CA2651033A1 - Constrained compounds as cgrp-receptor antagonists - Google Patents

Info

Publication number

CA2651033A1

CA2651033A1 CA002651033A CA2651033A CA2651033A1 CA 2651033 A1 CA2651033 A1 CA 2651033A1 CA 002651033 A CA002651033 A CA 002651033A CA 2651033 A CA2651033 A CA 2651033A CA 2651033 A1 CA2651033 A1 CA 2651033A1

Authority

CA

Canada

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
• CIPO
• Discuss

• 150000001875 compounds Chemical class 0.000 title claims description 248
• 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 title abstract description 18
• 102000008323 calcitonin gene-related peptide receptor activity proteins Human genes 0.000 title abstract description 16
• 229940044551 receptor antagonist Drugs 0.000 title abstract description 6
• 239000002464 receptor antagonist Substances 0.000 title abstract description 6
• 238000000034 method Methods 0.000 claims abstract description 32
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 15
• 206010027599 migraine Diseases 0.000 claims abstract description 15
• 239000000203 mixture Substances 0.000 claims description 559
• 125000000217 alkyl group Chemical group 0.000 claims description 66
• -1 N-(R9)-piperazinyl Chemical group 0.000 claims description 64
• 229910052739 hydrogen Inorganic materials 0.000 claims description 37
• 239000001257 hydrogen Substances 0.000 claims description 37
• 125000001475 halogen functional group Chemical group 0.000 claims description 28
• 125000001188 haloalkyl group Chemical group 0.000 claims description 22
• 125000003342 alkenyl group Chemical group 0.000 claims description 21
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
• 125000001424 substituent group Chemical group 0.000 claims description 14
• 150000003839 salts Chemical class 0.000 claims description 13
• 125000001624 naphthyl group Chemical group 0.000 claims description 12
• 125000004076 pyridyl group Chemical group 0.000 claims description 12
• 125000003545 alkoxy group Chemical group 0.000 claims description 9
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
• 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 8
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 7
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
• 125000006357 methylene carbonyl group Chemical group [H]C([H])([*:1])C([*:2])=O 0.000 claims description 5
• 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 5
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 4
• 239000005977 Ethylene Chemical group 0.000 claims description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000002757 morpholinyl group Chemical group 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000004620 quinolinyl-N-oxide group Chemical group 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
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
• 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 3
• LJKPDKASZYLYOU-KRWDZBQOSA-N 5-chloro-2-[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]-3,6-dihydro-2h-pyridin-4-yl]benzonitrile Chemical compound C([C@@H]1CC2=C(C=3C=NNC=3C(Cl)=C2)CN(C1=O)CC(F)(F)F)C(=O)N(CC=1)CCC=1C1=CC=C(Cl)C=C1C#N LJKPDKASZYLYOU-KRWDZBQOSA-N 0.000 claims description 3
• YFSWMEULGSJYQO-FQEVSTJZSA-N 6-[1-[2-[(4s)-7-chloro-2-(2,2-dimethylpropyl)-3-oxo-1,4,5,8-tetrahydropyrrolo[2,3-i][2]benzazepin-4-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=CSC=2C=1)=O)C1)N(CC(C)(C)C)CC2=C1C=C(Cl)C1=C2C=CN1 YFSWMEULGSJYQO-FQEVSTJZSA-N 0.000 claims description 3
• DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 claims description 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 description 2
• 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
• 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 description 2
• CHOQMYCCGRMOTP-AWEZNQCLSA-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-(2,2,2-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(Cl)C1=NNC(Cl)=C21 CHOQMYCCGRMOTP-AWEZNQCLSA-N 0.000 claims description 2
• 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 description 2
• MHTPTFZHGFHECJ-AWEZNQCLSA-N (7s)-4-bromo-1-chloro-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(Cl)=C21 MHTPTFZHGFHECJ-AWEZNQCLSA-N 0.000 claims description 2
• VSIIUJMHFDOMOT-HNNXBMFYSA-N (7s)-4-chloro-7-[2-[4-(4-fluoro-2-oxo-3h-benzimidazol-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 C1C2=CC(Cl)=C(NN=C3)C3=C2CN(CC(F)(F)F)C(=O)[C@@H]1CC(=O)N(CC1)CCC1N1C(C=CC=C2F)=C2NC1=O VSIIUJMHFDOMOT-HNNXBMFYSA-N 0.000 claims description 2
• 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 description 2
• 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 description 2
• FKYJBYRSUJTSRF-SFHVURJKSA-N (7s)-4-chloro-7-[2-[4-[3-(2-fluorophenyl)-2-oxoimidazolidin-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)CC1 FKYJBYRSUJTSRF-SFHVURJKSA-N 0.000 claims description 2
• 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 description 2
• DIEIHVLZNKHHJI-IBGZPJMESA-N (7s)-4-chloro-7-[2-oxo-2-[4-(2-oxo-3-phenylimidazol-1-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)CCC1N(C1=O)C=CN1C1=CC=CC=C1 DIEIHVLZNKHHJI-IBGZPJMESA-N 0.000 claims description 2
• RJSHCACLCUFPRJ-INIZCTEOSA-N (7s)-4-chloro-7-[2-oxo-2-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound O=C([C@H](CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C21)=O)C1)N(CC(F)(F)F)CC2=C1C=C(Cl)C1=C2C=NN1 RJSHCACLCUFPRJ-INIZCTEOSA-N 0.000 claims description 2
• UQWXGLUCMNJCLM-HNNXBMFYSA-N (7s)-4-chloro-7-[2-oxo-2-[4-(2-oxo-3h-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-3,6,7,10-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(Cl)C1=C2C=NN1 UQWXGLUCMNJCLM-HNNXBMFYSA-N 0.000 claims description 2
• KIHBNAPZVSKRKC-IBGZPJMESA-N (7s)-4-chloro-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)-3,6,7,10-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)C2=C3C=NN2)=C3CN(CC(F)(F)F)C1=O KIHBNAPZVSKRKC-IBGZPJMESA-N 0.000 claims description 2
• ARSXZGSGFZXNCY-INIZCTEOSA-N 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]spiro[1,3-dihydroquinazoline-4,4'-piperidine]-2-one Chemical compound O=C([C@H](CC(=O)N1CCC2(CC1)C1=CC=CC=C1NC(=O)N2)C1)N(CC(F)(F)F)CC2=C1C=C(Cl)C1=C2C=NN1 ARSXZGSGFZXNCY-INIZCTEOSA-N 0.000 claims description 2
• TZYVTSVREWREKC-SFHVURJKSA-N 3-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(Cl)=CSC=2C=1)=O)C1)N(CC(C)(C)C)CC2=C1C=C(Cl)C1=C2C=NN1 TZYVTSVREWREKC-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
• 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 description 2
• 239000002671 adjuvant Substances 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
• 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
• ZDNXZWURYKBPQQ-QFIPXVFZSA-N (7s)-3-benzyl-4-chloro-7-[2-oxo-2-[4-(2-oxo-3h-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-7,10-dihydro-6h-pyrazolo[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)CC(C=2C=N3)=C1C=C(Cl)C=2N3CC1=CC=CC=C1 ZDNXZWURYKBPQQ-QFIPXVFZSA-N 0.000 claims 1
• DVJWCUIHBUMFPY-SFHVURJKSA-N (7s)-4-bromo-1-chloro-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(Cl)NN=2)=C3CN(CC(F)(F)F)C1=O DVJWCUIHBUMFPY-SFHVURJKSA-N 0.000 claims 1
• LGTCBUIFWSHMEK-QFIPXVFZSA-N (7s)-4-chloro-3-(2-methoxyethyl)-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(CCOC)C3=C(Cl)C=C2C1 LGTCBUIFWSHMEK-QFIPXVFZSA-N 0.000 claims 1
• WJRDPNGIRFPVNA-KRWDZBQOSA-N (7s)-4-chloro-3-ethyl-7-[2-oxo-2-[4-(2-oxo-3h-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-7,10-dihydro-6h-pyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1C2=CC(Cl)=C3N(CC)N=CC3=C2CN(CC(F)(F)F)C(=O)[C@@H]1CC(=O)N1CCC(N2C(NC3=NC=CC=C32)=O)CC1 WJRDPNGIRFPVNA-KRWDZBQOSA-N 0.000 claims 1
• YBNBARNBEURTGF-INIZCTEOSA-N (7s)-4-chloro-3-methyl-7-[2-oxo-2-[4-(2-oxo-3h-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-7,10-dihydro-6h-pyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1C2=CC(Cl)=C3N(C)N=CC3=C2CN(CC(F)(F)F)C(=O)[C@@H]1CC(=O)N1CCC(N2C(NC3=NC=CC=C32)=O)CC1 YBNBARNBEURTGF-INIZCTEOSA-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
• 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 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
• 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 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
• 206010019233 Headaches Diseases 0.000 abstract description 13
• 231100000869 headache Toxicity 0.000 abstract description 9
• 208000007920 Neurogenic Inflammation Diseases 0.000 abstract description 5
• 208000027418 Wounds and injury Diseases 0.000 abstract description 5
• 230000008485 antagonism Effects 0.000 abstract description 5
• 230000006378 damage Effects 0.000 abstract description 5
• 208000014674 injury Diseases 0.000 abstract description 5
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
• 208000006673 asthma Diseases 0.000 abstract description 4
• 230000005796 circulatory shock Effects 0.000 abstract description 4
• 238000011010 flushing procedure Methods 0.000 abstract description 4
• 230000024883 vasodilation Effects 0.000 abstract description 4
• 230000001272 neurogenic effect Effects 0.000 abstract description 3
• 102000014468 Calcitonin Gene-Related Peptide Receptors Human genes 0.000 abstract description 2
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract description 2
• 208000027866 inflammatory disease Diseases 0.000 abstract description 2
• 230000009245 menopause Effects 0.000 abstract description 2
• 125000002619 bicyclic group Chemical group 0.000 abstract 1
• 238000002560 therapeutic procedure Methods 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 351
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 317
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 276
• 239000000543 intermediate Substances 0.000 description 238
• 238000006243 chemical reaction Methods 0.000 description 237
• 238000001819 mass spectrum Methods 0.000 description 207
• 239000007787 solid Substances 0.000 description 186
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 184
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 170
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 169
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 161
• 235000019439 ethyl acetate Nutrition 0.000 description 124
• 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
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 111
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 103
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 98
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 96
• 235000019341 magnesium sulphate Nutrition 0.000 description 92
• 239000000243 solution Substances 0.000 description 92
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 91
• 235000017557 sodium bicarbonate Nutrition 0.000 description 85
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 85
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 84
• 239000011541 reaction mixture Substances 0.000 description 77
• 238000005481 NMR spectroscopy Methods 0.000 description 74
• 239000002904 solvent Substances 0.000 description 72
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 71
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 66
• 239000008346 aqueous phase Substances 0.000 description 65
• 239000000047 product Substances 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
• 238000010898 silica gel chromatography Methods 0.000 description 52
• 239000012043 crude product Substances 0.000 description 51
• 238000005160 1H NMR spectroscopy Methods 0.000 description 49
• 101150041968 CDC13 gene Proteins 0.000 description 49
• 238000002360 preparation method Methods 0.000 description 49
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 42
• 239000000706 filtrate Substances 0.000 description 40
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 38
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 35
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
• 239000012071 phase Substances 0.000 description 35
• 229910000027 potassium carbonate Inorganic materials 0.000 description 33
