BRPI0709759A2 - compostos restrito como antagonista de receptor de cgrp,composição que compreende referido composto e uso do mesmo - Google Patents

Info

Publication number

BRPI0709759A2

BRPI0709759A2 BRPI0709759-0A BRPI0709759A BRPI0709759A2 BR PI0709759 A2 BRPI0709759 A2 BR PI0709759A2 BR PI0709759 A BRPI0709759 A BR PI0709759A BR PI0709759 A2 BRPI0709759 A2 BR PI0709759A2

Authority

BR

Brazil

Prior art keywords

oxo

formula

mixture

mmol

chloro

Prior art date

2006-05-03

Links

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• 239000000203 mixture Substances 0.000 title claims abstract description 560
• 150000001875 compounds Chemical class 0.000 title claims abstract description 225
• 239000003735 calcitonin gene related peptide receptor antagonist Substances 0.000 title 1
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 16
• 206010027599 migraine Diseases 0.000 claims abstract description 16
• -1 pyridinyl N-oxide Chemical group 0.000 claims description 216
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 69
• 125000000217 alkyl group Chemical group 0.000 claims description 65
• 229910052739 hydrogen Inorganic materials 0.000 claims description 39
• 239000001257 hydrogen Substances 0.000 claims description 36
• 125000003342 alkenyl group Chemical group 0.000 claims description 21
• 125000001188 haloalkyl group Chemical group 0.000 claims description 21
• 238000004519 manufacturing process Methods 0.000 claims description 21
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 18
• 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
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 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
• 150000003839 salts Chemical class 0.000 claims description 12
• 229910052799 carbon Inorganic materials 0.000 claims description 10
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
• 125000003545 alkoxy group Chemical group 0.000 claims description 8
• 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 7
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 6
• BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• 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
• 125000000719 pyrrolidinyl group Chemical group 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
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• 125000002757 morpholinyl group Chemical group 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000003386 piperidinyl 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
• 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 3
• DHZYXWMZLAKTQV-UHFFFAOYSA-N diazepin-3-one Chemical compound O=C1C=CC=CN=N1 DHZYXWMZLAKTQV-UHFFFAOYSA-N 0.000 claims description 3
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
• 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
• 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 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
• 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
• 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
• 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
• 239000002671 adjuvant Substances 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 14
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 3
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 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 1
• VBPMPNJTNKRJJE-AWEZNQCLSA-N (7s)-4-chloro-7-[2-oxo-2-[4-(2-oxo-1h-imidazol-3-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one Chemical compound C([C@@H]1CC2=C(C=3C=NNC=3C(Cl)=C2)CN(C1=O)CC(F)(F)F)C(=O)N(CC1)CCC1N1C=CNC1=O VBPMPNJTNKRJJE-AWEZNQCLSA-N 0.000 claims 1
• HPOQPYOUJYHQND-UHFFFAOYSA-N 1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one Chemical compound N1C(=O)NCCC2=CC=CC=C21 HPOQPYOUJYHQND-UHFFFAOYSA-N 0.000 claims 1
• 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 1
• PCKBLXLYWSCVKI-LJQANCHMSA-N [(7r)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-7-yl] 4-(2-oxo-3h-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate Chemical compound O=C([C@H](OC(=O)N1CCC(CC1)N1C(NC2=NC=CC=C21)=O)C1)N(CC(F)(F)F)CC2=C1C=C(Cl)C1=C2C=NN1 PCKBLXLYWSCVKI-LJQANCHMSA-N 0.000 claims 1
• WTVNFKVGGUWHQC-UHFFFAOYSA-N decane-2,4-dione Chemical compound CCCCCCC(=O)CC(C)=O WTVNFKVGGUWHQC-UHFFFAOYSA-N 0.000 claims 1
• WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 31
• 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 abstract description 28
• 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 abstract description 17
• 102000008323 calcitonin gene-related peptide receptor activity proteins Human genes 0.000 abstract description 16
• 206010019233 Headaches Diseases 0.000 abstract description 15
• 231100000869 headache Toxicity 0.000 abstract description 11
• 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
• 208000007920 Neurogenic Inflammation Diseases 0.000 abstract description 4
• 239000005557 antagonist Substances 0.000 abstract description 4
• 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
• 229940044551 receptor antagonist Drugs 0.000 abstract description 4
• 239000002464 receptor antagonist Substances 0.000 abstract description 4
• 230000024883 vasodilation Effects 0.000 abstract description 4
• 230000001272 neurogenic effect Effects 0.000 abstract description 3
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract description 2
• 230000002757 inflammatory effect Effects 0.000 abstract description 2
• 230000009245 menopause Effects 0.000 abstract description 2
• 208000023504 respiratory system disease Diseases 0.000 abstract description 2
• 102100025588 Calcitonin gene-related peptide 1 Human genes 0.000 abstract 1
• 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 344
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 321
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 261
• 239000000543 intermediate Substances 0.000 description 239
• 238000006243 chemical reaction Methods 0.000 description 236
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 233
• 238000001819 mass spectrum Methods 0.000 description 218
• 239000007787 solid Substances 0.000 description 182
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• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 132
• 239000000463 material Substances 0.000 description 130
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 124
• 235000019439 ethyl acetate Nutrition 0.000 description 121
• 238000005160 1H NMR spectroscopy Methods 0.000 description 115
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• 239000002253 acid Substances 0.000 description 107
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 106
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 102
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 99
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 96
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 95
• 239000000243 solution Substances 0.000 description 91
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• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 66
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• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 64
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• 235000019341 magnesium sulphate Nutrition 0.000 description 62
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• 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
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 49
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• 150000004702 methyl esters Chemical class 0.000 description 38
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• 238000004128 high performance liquid chromatography Methods 0.000 description 25
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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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