ES2553645T3 - Derivados sustituidos de azoantraceno, composiciones farmacéuticas y métodos de uso de los mismos - Google Patents
Derivados sustituidos de azoantraceno, composiciones farmacéuticas y métodos de uso de los mismos Download PDFInfo
- Publication number
- ES2553645T3 ES2553645T3 ES10779665.8T ES10779665T ES2553645T3 ES 2553645 T3 ES2553645 T3 ES 2553645T3 ES 10779665 T ES10779665 T ES 10779665T ES 2553645 T3 ES2553645 T3 ES 2553645T3
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- Spain
- Prior art keywords
- phenyl
- isoquinolin
- acid
- dioxino
- amino
- 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.)
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- 238000000034 method Methods 0.000 title description 105
- 239000008194 pharmaceutical composition Substances 0.000 title description 14
- -1 benzothiofeneyl Chemical group 0.000 abstract description 388
- 150000001875 compounds Chemical class 0.000 abstract description 101
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 48
- 150000003839 salts Chemical class 0.000 abstract description 8
- 239000001257 hydrogen Substances 0.000 abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 abstract 2
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 abstract 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 abstract 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 abstract 1
- 125000004076 pyridyl group Chemical group 0.000 abstract 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 151
- 239000002253 acid Substances 0.000 description 146
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 124
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 82
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- 150000004702 methyl esters Chemical class 0.000 description 75
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 62
- 235000019439 ethyl acetate Nutrition 0.000 description 52
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 50
- 239000000203 mixture Substances 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- 150000002148 esters Chemical class 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- 239000007832 Na2SO4 Substances 0.000 description 15
- 239000012267 brine Substances 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- GARVSVCVQCGHLY-UHFFFAOYSA-N isoquinoline-7,8-dicarboxylic acid Chemical compound C1=CN=CC2=C(C(O)=O)C(C(=O)O)=CC=C21 GARVSVCVQCGHLY-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- QUFUUBBLCOBJPH-UHFFFAOYSA-N isoquinoline-7-carboxylic acid Chemical compound C1=CN=CC2=CC(C(=O)O)=CC=C21 QUFUUBBLCOBJPH-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- XTVRPSBYSGATQQ-UHFFFAOYSA-N 1,2-dinitrosodioxidane Chemical compound O=NOON=O XTVRPSBYSGATQQ-UHFFFAOYSA-N 0.000 description 5
- LHGRUGVXZLHYKE-UHFFFAOYSA-N 2,5-dimethyl-1,3-oxazole-4-carboxylic acid Chemical compound CC1=NC(C(O)=O)=C(C)O1 LHGRUGVXZLHYKE-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- MBMJQYUNAQBQAB-XUZZJYLKSA-N (3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid Chemical compound C1=CC([C@H]2COC=3C=C4C[C@H](N(CC4=CC=3O2)C(O)=O)C(=O)O)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 MBMJQYUNAQBQAB-XUZZJYLKSA-N 0.000 description 4
- KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- YWTYCEGHQNUORQ-XUZZJYLKSA-N (3s,8s)-3-[4-(cyclohexylmethoxy)phenyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid Chemical compound C1=CC([C@H]2COC=3C=C4C[C@H](N(CC4=CC=3O2)C(O)=O)C(=O)O)=CC=C1OCC1CCCCC1 YWTYCEGHQNUORQ-XUZZJYLKSA-N 0.000 description 3