• 229910052757 nitrogen Inorganic materials 0.000 description 32
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
• 230000027455 binding Effects 0.000 description 31
• 230000002441 reversible effect Effects 0.000 description 31
• 238000004949 mass spectrometry Methods 0.000 description 29
• 238000000746 purification Methods 0.000 description 29
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 26
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 26
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 24
• 238000002953 preparative HPLC Methods 0.000 description 24
• 239000012044 organic layer Substances 0.000 description 23
• 239000012317 TBTU Substances 0.000 description 22
• CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 22
• GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 22
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 21
• PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 20
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 19
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
• 239000002253 acid Substances 0.000 description 19
• 239000010410 layer Substances 0.000 description 19
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 18
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 18
• CDMSEVFXYQUTEW-QMMMGPOBSA-N 2-[(7s)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetic acid Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)O)CC2=CC(Cl)=C(NN=C3)C3=C21 CDMSEVFXYQUTEW-QMMMGPOBSA-N 0.000 description 17
• 238000003818 flash chromatography Methods 0.000 description 17
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 16
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
• 238000004128 high performance liquid chromatography Methods 0.000 description 16
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 15
• 239000012074 organic phase Substances 0.000 description 15
• 229920006395 saturated elastomer Polymers 0.000 description 15
• GLRAHDCHUZLKKC-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid;hydrate Chemical compound O.CC#N.OC(=O)C(F)(F)F GLRAHDCHUZLKKC-UHFFFAOYSA-N 0.000 description 14
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
• OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 13
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
• KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 13
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 12
• 150000001412 amines Chemical class 0.000 description 12
• 239000012230 colorless oil Substances 0.000 description 12
• 239000006260 foam Substances 0.000 description 12
• 150000002431 hydrogen Chemical group 0.000 description 12
• 239000000725 suspension Substances 0.000 description 12
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
• 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 12
• OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 11
• OCFPEEXBJKVQQU-GOSISDBHSA-N methyl (2r)-3-[4-(chloromethyl)-1h-indazol-5-yl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound N([C@H](CC=1C(=C2C=NNC2=CC=1)CCl)C(=O)OC)C(=O)OCC1=CC=CC=C1 OCFPEEXBJKVQQU-GOSISDBHSA-N 0.000 description 11
• 239000003960 organic solvent Substances 0.000 description 11
• 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 11
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 10
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 10
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 10
• 230000003197 catalytic effect Effects 0.000 description 10
• 210000004027 cell Anatomy 0.000 description 10
• 229910000104 sodium hydride Inorganic materials 0.000 description 10
• NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 10
• KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 description 9
• XDIAMRVROCPPBK-UHFFFAOYSA-N 2,2-dimethylpropan-1-amine Chemical compound CC(C)(C)CN XDIAMRVROCPPBK-UHFFFAOYSA-N 0.000 description 9
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 9
• IUHCQWGVZXHWMM-ZDUSSCGKSA-N methyl 2-[(7s)-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-ZDUSSCGKSA-N 0.000 description 9
• 235000011056 potassium acetate Nutrition 0.000 description 9
• 102000005962 receptors Human genes 0.000 description 9
• 108020003175 receptors Proteins 0.000 description 9
• 239000000741 silica gel Substances 0.000 description 9
• 229910002027 silica gel Inorganic materials 0.000 description 9
• XPDQZRDRODSWAK-NSHDSACASA-N 2-[(7s)-4-bromo-9-(2,2-dimethylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetic acid Chemical compound C1[C@@H](CC(O)=O)C(=O)N(CC(C)(C)C)CC2=C1C=C(Br)C1=C2C=NN1 XPDQZRDRODSWAK-NSHDSACASA-N 0.000 description 8
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
• KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 8
• 239000013058 crude material Substances 0.000 description 8
• IEMGWBMVQLVHEY-UHFFFAOYSA-N ethyl 2-(3-amino-6,7-dihydro-5h-cyclopenta[b]pyridin-7-yl)acetate Chemical compound NC1=CN=C2C(CC(=O)OCC)CCC2=C1 IEMGWBMVQLVHEY-UHFFFAOYSA-N 0.000 description 8
• 229910000029 sodium carbonate Inorganic materials 0.000 description 8
• 235000017550 sodium carbonate Nutrition 0.000 description 8
• IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 7
• QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 7
• IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 7
• 229910021529 ammonia Inorganic materials 0.000 description 7
• 229940095074 cyclic amp Drugs 0.000 description 7
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 7
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
• 229940098779 methanesulfonic acid Drugs 0.000 description 7
• RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 7
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 7
• 230000036961 partial effect Effects 0.000 description 7
• MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 7
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 7
• 235000019345 sodium thiosulphate Nutrition 0.000 description 7
• RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 6
• YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 6
• USOSUQZREODCRK-UHFFFAOYSA-N 3-piperidin-4-yl-4,5-dihydro-1h-1,3-benzodiazepin-2-one Chemical compound O=C1NC2=CC=CC=C2CCN1C1CCNCC1 USOSUQZREODCRK-UHFFFAOYSA-N 0.000 description 6
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
• YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 6
• LGCZKWUOVYKCKK-UHFFFAOYSA-N [6-iodo-2-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]methyl acetate Chemical compound CC(=O)OCC1=C(I)C=CC(NC(=O)OC(C)(C)C)=C1C LGCZKWUOVYKCKK-UHFFFAOYSA-N 0.000 description 6
• 230000004913 activation Effects 0.000 description 6
• 230000015572 biosynthetic process Effects 0.000 description 6
• 229910001873 dinitrogen Inorganic materials 0.000 description 6
• 239000003814 drug Substances 0.000 description 6
• 238000001914 filtration Methods 0.000 description 6
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
• 239000007788 liquid Substances 0.000 description 6
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
• 229910052717 sulfur Inorganic materials 0.000 description 6
• LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 6
• CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 6
• OHUCGNJZMRINKX-UHFFFAOYSA-N 1-piperidin-1-ium-4-yl-3h-imidazo[4,5-b]pyridin-4-ium-2-one;dichloride Chemical compound Cl.Cl.O=C1NC2=NC=CC=C2N1C1CCNCC1 OHUCGNJZMRINKX-UHFFFAOYSA-N 0.000 description 5
• LUVYLURQXCSXOS-UHFFFAOYSA-N 4h-thieno[3,2-b]pyridin-5-one Chemical compound OC1=CC=C2SC=CC2=N1 LUVYLURQXCSXOS-UHFFFAOYSA-N 0.000 description 5
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
• YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 5
• XDFFYJGKULMBKM-UHFFFAOYSA-N azanium;acetonitrile;acetate;hydrate Chemical compound [NH4+].O.CC#N.CC([O-])=O XDFFYJGKULMBKM-UHFFFAOYSA-N 0.000 description 5
• LJDDIYSQQHLCLN-OYKVQYDMSA-N diethyl (2s)-2-[2-acetyloxy-1-[3-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]ethyl]butanedioate Chemical compound CCOC(=O)C[C@H](C(=O)OCC)C(COC(C)=O)C1=CC=C(NC(=O)OC(C)(C)C)C(C)=C1 LJDDIYSQQHLCLN-OYKVQYDMSA-N 0.000 description 5
• ZDBPLOJGFZJKTJ-HNNXBMFYSA-N diethyl (2s)-2-[[2-(acetyloxymethyl)-4-amino-3-methylphenyl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC=C(N)C(C)=C1COC(C)=O ZDBPLOJGFZJKTJ-HNNXBMFYSA-N 0.000 description 5
• 229940079593 drug Drugs 0.000 description 5
• 239000000284 extract Substances 0.000 description 5
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
• 230000001404 mediated effect Effects 0.000 description 5
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 5
• 150000004702 methyl esters Chemical class 0.000 description 5
• 239000011734 sodium Substances 0.000 description 5
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
• 239000003039 volatile agent Substances 0.000 description 5
• XWQRSVFRTSVQAH-MRXNPFEDSA-N (7r)-7-amino-9-(2-piperidin-1-ylethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C([C@H](C1=O)N)C2=CC=C3NN=CC3=C2CN1CCN1CCCCC1 XWQRSVFRTSVQAH-MRXNPFEDSA-N 0.000 description 4
• DVENHCKTCNZFFC-UHFFFAOYSA-N 6-piperidin-4-yl-4h-thieno[3,2-b]pyridin-5-one Chemical compound O=C1NC=2C=CSC=2C=C1C1CCNCC1 DVENHCKTCNZFFC-UHFFFAOYSA-N 0.000 description 4
• 102000056906 Calcitonin Receptor-Like Human genes 0.000 description 4
• 101710118454 Calcitonin gene-related peptide type 1 receptor Proteins 0.000 description 4
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
• 241000700159 Rattus Species 0.000 description 4
• 238000003556 assay Methods 0.000 description 4
• 230000008901 benefit Effects 0.000 description 4
• VJHSCCBWGUKJBQ-JTQLQIEISA-N dimethyl (2s)-2-[[4-(hydroxymethyl)-1h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@@H](C(=O)OC)CC1=CC=C2NN=CC2=C1CO VJHSCCBWGUKJBQ-JTQLQIEISA-N 0.000 description 4
• PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 4
• 239000012065 filter cake Substances 0.000 description 4
• XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 4
• 229910052740 iodine Inorganic materials 0.000 description 4
• DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 4
• KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
• 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 4
• CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 4
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
• 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 4
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
• MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
• 239000012299 nitrogen atmosphere Substances 0.000 description 4
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
• KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 4
• 102000004169 proteins and genes Human genes 0.000 description 4
• 108090000623 proteins and genes Proteins 0.000 description 4
• 230000002829 reductive effect Effects 0.000 description 4
• 239000000377 silicon dioxide Substances 0.000 description 4
• 230000009885 systemic effect Effects 0.000 description 4
• ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 4
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 4
• 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 4
• JCLWILJQNUOUSA-UHFFFAOYSA-N (2-iodo-5-phenylmethoxyphenyl)methyl acetate Chemical compound C1=C(I)C(COC(=O)C)=CC(OCC=2C=CC=CC=2)=C1 JCLWILJQNUOUSA-UHFFFAOYSA-N 0.000 description 3
• SJSJKHNBAZEEDK-UHFFFAOYSA-N (3-acetamido-6-iodo-2,4-dimethylphenyl)methyl acetate Chemical compound CC(=O)NC1=C(C)C=C(I)C(COC(C)=O)=C1C SJSJKHNBAZEEDK-UHFFFAOYSA-N 0.000 description 3
• LQBYRDGFLYNEGM-UHFFFAOYSA-N (5-methoxy-1h-pyrrolo[3,2-b]pyridin-6-yl)boronic acid Chemical compound C1=C(B(O)O)C(OC)=NC2=C1NC=C2 LQBYRDGFLYNEGM-UHFFFAOYSA-N 0.000 description 3
• XFWNDGAMYOYSJA-CYBMUJFWSA-N (7r)-7-amino-9-(2,2-dimethylpropyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1[C@@H](N)C(=O)N(CC(C)(C)C)CC2=C1C=CC1=C2C=NN1 XFWNDGAMYOYSJA-CYBMUJFWSA-N 0.000 description 3
• MHAYHURNANUDHE-UHFFFAOYSA-N 2,2-dimethyl-n-thiophen-3-ylpropanamide Chemical compound CC(C)(C)C(=O)NC=1C=CSC=1 MHAYHURNANUDHE-UHFFFAOYSA-N 0.000 description 3
