AU2007248038A1 - Constrained compounds as CGRP-receptor antagonists - Google Patents

Info

Publication number

AU2007248038A1

AU2007248038A1 AU2007248038A AU2007248038A AU2007248038A1 AU 2007248038 A1 AU2007248038 A1 AU 2007248038A1 AU 2007248038 A AU2007248038 A AU 2007248038A AU 2007248038 A AU2007248038 A AU 2007248038A AU 2007248038 A1 AU2007248038 A1 AU 2007248038A1

Authority

AU

Australia

Prior art keywords

oxo

mmol

mixture

indazol

chloro

Prior art date

2006-05-03

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• Discuss

• 150000001875 compounds Chemical class 0.000 title claims description 248
• 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 title description 16
• 102000008323 calcitonin gene-related peptide receptor activity proteins Human genes 0.000 title description 15
• 229940044551 receptor antagonist Drugs 0.000 title description 5
• 239000002464 receptor antagonist Substances 0.000 title description 5
• 239000000203 mixture Substances 0.000 claims description 562
• -1 N-(R 9 )-piperazinyl Chemical group 0.000 claims description 86
• 125000000217 alkyl group Chemical group 0.000 claims description 51
• 229910052739 hydrogen Inorganic materials 0.000 claims description 34
• 238000000034 method Methods 0.000 claims description 30
• 239000001257 hydrogen Substances 0.000 claims description 29
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
• 125000001188 haloalkyl group Chemical group 0.000 claims description 17
• 125000003342 alkenyl group Chemical group 0.000 claims description 16
• 208000019695 Migraine disease Diseases 0.000 claims description 14
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 14
• 206010027599 migraine Diseases 0.000 claims description 14
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
• WRBSNTFAQMMJNN-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1H-pyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1NNC2CC=C3C(=C12)C=NC(C=C3)=O WRBSNTFAQMMJNN-UHFFFAOYSA-N 0.000 claims description 11
• 150000003839 salts Chemical class 0.000 claims description 11
• 125000001424 substituent group Chemical group 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
• 125000001624 naphthyl group Chemical group 0.000 claims description 9
• 125000004076 pyridyl group Chemical group 0.000 claims description 9
• LUVYLURQXCSXOS-UHFFFAOYSA-N 4h-thieno[3,2-b]pyridin-5-one Chemical compound OC1=CC=C2SC=CC2=N1 LUVYLURQXCSXOS-UHFFFAOYSA-N 0.000 claims description 8
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 7
• QHABHDSXCLQTPN-UHFFFAOYSA-N 6,7,9,10-tetrahydro-3H-pyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1=NNC=2C=CC3=C(C12)CNC(CC3)=O QHABHDSXCLQTPN-UHFFFAOYSA-N 0.000 claims description 6
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
• 125000006357 methylene carbonyl group Chemical group [H]C([H])([*:1])C([*:2])=O 0.000 claims description 4
• 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 4
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
• BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 3
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 3
• 239000005977 Ethylene Chemical group 0.000 claims description 3
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000002757 morpholinyl group Chemical group 0.000 claims description 3
• GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 claims description 3
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000004620 quinolinyl-N-oxide group Chemical group 0.000 claims description 3
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
• WAAFGKPNMRAILP-FQEVSTJZSA-N (4s)-7-chloro-2-(2,2-dimethylpropyl)-4-[2-oxo-2-[4-(5-oxo-1,4-dihydropyrrolo[3,2-b]pyridin-6-yl)piperidin-1-yl]ethyl]-1,4,5,8-tetrahydropyrrolo[2,3-i][2]benzazepin-3-one Chemical compound O=C([C@H](CC(=O)N1CCC(CC1)C=1C(NC=2C=CNC=2C=1)=O)C1)N(CC(C)(C)C)CC2=C1C=C(Cl)C1=C2C=CN1 WAAFGKPNMRAILP-FQEVSTJZSA-N 0.000 claims description 2
• IFZLXSMKSSGVEI-IBGZPJMESA-N (4s)-7-chloro-4-[2-[4-(6-chloro-1h-pyrrolo[2,3-b]pyridin-4-yl)-4-hydroxypiperidin-1-yl]-2-oxoethyl]-2-(2,2-dimethylpropyl)-1,4,5,8-tetrahydropyrrolo[2,3-i][2]benzazepin-3-one Chemical compound O=C([C@H](CC(=O)N1CCC(O)(CC1)C=1C=2C=CNC=2N=C(Cl)C=1)C1)N(CC(C)(C)C)CC2=C1C=C(Cl)C1=C2C=CN1 IFZLXSMKSSGVEI-IBGZPJMESA-N 0.000 claims description 2
• SVCFEZDDZIQBJE-QFIPXVFZSA-N (7s)-4-chloro-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]ethyl]-3-propyl-9-(2,2,2-trifluoroethyl)-7,10-dihydro-6h-pyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1CC2=CC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)C[C@H]1C(=O)N(CC(F)(F)F)CC2=C3C=NN(CCC)C3=C(Cl)C=C2C1 SVCFEZDDZIQBJE-QFIPXVFZSA-N 0.000 claims description 2
• YZCARBAUHDWSEA-SFHVURJKSA-N 2-bromo-6-[1-[2-[(7s)-4-chloro-9-(2,2-dimethylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetyl]piperidin-4-yl]-4h-thieno[3,2-b]pyridin-5-one Chemical compound O=C([C@H](CC(=O)N1CCC(CC1)C=1C(NC=2C=C(Br)SC=2C=1)=O)C1)N(CC(C)(C)C)CC2=C1C=C(Cl)C1=C2C=NN1 YZCARBAUHDWSEA-SFHVURJKSA-N 0.000 claims description 2
• HEJMMTPRNAEVRN-SFHVURJKSA-N 3-bromo-6-[1-[2-[(7s)-4-chloro-9-(2,2-dimethylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetyl]piperidin-4-yl]-4h-thieno[3,2-b]pyridin-5-one Chemical compound O=C([C@H](CC(=O)N1CCC(CC1)C=1C(NC=2C(Br)=CSC=2C=1)=O)C1)N(CC(C)(C)C)CC2=C1C=C(Cl)C1=C2C=NN1 HEJMMTPRNAEVRN-SFHVURJKSA-N 0.000 claims description 2
• KKENTOLYUCKZFP-FVRDMJKUSA-N 5-[1-[2-[(7s)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetyl]piperidin-4-yl]imidazolidine-2,4-dione Chemical compound C([C@@H]1CC2=C(C=3C=NNC=3C(Cl)=C2)CN(C1=O)CC(F)(F)F)C(=O)N(CC1)CCC1C1NC(=O)NC1=O KKENTOLYUCKZFP-FVRDMJKUSA-N 0.000 claims description 2
• PCKBLXLYWSCVKI-LJQANCHMSA-N [(7r)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl] 4-(2-oxo-3h-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate Chemical compound O=C([C@H](OC(=O)N1CCC(CC1)N1C(NC2=NC=CC=C21)=O)C1)N(CC(F)(F)F)CC2=C1C=C(Cl)C1=C2C=NN1 PCKBLXLYWSCVKI-LJQANCHMSA-N 0.000 claims description 2
• 239000002671 adjuvant Substances 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 7