- XYHIWUWOCXFFNO-YLJHYDRVSA-N (3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(1r)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid Chemical compound C1=CC([C@@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(O)=O)[C@H](CC)C=2C=CC=CC=2)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 XYHIWUWOCXFFNO-YLJHYDRVSA-N 0.000 description 3
- XYHIWUWOCXFFNO-WSZLSEGOSA-N (3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(1s)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid Chemical compound C1=CC([C@@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(O)=O)[C@@H](CC)C=2C=CC=CC=2)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 XYHIWUWOCXFFNO-WSZLSEGOSA-N 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 3
- 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 3
- FHNRXEYKJBDNKP-UHFFFAOYSA-N 4-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazole-5-carboxylic acid Chemical compound CC=1N=C(NC(=O)OC(C)(C)C)SC=1C(O)=O FHNRXEYKJBDNKP-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
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- 239000003480 eluent Substances 0.000 description 3
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- 230000007062 hydrolysis Effects 0.000 description 3
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
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- 230000000979 retarding effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
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- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- HIKCRLDSCSWXML-VIFPVBQESA-N (3s)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=C(O)C=C2CN[C@H](C(=O)O)CC2=C1 HIKCRLDSCSWXML-VIFPVBQESA-N 0.000 description 2
- IIKGZTHZDODFSU-QMMMGPOBSA-N (3s)-7-hydroxy-6-nitro-3,4-dihydro-1h-isoquinoline-2,3-dicarboxylic acid Chemical compound [O-][N+](=O)C1=C(O)C=C2CN(C(O)=O)[C@H](C(=O)O)CC2=C1 IIKGZTHZDODFSU-QMMMGPOBSA-N 0.000 description 2
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 2
- VUWLYIRUBZGJJB-UHFFFAOYSA-N 1-[4-[(3,4-dichlorophenyl)methoxy]phenyl]ethane-1,2-diol Chemical compound C1=CC(C(O)CO)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 VUWLYIRUBZGJJB-UHFFFAOYSA-N 0.000 description 2
- OTRZIEWHELCVJX-UHFFFAOYSA-N 1-methoxy-2-(2-methoxyethoxy)ethane;1-methylpyrrolidin-2-one Chemical compound CN1CCCC1=O.COCCOCCOC OTRZIEWHELCVJX-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- WUQBOLHUTUTBDT-NRFANRHFSA-N 3-[(2r)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2-hydroxyethoxy]-4-fluorobenzonitrile Chemical compound C([C@H](O)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)OC1=CC(C#N)=CC=C1F WUQBOLHUTUTBDT-NRFANRHFSA-N 0.000 description 2
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 2
- 208000032841 Bulimia Diseases 0.000 description 2
- 206010006550 Bulimia nervosa Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 208000030814 Eating disease Diseases 0.000 description 2
- HYTRYEXINDDXJK-UHFFFAOYSA-N Ethyl isopropyl ketone Chemical compound CCC(=O)C(C)C HYTRYEXINDDXJK-UHFFFAOYSA-N 0.000 description 2
- 208000019454 Feeding and Eating disease Diseases 0.000 description 2
- 102000051325 Glucagon Human genes 0.000 description 2
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Classifications
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/06—Peri-condensed systems
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| US30934810P | 2010-03-01 | 2010-03-01 | |
| PCT/US2010/029172 WO2010114824A1 (en) | 2009-03-30 | 2010-03-30 | Substituted azoanthracene derivatives, pharmaceutical compositions, and methods of use thereof |
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| CN103030646B (zh) * | 2011-09-29 | 2016-08-24 | 上海恒瑞医药有限公司 | 苯并二氧六环类衍生物、其制备方法及其在医药上的应用 |