• XUINAUHFSJRUCI-LBPRGKRZSA-N 2-[(4s)-7-chloro-2-(2,2-dimethylpropyl)-3-oxo-1,4,5,8-tetrahydropyrrolo[2,3-i][2]benzazepin-4-yl]acetic acid Chemical compound C1[C@@H](CC(O)=O)C(=O)N(CC(C)(C)C)CC2=C1C=C(Cl)C1=C2C=CN1 XUINAUHFSJRUCI-LBPRGKRZSA-N 0.000 description 3
• AMALACANTITFHW-ZETCQYMHSA-N 2-[(7s)-1,4-dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetic acid Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)O)CC2=C1C1=C(Br)NN=C1C(Br)=C2 AMALACANTITFHW-ZETCQYMHSA-N 0.000 description 3
• RURYFXDQSTWYLV-NSHDSACASA-N 2-[(7s)-4-chloro-9-(2,2-dimethylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetic acid Chemical compound C1[C@@H](CC(O)=O)C(=O)N(CC(C)(C)C)CC2=C1C=C(Cl)C1=C2C=NN1 RURYFXDQSTWYLV-NSHDSACASA-N 0.000 description 3
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
• 240000007002 Eucalyptus tereticornis Species 0.000 description 3
• 208000002193 Pain Diseases 0.000 description 3
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 3
• 235000019270 ammonium chloride Nutrition 0.000 description 3
• 238000004458 analytical method Methods 0.000 description 3
• 239000005557 antagonist Substances 0.000 description 3
• 239000012131 assay buffer Substances 0.000 description 3
• BGPHFXRBPCTNQM-XMMPIXPASA-N benzyl n-[(7r)-8-oxo-9-(2-piperidin-1-ylethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound C([C@H](C1=O)NC(=O)OCC=2C=CC=CC=2)C2=CC=C3NN=CC3=C2CN1CCN1CCCCC1 BGPHFXRBPCTNQM-XMMPIXPASA-N 0.000 description 3
• XATGAFBYEMMISL-OAQYLSRUSA-N benzyl n-[(7r)-9-(2,2-dimethylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound N([C@@H]1CC2=C(C=3C=NNC=3C=C2)CN(C1=O)CC(C)(C)C)C(=O)OCC1=CC=CC=C1 XATGAFBYEMMISL-OAQYLSRUSA-N 0.000 description 3
• 108010050923 calcitonin gene-related peptide (8-37) Proteins 0.000 description 3
• 239000003054 catalyst Substances 0.000 description 3
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
• 238000001816 cooling Methods 0.000 description 3
• ROXVQIWGVGBGBY-AWEZNQCLSA-N diethyl (2s)-2-[[2-(acetyloxymethyl)-4-amino-5-bromo-3-methylphenyl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC(Br)=C(N)C(C)=C1COC(C)=O ROXVQIWGVGBGBY-AWEZNQCLSA-N 0.000 description 3
• NFCUYSFILTXWHL-AWEZNQCLSA-N diethyl (2s)-2-[[2-(acetyloxymethyl)-4-amino-5-chloro-3-methylphenyl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC(Cl)=C(N)C(C)=C1COC(C)=O NFCUYSFILTXWHL-AWEZNQCLSA-N 0.000 description 3
• JIWICRYTLWZKHS-ZDUSSCGKSA-N diethyl (2s)-2-[[4-(acetyloxymethyl)-7-chloro-1h-indazol-5-yl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC(Cl)=C2NN=CC2=C1COC(C)=O JIWICRYTLWZKHS-ZDUSSCGKSA-N 0.000 description 3
• HGPFTGAPPHDHPF-UHFFFAOYSA-N diethyl 2-[2-acetyloxy-1-[3-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]ethylidene]butanedioate Chemical compound CCOC(=O)CC(C(=O)OCC)=C(COC(C)=O)C1=CC=C(NC(=O)OC(C)(C)C)C(C)=C1 HGPFTGAPPHDHPF-UHFFFAOYSA-N 0.000 description 3
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
• GJCXCYYASHROHA-QMMMGPOBSA-N dimethyl (2s)-2-[[3,7-dichloro-4-(hydroxymethyl)-2h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@@H](C(=O)OC)CC1=CC(Cl)=C2NN=C(Cl)C2=C1CO GJCXCYYASHROHA-QMMMGPOBSA-N 0.000 description 3
• ICSVHLLZUDKUSA-PPHPATTJSA-N dimethyl (2s)-2-[[4-(chloromethyl)-1h-indazol-5-yl]methyl]butanedioate;hydrochloride Chemical compound Cl.COC(=O)C[C@@H](C(=O)OC)CC1=CC=C2NN=CC2=C1CCl ICSVHLLZUDKUSA-PPHPATTJSA-N 0.000 description 3
• PTJCEACDZMDJFW-VIFPVBQESA-N dimethyl (2s)-2-[[7-chloro-4-(chloromethyl)-1h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@@H](C(=O)OC)CC1=CC(Cl)=C2NN=CC2=C1CCl PTJCEACDZMDJFW-VIFPVBQESA-N 0.000 description 3
• 150000002148 esters Chemical class 0.000 description 3
• WRLFSXJSGVPOEC-UHFFFAOYSA-N ethyl 2-[7-amino-1-(2,2-dimethylpropyl)-8-methyl-2-oxo-3,4-dihydroquinolin-3-yl]acetate Chemical compound C1=C(N)C(C)=C2N(CC(C)(C)C)C(=O)C(CC(=O)OCC)CC2=C1 WRLFSXJSGVPOEC-UHFFFAOYSA-N 0.000 description 3
• 235000003528 grey gum Nutrition 0.000 description 3
• 238000010438 heat treatment Methods 0.000 description 3
• 210000004379 membrane Anatomy 0.000 description 3
• 239000012528 membrane Substances 0.000 description 3
• 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 3
• 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 3
• 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 3
• 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 3
• SXXWEJVOYOMBEV-GMUIIQOCSA-N methyl (2r)-3-[4-(chloromethyl)-1h-indazol-5-yl]-2-(phenylmethoxycarbonylamino)propanoate;hydrochloride Chemical compound Cl.N([C@H](CC=1C(=C2C=NNC2=CC=1)CCl)C(=O)OC)C(=O)OCC1=CC=CC=C1 SXXWEJVOYOMBEV-GMUIIQOCSA-N 0.000 description 3
• 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 3
• UVBVUCARTKSNMW-LBPRGKRZSA-N methyl 2-[(7s)-4-bromo-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(Br)=C(NN=C3)C3=C21 UVBVUCARTKSNMW-LBPRGKRZSA-N 0.000 description 3
• 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 3
• 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 3
• 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 3
• HYMWXVZOYWBBJS-UHFFFAOYSA-N methyl 3-[4-acetamido-2-(acetyloxymethyl)-3,5-dimethylphenyl]-2-(phenylmethoxycarbonylamino)prop-2-enoate Chemical compound C=1C(C)=C(NC(C)=O)C(C)=C(COC(C)=O)C=1C=C(C(=O)OC)NC(=O)OCC1=CC=CC=C1 HYMWXVZOYWBBJS-UHFFFAOYSA-N 0.000 description 3
• KHCJQXVEDLDHKF-UHFFFAOYSA-N n-(2-formylthiophen-3-yl)-2,2-dimethylpropanamide Chemical compound CC(C)(C)C(=O)NC=1C=CSC=1C=O KHCJQXVEDLDHKF-UHFFFAOYSA-N 0.000 description 3
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
• PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
• LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 3
• 239000008188 pellet Substances 0.000 description 3
• 239000000843 powder Substances 0.000 description 3
• 108090000765 processed proteins & peptides Proteins 0.000 description 3
• 238000000926 separation method Methods 0.000 description 3
• 241000894007 species Species 0.000 description 3
• 239000007858 starting material Substances 0.000 description 3
• 125000000547 substituted alkyl group Chemical group 0.000 description 3
• XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
• OETSYIPQXZPLST-UHFFFAOYSA-N (5-amino-2-iodo-4-methylphenyl)methanol Chemical compound CC1=CC(I)=C(CO)C=C1N OETSYIPQXZPLST-UHFFFAOYSA-N 0.000 description 2
• FQQNBFVWDZFQKH-UHFFFAOYSA-N (5-methoxy-1-methylpyrrolo[3,2-b]pyridin-6-yl)boronic acid Chemical compound C1=C(B(O)O)C(OC)=NC2=C1N(C)C=C2 FQQNBFVWDZFQKH-UHFFFAOYSA-N 0.000 description 2
• NBUOYVBSFOCTOF-UHFFFAOYSA-N (5-methoxypyrrolo[3,2-b]pyridin-1-yl)-tri(propan-2-yl)silane Chemical compound COC1=CC=C2N([Si](C(C)C)(C(C)C)C(C)C)C=CC2=N1 NBUOYVBSFOCTOF-UHFFFAOYSA-N 0.000 description 2
• NBRLRDAKWUNZIN-UHFFFAOYSA-N (6-chloropyrrolo[2,3-b]pyridin-1-yl)-tri(propan-2-yl)silane Chemical compound C1=C(Cl)N=C2N([Si](C(C)C)(C(C)C)C(C)C)C=CC2=C1 NBRLRDAKWUNZIN-UHFFFAOYSA-N 0.000 description 2
• NYSGFQBNMXCTNT-OAHLLOKOSA-N (7r)-7-amino-9-(2-pyrrolidin-1-ylethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C([C@H](C1=O)N)C2=CC=C3NN=CC3=C2CN1CCN1CCCC1 NYSGFQBNMXCTNT-OAHLLOKOSA-N 0.000 description 2
• NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
• WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
• SJLIPOVZERLCNL-UHFFFAOYSA-N 1-(2-bromoethyl)-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1CCBr SJLIPOVZERLCNL-UHFFFAOYSA-N 0.000 description 2
• OHQQVEJCSPBMLN-UHFFFAOYSA-N 1-(2-fluorophenyl)-3-piperidin-4-ylimidazolidin-2-one;hydrochloride Chemical compound Cl.FC1=CC=CC=C1N1C(=O)N(C2CCNCC2)CC1 OHQQVEJCSPBMLN-UHFFFAOYSA-N 0.000 description 2
• LTOLEFMMYMSLPR-UHFFFAOYSA-N 1-benzyl-n-[2-(2-nitrophenyl)ethyl]piperidin-4-amine Chemical compound [O-][N+](=O)C1=CC=CC=C1CCNC1CCN(CC=2C=CC=CC=2)CC1 LTOLEFMMYMSLPR-UHFFFAOYSA-N 0.000 description 2
• RHYRVVISBLNCJH-UHFFFAOYSA-N 1-benzyl-n-[2-(3-fluoro-2-nitrophenyl)ethyl]piperidin-4-amine Chemical compound [O-][N+](=O)C1=C(F)C=CC=C1CCNC1CCN(CC=2C=CC=CC=2)CC1 RHYRVVISBLNCJH-UHFFFAOYSA-N 0.000 description 2
• YUBDLZGUSSWQSS-UHFFFAOYSA-N 1-benzylpiperidin-4-amine Chemical compound C1CC(N)CCN1CC1=CC=CC=C1 YUBDLZGUSSWQSS-UHFFFAOYSA-N 0.000 description 2
• AMCXCJRGBUPXJZ-UHFFFAOYSA-N 1-methyl-6-piperidin-4-yl-4h-pyrrolo[3,2-b]pyridin-5-one Chemical compound C=1C=2N(C)C=CC=2NC(=O)C=1C1CCNCC1 AMCXCJRGBUPXJZ-UHFFFAOYSA-N 0.000 description 2
• QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 2
• FJJYHTVHBVXEEQ-UHFFFAOYSA-N 2,2-dimethylpropanal Chemical compound CC(C)(C)C=O FJJYHTVHBVXEEQ-UHFFFAOYSA-N 0.000 description 2
• ZHQHUGDDYSPNTM-UHFFFAOYSA-N 2-(3-fluoro-2-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(F)=C1[N+]([O-])=O ZHQHUGDDYSPNTM-UHFFFAOYSA-N 0.000 description 2
• RCZCIUDRJJLYCZ-ZETCQYMHSA-N 2-[(7s)-1,4-dichloro-8-oxo-9-(2,2,2-trifluoroethyl)-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetic acid Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](CC(=O)O)CC2=C1C1=C(Cl)NN=C1C(Cl)=C2 RCZCIUDRJJLYCZ-ZETCQYMHSA-N 0.000 description 2
• VJASAFJCFHYUGJ-ZDUSSCGKSA-N 2-[(7s)-1,4-dichloro-8-oxo-9-(2-piperidin-1-ylethyl)-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetic acid Chemical compound C([C@H](C1=O)CC(=O)O)C=2C=C(Cl)C3=NNC(Cl)=C3C=2CN1CCN1CCCCC1 VJASAFJCFHYUGJ-ZDUSSCGKSA-N 0.000 description 2
• UKMJFNZNNAJLBE-JTQLQIEISA-N 2-[(7s)-4-bromo-1-chloro-9-(2,2-dimethylpropyl)-8-oxo-2,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetic acid Chemical compound C1[C@@H](CC(O)=O)C(=O)N(CC(C)(C)C)CC2=C1C=C(Br)C1=NNC(Cl)=C21 UKMJFNZNNAJLBE-JTQLQIEISA-N 0.000 description 2
• OFGXCOZNODYHEQ-OAHLLOKOSA-N 2-[(7s)-9-(2,2-dimethylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]ethyl acetate Chemical compound C1N(CC(C)(C)C)C(=O)[C@H](CCOC(=O)C)CC2=CC=C(NN=C3)C3=C21 OFGXCOZNODYHEQ-OAHLLOKOSA-N 0.000 description 2
• NMXHOLHJCGKMIM-UHFFFAOYSA-N 2-bromo-6-piperidin-4-yl-4h-thieno[3,2-b]pyridin-5-one Chemical compound C=1C=2SC(Br)=CC=2NC(=O)C=1C1CCNCC1 NMXHOLHJCGKMIM-UHFFFAOYSA-N 0.000 description 2
• NFMICTOBQBVEOG-UHFFFAOYSA-N 2-chloro-6-piperidin-4-yl-4h-thieno[3,2-b]pyridin-5-one Chemical compound C=1C=2SC(Cl)=CC=2NC(=O)C=1C1CCNCC1 NFMICTOBQBVEOG-UHFFFAOYSA-N 0.000 description 2
• ANSJTRRYCNYUJD-UHFFFAOYSA-N 2-ethenyl-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1C=C ANSJTRRYCNYUJD-UHFFFAOYSA-N 0.000 description 2
• BWZDDDSWGATMHF-UHFFFAOYSA-N 2-fluoro-6-[[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]amino]benzoic acid Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1NC1=CC=CC(F)=C1C(O)=O BWZDDDSWGATMHF-UHFFFAOYSA-N 0.000 description 2
• KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
• CJNRGSHEMCMUOE-UHFFFAOYSA-N 2-piperidin-1-ylethanamine Chemical compound NCCN1CCCCC1 CJNRGSHEMCMUOE-UHFFFAOYSA-N 0.000 description 2
• IDTTYANIUTZKHE-UHFFFAOYSA-N 3-bromo-6-piperidin-4-yl-4h-thieno[3,2-b]pyridin-5-one Chemical compound O=C1NC=2C(Br)=CSC=2C=C1C1CCNCC1 IDTTYANIUTZKHE-UHFFFAOYSA-N 0.000 description 2
• CWWPGYUYJZYURK-UHFFFAOYSA-N 3-chloro-6-piperidin-4-yl-4h-thieno[3,2-b]pyridin-5-one Chemical compound O=C1NC=2C(Cl)=CSC=2C=C1C1CCNCC1 CWWPGYUYJZYURK-UHFFFAOYSA-N 0.000 description 2
• BRQJTDURZKRGHM-UHFFFAOYSA-N 3-ethenyl-2-nitropyridine Chemical compound [O-][N+](=O)C1=NC=CC=C1C=C BRQJTDURZKRGHM-UHFFFAOYSA-N 0.000 description 2
• XGQQDTBAMLGWRZ-UHFFFAOYSA-N 4-iodo-2-methyl-3-nitroaniline Chemical compound CC1=C(N)C=CC(I)=C1[N+]([O-])=O XGQQDTBAMLGWRZ-UHFFFAOYSA-N 0.000 description 2
• OAANNRLYCHHWRZ-UHFFFAOYSA-N 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile Chemical class N#CC1=CC(Cl)=CC=C1C1=CCNCC1 OAANNRLYCHHWRZ-UHFFFAOYSA-N 0.000 description 2
• 102100027499 5-hydroxytryptamine receptor 1B Human genes 0.000 description 2
• 101710138639 5-hydroxytryptamine receptor 1B Proteins 0.000 description 2
• OEALRKAINBDHEZ-UHFFFAOYSA-N 5-piperidin-4-ylimidazolidine-2,4-dione Chemical compound O=C1NC(=O)NC1C1CCNCC1 OEALRKAINBDHEZ-UHFFFAOYSA-N 0.000 description 2