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 3
• AVRPHUJQACDXTJ-NRFANRHFSA-N (4s)-7-chloro-2-(2,2-dimethylpropyl)-4-[2-[4-(1-methyl-5-oxo-4h-pyrrolo[3,2-b]pyridin-6-yl)piperidin-1-yl]-2-oxoethyl]-1,4,5,8-tetrahydropyrrolo[2,3-i][2]benzazepin-3-one Chemical compound C1C2=CC(Cl)=C(NC=C3)C3=C2CN(CC(C)(C)C)C(=O)[C@@H]1CC(=O)N(CC1)CCC1C(C(=O)N1)=CC2=C1C=CN2C AVRPHUJQACDXTJ-NRFANRHFSA-N 0.000 claims 1
• BNOLTBNZJYQCKX-AWEZNQCLSA-N (7s)-1,4-dibromo-7-[2-oxo-2-[4-(2-oxo-3h-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound O=C([C@H](CC(=O)N1CCC(CC1)N1C(NC2=NC=CC=C21)=O)C1)N(CC(F)(F)F)CC2=C1C=C(Br)C1=NNC(Br)=C21 BNOLTBNZJYQCKX-AWEZNQCLSA-N 0.000 claims 1
• NYJCQZLYDFUEFM-SFHVURJKSA-N (7s)-1,4-dibromo-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1CC2=CC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)C[C@@H]1CC(C=C(Br)C=2C3=C(Br)NN=2)=C3CN(CC(F)(F)F)C1=O NYJCQZLYDFUEFM-SFHVURJKSA-N 0.000 claims 1
• MRYRTENYDMVYEJ-FQEVSTJZSA-N (7s)-1,4-dichloro-7-[2-oxo-2-[4-(2-oxo-3h-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]ethyl]-9-(2-piperidin-1-ylethyl)-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound O=C([C@H](CC(=O)N1CCC(CC1)N1C(NC2=NC=CC=C21)=O)CC=1C=C(Cl)C2=NNC(=C2C=1C1)Cl)N1CCN1CCCCC1 MRYRTENYDMVYEJ-FQEVSTJZSA-N 0.000 claims 1
• PZLKMJOFBUQDRD-SFHVURJKSA-N (7s)-1,4-dichloro-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1CC2=CC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)C[C@@H]1CC(C=C(Cl)C=2C3=C(Cl)NN=2)=C3CN(CC(F)(F)F)C1=O PZLKMJOFBUQDRD-SFHVURJKSA-N 0.000 claims 1
• CBKVZMXPZXYYRC-NRFANRHFSA-N (7s)-4-chloro-3-(methoxymethyl)-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-7,10-dihydro-6h-pyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1CC2=CC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)C[C@H]1C(=O)N(CC(F)(F)F)CC2=C3C=NN(COC)C3=C(Cl)C=C2C1 CBKVZMXPZXYYRC-NRFANRHFSA-N 0.000 claims 1
• OBDBVSGXUVGBBY-FQEVSTJZSA-N (7s)-4-chloro-3-methyl-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-7,10-dihydro-6h-pyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1CC2=CC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)C[C@H]1C(=O)N(CC(F)(F)F)CC2=C3C=NN(C)C3=C(Cl)C=C2C1 OBDBVSGXUVGBBY-FQEVSTJZSA-N 0.000 claims 1
• GVAXLVWGZFNSQX-SFHVURJKSA-N (7s)-4-chloro-7-[2-[4-(9-fluoro-2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-2-oxoethyl]-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1C2=CC(Cl)=C(NN=C3)C3=C2CN(CC(F)(F)F)C(=O)[C@@H]1CC(=O)N(CC1)CCC1N1CCC(C=CC=C2F)=C2NC1=O GVAXLVWGZFNSQX-SFHVURJKSA-N 0.000 claims 1
• KTGHSVZLFVDMGQ-SFHVURJKSA-N (7s)-4-chloro-7-[2-[4-[3-(2-fluorophenyl)-2-oxoimidazol-1-yl]piperidin-1-yl]-2-oxoethyl]-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound FC1=CC=CC=C1N1C(=O)N(C2CCN(CC2)C(=O)C[C@H]2C(N(CC(F)(F)F)CC3=C4C=NNC4=C(Cl)C=C3C2)=O)C=C1 KTGHSVZLFVDMGQ-SFHVURJKSA-N 0.000 claims 1
