PKHHJECXXHOADW-IRXDYDNUSA-N methyl (1s,3s)-1-phenyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1([C@H]2C3=C(C4=CC=CC=C4N3)C[C@H](N2)C(=O)OC)=CC=CC=C1 PKHHJECXXHOADW-IRXDYDNUSA-N 0.000 description 1
- BNAZOOCFECXZBZ-MRXNPFEDSA-N methyl (2r)-2-(1,3-benzodioxole-5-carbonylamino)-3-(1h-indol-3-yl)propanoate Chemical compound C1=C2OCOC2=CC(C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)OC)=C1 BNAZOOCFECXZBZ-MRXNPFEDSA-N 0.000 description 1
- VHUUQEZRMVBQHC-MRXNPFEDSA-N methyl (2r)-2-(1,3-benzodioxole-5-carbothioylamino)-3-(1h-indol-3-yl)propanoate Chemical compound C1=C2OCOC2=CC(C(=S)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)OC)=C1 VHUUQEZRMVBQHC-MRXNPFEDSA-N 0.000 description 1
- MNJWYOVJMKMIFA-NSHDSACASA-N methyl (2s)-2-amino-3-(5-methyl-1h-indol-3-yl)propanoate Chemical compound C1=C(C)C=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 MNJWYOVJMKMIFA-NSHDSACASA-N 0.000 description 1
- LIPVUDSNGRJSQE-UHFFFAOYSA-N methyl 1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2OCOC2=CC(C2C3=C(C4=CC=CC=C4N3)CC(N2)C(=O)OC)=C1 LIPVUDSNGRJSQE-UHFFFAOYSA-N 0.000 description 1
- ZLZCDKZCCDYRJF-UHFFFAOYSA-N methyl 1-(1,3-benzodioxol-5-yl)-6-fluoro-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2OCOC2=CC(C2C3=C(C4=CC(F)=CC=C4N3)CC(N2)C(=O)OC)=C1 ZLZCDKZCCDYRJF-UHFFFAOYSA-N 0.000 description 1
- CEKZLEXKVZHVSL-UHFFFAOYSA-N methyl 1-(2,3-dihydro-1-benzofuran-5-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2OCCC2=CC(C2C3=C(C4=CC=CC=C4N3)CC(N2)C(=O)OC)=C1 CEKZLEXKVZHVSL-UHFFFAOYSA-N 0.000 description 1
- YKRANILUQAWNOP-UHFFFAOYSA-N methyl 1-(2-chlorophenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=CC=C1Cl YKRANILUQAWNOP-UHFFFAOYSA-N 0.000 description 1
- CWEDPVSIJOZZDP-UHFFFAOYSA-N methyl 1-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=C(Cl)C(Cl)=C1 CWEDPVSIJOZZDP-UHFFFAOYSA-N 0.000 description 1
- XXQPNGWFNGRDEE-UHFFFAOYSA-N methyl 1-(3-hydroxy-4-methoxyphenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=C(OC)C(O)=C1 XXQPNGWFNGRDEE-UHFFFAOYSA-N 0.000 description 1
- TVICYPJVNPJQDC-UHFFFAOYSA-N methyl 1-(3-methylphenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=CC(C)=C1 TVICYPJVNPJQDC-UHFFFAOYSA-N 0.000 description 1
- YTIAFXJMADYHLR-UHFFFAOYSA-N methyl 1-(4-bromothiophen-2-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC(Br)=CS1 YTIAFXJMADYHLR-UHFFFAOYSA-N 0.000 description 1
- XGVZWMNWLZHJDM-UHFFFAOYSA-N methyl 1-(4-chlorophenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=C(Cl)C=C1 XGVZWMNWLZHJDM-UHFFFAOYSA-N 0.000 description 1
- JBCUNMDPNMFOHP-UHFFFAOYSA-N methyl 1-(4-ethylphenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=CC(CC)=CC=C1C1C(NC=2C3=CC=CC=2)=C3CC(C(=O)OC)N1 JBCUNMDPNMFOHP-UHFFFAOYSA-N 0.000 description 1
- IRELGTNBKRWOMX-UHFFFAOYSA-N methyl 1-(4-hydroxyphenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=C(O)C=C1 IRELGTNBKRWOMX-UHFFFAOYSA-N 0.000 description 1
- YCCPHMBIMIJBPW-UHFFFAOYSA-N methyl 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=C(OC)C=C1 YCCPHMBIMIJBPW-UHFFFAOYSA-N 0.000 description 1
- PYFUFWIRRAVVMB-UHFFFAOYSA-N methyl 1-(4-propan-2-ylphenyl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=C(C(C)C)C=C1 PYFUFWIRRAVVMB-UHFFFAOYSA-N 0.000 description 1
- SVTATKBJPRFFKB-UHFFFAOYSA-N methyl 1-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1CCCC2=CC(C3C4=C(C5=CC=CC=C5N4)CC(N3)C(=O)OC)=CC=C21 SVTATKBJPRFFKB-UHFFFAOYSA-N 0.000 description 1
- REUSWCPFIQPKBO-UHFFFAOYSA-N methyl 1-(5-bromothiophen-2-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=C(Br)S1 REUSWCPFIQPKBO-UHFFFAOYSA-N 0.000 description 1
- XCMDENFSIZNEEQ-UHFFFAOYSA-N methyl 1-(5-methylthiophen-2-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=C(C)S1 XCMDENFSIZNEEQ-UHFFFAOYSA-N 0.000 description 1
- GXDCHRVHRZKFMX-UHFFFAOYSA-N methyl 1-(furan-3-yl)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C=1C=COC=1 GXDCHRVHRZKFMX-UHFFFAOYSA-N 0.000 description 1