• PSTHZSJHIQNATE-UHFFFAOYSA-N 6-piperidin-4-yl-1,4-dihydropyrrolo[3,2-b]pyridin-5-one Chemical compound O=C1NC=2C=CNC=2C=C1C1CCNCC1 PSTHZSJHIQNATE-UHFFFAOYSA-N 0.000 description 2
• 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 description 2
• RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
• 208000006386 Bone Resorption Diseases 0.000 description 2
• 208000006561 Cluster Headache Diseases 0.000 description 2
• 101000988651 Homo sapiens Humanin-like 1 Proteins 0.000 description 2
• 101000584583 Homo sapiens Receptor activity-modifying protein 1 Proteins 0.000 description 2
• 229910013470 LiC1 Inorganic materials 0.000 description 2
• 239000002033 PVDF binder Substances 0.000 description 2
• 229940083963 Peptide antagonist Drugs 0.000 description 2
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
• 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
• 102100030697 Receptor activity-modifying protein 1 Human genes 0.000 description 2
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
• 206010047139 Vasoconstriction Diseases 0.000 description 2
• WKFOTPNKVANMMO-LJQANCHMSA-N [(2r)-3-[2-(acetyloxymethyl)-4-amino-3-methylphenyl]-1-methoxy-1-oxopropan-2-yl] benzoate Chemical compound C([C@H](C(=O)OC)OC(=O)C=1C=CC=CC=1)C1=CC=C(N)C(C)=C1COC(C)=O WKFOTPNKVANMMO-LJQANCHMSA-N 0.000 description 2
• FQUGUVPNKDCZFK-GOSISDBHSA-N [(2r)-3-[2-(acetyloxymethyl)-4-amino-5-chloro-3-methylphenyl]-1-methoxy-1-oxopropan-2-yl] benzoate Chemical compound C([C@H](C(=O)OC)OC(=O)C=1C=CC=CC=1)C1=CC(Cl)=C(N)C(C)=C1COC(C)=O FQUGUVPNKDCZFK-GOSISDBHSA-N 0.000 description 2
• HLHMGXQRSVSADC-GOSISDBHSA-N [(2r)-3-[4-(acetyloxymethyl)-7-chloro-1h-indazol-5-yl]-1-methoxy-1-oxopropan-2-yl] benzoate Chemical compound O([C@H](CC=1C(=C2C=NNC2=C(Cl)C=1)COC(C)=O)C(=O)OC)C(=O)C1=CC=CC=C1 HLHMGXQRSVSADC-GOSISDBHSA-N 0.000 description 2
• YBQYUUYRWXKAQI-MRXNPFEDSA-N [(2r)-3-[7-chloro-4-(hydroxymethyl)-1h-indazol-5-yl]-1-methoxy-1-oxopropan-2-yl] benzoate Chemical compound O([C@H](CC=1C(=C2C=NNC2=C(Cl)C=1)CO)C(=O)OC)C(=O)C1=CC=CC=C1 YBQYUUYRWXKAQI-MRXNPFEDSA-N 0.000 description 2
• DMBOVHGWVKUNCH-MRXNPFEDSA-N [(7r)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl] benzoate Chemical compound O([C@@H]1CC2=C(C=3C=NNC=3C(Cl)=C2)CN(C1=O)CC(F)(F)F)C(=O)C1=CC=CC=C1 DMBOVHGWVKUNCH-MRXNPFEDSA-N 0.000 description 2
• KGBRESBAPMQXDH-HMAPJEAMSA-N [(z)-1-[2-(acetyloxymethyl)-3-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-3-methoxy-3-oxoprop-1-en-2-yl] benzoate Chemical compound C=1C=C(NC(=O)OC(C)(C)C)C(C)=C(COC(C)=O)C=1/C=C(C(=O)OC)\OC(=O)C1=CC=CC=C1 KGBRESBAPMQXDH-HMAPJEAMSA-N 0.000 description 2
• PXESGSDDIFQOFB-UHFFFAOYSA-N [5-methoxy-1-tri(propan-2-yl)silylpyrrolo[3,2-b]pyridin-6-yl]boronic acid Chemical compound C1=C(B(O)O)C(OC)=NC2=C1N([Si](C(C)C)(C(C)C)C(C)C)C=C2 PXESGSDDIFQOFB-UHFFFAOYSA-N 0.000 description 2
• 229940022663 acetate Drugs 0.000 description 2
• 150000007513 acids Chemical class 0.000 description 2
• OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
• 108060000200 adenylate cyclase Proteins 0.000 description 2
• 102000030621 adenylate cyclase Human genes 0.000 description 2
• 239000000556 agonist Substances 0.000 description 2
• VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
• 150000001408 amides Chemical class 0.000 description 2
• 150000001413 amino acids Chemical class 0.000 description 2
• 229940124433 antimigraine drug Drugs 0.000 description 2
• 125000003118 aryl group Chemical group 0.000 description 2
• DXZDEAJXVCLRLE-UHFFFAOYSA-N azepin-2-one Chemical class O=C1C=CC=CC=N1 DXZDEAJXVCLRLE-UHFFFAOYSA-N 0.000 description 2
• RXGNFMJFRLWOAW-HSZRJFAPSA-N benzyl n-[(7r)-8-oxo-9-(2-pyrrolidin-1-ylethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound C([C@H](C1=O)NC(=O)OCC=2C=CC=CC=2)C2=CC=C3NN=CC3=C2CN1CCN1CCCC1 RXGNFMJFRLWOAW-HSZRJFAPSA-N 0.000 description 2
• XZGRVPRKWZSCOF-VZYDHVRKSA-N benzyl n-[(7r)-8-oxo-9-piperidin-4-yl-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate;methanesulfonic acid Chemical compound CS(O)(=O)=O.C([C@H](C1=O)NC(=O)OCC=2C=CC=CC=2)C2=CC=C3NN=CC3=C2CN1C1CCNCC1 XZGRVPRKWZSCOF-VZYDHVRKSA-N 0.000 description 2
• SVBNTRHPSOHKJK-XMMPIXPASA-N benzyl n-[(7r)-9-(1-acetylpiperidin-4-yl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound C1CN(C(=O)C)CCC1N1C(=O)[C@H](NC(=O)OCC=2C=CC=CC=2)CC(C=CC2=C3C=NN2)=C3C1 SVBNTRHPSOHKJK-XMMPIXPASA-N 0.000 description 2
• NJVMLADCTMMZSB-UHFFFAOYSA-N benzyl n-[8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC(C1=O)CC2=CC=C3NN=CC3=C2CN1CC1=CC=NC=C1 NJVMLADCTMMZSB-UHFFFAOYSA-N 0.000 description 2
• YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
• 230000024279 bone resorption Effects 0.000 description 2
• 210000004556 brain Anatomy 0.000 description 2
• 229910052794 bromium Inorganic materials 0.000 description 2
• 229940045348 brown mixture Drugs 0.000 description 2
• RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
• 229950005499 carbon tetrachloride Drugs 0.000 description 2
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
• 230000000747 cardiac effect Effects 0.000 description 2
• 210000003169 central nervous system Anatomy 0.000 description 2
• KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
• 239000003153 chemical reaction reagent Substances 0.000 description 2
• IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
• 208000018912 cluster headache syndrome Diseases 0.000 description 2
• 238000004440 column chromatography Methods 0.000 description 2
• 230000008878 coupling Effects 0.000 description 2
• 238000010168 coupling process Methods 0.000 description 2
• 238000005859 coupling reaction Methods 0.000 description 2
• RXBQVRWXGHALRZ-XYOKQWHBSA-N diethyl (2e)-2-[(4-amino-3-methyl-2-nitrophenyl)methylidene]butanedioate Chemical compound CCOC(=O)C\C(C(=O)OCC)=C/C1=CC=C(N)C(C)=C1[N+]([O-])=O RXBQVRWXGHALRZ-XYOKQWHBSA-N 0.000 description 2
• LJDDIYSQQHLCLN-MRTLOADZSA-N diethyl (2r)-2-[2-acetyloxy-1-[3-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]ethyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)C(COC(C)=O)C1=CC=C(NC(=O)OC(C)(C)C)C(C)=C1 LJDDIYSQQHLCLN-MRTLOADZSA-N 0.000 description 2
• ZDBPLOJGFZJKTJ-OAHLLOKOSA-N diethyl (2r)-2-[[2-(acetyloxymethyl)-4-amino-3-methylphenyl]methyl]butanedioate Chemical compound CCOC(=O)C[C@H](C(=O)OCC)CC1=CC=C(N)C(C)=C1COC(C)=O ZDBPLOJGFZJKTJ-OAHLLOKOSA-N 0.000 description 2
• LCTYXZYFHQXOBE-CQSZACIVSA-N diethyl (2r)-2-[[4-(acetyloxymethyl)-1h-indazol-5-yl]methyl]butanedioate Chemical compound CCOC(=O)C[C@H](C(=O)OCC)CC1=CC=C2NN=CC2=C1COC(C)=O LCTYXZYFHQXOBE-CQSZACIVSA-N 0.000 description 2
• LCTYXZYFHQXOBE-AWEZNQCLSA-N diethyl (2s)-2-[[4-(acetyloxymethyl)-1h-indazol-5-yl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC=C2NN=CC2=C1COC(C)=O LCTYXZYFHQXOBE-AWEZNQCLSA-N 0.000 description 2
• LIEHOMCUVFPELQ-ZDUSSCGKSA-N diethyl (2s)-2-[[4-(acetyloxymethyl)-7-bromo-1h-indazol-5-yl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC(Br)=C2NN=CC2=C1COC(C)=O LIEHOMCUVFPELQ-ZDUSSCGKSA-N 0.000 description 2
• ZEFVHSWKYCYFFL-UHFFFAOYSA-N diethyl 2-methylidenebutanedioate Chemical compound CCOC(=O)CC(=C)C(=O)OCC ZEFVHSWKYCYFFL-UHFFFAOYSA-N 0.000 description 2
• VJHSCCBWGUKJBQ-SNVBAGLBSA-N dimethyl (2r)-2-[[4-(hydroxymethyl)-1h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@H](C(=O)OC)CC1=CC=C2NN=CC2=C1CO VJHSCCBWGUKJBQ-SNVBAGLBSA-N 0.000 description 2
• PENMNBXLXCNEND-QMMMGPOBSA-N dimethyl (2s)-2-[[3,7-dibromo-4-(hydroxymethyl)-2h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@@H](C(=O)OC)CC1=CC(Br)=C2NN=C(Br)C2=C1CO PENMNBXLXCNEND-QMMMGPOBSA-N 0.000 description 2
• PFKMDWPABTVNJG-NSHDSACASA-N dimethyl (2s)-2-[[4-(hydroxymethyl)-7-methyl-1h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@@H](C(=O)OC)CC1=CC(C)=C2NN=CC2=C1CO PFKMDWPABTVNJG-NSHDSACASA-N 0.000 description 2
• AGZBRBHITUJSID-VIFPVBQESA-N dimethyl (2s)-2-[[7-bromo-4-(chloromethyl)-1h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@@H](C(=O)OC)CC1=CC(Br)=C2NN=CC2=C1CCl AGZBRBHITUJSID-VIFPVBQESA-N 0.000 description 2
• BUGGIRYQNWHNFY-VIFPVBQESA-N dimethyl (2s)-2-[[7-bromo-4-(hydroxymethyl)-1h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@@H](C(=O)OC)CC1=CC(Br)=C2NN=CC2=C1CO BUGGIRYQNWHNFY-VIFPVBQESA-N 0.000 description 2
• WHRBLXJQSRHFDR-VIFPVBQESA-N dimethyl (2s)-2-[[7-chloro-4-(hydroxymethyl)-1h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@@H](C(=O)OC)CC1=CC(Cl)=C2NN=CC2=C1CO WHRBLXJQSRHFDR-VIFPVBQESA-N 0.000 description 2
• OGJCUSFTJIEQRF-UHFFFAOYSA-N dimethyl 2-(3-fluoro-2-nitrophenyl)propanedioate Chemical compound COC(=O)C(C(=O)OC)C1=CC=CC(F)=C1[N+]([O-])=O OGJCUSFTJIEQRF-UHFFFAOYSA-N 0.000 description 2
• 239000003937 drug carrier Substances 0.000 description 2
• 230000002526 effect on cardiovascular system Effects 0.000 description 2
• 230000000694 effects Effects 0.000 description 2
• 239000003480 eluent Substances 0.000 description 2
• LRUJOFUURXUABL-UHFFFAOYSA-N ethyl 2-amino-3,3-diethoxypropanoate Chemical compound CCOC(OCC)C(N)C(=O)OCC LRUJOFUURXUABL-UHFFFAOYSA-N 0.000 description 2
• 238000009472 formulation Methods 0.000 description 2
• 230000000004 hemodynamic effect Effects 0.000 description 2
• 230000007062 hydrolysis Effects 0.000 description 2
• 238000006460 hydrolysis reaction Methods 0.000 description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
• 238000001802 infusion Methods 0.000 description 2
• 239000003112 inhibitor Substances 0.000 description 2
• 230000005764 inhibitory process Effects 0.000 description 2
• 238000001990 intravenous administration Methods 0.000 description 2
• 239000003456 ion exchange resin Substances 0.000 description 2
• 229920003303 ion-exchange polymer Polymers 0.000 description 2
• 230000002045 lasting effect Effects 0.000 description 2
• WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 2
• 239000012139 lysis buffer Substances 0.000 description 2
• 238000004519 manufacturing process Methods 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
• 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 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
• 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 2
• ZEXZSCMJWQKYIB-QGZVFWFLSA-N methyl (2r)-3-[7-chloro-4-(chloromethyl)-1h-indazol-5-yl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound N([C@H](CC=1C(=C2C=NNC2=C(Cl)C=1)CCl)C(=O)OC)C(=O)OCC1=CC=CC=C1 ZEXZSCMJWQKYIB-QGZVFWFLSA-N 0.000 description 2
• 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 2
• STFUIEDYPRMRNN-UHFFFAOYSA-N methyl 2-(phenylmethoxycarbonylamino)prop-2-enoate Chemical compound COC(=O)C(=C)NC(=O)OCC1=CC=CC=C1 STFUIEDYPRMRNN-UHFFFAOYSA-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
• 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 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
• 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 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
• 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 2
• GDIMPLXZECZDDA-UHFFFAOYSA-N methyl 3-[2-(acetyloxymethyl)-4-phenylmethoxyphenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C1=C(COC(C)=O)C(CC(C(=O)OC)NC(=O)OC(C)(C)C)=CC=C1OCC1=CC=CC=C1 GDIMPLXZECZDDA-UHFFFAOYSA-N 0.000 description 2
• OCFPEEXBJKVQQU-UHFFFAOYSA-N methyl 3-[4-(chloromethyl)-1h-indazol-5-yl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C=1C=C2NN=CC2=C(CCl)C=1CC(C(=O)OC)NC(=O)OCC1=CC=CC=C1 OCFPEEXBJKVQQU-UHFFFAOYSA-N 0.000 description 2
• 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
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
• SHSWVNSGEPSNKO-UHFFFAOYSA-N n-(1-benzylpiperidin-4-yl)-2-(3-fluoro-2-nitrophenyl)acetamide Chemical compound [O-][N+](=O)C1=C(F)C=CC=C1CC(=O)NC1CCN(CC=2C=CC=CC=2)CC1 SHSWVNSGEPSNKO-UHFFFAOYSA-N 0.000 description 2
• MXVUKXAMXQZAAA-UHFFFAOYSA-N n-[2-(2-amino-3-fluorophenyl)ethyl]-1-benzylpiperidin-4-amine Chemical compound NC1=C(F)C=CC=C1CCNC1CCN(CC=2C=CC=CC=2)CC1 MXVUKXAMXQZAAA-UHFFFAOYSA-N 0.000 description 2