• VBPMPNJTNKRJJE-AWEZNQCLSA-N (7s)-4-chloro-7-[2-oxo-2-[4-(2-oxo-1h-imidazol-3-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C([C@@H]1CC2=C(C=3C=NNC=3C(Cl)=C2)CN(C1=O)CC(F)(F)F)C(=O)N(CC1)CCC1N1C=CNC1=O VBPMPNJTNKRJJE-AWEZNQCLSA-N 0.000 claims 1
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
• JDXAIRURQACNQA-SFHVURJKSA-N 2-chloro-6-[1-[2-[(7s)-4-chloro-9-(2,2-dimethylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetyl]piperidin-4-yl]-4h-thieno[3,2-b]pyridin-5-one Chemical compound O=C([C@H](CC(=O)N1CCC(CC1)C=1C(NC=2C=C(Cl)SC=2C=1)=O)C1)N(CC(C)(C)C)CC2=C1C=C(Cl)C1=C2C=NN1 JDXAIRURQACNQA-SFHVURJKSA-N 0.000 claims 1
• NEDLAVAEXSUBDX-AWEZNQCLSA-N 3-[1-[2-[(7s)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetyl]piperidin-4-yl]-2-oxo-1h-imidazole-5-carbonitrile Chemical compound C([C@@H]1CC2=C(C=3C=NNC=3C(Cl)=C2)CN(C1=O)CC(F)(F)F)C(=O)N(CC1)CCC1N1C=C(C#N)NC1=O NEDLAVAEXSUBDX-AWEZNQCLSA-N 0.000 claims 1
• FIIMYCJTIKXHQA-LBPRGKRZSA-N 8-[2-[(7s)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound C([C@@H]1CC2=C(C=3C=NNC=3C(Cl)=C2)CN(C1=O)CC(F)(F)F)C(=O)N(CC1)CCC21NC(=O)NC2=O FIIMYCJTIKXHQA-LBPRGKRZSA-N 0.000 claims 1
• GCUCEZBWWAUVQK-HSZRJFAPSA-N [(7r)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl] 4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidine-1-carboxylate Chemical compound C1CC2=CC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)O[C@@H]1CC(C=C(Cl)C2=C3C=NN2)=C3CN(CC(F)(F)F)C1=O GCUCEZBWWAUVQK-HSZRJFAPSA-N 0.000 claims 1
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 345
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 321
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 279
• 238000006243 chemical reaction Methods 0.000 description 238
• 239000000543 intermediate Substances 0.000 description 238
• 238000001819 mass spectrum Methods 0.000 description 207
• 239000007787 solid Substances 0.000 description 190
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 168
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 159
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 144
• 235000019439 ethyl acetate Nutrition 0.000 description 122
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 115
• 239000000463 material Substances 0.000 description 112
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 111
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 101
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 98
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 98
• 238000005160 1H NMR spectroscopy Methods 0.000 description 92
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 92
• 239000000243 solution Substances 0.000 description 92
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 92
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 91
• 239000011541 reaction mixture Substances 0.000 description 76
• 239000002904 solvent Substances 0.000 description 73
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 72
• 235000017557 sodium bicarbonate Nutrition 0.000 description 72
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
• 239000000047 product Substances 0.000 description 68