- GPKLVGREGDFVRR-UHFFFAOYSA-N methyl 1-[4-(trifluoromethyl)phenyl]-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=C(C(F)(F)F)C=C1 GPKLVGREGDFVRR-UHFFFAOYSA-N 0.000 description 1
- RICWOOUOBOCYNQ-UHFFFAOYSA-N methyl 1-naphthalen-2-yl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=CC=CC2=CC(C3C4=C(C5=CC=CC=C5N4)CC(N3)C(=O)OC)=CC=C21 RICWOOUOBOCYNQ-UHFFFAOYSA-N 0.000 description 1
- KYUMJWNDZQTKTB-UHFFFAOYSA-N methyl 1-thiophen-2-yl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound N1C(C(=O)OC)CC(C2=CC=CC=C2N2)=C2C1C1=CC=CS1 KYUMJWNDZQTKTB-UHFFFAOYSA-N 0.000 description 1
- FEIOASZZURHTHB-UHFFFAOYSA-N methyl 4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1 FEIOASZZURHTHB-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
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- 150000002772 monosaccharides Chemical class 0.000 description 1
- VEBLEROFGPOMPB-UHFFFAOYSA-N n-methylcyclopropanamine Chemical compound CNC1CC1 VEBLEROFGPOMPB-UHFFFAOYSA-N 0.000 description 1
- FVSUYFWWFUVGRG-UHFFFAOYSA-N naphthalen-1-ylurea Chemical compound C1=CC=C2C(NC(=O)N)=CC=CC2=C1 FVSUYFWWFUVGRG-UHFFFAOYSA-N 0.000 description 1
- 230000001452 natriuretic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 1
- SEVSMVUOKAMPDO-UHFFFAOYSA-N para-Acetoxybenzaldehyde Natural products CC(=O)OC1=CC=C(C=O)C=C1 SEVSMVUOKAMPDO-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- 108010043671 prostatic acid phosphatase Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
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- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 1
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 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
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940095064 tartrate Drugs 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001391 thioamide group Chemical group 0.000 description 1
- FKKJJPMGAWGYPN-UHFFFAOYSA-N thiophen-2-ylmethanamine Chemical compound NCC1=CC=CS1 FKKJJPMGAWGYPN-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- DKZBBWMURDFHNE-UHFFFAOYSA-N trans-coniferylaldehyde Natural products COC1=CC(C=CC=O)=CC=C1O DKZBBWMURDFHNE-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- DJXRIQMCROIRCZ-XOEOCAAJSA-N vibegron Chemical compound C1([C@H]([C@@H]2N[C@H](CC=3C=CC(NC(=O)[C@H]4N5C(=O)C=CN=C5CC4)=CC=3)CC2)O)=CC=CC=C1 DJXRIQMCROIRCZ-XOEOCAAJSA-N 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
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Classifications
-
- A—HUMAN NECESSITIES
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| GB9401090A GB9401090D0 (en) | 1994-01-21 | 1994-01-21 | Chemical compounds |
| PCT/EP1995/000183 WO1995019978A1 (en) | 1994-01-21 | 1995-01-19 | Tetracyclic derivatives, process of preparation and use |
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| DE69503753D1 DE69503753D1 (de) | 1998-09-03 |
| DE69503753T2 true DE69503753T2 (de) | 1999-01-21 |
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| DE2003199006 Active DE10399006I2 (de) | 1994-01-21 | 1995-01-19 | Tetracyclische Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung. |
| DE69503753T Expired - Lifetime DE69503753T2 (de) | 1994-01-21 | 1995-01-19 | Tetracyclische derivate, verfahren zu ihrer herstellung und ihre verwendung |
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| Application Number | Title | Priority Date | Filing Date |
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| DE2003199006 Active DE10399006I2 (de) | 1994-01-21 | 1995-01-19 | Tetracyclische Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung. |
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| US6225315B1 (en) * | 1998-11-30 | 2001-05-01 | Pfizer Inc | Method of treating nitrate-induced tolerance |
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1994
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