TWI457337B - 呋呫基苯并咪唑 - Google Patents

Info

Publication number

TWI457337B

TWI457337B TW099124742A TW99124742A TWI457337B TW I457337 B TWI457337 B TW I457337B TW 099124742 A TW099124742 A TW 099124742A TW 99124742 A TW99124742 A TW 99124742A TW I457337 B TWI457337 B TW I457337B

Authority

TW

Taiwan

Prior art keywords

compound

formula

group

alkyl

acid

Prior art date

2009-07-27

Links

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• 150000001875 compounds Chemical class 0.000 claims description 136
• 125000000217 alkyl group Chemical group 0.000 claims description 54
• 239000003814 drug Substances 0.000 claims description 54
• 150000003839 salts Chemical class 0.000 claims description 50
• 239000000203 mixture Substances 0.000 claims description 47
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 43
• 201000010099 disease Diseases 0.000 claims description 42
• -1 aminobutyl Chemical group 0.000 claims description 39
• 150000001413 amino acids Chemical class 0.000 claims description 29
• 235000001014 amino acid Nutrition 0.000 claims description 28
• 238000000034 method Methods 0.000 claims description 28
• 125000003545 alkoxy group Chemical group 0.000 claims description 27
• 238000011282 treatment Methods 0.000 claims description 23
• 239000008194 pharmaceutical composition Substances 0.000 claims description 21
• 125000006239 protecting group Chemical group 0.000 claims description 20
• 230000001613 neoplastic effect Effects 0.000 claims description 19
• 125000003277 amino group Chemical group 0.000 claims description 18
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 16
• 208000023275 Autoimmune disease Diseases 0.000 claims description 15
• 125000001424 substituent group Chemical group 0.000 claims description 15
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 14
• KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 14
• 238000002360 preparation method Methods 0.000 claims description 14
• 239000002253 acid Substances 0.000 claims description 13
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 12
• 239000002585 base Substances 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 239000003795 chemical substances by application Substances 0.000 claims description 10
• 125000000524 functional group Chemical group 0.000 claims description 9
• 229910052736 halogen Inorganic materials 0.000 claims description 9
• 150000002367 halogens Chemical class 0.000 claims description 9
• 239000001257 hydrogen Substances 0.000 claims description 9
• 229910052739 hydrogen Inorganic materials 0.000 claims description 9
• 239000004472 Lysine Substances 0.000 claims description 8
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
• 235000018977 lysine Nutrition 0.000 claims description 8
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
• 239000004471 Glycine Substances 0.000 claims description 7
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
• 125000003342 alkenyl group Chemical group 0.000 claims description 7
• 150000001412 amines Chemical class 0.000 claims description 7
• 239000007864 aqueous solution Substances 0.000 claims description 7
• 239000003153 chemical reaction reagent Substances 0.000 claims description 7
• 238000007911 parenteral administration Methods 0.000 claims description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
• 229910052794 bromium Inorganic materials 0.000 claims description 6
• 239000003054 catalyst Substances 0.000 claims description 6
• QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 5
• 235000004279 alanine Nutrition 0.000 claims description 5
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
• 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 4
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
• 230000008569 process Effects 0.000 claims description 4
• 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 3
• 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 3
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 3
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
• 230000003213 activating effect Effects 0.000 claims description 2
• 235000008206 alpha-amino acids Nutrition 0.000 claims description 2
• 125000006242 amine protecting group Chemical group 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
• 239000008365 aqueous carrier Substances 0.000 claims 1
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 92
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• 229940002612 prodrug Drugs 0.000 description 40
• 235000019439 ethyl acetate Nutrition 0.000 description 37
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
• 238000006243 chemical reaction Methods 0.000 description 25
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• 229940024606 amino acid Drugs 0.000 description 24
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
• 241001465754 Metazoa Species 0.000 description 19
• 239000004480 active ingredient Substances 0.000 description 19
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• 210000004369 blood Anatomy 0.000 description 16
• 239000008280 blood Substances 0.000 description 16
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• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
• 238000005160 1H NMR spectroscopy Methods 0.000 description 13
• 241000699670 Mus sp. Species 0.000 description 13
• 239000002904 solvent Substances 0.000 description 13
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 239000007787 solid Substances 0.000 description 12
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• 230000006907 apoptotic process Effects 0.000 description 11
• 238000001990 intravenous administration Methods 0.000 description 11
• ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 201000011510 cancer Diseases 0.000 description 9
• 238000005481 NMR spectroscopy Methods 0.000 description 8
• 125000003118 aryl group Chemical group 0.000 description 8
• 239000000706 filtrate Substances 0.000 description 8
• 125000001072 heteroaryl group Chemical group 0.000 description 8
• 239000007821 HATU Substances 0.000 description 7
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
• 239000012267 brine Substances 0.000 description 7
• 239000000546 pharmaceutical excipient Substances 0.000 description 7
• 239000002244 precipitate Substances 0.000 description 7
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
• 230000001225 therapeutic effect Effects 0.000 description 7
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
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• 239000012043 crude product Substances 0.000 description 6
• 238000001914 filtration Methods 0.000 description 6
• 229910000027 potassium carbonate Inorganic materials 0.000 description 6
• VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 5
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
• 206010009944 Colon cancer Diseases 0.000 description 5
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
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• 125000002619 bicyclic group Chemical group 0.000 description 5
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• BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 4
• 208000001333 Colorectal Neoplasms Diseases 0.000 description 4
• WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
• CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
• WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
• KDXKERNSBIXSRK-YFKPBYRVSA-O L-lysinium(1+) Chemical compound [NH3+]CCCC[C@H]([NH3+])C([O-])=O KDXKERNSBIXSRK-YFKPBYRVSA-O 0.000 description 4
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
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• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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