• 239000008346 aqueous phase Substances 0.000 description 64
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 64
• 239000003921 oil Substances 0.000 description 62
• 235000019198 oils Nutrition 0.000 description 62
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 61
• 238000010992 reflux Methods 0.000 description 61
• 238000003756 stirring Methods 0.000 description 60
• 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 57
• 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 description 57
• 239000012267 brine Substances 0.000 description 55
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 55
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• KPFKISFXMZLWSI-HSZRJFAPSA-N methyl (2r)-3-[2-(acetyloxymethyl)-3-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(NC(=O)OC(C)(C)C)C(C)=C1COC(C)=O KPFKISFXMZLWSI-HSZRJFAPSA-N 0.000 description 2
• PTAFWCDCAJQIQW-HXUWFJFHSA-N methyl (2r)-3-[2-(acetyloxymethyl)-4-amino-3-methylphenyl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(N)C(C)=C1COC(C)=O PTAFWCDCAJQIQW-HXUWFJFHSA-N 0.000 description 2
• SQXSEDLWRFYTJZ-LJQANCHMSA-N methyl (2r)-3-[2-(acetyloxymethyl)-4-amino-5-chloro-3-methylphenyl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC(Cl)=C(N)C(C)=C1COC(C)=O SQXSEDLWRFYTJZ-LJQANCHMSA-N 0.000 description 2
• WNGCERFSYGDKLR-ZMBIFBSDSA-N methyl (2r)-3-[2-(hydroxymethyl)-3-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-2-(phenylmethoxycarbonylamino)propanoate;hydrochloride Chemical compound Cl.C([C@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(NC(=O)OC(C)(C)C)C(C)=C1CO WNGCERFSYGDKLR-ZMBIFBSDSA-N 0.000 description 2
• LQYMESVTIGCWCM-OAQYLSRUSA-N methyl (2r)-3-[2-(hydroxymethyl)-5-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC(C)=C(NC(=O)OC(C)(C)C)C=C1CO LQYMESVTIGCWCM-OAQYLSRUSA-N 0.000 description 2
• JECAIEBOZZVBPR-QMMMGPOBSA-N methyl 2-[(7s)-1,4-dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)CC2=C1C1=C(Br)NN=C1C(Br)=C2 JECAIEBOZZVBPR-QMMMGPOBSA-N 0.000 description 2
• UMZPECXJRCEKGD-AWEZNQCLSA-N methyl 2-[(7s)-1,4-dichloro-8-oxo-9-(2-piperidin-1-ylethyl)-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C([C@H](C1=O)CC(=O)OC)C=2C=C(Cl)C3=NNC(Cl)=C3C=2CN1CCN1CCCCC1 UMZPECXJRCEKGD-AWEZNQCLSA-N 0.000 description 2
• SGOBGCHGRNNWHE-VIFPVBQESA-N methyl 2-[(7s)-4-bromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)CC2=CC(Br)=C(NN=C3)C3=C21 SGOBGCHGRNNWHE-VIFPVBQESA-N 0.000 description 2
• MIUFXYKTEVUSLL-LBPRGKRZSA-N methyl 2-[(7s)-4-bromo-9-(cyclopropylmethyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C([C@H](C1=O)CC(=O)OC)C2=CC(Br)=C3NN=CC3=C2CN1CC1CC1 MIUFXYKTEVUSLL-LBPRGKRZSA-N 0.000 description 2
• AWCZWEAHSBURQH-AWEZNQCLSA-N methyl 2-[(7s)-4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C([C@H](C1=O)CC(=O)OC)C2=CC(Cl)=C3NN=CC3=C2CN1CC1=CC=NC=C1 AWCZWEAHSBURQH-AWEZNQCLSA-N 0.000 description 2
• BWYHVIGCNNRQPI-AWEZNQCLSA-N methyl 2-[(7s)-9-(2,2-dimethylpropyl)-4-methyl-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(C)(C)C)C(=O)[C@H](CC(=O)OC)CC2=CC(C)=C(NN=C3)C3=C21 BWYHVIGCNNRQPI-AWEZNQCLSA-N 0.000 description 2