• CNYQVNWECNEWJI-UHFFFAOYSA-N n-[2-(2-aminophenyl)ethyl]-1-benzylpiperidin-4-amine Chemical compound NC1=CC=CC=C1CCNC1CCN(CC=2C=CC=CC=2)CC1 CNYQVNWECNEWJI-UHFFFAOYSA-N 0.000 description 2
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 2
• 230000008506 pathogenesis Effects 0.000 description 2
• 230000001991 pathophysiological effect Effects 0.000 description 2
• 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
• 230000002093 peripheral effect Effects 0.000 description 2
• 230000000144 pharmacologic effect Effects 0.000 description 2
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
• 230000035479 physiological effects, processes and functions Effects 0.000 description 2
• 239000004810 polytetrafluoroethylene Substances 0.000 description 2
• 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
• 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
• 239000002244 precipitate Substances 0.000 description 2
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
• 230000001681 protective effect Effects 0.000 description 2
• TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 2
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
• 230000004895 regional blood flow Effects 0.000 description 2
• 230000000284 resting effect Effects 0.000 description 2
• 238000013207 serial dilution Methods 0.000 description 2
• 210000002966 serum Anatomy 0.000 description 2
• 239000012312 sodium hydride Substances 0.000 description 2
• 239000008247 solid mixture Substances 0.000 description 2
• 238000001228 spectrum Methods 0.000 description 2
• 210000005250 spinal neuron Anatomy 0.000 description 2
• KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
• KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 2
• 229960003708 sumatriptan Drugs 0.000 description 2
• 238000003786 synthesis reaction Methods 0.000 description 2
• OXEKYXNGJRGPGG-UHFFFAOYSA-N tert-butyl 3-(acetyloxymethyl)-2-methyl-4-[(5-oxo-2h-furan-4-yl)methyl]benzoate Chemical compound C1=CC(C(=O)OC(C)(C)C)=C(C)C(COC(=O)C)=C1CC1=CCOC1=O OXEKYXNGJRGPGG-UHFFFAOYSA-N 0.000 description 2
• MKQVGJJTCKZYOD-OAHLLOKOSA-N tert-butyl 3-(acetyloxymethyl)-2-methyl-4-[[(3s)-2-oxooxolan-3-yl]methyl]benzoate Chemical compound C1=CC(C(=O)OC(C)(C)C)=C(C)C(COC(=O)C)=C1C[C@@H]1C(=O)OCC1 MKQVGJJTCKZYOD-OAHLLOKOSA-N 0.000 description 2
• UEXIKULFPYHJKF-UHFFFAOYSA-N tert-butyl 4-(2,2-dimethoxyethylamino)piperidine-1-carboxylate Chemical compound COC(OC)CNC1CCN(C(=O)OC(C)(C)C)CC1 UEXIKULFPYHJKF-UHFFFAOYSA-N 0.000 description 2
• ADFSCQGCEAKLOE-UHFFFAOYSA-N tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate Chemical compound COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1 ADFSCQGCEAKLOE-UHFFFAOYSA-N 0.000 description 2
• KNQKQXNVPIKRRT-UHFFFAOYSA-N tert-butyl 4-(4-chloro-2-cyanophenyl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2C(=CC(Cl)=CC=2)C#N)=C1 KNQKQXNVPIKRRT-UHFFFAOYSA-N 0.000 description 2
• WUBVEMGCQRSBBT-UHFFFAOYSA-N tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)C(F)(F)F)=CC1 WUBVEMGCQRSBBT-UHFFFAOYSA-N 0.000 description 2
• MTECSPWZXKDPGZ-RUZDIDTESA-N tert-butyl 4-[(7r)-8-oxo-7-(phenylmethoxycarbonylamino)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-9-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)[C@H](NC(=O)OCC=2C=CC=CC=2)CC(C=CC2=C3C=NN2)=C3C1 MTECSPWZXKDPGZ-RUZDIDTESA-N 0.000 description 2
• LXIFKHQOJBOGIE-UHFFFAOYSA-N tert-butyl 4-[1-[3-(2,2-dimethylpropanoylamino)thiophen-2-yl]-1-hydroxy-3-methoxy-3-oxopropan-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(C(=O)OC)C(O)C=1SC=CC=1NC(=O)C(C)(C)C LXIFKHQOJBOGIE-UHFFFAOYSA-N 0.000 description 2
• MCLFTIKDXCUXPY-UHFFFAOYSA-N tert-butyl 4-[5-methoxy-1-tri(propan-2-yl)silylpyrrolo[3,2-b]pyridin-6-yl]-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound COC1=NC=2C=CN([Si](C(C)C)(C(C)C)C(C)C)C=2C=C1C1=CCN(C(=O)OC(C)(C)C)CC1 MCLFTIKDXCUXPY-UHFFFAOYSA-N 0.000 description 2
• GNAKGSNPIDUYKO-UHFFFAOYSA-N tert-butyl 4-[5-methoxy-1-tri(propan-2-yl)silylpyrrolo[3,2-b]pyridin-6-yl]piperidine-1-carboxylate Chemical compound COC1=NC=2C=CN([Si](C(C)C)(C(C)C)C(C)C)C=2C=C1C1CCN(C(=O)OC(C)(C)C)CC1 GNAKGSNPIDUYKO-UHFFFAOYSA-N 0.000 description 2
• FLWASXZWXDVNNH-UHFFFAOYSA-N tert-butyl 4-[6-chloro-1-tri(propan-2-yl)silylpyrrolo[2,3-b]pyridin-4-yl]-4-hydroxypiperidine-1-carboxylate Chemical compound C1=C(Cl)N=C2N([Si](C(C)C)(C(C)C)C(C)C)C=CC2=C1C1(O)CCN(C(=O)OC(C)(C)C)CC1 FLWASXZWXDVNNH-UHFFFAOYSA-N 0.000 description 2
• NFTAHHNEQDHFTG-UHFFFAOYSA-N tert-butyl n-[3-(hydroxymethyl)-4-iodo-2-methylphenyl]carbamate Chemical compound CC1=C(NC(=O)OC(C)(C)C)C=CC(I)=C1CO NFTAHHNEQDHFTG-UHFFFAOYSA-N 0.000 description 2
• RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 2
• HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
• VXKWYPOMXBVZSJ-UHFFFAOYSA-N tetramethyltin Chemical compound C[Sn](C)(C)C VXKWYPOMXBVZSJ-UHFFFAOYSA-N 0.000 description 2
• 230000001225 therapeutic effect Effects 0.000 description 2
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
• QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 2
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
• 230000025033 vasoconstriction Effects 0.000 description 2
• RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
• RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
• CXSZODDHFZIYBY-UHFFFAOYSA-N (2-iodo-5-phenylmethoxyphenyl)methanol Chemical compound C1=C(I)C(CO)=CC(OCC=2C=CC=CC=2)=C1 CXSZODDHFZIYBY-UHFFFAOYSA-N 0.000 description 1
• GVVCHDNSTMEUCS-UAFMIMERSA-N (2r,5r)-1-[2-[(2r,5r)-2,5-diethylphospholan-1-yl]phenyl]-2,5-diethylphospholane Chemical compound CC[C@@H]1CC[C@@H](CC)P1C1=CC=CC=C1P1[C@H](CC)CC[C@H]1CC GVVCHDNSTMEUCS-UAFMIMERSA-N 0.000 description 1
• ZBKIFLUMOTZCND-ZETCQYMHSA-N (2s)-2-[[7-bromo-4-(hydroxymethyl)-1h-indazol-5-yl]methyl]butanedioic acid Chemical compound OCC1=C(C[C@@H](CC(O)=O)C(O)=O)C=C(Br)C2=C1C=NN2 ZBKIFLUMOTZCND-ZETCQYMHSA-N 0.000 description 1
• YVCNCCWEYVQDAC-UHFFFAOYSA-N (3-amino-2,4-dimethylphenyl)methanol Chemical compound CC1=CC=C(CO)C(C)=C1N YVCNCCWEYVQDAC-UHFFFAOYSA-N 0.000 description 1
• UVYZMJMDIMWDNJ-UHFFFAOYSA-N (3-amino-2-methylphenyl)methanol Chemical compound CC1=C(N)C=CC=C1CO UVYZMJMDIMWDNJ-UHFFFAOYSA-N 0.000 description 1
• BCQKYGYTOHXGLL-UHFFFAOYSA-N (3-amino-4-methylphenyl)methanol Chemical compound CC1=CC=C(CO)C=C1N BCQKYGYTOHXGLL-UHFFFAOYSA-N 0.000 description 1
• WWNGBMDVYSNISP-UHFFFAOYSA-N (3-methoxy-3-oxoprop-1-en-2-yl) benzoate Chemical compound COC(=O)C(=C)OC(=O)C1=CC=CC=C1 WWNGBMDVYSNISP-UHFFFAOYSA-N 0.000 description 1
• AFKLSWIRJUJWKY-UHFFFAOYSA-N (3-phenylmethoxyphenyl)methanol Chemical compound OCC1=CC=CC(OCC=2C=CC=CC=2)=C1 AFKLSWIRJUJWKY-UHFFFAOYSA-N 0.000 description 1
• TXSUNOURMQFQER-SECBINFHSA-N (3s)-3-[[4-(hydroxymethyl)-1h-indazol-5-yl]methyl]oxolan-2-one Chemical compound C1=CC=2NN=CC=2C(CO)=C1C[C@H]1CCOC1=O TXSUNOURMQFQER-SECBINFHSA-N 0.000 description 1
• NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
• LOVPHSMOAVXQIH-UHFFFAOYSA-N (4-nitrophenyl) hydrogen carbonate Chemical compound OC(=O)OC1=CC=C([N+]([O-])=O)C=C1 LOVPHSMOAVXQIH-UHFFFAOYSA-N 0.000 description 1
• ZWCRLWCTGOZNEP-SNVBAGLBSA-N (7r)-4-chloro-7-hydroxy-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](O)CC2=CC(Cl)=C(NN=C3)C3=C21 ZWCRLWCTGOZNEP-SNVBAGLBSA-N 0.000 description 1
• NLPJHEXNDOIYOH-SNVBAGLBSA-N (7r)-7-amino-4-chloro-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1N(CC(F)(F)F)C(=O)[C@H](N)CC2=CC(Cl)=C(NN=C3)C3=C21 NLPJHEXNDOIYOH-SNVBAGLBSA-N 0.000 description 1
• OFCPUXCAWXIYJV-FFXKMJQXSA-N (7r)-7-amino-9-(2,2-dimethylpropyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.C1[C@@H](N)C(=O)N(CC(C)(C)C)CC2=C1C=CC1=C2C=NN1 OFCPUXCAWXIYJV-FFXKMJQXSA-N 0.000 description 1
• VEEQSDHLLWZNFK-FMOMHUKBSA-N (7r)-7-amino-9-(3,3-dimethylbutyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.C1[C@@H](N)C(=O)N(CCC(C)(C)C)CC2=C1C=CC1=C2C=NN1 VEEQSDHLLWZNFK-FMOMHUKBSA-N 0.000 description 1
• XLRWRBBUBQSBPG-CYBMUJFWSA-N (7r)-7-amino-9-[2-(dimethylamino)ethyl]-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1[C@@H](N)C(=O)N(CCN(C)C)CC2=C1C=CC1=C2C=NN1 XLRWRBBUBQSBPG-CYBMUJFWSA-N 0.000 description 1
• JXRNTXXAZHBVOT-CURYUGHLSA-N (7r)-7-amino-9-propan-2-yl-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.C1[C@@H](N)C(=O)N(C(C)C)CC2=C1C=CC1=C2C=NN1 JXRNTXXAZHBVOT-CURYUGHLSA-N 0.000 description 1
• LGTDEFKPOXSYRN-PKLMIRHRSA-N (7r)-9-(1-acetylpiperidin-4-yl)-7-amino-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1CN(C(=O)C)CCC1N1C(=O)[C@H](N)CC(C=CC2=C3C=NN2)=C3C1 LGTDEFKPOXSYRN-PKLMIRHRSA-N 0.000 description 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 description 1
• VPMKKYQPCYCWAE-DEOSSOPVSA-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-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=CC=CC=C2CC1)=O)CC=1C=C(Cl)C2=NNC(=C2C=1C1)Cl)N1CCN1CCCCC1 VPMKKYQPCYCWAE-DEOSSOPVSA-N 0.000 description 1
• BMAGIGCFYXYXDM-SFHVURJKSA-N (7s)-4-chloro-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1h-pyrido[2,3-d][1,3]diazepin-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 C1CC2=CC=CN=C2NC(=O)N1C(CC1)CCN1C(=O)C[C@@H]1CC(C=C(Cl)C2=C3C=NN2)=C3CN(CC(F)(F)F)C1=O BMAGIGCFYXYXDM-SFHVURJKSA-N 0.000 description 1
• JBEQHGBBETWIAO-KRWDZBQOSA-N (7s)-4-chloro-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1h-pyrido[3,2-d][1,3]diazepin-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 C1CC2=NC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)C[C@@H]1CC(C=C(Cl)C2=C3C=NN2)=C3CN(CC(F)(F)F)C1=O JBEQHGBBETWIAO-KRWDZBQOSA-N 0.000 description 1
• DVJPIPGZNPEWIX-CYBMUJFWSA-N (7s)-9-(2,2-dimethylpropyl)-7-(2-hydroxyethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C1[C@@H](CCO)C(=O)N(CC(C)(C)C)CC2=C1C=CC1=C2C=NN1 DVJPIPGZNPEWIX-CYBMUJFWSA-N 0.000 description 1
• DPEYHNFHDIXMNV-UHFFFAOYSA-N (9-amino-3-bicyclo[3.3.1]nonanyl)-(4-benzyl-5-methyl-1,4-diazepan-1-yl)methanone dihydrochloride Chemical compound Cl.Cl.CC1CCN(CCN1Cc1ccccc1)C(=O)C1CC2CCCC(C1)C2N DPEYHNFHDIXMNV-UHFFFAOYSA-N 0.000 description 1
• SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
• SSNCMIDZGFCTST-UHFFFAOYSA-N 1,3-difluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=C(F)C=CC=C1F SSNCMIDZGFCTST-UHFFFAOYSA-N 0.000 description 1
• AFFHYIJOENZACX-UHFFFAOYSA-N 1-(2-fluorophenyl)-3-piperidin-4-ylimidazol-2-one;hydrochloride Chemical compound Cl.FC1=CC=CC=C1N1C(=O)N(C2CCNCC2)C=C1 AFFHYIJOENZACX-UHFFFAOYSA-N 0.000 description 1
• NSHZQGGNPXEZFC-UHFFFAOYSA-N 1-(2-hydroxyethyl)-2,6-dimethylpyridine-4-thione Chemical compound CC1=CC(=S)C=C(C)N1CCO NSHZQGGNPXEZFC-UHFFFAOYSA-N 0.000 description 1
• DBEYPHSUTNANMS-UHFFFAOYSA-N 1-fluoro-3-piperidin-4-ylbenzimidazol-2-one;hydrochloride Chemical compound Cl.O=C1N(F)C2=CC=CC=C2N1C1CCNCC1 DBEYPHSUTNANMS-UHFFFAOYSA-N 0.000 description 1
• JKCLTOINPPVNRV-UHFFFAOYSA-N 1-fluoro-4,5-dihydro-3H-1,3-benzodiazepin-2-one Chemical compound FN1C(NCCC2=C1C=CC=C2)=O JKCLTOINPPVNRV-UHFFFAOYSA-N 0.000 description 1
• ANLHHEIMCNZGLV-UHFFFAOYSA-N 1-phenyl-3-piperidin-4-ylimidazol-2-one;hydrochloride Chemical compound Cl.O=C1N(C2CCNCC2)C=CN1C1=CC=CC=C1 ANLHHEIMCNZGLV-UHFFFAOYSA-N 0.000 description 1
• NNTFPLKBXGDCPG-UHFFFAOYSA-N 1-piperidin-4-yl-3h-imidazo[4,5-b]pyridin-2-one Chemical compound O=C1NC2=NC=CC=C2N1C1CCNCC1 NNTFPLKBXGDCPG-UHFFFAOYSA-N 0.000 description 1
• XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
• BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
• IDRZVSHODUJUIL-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridin-6-ylboronic acid Chemical compound OB(O)C1=CN=C2C=CNC2=C1 IDRZVSHODUJUIL-UHFFFAOYSA-N 0.000 description 1
• JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
• SLRIOXRBAPBGEI-UHFFFAOYSA-N 2-(2-nitrophenyl)ethanol Chemical compound OCCC1=CC=CC=C1[N+]([O-])=O SLRIOXRBAPBGEI-UHFFFAOYSA-N 0.000 description 1
• ZJOABMGBRJYBCM-ZETCQYMHSA-N 2-[(7s)-4-bromo-8-oxo-3,6,7,10-tetrahydrooxepino[3,4-e]indazol-7-yl]acetic acid Chemical compound C1OC(=O)[C@H](CC(=O)O)CC2=CC(Br)=C(NN=C3)C3=C21 ZJOABMGBRJYBCM-ZETCQYMHSA-N 0.000 description 1
