MX2008013760A - Compuestos restringidos como antagonistas del receptor del peptido relacionado con el gen de calcitonica (cgrp). - Google Patents

Info

Publication number

MX2008013760A

MX2008013760A MX2008013760A MX2008013760A MX2008013760A MX 2008013760 A MX2008013760 A MX 2008013760A MX 2008013760 A MX2008013760 A MX 2008013760A MX 2008013760 A MX2008013760 A MX 2008013760A MX 2008013760 A MX2008013760 A MX 2008013760A

Authority

MX

Mexico

Prior art keywords

oxo

mmol

mixture

chloro

indazol

Prior art date

2006-05-03

Links

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• Global Dossier
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• 150000001875 compounds Chemical class 0.000 title claims description 225
• 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 title abstract description 13
• 102000008323 calcitonin gene-related peptide receptor activity proteins Human genes 0.000 title abstract description 11
• 229940044551 receptor antagonist Drugs 0.000 title abstract description 4
• 239000002464 receptor antagonist Substances 0.000 title abstract description 4
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 20
• 206010027599 migraine Diseases 0.000 claims abstract description 20
• 238000011282 treatment Methods 0.000 claims abstract description 18
• 239000000203 mixture Substances 0.000 claims description 558
• -1 N- (R9) -piperazinyl Chemical group 0.000 claims description 369
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 67
• 125000000217 alkyl group Chemical group 0.000 claims description 64
• 239000001257 hydrogen Substances 0.000 claims description 35
• 229910052739 hydrogen Inorganic materials 0.000 claims description 35
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
• 125000001475 halogen functional group Chemical group 0.000 claims description 27
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 22
• 125000003342 alkenyl group Chemical group 0.000 claims description 21
• 125000001188 haloalkyl group Chemical group 0.000 claims description 21
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
• 125000001424 substituent group Chemical group 0.000 claims description 14
• 150000003839 salts Chemical class 0.000 claims description 13
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
• 125000001624 naphthyl group Chemical group 0.000 claims description 12
• 125000004076 pyridyl group Chemical group 0.000 claims description 12
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
• 229910052799 carbon Inorganic materials 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
• 125000003545 alkoxy group Chemical group 0.000 claims description 8
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 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
• LUVYLURQXCSXOS-UHFFFAOYSA-N 4h-thieno[3,2-b]pyridin-5-one Chemical compound OC1=CC=C2SC=CC2=N1 LUVYLURQXCSXOS-UHFFFAOYSA-N 0.000 claims description 4
• 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
• 125000000392 cycloalkenyl group Chemical group 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
• 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 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
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
• 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 description 3
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
• 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
• 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
• 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
• DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 claims description 2
• YZCARBAUHDWSEA-SFHVURJKSA-N 2-bromo-6-[1-[2-[(7s)-4-chloro-9-(2,2-dimethylpropyl)-8-oxo-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl]acetyl]piperidin-4-yl]-4h-thieno[3,2-b]pyridin-5-one Chemical compound O=C([C@H](CC(=O)N1CCC(CC1)C=1C(NC=2C=C(Br)SC=2C=1)=O)C1)N(CC(C)(C)C)CC2=C1C=C(Cl)C1=C2C=NN1 YZCARBAUHDWSEA-SFHVURJKSA-N 0.000 claims description 2
• 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
• 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
• AVRPHUJQACDXTJ-NRFANRHFSA-N (4s)-7-chloro-2-(2,2-dimethylpropyl)-4-[2-[4-(1-methyl-5-oxo-4h-pyrrolo[3,2-b]pyridin-6-yl)piperidin-1-yl]-2-oxoethyl]-1,4,5,8-tetrahydropyrrolo[2,3-i][2]benzazepin-3-one Chemical compound C1C2=CC(Cl)=C(NC=C3)C3=C2CN(CC(C)(C)C)C(=O)[C@@H]1CC(=O)N(CC1)CCC1C(C(=O)N1)=CC2=C1C=CN2C AVRPHUJQACDXTJ-NRFANRHFSA-N 0.000 claims 1
• 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 1
• XBCYIRSPAKJFDL-UHFFFAOYSA-N 1-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydro-2H-pyrazolo[3,4-i][2]benzazepin-8-one Chemical compound FC(CC1=NNC=2C=CC3=C(C1=2)CNC(CC3)=O)(F)F XBCYIRSPAKJFDL-UHFFFAOYSA-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
• WTVNFKVGGUWHQC-UHFFFAOYSA-N decane-2,4-dione Chemical compound CCCCCCC(=O)CC(C)=O WTVNFKVGGUWHQC-UHFFFAOYSA-N 0.000 claims 1
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• 208000006673 asthma Diseases 0.000 abstract description 4
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• 208000014674 injury Diseases 0.000 abstract description 4
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• 230000024883 vasodilation Effects 0.000 abstract description 4
• 230000005796 circulatory shock Effects 0.000 abstract description 3
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• 239000007787 solid Substances 0.000 description 183
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• 235000019439 ethyl acetate Nutrition 0.000 description 128
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• 239000000243 solution Substances 0.000 description 93
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• 235000019341 magnesium sulphate Nutrition 0.000 description 92
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• 150000004702 methyl esters Chemical class 0.000 description 87
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• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 78
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• 239000002904 solvent Substances 0.000 description 72
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• 239000008346 aqueous phase Substances 0.000 description 67
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 66
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 65
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• 239000012267 brine Substances 0.000 description 56
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 56
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• 239000000706 filtrate Substances 0.000 description 39
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• 238000004587 chromatography analysis Methods 0.000 description 37
• 238000002953 preparative HPLC Methods 0.000 description 36
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 35
• 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 description 34
• 229910000027 potassium carbonate Inorganic materials 0.000 description 33
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• 238000000746 purification Methods 0.000 description 29
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• 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 21
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