• OZZPXUDOSXJZNE-UHFFFAOYSA-N methyl 3-[2-(acetyloxymethyl)-3-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-2-(phenylmethoxycarbonylamino)prop-2-enoate Chemical compound C=1C=C(NC(=O)OC(C)(C)C)C(C)=C(COC(C)=O)C=1C=C(C(=O)OC)NC(=O)OCC1=CC=CC=C1 OZZPXUDOSXJZNE-UHFFFAOYSA-N 0.000 description 2
• MRWRSTHVSJHZGK-UHFFFAOYSA-N methyl 3-[2-(acetyloxymethyl)-4-phenylmethoxyphenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]prop-2-enoate Chemical compound C1=C(COC(C)=O)C(C=C(NC(=O)OC(C)(C)C)C(=O)OC)=CC=C1OCC1=CC=CC=C1 MRWRSTHVSJHZGK-UHFFFAOYSA-N 0.000 description 2
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• VRUKVNKYXZIDLI-UHFFFAOYSA-N methyl 3-[4-acetamido-2-(acetyloxymethyl)-3,5-dimethylphenyl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C=1C=CC=CC=1COC(=O)NC(C(=O)OC)CC1=CC(C)=C(NC(C)=O)C(C)=C1COC(C)=O VRUKVNKYXZIDLI-UHFFFAOYSA-N 0.000 description 2
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• QEYJJGVWJDWLQA-HSZRJFAPSA-N methyl (2r)-3-[2-(acetyloxymethyl)-5-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC(C)=C(NC(=O)OC(C)(C)C)C=C1COC(C)=O QEYJJGVWJDWLQA-HSZRJFAPSA-N 0.000 description 1
• SBMPLXTUKSODEU-OAQYLSRUSA-N methyl (2r)-3-[2-(chloromethyl)-3-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(NC(=O)OC(C)(C)C)C(C)=C1CCl SBMPLXTUKSODEU-OAQYLSRUSA-N 0.000 description 1
• HNSAWIFLVOGYFO-OAQYLSRUSA-N methyl (2r)-3-[2-(chloromethyl)-5-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC(C)=C(NC(=O)OC(C)(C)C)C=C1CCl HNSAWIFLVOGYFO-OAQYLSRUSA-N 0.000 description 1
• LHHQTEBKGWFQBV-OAQYLSRUSA-N methyl (2r)-3-[2-(hydroxymethyl)-3-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(NC(=O)OC(C)(C)C)C(C)=C1CO LHHQTEBKGWFQBV-OAQYLSRUSA-N 0.000 description 1
• ZTJSRQDMMSSEPT-HXUWFJFHSA-N methyl (2r)-3-[4-(acetyloxymethyl)-1h-indazol-5-yl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound N([C@H](CC=1C(=C2C=NNC2=CC=1)COC(C)=O)C(=O)OC)C(=O)OCC1=CC=CC=C1 ZTJSRQDMMSSEPT-HXUWFJFHSA-N 0.000 description 1
• RYOCYOZSFZZNCK-LJQANCHMSA-N methyl (2r)-3-[4-(acetyloxymethyl)-7-chloro-1h-indazol-5-yl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound N([C@H](CC=1C(=C2C=NNC2=C(Cl)C=1)COC(C)=O)C(=O)OC)C(=O)OCC1=CC=CC=C1 RYOCYOZSFZZNCK-LJQANCHMSA-N 0.000 description 1
• PNEDTZUWNNMCAO-QGZVFWFLSA-N methyl (2r)-3-[7-chloro-4-(hydroxymethyl)-1h-indazol-5-yl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound N([C@H](CC=1C(=C2C=NNC2=C(Cl)C=1)CO)C(=O)OC)C(=O)OCC1=CC=CC=C1 PNEDTZUWNNMCAO-QGZVFWFLSA-N 0.000 description 1
• MGBHVVGQPZDMHA-UHFFFAOYSA-N methyl 2-[(2-methylpropan-2-yl)oxycarbonylamino]prop-2-enoate Chemical compound COC(=O)C(=C)NC(=O)OC(C)(C)C MGBHVVGQPZDMHA-UHFFFAOYSA-N 0.000 description 1
• IUHCQWGVZXHWMM-CYBMUJFWSA-N methyl 2-[(7r)-9-(2,2-dimethylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(C)(C)C)C(=O)[C@@H](CC(=O)OC)CC2=CC=C(NN=C3)C3=C21 IUHCQWGVZXHWMM-CYBMUJFWSA-N 0.000 description 1