• ROGQUNNTHOOXBR-NSHDSACASA-N 2-[(7s)-4-bromo-9-(cyclopropylmethyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetic acid Chemical compound C([C@H](C1=O)CC(=O)O)C2=CC(Br)=C3NN=CC3=C2CN1CC1CC1 ROGQUNNTHOOXBR-NSHDSACASA-N 0.000 description 1
• ZHAHMNBIWDCXKW-GXKRWWSZSA-N 2-[(7s)-4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetic acid;dihydrochloride Chemical compound Cl.Cl.C([C@H](C1=O)CC(=O)O)C2=CC(Cl)=C3NN=CC3=C2CN1CC1=CC=NC=C1 ZHAHMNBIWDCXKW-GXKRWWSZSA-N 0.000 description 1
• DKJWFKDJXPEAGS-LBPRGKRZSA-N 2-[(7s)-9-(2,2-dimethylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetic acid Chemical compound C1[C@@H](CC(O)=O)C(=O)N(CC(C)(C)C)CC2=C1C=CC1=C2C=NN1 DKJWFKDJXPEAGS-LBPRGKRZSA-N 0.000 description 1
• DZJKWSGTMLVFJA-UHFFFAOYSA-N 2-[1-(2,2-dimethylpropyl)-2-oxo-4,7-dihydro-3h-pyrazolo[3,4-h]quinolin-3-yl]acetic acid Chemical compound C1=C2NN=CC2=C2N(CC(C)(C)C)C(=O)C(CC(O)=O)CC2=C1 DZJKWSGTMLVFJA-UHFFFAOYSA-N 0.000 description 1
• RWSFZKWMVWPDGZ-UHFFFAOYSA-N 2-amino-6-fluorobenzoic acid Chemical compound NC1=CC=CC(F)=C1C(O)=O RWSFZKWMVWPDGZ-UHFFFAOYSA-N 0.000 description 1
• UUOLETYDNTVQDY-UHFFFAOYSA-N 2-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1Cl UUOLETYDNTVQDY-UHFFFAOYSA-N 0.000 description 1
• FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
• ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
• HFCFJYRLBAANKN-UHFFFAOYSA-N 2-methyl-3-nitroaniline Chemical compound CC1=C(N)C=CC=C1[N+]([O-])=O HFCFJYRLBAANKN-UHFFFAOYSA-N 0.000 description 1
• HRSWSISJJJDBOQ-UHFFFAOYSA-N 2-oxo-1,3-diaza-8-azoniaspiro[4.5]dec-3-en-4-olate Chemical compound N1C(=O)NC(=O)C11CCNCC1 HRSWSISJJJDBOQ-UHFFFAOYSA-N 0.000 description 1
• UJTUCYBYKAXMMJ-UHFFFAOYSA-N 2-oxo-3-piperidin-4-yl-1h-imidazole-5-carbonitrile;hydrochloride Chemical compound Cl.O=C1NC(C#N)=CN1C1CCNCC1 UJTUCYBYKAXMMJ-UHFFFAOYSA-N 0.000 description 1
• WRXNJTBODVGDRY-UHFFFAOYSA-N 2-pyrrolidin-1-ylethanamine Chemical compound NCCN1CCCC1 WRXNJTBODVGDRY-UHFFFAOYSA-N 0.000 description 1
• GPWHFPWZAPOYNO-UHFFFAOYSA-N 3,3-dimethylbutan-1-amine Chemical compound CC(C)(C)CCN GPWHFPWZAPOYNO-UHFFFAOYSA-N 0.000 description 1
• MXJNFSQCMIGUDB-UHFFFAOYSA-N 3-(1-benzylpiperidin-4-yl)-4,5-dihydro-1h-1,3-benzodiazepin-2-one Chemical compound O=C1NC2=CC=CC=C2CCN1C(CC1)CCN1CC1=CC=CC=C1 MXJNFSQCMIGUDB-UHFFFAOYSA-N 0.000 description 1
• SYTRWWIHWDEIPI-UHFFFAOYSA-N 3-(1-benzylpiperidin-4-yl)-9-fluoro-4,5-dihydro-1h-1,3-benzodiazepin-2-one Chemical compound O=C1NC=2C(F)=CC=CC=2CCN1C(CC1)CCN1CC1=CC=CC=C1 SYTRWWIHWDEIPI-UHFFFAOYSA-N 0.000 description 1
• NHMRCEBBPISQJV-CQSZACIVSA-N 3-O-benzyl 1-O-methyl (2R)-2-[[7-chloro-4-(chloromethyl)-1H-indazol-5-yl]methyl]propanedioate Chemical compound O=C([C@H](CC=1C(=C2C=NNC2=C(Cl)C=1)CCl)C(=O)OC)OCC1=CC=CC=C1 NHMRCEBBPISQJV-CQSZACIVSA-N 0.000 description 1
• WZYSKVMEVNRNLB-UHFFFAOYSA-N 3-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]-2-oxo-1h-imidazole-5-carboxylic acid Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)NC(C(O)=O)=C1 WZYSKVMEVNRNLB-UHFFFAOYSA-N 0.000 description 1
• WFNISJZUJCKTLT-UHFFFAOYSA-N 3-bromo-2-nitropyridine Chemical compound [O-][N+](=O)C1=NC=CC=C1Br WFNISJZUJCKTLT-UHFFFAOYSA-N 0.000 description 1
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
• BYNBAMHAURJNTR-UHFFFAOYSA-N 3-piperidin-4-yl-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC=CC=C2N1C1CCNCC1 BYNBAMHAURJNTR-UHFFFAOYSA-N 0.000 description 1
• MWBCICNNADRJTA-UHFFFAOYSA-N 3-piperidin-4-yl-1h-imidazol-2-one;hydrochloride Chemical compound Cl.O=C1NC=CN1C1CCNCC1 MWBCICNNADRJTA-UHFFFAOYSA-N 0.000 description 1
• YSAYOPCAHDPABZ-UHFFFAOYSA-N 3-piperidin-4-yl-4,5-dihydro-1h-pyrido[2,3-d][1,3]diazepin-2-one;dihydrochloride Chemical compound Cl.Cl.O=C1NC2=NC=CC=C2CCN1C1CCNCC1 YSAYOPCAHDPABZ-UHFFFAOYSA-N 0.000 description 1
• AGYMODODHJGOJT-UHFFFAOYSA-N 3-piperidin-4-yl-4,5-dihydro-1h-pyrido[3,2-d][1,3]diazepin-2-one;dihydrochloride Chemical compound Cl.Cl.O=C1NC2=CC=CN=C2CCN1C1CCNCC1 AGYMODODHJGOJT-UHFFFAOYSA-N 0.000 description 1
• FPGGLMIYNLQOID-UHFFFAOYSA-N 3h-pyridin-2-one Chemical compound O=C1CC=CC=N1 FPGGLMIYNLQOID-UHFFFAOYSA-N 0.000 description 1
• JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 description 1
• ZWMTWCIWYCWUQV-UHFFFAOYSA-N 4-(6-chloro-1h-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-ol Chemical compound C=1C(Cl)=NC=2NC=CC=2C=1C1(O)CCNCC1 ZWMTWCIWYCWUQV-UHFFFAOYSA-N 0.000 description 1
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
• SJISCEAZUHNOMD-UHFFFAOYSA-N 4-phenylcyclohexan-1-amine Chemical compound C1CC(N)CCC1C1=CC=CC=C1 SJISCEAZUHNOMD-UHFFFAOYSA-N 0.000 description 1
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
• SKMJOYUGRCIODX-UHFFFAOYSA-N 5-chloro-2-(2,3-dihydropyridin-4-yl)benzonitrile;hydrochloride Chemical compound Cl.N#CC1=CC(Cl)=CC=C1C1=CC=NCC1 SKMJOYUGRCIODX-UHFFFAOYSA-N 0.000 description 1
• WTIFEVSWZUSXQL-UHFFFAOYSA-N 5-methoxy-1h-pyrrolo[3,2-b]pyridine Chemical compound COC1=CC=C2NC=CC2=N1 WTIFEVSWZUSXQL-UHFFFAOYSA-N 0.000 description 1
• DSCOSIUAQUDGJM-UHFFFAOYSA-N 6-chloro-1h-pyrrolo[2,3-b]pyridine Chemical compound ClC1=CC=C2C=CNC2=N1 DSCOSIUAQUDGJM-UHFFFAOYSA-N 0.000 description 1
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
• QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
• ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
• 206010002198 Anaphylactic reaction Diseases 0.000 description 1
• 206010062542 Arterial insufficiency Diseases 0.000 description 1
• BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
• 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
• 229940127597 CGRP antagonist Drugs 0.000 description 1
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
• 241000700199 Cavia porcellus Species 0.000 description 1
• KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
• KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
• TXDUTHBFYKGSAH-SFHVURJKSA-N Evodiamine Chemical compound C1=CC=C2N(C)[C@@H]3C(NC=4C5=CC=CC=4)=C5CCN3C(=O)C2=C1 TXDUTHBFYKGSAH-SFHVURJKSA-N 0.000 description 1
• HMXRXBIGGYUEAX-SFHVURJKSA-N Evodiamine Natural products CN1[C@H]2N(CCc3[nH]c4ccccc4c23)C(=O)c5ccccc15 HMXRXBIGGYUEAX-SFHVURJKSA-N 0.000 description 1
• 102000020897 Formins Human genes 0.000 description 1
• 108091022623 Formins Proteins 0.000 description 1
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
• 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
• 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
• 108091006065 Gs proteins Proteins 0.000 description 1
• 238000007341 Heck reaction Methods 0.000 description 1
• 208000032843 Hemorrhage Diseases 0.000 description 1
• 241000282412 Homo Species 0.000 description 1
• 101001081172 Homo sapiens Humanin-like 11 Proteins 0.000 description 1
• 101100079846 Homo sapiens NEU1 gene Proteins 0.000 description 1
• 102100027736 Humanin-like 11 Human genes 0.000 description 1
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
• 206010020751 Hypersensitivity Diseases 0.000 description 1
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
• 206010061218 Inflammation Diseases 0.000 description 1
• 102000000589 Interleukin-1 Human genes 0.000 description 1
• 108010002352 Interleukin-1 Proteins 0.000 description 1
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
• LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
• 239000007836 KH2PO4 Substances 0.000 description 1
• ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
• 229930182816 L-glutamine Natural products 0.000 description 1
• JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
• 239000012448 Lithium borohydride Substances 0.000 description 1
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
• 241000699670 Mus sp. Species 0.000 description 1
• MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
• NVGXTBVIXRHOSX-UHFFFAOYSA-N N1=CC=C2NC(CC=C21)=O Chemical compound N1=CC=C2NC(CC=C21)=O NVGXTBVIXRHOSX-UHFFFAOYSA-N 0.000 description 1
• 229910002651 NO3 Inorganic materials 0.000 description 1
• 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 1
• 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 1
• NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
• 235000019502 Orange oil Nutrition 0.000 description 1
• 229910019142 PO4 Inorganic materials 0.000 description 1
• 239000004743 Polypropylene Substances 0.000 description 1
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
• 208000002200 Respiratory Hypersensitivity Diseases 0.000 description 1
• 108091006629 SLC13A2 Proteins 0.000 description 1
• 102100028760 Sialidase-1 Human genes 0.000 description 1
• VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
• 239000004133 Sodium thiosulphate Substances 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
• OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
• 239000007983 Tris buffer Substances 0.000 description 1
• 229920004890 Triton X-100 Polymers 0.000 description 1
• 239000013504 Triton X-100 Substances 0.000 description 1
• 229910052770 Uranium Inorganic materials 0.000 description 1
• 240000008042 Zea mays Species 0.000 description 1
• 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 1
• 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
• ICRMWRWLIVAERB-JOCHJYFZSA-N [(2r)-3-[2-(acetyloxymethyl)-3-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-1-methoxy-1-oxopropan-2-yl] benzoate Chemical compound C([C@H](C(=O)OC)OC(=O)C=1C=CC=CC=1)C1=CC=C(NC(=O)OC(C)(C)C)C(C)=C1COC(C)=O ICRMWRWLIVAERB-JOCHJYFZSA-N 0.000 description 1
• KDJQNVHWQQKBMU-MRXNPFEDSA-N [(2r)-3-[7-chloro-4-(chloromethyl)-1h-indazol-5-yl]-1-methoxy-1-oxopropan-2-yl] benzoate Chemical compound O([C@H](CC=1C(=C2C=NNC2=C(Cl)C=1)CCl)C(=O)OC)C(=O)C1=CC=CC=C1 KDJQNVHWQQKBMU-MRXNPFEDSA-N 0.000 description 1
• KSHQHLBBXAULAJ-QGZVFWFLSA-N [(2r)-3-[7-chloro-4-[(2,2,2-trifluoroethylamino)methyl]-1h-indazol-5-yl]-1-methoxy-1-oxopropan-2-yl] benzoate Chemical compound O([C@H](CC=1C(=C2C=NNC2=C(Cl)C=1)CNCC(F)(F)F)C(=O)OC)C(=O)C1=CC=CC=C1 KSHQHLBBXAULAJ-QGZVFWFLSA-N 0.000 description 1
• PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 1
• SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
• 230000001594 aberrant effect Effects 0.000 description 1
• YZHCOAVEPYWBHZ-UHFFFAOYSA-N acetic acid;3-piperidin-4-yl-1,4-dihydroquinazolin-2-one Chemical compound CC(O)=O.O=C1NC2=CC=CC=C2CN1C1CCNCC1 YZHCOAVEPYWBHZ-UHFFFAOYSA-N 0.000 description 1
• GGISZLOBBISXOZ-UHFFFAOYSA-N acetic acid;chloroform Chemical compound CC(O)=O.ClC(Cl)Cl GGISZLOBBISXOZ-UHFFFAOYSA-N 0.000 description 1
• JAJZDGGVQLTPMD-UHFFFAOYSA-N acetic acid;tert-butyl piperidine-1-carboxylate Chemical compound CC(O)=O.CC(C)(C)OC(=O)N1CCCCC1 JAJZDGGVQLTPMD-UHFFFAOYSA-N 0.000 description 1
• XMGZWGBXVLJOKE-UHFFFAOYSA-N acetic acid;toluene Chemical compound CC(O)=O.CC1=CC=CC=C1 XMGZWGBXVLJOKE-UHFFFAOYSA-N 0.000 description 1
• 229960001138 acetylsalicylic acid Drugs 0.000 description 1
• 230000002378 acidificating effect Effects 0.000 description 1
• 229950010850 acistrate Drugs 0.000 description 1
• 239000004480 active ingredient Substances 0.000 description 1
• 229960005305 adenosine Drugs 0.000 description 1
• 230000010085 airway hyperresponsiveness Effects 0.000 description 1
• 150000001298 alcohols Chemical class 0.000 description 1
• 150000001350 alkyl halides Chemical class 0.000 description 1
• 208000026935 allergic disease Diseases 0.000 description 1
• 230000007815 allergy Effects 0.000 description 1
• GSLDEZOOOSBFGP-UHFFFAOYSA-N alpha-methylene gamma-butyrolactone Chemical compound C=C1CCOC1=O GSLDEZOOOSBFGP-UHFFFAOYSA-N 0.000 description 1
• 229910052782 aluminium Inorganic materials 0.000 description 1
• XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
• 125000000539 amino acid group Chemical group 0.000 description 1
• 239000001099 ammonium carbonate Substances 0.000 description 1
• 235000012501 ammonium carbonate Nutrition 0.000 description 1
• 230000002052 anaphylactic effect Effects 0.000 description 1
• 230000036783 anaphylactic response Effects 0.000 description 1
