TW201714885A - 經取代之1,2-二氫-3H-吡咯并[1,2-c]咪唑-3-酮抗菌化合物 - Google Patents

Info

Publication number

TW201714885A

TW201714885A TW105128540A TW105128540A TW201714885A TW 201714885 A TW201714885 A TW 201714885A TW 105128540 A TW105128540 A TW 105128540A TW 105128540 A TW105128540 A TW 105128540A TW 201714885 A TW201714885 A TW 201714885A

Authority

TW

Taiwan

Prior art keywords

methyl

hydroxy

methylsulfonyl

pyrrolo

imidazole

Prior art date

2015-09-03

Links

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• Global Dossier
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• 150000001875 compounds Chemical class 0.000 title claims abstract description 598
• 230000000844 anti-bacterial effect Effects 0.000 title abstract description 16
• XTYMYZJHPHOJAW-UHFFFAOYSA-N 1,2-dihydropyrrolo[1,2-c]imidazol-3-one Chemical class C1=CN2C(=O)NCC2=C1 XTYMYZJHPHOJAW-UHFFFAOYSA-N 0.000 title description 4
• 150000003839 salts Chemical class 0.000 claims abstract description 74
• -1 3-fluoroazetidin-3-yl Chemical group 0.000 claims description 631
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 449
• HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 190
• 125000000217 alkyl group Chemical group 0.000 claims description 78
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 71
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 65
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 55
• 239000011737 fluorine Chemical group 0.000 claims description 48
• 229910052731 fluorine Chemical group 0.000 claims description 48
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 45
• 229910052736 halogen Inorganic materials 0.000 claims description 42
• 150000002367 halogens Chemical class 0.000 claims description 42
• 238000011282 treatment Methods 0.000 claims description 42
• 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 35
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 34
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 31
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 30
• 229910052739 hydrogen Inorganic materials 0.000 claims description 24
• 208000035143 Bacterial infection Diseases 0.000 claims description 23
• 208000022362 bacterial infectious disease Diseases 0.000 claims description 23
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
• 239000001257 hydrogen Substances 0.000 claims description 21
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 19
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
• 239000003814 drug Substances 0.000 claims description 19
• 230000002265 prevention Effects 0.000 claims description 19
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
• 125000003282 alkyl amino group Chemical group 0.000 claims description 15
• 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 15
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 11
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
• 125000001188 haloalkyl group Chemical group 0.000 claims description 10
• 150000004702 methyl esters Chemical class 0.000 claims description 8
• 229910052757 nitrogen Inorganic materials 0.000 claims description 8
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 6
• 125000000623 heterocyclic group Chemical group 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 125000002252 acyl group Chemical group 0.000 claims description 5
• KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 5
• 125000001153 fluoro group Chemical group F* 0.000 claims description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
• XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 2
• 239000004480 active ingredient Substances 0.000 claims description 2
• 150000001350 alkyl halides Chemical class 0.000 claims description 2
• IVHKZGYFKJRXBD-UHFFFAOYSA-N amino carbamate Chemical compound NOC(N)=O IVHKZGYFKJRXBD-UHFFFAOYSA-N 0.000 claims description 2
• 208000027096 gram-negative bacterial infections Diseases 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 6
• WWYVZTLIFYLZFM-UHFFFAOYSA-N 1-methylazetidine Chemical compound CN1CCC1 WWYVZTLIFYLZFM-UHFFFAOYSA-N 0.000 claims 1
• 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
• 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims 1
• KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims 1
• 239000002585 base Substances 0.000 description 489
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 386
• VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 350
• 150000001412 amines Chemical class 0.000 description 287
• 238000002360 preparation method Methods 0.000 description 252
• 238000005481 NMR spectroscopy Methods 0.000 description 240
• 238000000034 method Methods 0.000 description 216
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 179
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 151
• 239000000543 intermediate Substances 0.000 description 135
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 124
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 112
• 238000006243 chemical reaction Methods 0.000 description 112
• 239000007787 solid Substances 0.000 description 106
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 97
• 239000000243 solution Substances 0.000 description 92
• 235000019439 ethyl acetate Nutrition 0.000 description 89
• 239000000203 mixture Substances 0.000 description 89
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 78
• 239000011541 reaction mixture Substances 0.000 description 75
• 239000010410 layer Substances 0.000 description 55
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 52
• 206010057190 Respiratory tract infections Diseases 0.000 description 47
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 43
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 41
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 38
• 238000004128 high performance liquid chromatography Methods 0.000 description 32
• 241000894006 Bacteria Species 0.000 description 31
• 239000002904 solvent Substances 0.000 description 30
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 29
• 239000007864 aqueous solution Substances 0.000 description 29
• BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 27
• 208000015181 infectious disease Diseases 0.000 description 27
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
• 239000013078 crystal Substances 0.000 description 25
• 150000002148 esters Chemical class 0.000 description 25
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• 229920006395 saturated elastomer Polymers 0.000 description 24
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 23
• 239000011630 iodine Substances 0.000 description 23
• 229910052740 iodine Inorganic materials 0.000 description 23
• 125000004432 carbon atom Chemical group C* 0.000 description 22
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 22
• 238000000746 purification Methods 0.000 description 22
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 21
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 21
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
• 239000003480 eluent Substances 0.000 description 19
• 239000000725 suspension Substances 0.000 description 19
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
• IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 18
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 16
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
• 239000003921 oil Substances 0.000 description 16
• 235000019198 oils Nutrition 0.000 description 16
• 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 16
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
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• 238000000926 separation method Methods 0.000 description 15
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• 238000002953 preparative HPLC Methods 0.000 description 14
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
• 150000001345 alkine derivatives Chemical class 0.000 description 13
• 238000010586 diagram Methods 0.000 description 13
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• ILKWEPWYWBCGSR-UHFFFAOYSA-N 1-methylazepine Chemical compound CN1C=CC=CC=C1 ILKWEPWYWBCGSR-UHFFFAOYSA-N 0.000 description 10
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 10
• 125000006239 protecting group Chemical group 0.000 description 10
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• 125000003545 alkoxy group Chemical group 0.000 description 9
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• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
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• MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 7
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• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
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