• RTFGAADAXMJONW-QMMMGPOBSA-N methyl 2-[(7s)-1,4-dichloro-8-oxo-9-(2,2,2-trifluoroethyl)-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)CC2=C1C1=C(Cl)NN=C1C(Cl)=C2 RTFGAADAXMJONW-QMMMGPOBSA-N 0.000 description 1
• YMTUFLLYHRIRMS-INIZCTEOSA-N methyl 2-[(7s)-3-benzyl-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-7,10-dihydro-6h-pyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C([C@H](C(N(CC(F)(F)F)CC1=C2C=N3)=O)CC(=O)OC)C1=CC(Cl)=C2N3CC1=CC=CC=C1 YMTUFLLYHRIRMS-INIZCTEOSA-N 0.000 description 1
• IGLONUDCYDDABX-QMMMGPOBSA-N methyl 2-[(7s)-4-bromo-1-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)CC2=C1C1=C(Cl)NN=C1C(Br)=C2 IGLONUDCYDDABX-QMMMGPOBSA-N 0.000 description 1
• JVMIVFSXXBKAIZ-QMMMGPOBSA-N methyl 2-[(7s)-4-bromo-8-oxo-3,6,7,10-tetrahydrooxepino[3,4-e]indazol-7-yl]acetate Chemical compound C1OC(=O)[C@H](CC(=O)OC)CC2=CC(Br)=C(NN=C3)C3=C21 JVMIVFSXXBKAIZ-QMMMGPOBSA-N 0.000 description 1
• WNJCYVPDPWOJMP-NSHDSACASA-N methyl 2-[(7s)-4-bromo-9-(2-methoxyethyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1[C@@H](CC(=O)OC)C(=O)N(CCOC)CC2=C1C=C(Br)C1=C2C=NN1 WNJCYVPDPWOJMP-NSHDSACASA-N 0.000 description 1
• UKIGUBVHPRWVPE-NSHDSACASA-N methyl 2-[(7s)-4-chloro-3-ethyl-8-oxo-9-(2,2,2-trifluoroethyl)-7,10-dihydro-6h-pyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)CC2=CC(Cl)=C3N(CC)N=CC3=C21 UKIGUBVHPRWVPE-NSHDSACASA-N 0.000 description 1
• SRBUUURTTXGGBX-JTQLQIEISA-N methyl 2-[(7s)-4-chloro-3-methyl-8-oxo-9-(2,2,2-trifluoroethyl)-7,10-dihydro-6h-pyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)CC2=CC(Cl)=C(N(C)N=C3)C3=C21 SRBUUURTTXGGBX-JTQLQIEISA-N 0.000 description 1
• AASNUGITJMHCKK-LBPRGKRZSA-N methyl 2-[(7s)-4-chloro-8-oxo-3-propyl-9-(2,2,2-trifluoroethyl)-7,10-dihydro-6h-pyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)CC2=CC(Cl)=C3N(CCC)N=CC3=C21 AASNUGITJMHCKK-LBPRGKRZSA-N 0.000 description 1
• MYMVWSPXOWZDHU-NSHDSACASA-N methyl 2-[(7s)-4-chloro-9-(1h-imidazol-2-ylmethyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C([C@H](C1=O)CC(=O)OC)C2=CC(Cl)=C3NN=CC3=C2CN1CC1=NC=CN1 MYMVWSPXOWZDHU-NSHDSACASA-N 0.000 description 1
• MEOOLMDQDDUHRY-LBPRGKRZSA-N methyl 2-[(7s)-4-ethyl-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1[C@@H](CC(=O)OC)C(=O)N(CC(F)(F)F)CC2=C1C=C(CC)C1=C2C=NN1 MEOOLMDQDDUHRY-LBPRGKRZSA-N 0.000 description 1
• HQWDZGQVAPUAKS-NSHDSACASA-N methyl 2-[(7s)-4-methyl-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)CC2=CC(C)=C(NN=C3)C3=C21 HQWDZGQVAPUAKS-NSHDSACASA-N 0.000 description 1
• KPWASBPNCAGRFI-LBPRGKRZSA-N methyl 2-[(7s)-8-oxo-4-prop-1-en-2-yl-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)CC2=CC(C(C)=C)=C(NN=C3)C3=C21 KPWASBPNCAGRFI-LBPRGKRZSA-N 0.000 description 1
• LUCIQNFUTVGRGB-HNNXBMFYSA-N methyl 2-[(7s)-9-(2,2-dimethylpropyl)-8-oxo-4-propan-2-yl-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetate Chemical compound C1N(CC(C)(C)C)C(=O)[C@H](CC(=O)OC)CC2=CC(C(C)C)=C(NN=C3)C3=C21 LUCIQNFUTVGRGB-HNNXBMFYSA-N 0.000 description 1
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