• 208000003455 anaphylaxis Diseases 0.000 description 1
• 125000000129 anionic group Chemical group 0.000 description 1
• 150000001450 anions Chemical class 0.000 description 1
• 230000003110 anti-inflammatory effect Effects 0.000 description 1
• 239000000043 antiallergic agent Substances 0.000 description 1
• 239000000427 antigen Substances 0.000 description 1
• 102000036639 antigens Human genes 0.000 description 1
• 108091007433 antigens Proteins 0.000 description 1
• 239000007864 aqueous solution Substances 0.000 description 1
• 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
• 150000001503 aryl iodides Chemical class 0.000 description 1
• 239000012298 atmosphere Substances 0.000 description 1
• JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
• AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
• JWUZONHDICLAFJ-UHFFFAOYSA-N benzyl n-(4,9-dimethyl-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl)carbamate Chemical compound O=C1N(C)CC(C=2C=NNC=2C(C)=C2)=C2CC1NC(=O)OCC1=CC=CC=C1 JWUZONHDICLAFJ-UHFFFAOYSA-N 0.000 description 1
• IBHYYMRWUVDGGS-UHFFFAOYSA-N benzyl n-(8-acetamido-2,7,9-trimethyl-3-oxo-4,5-dihydro-1h-2-benzazepin-4-yl)carbamate Chemical compound O=C1N(C)CC(C(=C(NC(C)=O)C(C)=C2)C)=C2CC1NC(=O)OCC1=CC=CC=C1 IBHYYMRWUVDGGS-UHFFFAOYSA-N 0.000 description 1
• XHXDYFBTOSBVOR-QGZVFWFLSA-N benzyl n-[(7r)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound N([C@@H]1CC2=C(C=3C=NNC=3C(Cl)=C2)CN(C1=O)CC(F)(F)F)C(=O)OCC1=CC=CC=C1 XHXDYFBTOSBVOR-QGZVFWFLSA-N 0.000 description 1
• FPXPDKPCDQWJEC-HXUWFJFHSA-N benzyl n-[(7r)-4-chloro-9-(2,2-dimethylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound N([C@@H]1CC2=C(C=3C=NNC=3C(Cl)=C2)CN(C1=O)CC(C)(C)C)C(=O)OCC1=CC=CC=C1 FPXPDKPCDQWJEC-HXUWFJFHSA-N 0.000 description 1
• URWSEKARDQVYNG-IQGLISFBSA-N benzyl n-[(7r)-8-oxo-9-[(1r)-1-phenylethyl]-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound N([C@@H]1CC2=C(C=3C=NNC=3C=C2)CN(C1=O)[C@H](C)C=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 URWSEKARDQVYNG-IQGLISFBSA-N 0.000 description 1
• URWSEKARDQVYNG-AVRWGWEMSA-N benzyl n-[(7r)-8-oxo-9-[(1s)-1-phenylethyl]-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound N([C@@H]1CC2=C(C=3C=NNC=3C=C2)CN(C1=O)[C@@H](C)C=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 URWSEKARDQVYNG-AVRWGWEMSA-N 0.000 description 1
• FWTAKRSSDLWRKM-XMMPIXPASA-N benzyl n-[(7r)-8-oxo-9-[[4-(trifluoromethyl)phenyl]methyl]-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound C1=CC(C(F)(F)F)=CC=C1CN1C(=O)[C@H](NC(=O)OCC=2C=CC=CC=2)CC(C=CC2=C3C=NN2)=C3C1 FWTAKRSSDLWRKM-XMMPIXPASA-N 0.000 description 1
• KMFGBWGGIMSCGX-HXUWFJFHSA-N benzyl n-[(7r)-8-oxo-9-propan-2-yl-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound N([C@@H]1CC2=C(C=3C=NNC=3C=C2)CN(C1=O)C(C)C)C(=O)OCC1=CC=CC=C1 KMFGBWGGIMSCGX-HXUWFJFHSA-N 0.000 description 1
• ACALXESZIPPTDE-HSZRJFAPSA-N benzyl n-[(7r)-9-(2-morpholin-4-ylethyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound C([C@H](C1=O)NC(=O)OCC=2C=CC=CC=2)C2=CC=C3NN=CC3=C2CN1CCN1CCOCC1 ACALXESZIPPTDE-HSZRJFAPSA-N 0.000 description 1
• PKQYFGDRSYPNBW-JOCHJYFZSA-N benzyl n-[(7r)-9-(3,3-dimethylbutyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound N([C@@H]1CC2=C(C=3C=NNC=3C=C2)CN(C1=O)CCC(C)(C)C)C(=O)OCC1=CC=CC=C1 PKQYFGDRSYPNBW-JOCHJYFZSA-N 0.000 description 1
• ZIWQXGDCZDZTPE-OAQYLSRUSA-N benzyl n-[(7r)-9-[2-(dimethylamino)ethyl]-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound N([C@@H]1CC2=C(C=3C=NNC=3C=C2)CN(C1=O)CCN(C)C)C(=O)OCC1=CC=CC=C1 ZIWQXGDCZDZTPE-OAQYLSRUSA-N 0.000 description 1
• WAZWRYNQGGUFBS-UHFFFAOYSA-N benzyl n-[9-(2-methylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]carbamate Chemical compound O=C1N(CC(C)C)CC(C=2C=NNC=2C=C2)=C2CC1NC(=O)OCC1=CC=CC=C1 WAZWRYNQGGUFBS-UHFFFAOYSA-N 0.000 description 1
• 239000011230 binding agent Substances 0.000 description 1
• 230000004071 biological effect Effects 0.000 description 1
• 238000010170 biological method Methods 0.000 description 1
• 230000031018 biological processes and functions Effects 0.000 description 1
• 239000004305 biphenyl Substances 0.000 description 1
• 235000010290 biphenyl Nutrition 0.000 description 1
• 125000006267 biphenyl group Chemical group 0.000 description 1
• 229910052797 bismuth Inorganic materials 0.000 description 1
• JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
• 230000037396 body weight Effects 0.000 description 1
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
• 229910000024 caesium carbonate Inorganic materials 0.000 description 1
• 229960001948 caffeine Drugs 0.000 description 1
• VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
• 229910052791 calcium Inorganic materials 0.000 description 1
• 239000011575 calcium Substances 0.000 description 1
• 239000002775 capsule Substances 0.000 description 1
• 239000004202 carbamide Substances 0.000 description 1
• 125000002837 carbocyclic group Chemical group 0.000 description 1
• 125000004432 carbon atom Chemical group C* 0.000 description 1
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
• 239000000969 carrier Substances 0.000 description 1
• 125000002091 cationic group Chemical group 0.000 description 1
• 210000000170 cell membrane Anatomy 0.000 description 1
• DNKYDHSONDSTNJ-XJVRLEFXSA-N chembl1910953 Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)N)[C@@H](C)O)[C@@H](C)O)C(C)C)[C@@H](C)O)C1=CN=CN1 DNKYDHSONDSTNJ-XJVRLEFXSA-N 0.000 description 1
• 239000003795 chemical substances by application Substances 0.000 description 1
• QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 1
• OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
• 229960001231 choline Drugs 0.000 description 1
• 238000004587 chromatography analysis Methods 0.000 description 1
• 239000007819 coupling partner Substances 0.000 description 1
• 229940111134 coxibs Drugs 0.000 description 1
• 239000013078 crystal Substances 0.000 description 1
• 238000002425 crystallisation Methods 0.000 description 1
• 230000008025 crystallization Effects 0.000 description 1
• 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
• NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
• IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
• 230000009089 cytolysis Effects 0.000 description 1
• WTVNFKVGGUWHQC-UHFFFAOYSA-N decane-2,4-dione Chemical compound CCCCCCC(=O)CC(C)=O WTVNFKVGGUWHQC-UHFFFAOYSA-N 0.000 description 1
• 230000002950 deficient Effects 0.000 description 1
• 230000001419 dependent effect Effects 0.000 description 1
• 238000001514 detection method Methods 0.000 description 1
• 206010012601 diabetes mellitus Diseases 0.000 description 1
• ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
• QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
• ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
• QIFCVOVBZKZCFA-INIZCTEOSA-N diethyl (2s)-2-[[2-(acetyloxymethyl)-4-amino-3,5-dimethylphenyl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC(C)=C(N)C(C)=C1COC(C)=O QIFCVOVBZKZCFA-INIZCTEOSA-N 0.000 description 1
• CKPIZWKRQJRCGB-LBPRGKRZSA-N diethyl (2s)-2-[[4-(acetyloxymethyl)-3,7-dichloro-2h-indazol-5-yl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC(Cl)=C2NN=C(Cl)C2=C1COC(C)=O CKPIZWKRQJRCGB-LBPRGKRZSA-N 0.000 description 1
• LSGVWGYIJBKPDS-LBPRGKRZSA-N diethyl (2s)-2-[[4-(acetyloxymethyl)-7-bromo-3-chloro-2h-indazol-5-yl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC(Br)=C2NN=C(Cl)C2=C1COC(C)=O LSGVWGYIJBKPDS-LBPRGKRZSA-N 0.000 description 1
• WDBVVEVKMSONLU-HNNXBMFYSA-N diethyl (2s)-2-[[4-(acetyloxymethyl)-7-methyl-1h-indazol-5-yl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC(C)=C2NN=CC2=C1COC(C)=O WDBVVEVKMSONLU-HNNXBMFYSA-N 0.000 description 1
• VNBQZBYUJDDYPR-ZDUSSCGKSA-N diethyl (2s)-2-[[4-(chloromethyl)-7-methyl-1h-indazol-5-yl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC(C)=C2NN=CC2=C1CCl VNBQZBYUJDDYPR-ZDUSSCGKSA-N 0.000 description 1
• UYCLWJTZLFKVIK-NSHDSACASA-N diethyl (2s)-2-[[7-bromo-4-(chloromethyl)-1h-indazol-5-yl]methyl]butanedioate Chemical compound CCOC(=O)C[C@@H](C(=O)OCC)CC1=CC(Br)=C2NN=CC2=C1CCl UYCLWJTZLFKVIK-NSHDSACASA-N 0.000 description 1
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
• 230000029087 digestion Effects 0.000 description 1
• 229940043279 diisopropylamine Drugs 0.000 description 1
• UCKDKUGECHJNOZ-JTQLQIEISA-N dimethyl (2s)-2-[[4-(chloromethyl)-1h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@@H](C(=O)OC)CC1=CC=C2NN=CC2=C1CCl UCKDKUGECHJNOZ-JTQLQIEISA-N 0.000 description 1
• BLOWYNXZIVXBQF-NSHDSACASA-N dimethyl (2s)-2-[[4-(chloromethyl)-7-methyl-1h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@@H](C(=O)OC)CC1=CC(C)=C2NN=CC2=C1CCl BLOWYNXZIVXBQF-NSHDSACASA-N 0.000 description 1
• ASIPTCCOYSUFQA-QMMMGPOBSA-N dimethyl (2s)-2-[[7-bromo-3-chloro-4-(hydroxymethyl)-2h-indazol-5-yl]methyl]butanedioate Chemical compound COC(=O)C[C@@H](C(=O)OC)CC1=CC(Br)=C2NN=C(Cl)C2=C1CO ASIPTCCOYSUFQA-QMMMGPOBSA-N 0.000 description 1
• BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
• 208000035475 disorder Diseases 0.000 description 1
• 231100000673 dose–response relationship Toxicity 0.000 description 1
• 238000000921 elemental analysis Methods 0.000 description 1
• 239000000839 emulsion Substances 0.000 description 1
• 239000011982 enantioselective catalyst Substances 0.000 description 1
• 238000005516 engineering process Methods 0.000 description 1
• XCGSFFUVFURLIX-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C=3C=CC=C4NC=C(C=34)C2)=C1)C)C1=CC=CC=C1 XCGSFFUVFURLIX-VFGNJEKYSA-N 0.000 description 1
• 229960004943 ergotamine Drugs 0.000 description 1
• XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 1
• HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
• FTKASJMIPSSXBP-UHFFFAOYSA-N ethyl 2-nitroacetate Chemical compound CCOC(=O)C[N+]([O-])=O FTKASJMIPSSXBP-UHFFFAOYSA-N 0.000 description 1
• TVIGDTGNGQHJJI-UHFFFAOYSA-N ethyl 3,3-diethoxy-2-nitropropanoate Chemical compound CCOC(OCC)C([N+]([O-])=O)C(=O)OCC TVIGDTGNGQHJJI-UHFFFAOYSA-N 0.000 description 1
• 239000012091 fetal bovine serum Substances 0.000 description 1
• 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
• 230000002496 gastric effect Effects 0.000 description 1
• 239000003365 glass fiber Substances 0.000 description 1
• 210000005205 gut mucosa Anatomy 0.000 description 1
• 125000004438 haloalkoxy group Chemical group 0.000 description 1
• 238000005984 hydrogenation reaction Methods 0.000 description 1
• 238000007327 hydrogenolysis reaction Methods 0.000 description 1
• 230000003301 hydrolyzing effect Effects 0.000 description 1
• KYUDBQDDNKPSIC-UHFFFAOYSA-N hydron;1h-imidazol-2-ylmethanamine;dichloride Chemical compound Cl.Cl.NCC1=NC=CN1 KYUDBQDDNKPSIC-UHFFFAOYSA-N 0.000 description 1
• 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
• 210000002865 immune cell Anatomy 0.000 description 1
• 230000003832 immune regulation Effects 0.000 description 1
• 230000002757 inflammatory effect Effects 0.000 description 1
• 230000004054 inflammatory process Effects 0.000 description 1
• UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 1
• 230000003834 intracellular effect Effects 0.000 description 1
• 108091008582 intracellular receptors Proteins 0.000 description 1
• 102000027411 intracellular receptors Human genes 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
• 150000002500 ions Chemical class 0.000 description 1
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
• 239000003446 ligand Substances 0.000 description 1
• 239000006194 liquid suspension Substances 0.000 description 1
• 229910052744 lithium Inorganic materials 0.000 description 1
• 239000011777 magnesium Substances 0.000 description 1
• 229910052749 magnesium Inorganic materials 0.000 description 1
• 230000014759 maintenance of location Effects 0.000 description 1
• 235000009973 maize Nutrition 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
• 238000005259 measurement Methods 0.000 description 1