| US8822527B2 (en) | 2011-10-17 | 2014-09-02 | Biotheryx, Inc. | Substituted biaryl alkyl amides |
| KR102165434B1 (ko) * | 2013-01-17 | 2020-10-14 | 브이티브이 테라퓨틱스 엘엘씨 | 2형 당뇨병 및 다른 장애의 치료를 위한 glp1r 작용제 및 메트포민의 조합 및 이것들의 사용법 |
| CN107072970B (zh) | 2014-08-29 | 2021-05-25 | 得克萨斯州大学系统董事会 | 用于治疗癌症和其他增殖性疾病的新的辣椒平类似物 |
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| CA3090823A1 (en) * | 2018-05-08 | 2019-11-14 | Vtv Therapeutics Llc | Therapeutic uses of glp1r agonists |
| US10934279B2 (en) | 2018-06-13 | 2021-03-02 | Pfizer Inc. | GLP-1 receptor agonists and uses thereof |
| CA3140972C (en) | 2019-05-20 | 2024-06-18 | Pfizer Inc. | Combinations comprising benzodioxol as glp-1r agonists for use in the treatment of nash/nafld and related diseases |
| MX2022008938A (es) * | 2020-01-20 | 2022-10-18 | Crescenta Biosciences | Nuevos compuestos moduladores del metabolismo celular y usos de los mismos. |
| WO2021196951A1 (zh) | 2020-04-01 | 2021-10-07 | 杭州中美华东制药有限公司 | Glp-1受体激动剂游离碱的药学上可接受的酸式盐及其制备方法 |
| CN115461344B (zh) * | 2020-04-01 | 2024-01-12 | 杭州中美华东制药有限公司 | 一种glp-1受体激动剂的晶型a及其制备方法 |
| TW202144340A (zh) | 2020-04-03 | 2021-12-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | 稠合咪唑類衍生物、其製備方法及其在醫藥上的應用 |
| TW202210461A (zh) | 2020-05-28 | 2022-03-16 | 中國大陸商杭州中美華東製藥有限公司 | 一種（ｓ）—２—胺基—３—（４—（２，３—二甲基吡啶—４—基）苯基）丙酸甲酯二酸鹽的製備方法 |
| TW202206420A (zh) | 2020-05-28 | 2022-02-16 | 美商維特衛治療有限責任公司 | 用於製備glp-1受體促效劑的中間體和方法 |
| CN115697968B (zh) * | 2020-05-28 | 2024-03-29 | 杭州中美华东制药有限公司 | (s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯及其盐的制备方法 |
| CN115667222B (zh) * | 2020-05-28 | 2023-09-29 | 杭州中美华东制药有限公司 | 一种制备glp-1受体激动剂的方法 |
| EP4159737A4 (en) * | 2020-05-28 | 2024-10-09 | Hangzhou Zhongmeihuadong Pharmaceutical Co., Ltd. | METHOD FOR PREPARING A GLP-1 RECEPTOR AGONIST-FREE BASE |
| TW202206412A (zh) | 2020-05-28 | 2022-02-16 | 美商維特衛治療有限責任公司 | 製備（ｓ）－２－胺基－３－（４－（２，３－二甲基吡啶－４－基）苯基）丙酸甲酯及其鹽酸鹽的方法 |
| JP2023539584A (ja) | 2020-09-01 | 2023-09-15 | 江蘇恒瑞医薬股▲ふん▼有限公司 | 縮合イミダゾール誘導体、その調製方法及びその医薬的応用 |
| US20230382921A1 (en) * | 2020-09-21 | 2023-11-30 | Vtv Therapeutics Llc | Amorphous Form of Isoquinoline Derivative |
| US12454511B2 (en) | 2020-10-08 | 2025-10-28 | Eli Lilly And Company | 6-methoxy-3,4-dihydro-1H-isoquinolin compounds |
| WO2022078152A1 (zh) | 2020-10-12 | 2022-04-21 | 杭州中美华东制药有限公司 | 苯并咪唑酮类glp-1受体激动剂及其用途 |
| US20240246959A1 (en) | 2020-11-27 | 2024-07-25 | Shenzhen Salubris Pharmaceuticals Co., Ltd. | Benzimidazole derivative and preparation method therefor and medical use thereof |
| US20240208952A1 (en) | 2021-03-22 | 2024-06-27 | Hangzhou Zhongmeihuadong Pharmaceutical Co., Ltd. | Thiophene glp-1 receptor agonist and use thereof |
| WO2022202864A1 (ja) | 2021-03-24 | 2022-09-29 | 塩野義製薬株式会社 | 縮合環を有するｇｌｐ－１受容体作動薬を含有する医薬組成物 |
| CN117500789A (zh) * | 2021-06-17 | 2024-02-02 | 杭州中美华东制药有限公司 | 一种吡啶硼酸酯的制备方法 |
| WO2022262615A1 (zh) * | 2021-06-17 | 2022-12-22 | 杭州中美华东制药有限公司 | 蒽类化合物、其制备方法和医药用途 |
| CN117098758A (zh) | 2021-06-24 | 2023-11-21 | 杭州中美华东制药有限公司 | Glp-1受体激动剂及其组合物和用途 |
| WO2023029979A1 (zh) * | 2021-09-03 | 2023-03-09 | 杭州中美华东制药有限公司 | Glp-1受体激动剂中间体的制备方法 |
| CN118948849A (zh) | 2021-09-08 | 2024-11-15 | 盐野义制药株式会社 | 用于预防和治疗与抗肥胖作用有关的疾病的药物 |
| CA3233453A1 (en) * | 2021-09-28 | 2023-04-06 | Meimei Chen | Solid composition of glp-1 receptor agonist |
| JPWO2024063143A1 (enExample) | 2022-09-22 | 2024-03-28 | ||
| WO2025057134A2 (en) | 2023-09-14 | 2025-03-20 | Ascletis Pharma (China) Co., Limited | Glp-1r agonist and therapeutic method thereof |