• 229960003194 meglumine Drugs 0.000 description 1
• DWWOFSJECYHQPK-UHFFFAOYSA-N methoxy-[5-methoxy-1-tri(propan-2-yl)silylpyrrolo[3,2-b]pyridin-6-yl]borinic acid Chemical compound N1=C(OC)C(B(O)OC)=CC2=C1C=CN2[Si](C(C)C)(C(C)C)C(C)C DWWOFSJECYHQPK-UHFFFAOYSA-N 0.000 description 1
• 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
• 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
• 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
• 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
• PZDPHPTZIJTPLH-LBPRGKRZSA-N methyl 2-[(7s)-4-chloro-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(Cl)=C(NN=C3)C3=C21 PZDPHPTZIJTPLH-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
• VNMZCBNMDSATOT-LBPRGKRZSA-N methyl 2-[(7s)-8-oxo-4-propan-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 VNMZCBNMDSATOT-LBPRGKRZSA-N 0.000 description 1
• HPCUQXPWPGPYOZ-HNNXBMFYSA-N methyl 2-[(7s)-9-(2,2-dimethylpropyl)-8-oxo-4-prop-1-en-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 HPCUQXPWPGPYOZ-HNNXBMFYSA-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
• NDIRASSBOZYSNW-INIZCTEOSA-N methyl 2-[(7s)-9-benzyl-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=C3NN=CC3=C2CN1CC1=CC=CC=C1 NDIRASSBOZYSNW-INIZCTEOSA-N 0.000 description 1
• KYUAIKDCVWXOGE-UHFFFAOYSA-N methyl 3-[2-(acetyloxymethyl)-5-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-2-(phenylmethoxycarbonylamino)prop-2-enoate Chemical compound C=1C(C)=C(NC(=O)OC(C)(C)C)C=C(COC(C)=O)C=1C=C(C(=O)OC)NC(=O)OCC1=CC=CC=C1 KYUAIKDCVWXOGE-UHFFFAOYSA-N 0.000 description 1
• JSRBRGCVEHNXQQ-UHFFFAOYSA-N methyl 3-[2-(hydroxymethyl)-4-phenylmethoxyphenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C1=C(CO)C(CC(C(=O)OC)NC(=O)OC(C)(C)C)=CC=C1OCC1=CC=CC=C1 JSRBRGCVEHNXQQ-UHFFFAOYSA-N 0.000 description 1
• ZTJSRQDMMSSEPT-UHFFFAOYSA-N methyl 3-[4-(acetyloxymethyl)-1h-indazol-5-yl]-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C=1C=C2NN=CC2=C(COC(C)=O)C=1CC(C(=O)OC)NC(=O)OCC1=CC=CC=C1 ZTJSRQDMMSSEPT-UHFFFAOYSA-N 0.000 description 1
• AEVGAWFKCSEVCU-UHFFFAOYSA-N methyl 3-[4-acetamido-2-(chloromethyl)-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)=C1CCl AEVGAWFKCSEVCU-UHFFFAOYSA-N 0.000 description 1
• TWEQNZZOOFKOER-UHFFFAOYSA-N methyl 3-aminothiophene-2-carboxylate Chemical compound COC(=O)C=1SC=CC=1N TWEQNZZOOFKOER-UHFFFAOYSA-N 0.000 description 1
• 239000002808 molecular sieve Substances 0.000 description 1
• 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
• 235000019796 monopotassium phosphate Nutrition 0.000 description 1
• SCZVXVGZMZRGRU-UHFFFAOYSA-N n'-ethylethane-1,2-diamine Chemical compound CCNCCN SCZVXVGZMZRGRU-UHFFFAOYSA-N 0.000 description 1
• RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
• PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
• 210000002569 neuron Anatomy 0.000 description 1
• 230000007935 neutral effect Effects 0.000 description 1
• 101150009274 nhr-1 gene Proteins 0.000 description 1
• 229910052759 nickel Inorganic materials 0.000 description 1
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
• 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
• 230000009871 nonspecific binding Effects 0.000 description 1
• 239000010502 orange oil Substances 0.000 description 1
• 230000000399 orthopedic effect Effects 0.000 description 1
• 229910052763 palladium Inorganic materials 0.000 description 1
• 229960005489 paracetamol Drugs 0.000 description 1
• 235000019371 penicillin G benzathine Nutrition 0.000 description 1
• 239000000546 pharmaceutical excipient Substances 0.000 description 1
• 238000001050 pharmacotherapy Methods 0.000 description 1
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
• 239000010452 phosphate Substances 0.000 description 1
• 239000002953 phosphate buffered saline Substances 0.000 description 1
• 230000001766 physiological effect Effects 0.000 description 1
• HDOWRFHMPULYOA-PTQBSOBMSA-N piperidin-4-ol Chemical compound OC1CC[15NH]CC1 HDOWRFHMPULYOA-PTQBSOBMSA-N 0.000 description 1
• BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
• 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
• 229920001155 polypropylene Polymers 0.000 description 1
• 239000011591 potassium Substances 0.000 description 1
• 229910052700 potassium Inorganic materials 0.000 description 1
• GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
• 150000003141 primary amines Chemical class 0.000 description 1
• 125000006239 protecting group Chemical group 0.000 description 1
• 238000000159 protein binding assay Methods 0.000 description 1
• 230000002685 pulmonary effect Effects 0.000 description 1
• ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 1
• 238000010791 quenching Methods 0.000 description 1
• 238000003127 radioimmunoassay Methods 0.000 description 1
• 239000002287 radioligand Substances 0.000 description 1
• 238000003653 radioligand binding assay Methods 0.000 description 1
• 230000009467 reduction Effects 0.000 description 1
• 238000011160 research Methods 0.000 description 1
• 229910052703 rhodium Inorganic materials 0.000 description 1
• 239000010948 rhodium Substances 0.000 description 1
• 238000007423 screening assay Methods 0.000 description 1
• 150000003335 secondary amines Chemical class 0.000 description 1
• 230000001953 sensory effect Effects 0.000 description 1
• 230000019491 signal transduction Effects 0.000 description 1
• 239000002356 single layer Substances 0.000 description 1
• 239000002002 slurry Substances 0.000 description 1
• 150000003384 small molecules Chemical class 0.000 description 1
• 229910052708 sodium Inorganic materials 0.000 description 1
• 239000001632 sodium acetate Substances 0.000 description 1
• 235000017281 sodium acetate Nutrition 0.000 description 1
• URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
• ZMRHBJQLCDZMAH-UHFFFAOYSA-M sodium chloride hydrate hydrochloride Chemical compound [OH-].[Na+].Cl.Cl ZMRHBJQLCDZMAH-UHFFFAOYSA-M 0.000 description 1
• BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
• CFLDCJYCZAHJCK-UHFFFAOYSA-N spiro[1,3-dihydroquinazoline-4,4'-piperidine]-2-one Chemical compound N1C(=O)NC2=CC=CC=C2C21CCNCC2 CFLDCJYCZAHJCK-UHFFFAOYSA-N 0.000 description 1
• 230000004936 stimulating effect Effects 0.000 description 1
• 239000000126 substance Substances 0.000 description 1
• 239000001384 succinic acid Substances 0.000 description 1
• 230000002459 sustained effect Effects 0.000 description 1
• 208000011580 syndromic disease Diseases 0.000 description 1
• 238000010189 synthetic method Methods 0.000 description 1
• 239000006188 syrup Substances 0.000 description 1
• 235000020357 syrup Nutrition 0.000 description 1
• 229940095064 tartrate Drugs 0.000 description 1
• IDGXMFMWNDFRKE-UHFFFAOYSA-N tert-butyl 4-(2,2-dimethoxyethylcarbamoylamino)piperidine-1-carboxylate Chemical compound COC(OC)CNC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1 IDGXMFMWNDFRKE-UHFFFAOYSA-N 0.000 description 1
• IIGBENFKIOPRFC-UHFFFAOYSA-N tert-butyl 4-(2-oxo-3-phenylimidazol-1-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)N(C=2C=CC=CC=2)C=C1 IIGBENFKIOPRFC-UHFFFAOYSA-N 0.000 description 1
• UEYCLJSSTRYKOH-UHFFFAOYSA-N tert-butyl 4-(2-oxo-4,5-dihydro-1h-pyrido[2,3-d][1,3]diazepin-3-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)NC2=NC=CC=C2CC1 UEYCLJSSTRYKOH-UHFFFAOYSA-N 0.000 description 1
• MFUSVNJAETWBDR-UHFFFAOYSA-N tert-butyl 4-(2-oxo-4,5-dihydro-1h-pyrido[3,2-d][1,3]diazepin-3-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)NC2=CC=CN=C2CC1 MFUSVNJAETWBDR-UHFFFAOYSA-N 0.000 description 1
• CENAYNKEZDZBJH-UHFFFAOYSA-N tert-butyl 4-(4-fluoro-2-oxo-3h-benzimidazol-1-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)NC2=C(F)C=CC=C21 CENAYNKEZDZBJH-UHFFFAOYSA-N 0.000 description 1
• UXTFTGGKZCCWLI-UHFFFAOYSA-N tert-butyl 4-(5-carbamoyl-2-oxo-1h-imidazol-3-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)NC(C(N)=O)=C1 UXTFTGGKZCCWLI-UHFFFAOYSA-N 0.000 description 1
• GQRQBBAMBQPYFR-UHFFFAOYSA-N tert-butyl 4-(5-cyano-2-oxo-1h-imidazol-3-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)NC(C#N)=C1 GQRQBBAMBQPYFR-UHFFFAOYSA-N 0.000 description 1
• MBEYZGWZJZRWFR-UHFFFAOYSA-N tert-butyl 4-(5-methoxy-1-methylpyrrolo[3,2-b]pyridin-6-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound COC1=NC=2C=CN(C)C=2C=C1C1=CCN(C(=O)OC(C)(C)C)CC1 MBEYZGWZJZRWFR-UHFFFAOYSA-N 0.000 description 1
• RSQMNAPBHIBAHL-UHFFFAOYSA-N tert-butyl 4-(5-methoxy-1-methylpyrrolo[3,2-b]pyridin-6-yl)piperidine-1-carboxylate Chemical compound COC1=NC=2C=CN(C)C=2C=C1C1CCN(C(=O)OC(C)(C)C)CC1 RSQMNAPBHIBAHL-UHFFFAOYSA-N 0.000 description 1
• NRYFFLQIEZSPBO-UHFFFAOYSA-N tert-butyl 4-[(2-aminopyridin-3-yl)amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1NC1=CC=CN=C1N NRYFFLQIEZSPBO-UHFFFAOYSA-N 0.000 description 1
• HAWXLESKQOEOBT-UHFFFAOYSA-N tert-butyl 4-[2,2-dimethoxyethyl(phenylcarbamoyl)amino]piperidine-1-carboxylate Chemical compound C=1C=CC=CC=1NC(=O)N(CC(OC)OC)C1CCN(C(=O)OC(C)(C)C)CC1 HAWXLESKQOEOBT-UHFFFAOYSA-N 0.000 description 1
• BGQUZUSCTWGIIO-UHFFFAOYSA-N tert-butyl 4-[2,2-dimethoxyethyl-[(2-fluorophenyl)carbamoyl]amino]piperidine-1-carboxylate Chemical compound C=1C=CC=C(F)C=1NC(=O)N(CC(OC)OC)C1CCN(C(=O)OC(C)(C)C)CC1 BGQUZUSCTWGIIO-UHFFFAOYSA-N 0.000 description 1
• BELDFCGNBPTQBO-UHFFFAOYSA-N tert-butyl 4-[2-(2-nitropyridin-3-yl)ethylamino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1NCCC1=CC=CN=C1[N+]([O-])=O BELDFCGNBPTQBO-UHFFFAOYSA-N 0.000 description 1
• JTOYMRROBPBLNQ-UHFFFAOYSA-N tert-butyl 4-[2-(3-nitropyridin-2-yl)ethylamino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1NCCC1=NC=CC=C1[N+]([O-])=O JTOYMRROBPBLNQ-UHFFFAOYSA-N 0.000 description 1
• JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 description 1
• UWHFTEXJAGPULX-UHFFFAOYSA-N tert-butyl 5-(acetyloxymethyl)-4-iodo-2-methylbenzoate Chemical compound CC(=O)OCC1=CC(C(=O)OC(C)(C)C)=C(C)C=C1I UWHFTEXJAGPULX-UHFFFAOYSA-N 0.000 description 1
• NRLJBOAEBIILEW-UHFFFAOYSA-N tert-butyl n-(2-methyl-3-oxo-8-phenylmethoxy-4,5-dihydro-1h-2-benzazepin-4-yl)carbamate Chemical compound C=1C=C2CC(NC(=O)OC(C)(C)C)C(=O)N(C)CC2=CC=1OCC1=CC=CC=C1 NRLJBOAEBIILEW-UHFFFAOYSA-N 0.000 description 1
• VVZNTSDRXGDNPW-LJQANCHMSA-N tert-butyl n-[(4r)-4-amino-2-benzyl-7-methyl-3-oxo-4,5-dihydro-1h-2-benzazepin-8-yl]carbamate Chemical compound O=C([C@H](N)CC=1C=C(C(=CC=1C1)NC(=O)OC(C)(C)C)C)N1CC1=CC=CC=C1 VVZNTSDRXGDNPW-LJQANCHMSA-N 0.000 description 1
• WOGYDSNKMAALKC-UHFFFAOYSA-N tert-butyl n-[5-(hydroxymethyl)-4-iodo-2-methylphenyl]carbamate Chemical compound CC1=CC(I)=C(CO)C=C1NC(=O)OC(C)(C)C WOGYDSNKMAALKC-UHFFFAOYSA-N 0.000 description 1
• 150000003512 tertiary amines Chemical group 0.000 description 1
• FODWRUPJCKASBN-UHFFFAOYSA-M tetrabutylazanium;chloride;hydrate Chemical compound O.[Cl-].CCCC[N+](CCCC)(CCCC)CCCC FODWRUPJCKASBN-UHFFFAOYSA-M 0.000 description 1
• RWWNQEOPUOCKGR-UHFFFAOYSA-N tetraethyltin Chemical compound CC[Sn](CC)(CC)CC RWWNQEOPUOCKGR-UHFFFAOYSA-N 0.000 description 1
• CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
• 210000001519 tissue Anatomy 0.000 description 1
• XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
• 231100000419 toxicity Toxicity 0.000 description 1
• 230000001988 toxicity Effects 0.000 description 1
• 231100000027 toxicology Toxicity 0.000 description 1
• 102000027257 transmembrane receptors Human genes 0.000 description 1
• 108091008578 transmembrane receptors Proteins 0.000 description 1
• GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
• WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
• 238000001665 trituration Methods 0.000 description 1
• 229960000281 trometamol Drugs 0.000 description 1
• 230000004614 tumor growth Effects 0.000 description 1
• 239000003981 vehicle Substances 0.000 description 1
• 239000011534 wash buffer Substances 0.000 description 1
• 238000005406 washing Methods 0.000 description 1
• 239000000080 wetting agent Substances 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1