| US12291530B1 (en) | 2023-11-24 | 2025-05-06 | Ascletis Pharma (China) Co., Limited | GLP-1R agonist and therapeutic method thereof |
| WO2025189141A1 (en) | 2024-03-08 | 2025-09-12 | Annapurna Bio, Inc. | Methods for treating obesity and increasing weight loss |
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| BE795265A (fr) * | 1972-02-09 | 1973-08-09 | Philips Nv | Nouveaux derives de quinoleine a activite pharmacologique |
| EP0233728A1 (en) * | 1986-02-11 | 1987-08-26 | Takeda Chemical Industries, Ltd. | 1,4-Benzoxazine derivatives their production and use |
| US5756532A (en) | 1995-11-06 | 1998-05-26 | American Home Products Corporation | Aminomethyl-2 3 8 9-tetrahydro-7H-1 4-dioxino 2 3-E!-indol-8-ones and derivatives |
| WO2000042026A1 (en) | 1999-01-15 | 2000-07-20 | Novo Nordisk A/S | Non-peptide glp-1 agonists |
| US6815451B2 (en) * | 2001-03-27 | 2004-11-09 | Actelion Pharmaceuticals Ltd. | 1,2,3,4-Tetrahydroisoquinolines derivatives as urotensin II receptor antagonists |
| ES2278064T3 (es) * | 2001-10-19 | 2007-08-01 | Transtech Pharma Inc. | Derivados de beta-carbolina como inhibidores de ptp. |
| EP1458382A1 (en) | 2001-12-21 | 2004-09-22 | Novo Nordisk A/S | Amide derivatives as gk activators |
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| WO2005014532A1 (en) * | 2003-08-08 | 2005-02-17 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds, compositions and methods of use |
| RU2284325C2 (ru) | 2003-12-17 | 2006-09-27 | Общество С Ограниченной Ответственностью "Асинэкс Медхим" | Производные фенил-3-аминометил-хинолона-2 в качестве ингибиторов no-синтетазы, способ их получения, биологически активные соединения и фармацевтическая композиция на их основе |
| WO2008118935A1 (en) * | 2007-03-26 | 2008-10-02 | Neurogen Corporation | Compounds and processes for preparing substituted aminomethyl-2,3,8,9-tetrahydro-7h-1,4-dioxino[2,3-e]indol-8-ones |
| WO2009111700A2 (en) * | 2008-03-07 | 2009-09-11 | Transtech Pharma, Inc. | Oxadiazoanthracene compounds for the treatment of diabetes |
| US8718994B2 (en) | 2008-04-09 | 2014-05-06 | Transtech Pharma, Llc | Ligands for the GLP-1 receptor and methods for discovery thereof |
| CN102378574B (zh) | 2009-03-30 | 2013-11-20 | 转化技术制药公司 | 取代的偶氮蒽衍生物、药物组合物及其使用方法 |
| US8501982B2 (en) | 2010-06-09 | 2013-08-06 | Receptos, Inc. | GLP-1 receptor stabilizers and modulators |
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| US8383644B2 (en) | 2013-02-26 |
| KR101732978B1 (ko) | 2017-05-08 |
| CN102378574A (zh) | 2012-03-14 |
| US20150148539A1 (en) | 2015-05-28 |
| EA023430B1 (ru) | 2016-06-30 |
| US20110160198A1 (en) | 2011-06-30 |
| IL214822A0 (en) | 2011-11-30 |
| CA2757084A1 (en) | 2010-10-07 |
| MA33219B1 (fr) | 2012-04-02 |
| AU2010232750A1 (en) | 2011-09-08 |
| BRPI1013579A2 (pt) | 2020-11-03 |
| CA2757084C (en) | 2017-08-29 |
| EP2413693B1 (en) | 2015-09-09 |
| TN2011000437A1 (en) | 2013-03-27 |
| JP2012522060A (ja) | 2012-09-20 |
| WO2010114824A8 (en) | 2011-10-06 |
| CN102378574B (zh) | 2013-11-20 |
| SG174205A1 (en) | 2011-10-28 |
| EA201171197A1 (ru) | 2012-04-30 |
| JP5755217B2 (ja) | 2015-07-29 |
| HK1164050A1 (en) | 2012-09-21 |
| DK2413693T3 (en) | 2015-11-16 |
| EA201171197A8 (ru) | 2014-10-30 |
| US9175003B2 (en) | 2015-11-03 |
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| EP2413693A1 (en) | 2012-02-08 |
| AU2010232750B2 (en) | 2015-10-29 |
| US20130096150A1 (en) | 2013-04-18 |
| IL214822A (en) | 2016-08-31 |
| MX2011010347A (es) | 2011-11-29 |
| KR20120006506A (ko) | 2012-01-18 |
| US8987295B2 (en) | 2015-03-24 |
| WO2010114824A1 (en) | 2010-10-07 |
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