KR20180049017A - 치환 1,2-디히드로-3H-피롤로[1,2-c]이미다졸-3-온 항균 화합물 - Google Patents

Info

Publication number

KR20180049017A

KR20180049017A KR1020187009472A KR20187009472A KR20180049017A KR 20180049017 A KR20180049017 A KR 20180049017A KR 1020187009472 A KR1020187009472 A KR 1020187009472A KR 20187009472 A KR20187009472 A KR 20187009472A KR 20180049017 A KR20180049017 A KR 20180049017A

Authority

KR

South Korea

Prior art keywords

methyl

methylsulfonyl

imidazol

hydroxy

pyrrolo

Prior art date

2015-09-03

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.)

Withdrawn

Links

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• 150000001875 compounds Chemical class 0.000 claims abstract description 622
• 150000003839 salts Chemical class 0.000 claims abstract description 69
• -1 3-fluoroazetidin-3-yl Chemical group 0.000 claims description 645
• 125000000217 alkyl group Chemical group 0.000 claims description 72
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 64
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 64
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 63
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 53
• 238000011282 treatment Methods 0.000 claims description 50
• 229910052736 halogen Inorganic materials 0.000 claims description 43
• 150000002367 halogens Chemical class 0.000 claims description 43
• DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 39
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 39
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 37
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 31
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 31
• 229910052731 fluorine Chemical group 0.000 claims description 31
• 239000011737 fluorine Chemical group 0.000 claims description 31
• 208000035143 Bacterial infection Diseases 0.000 claims description 25
• 208000022362 bacterial infectious disease Diseases 0.000 claims description 25
• 239000003814 drug Substances 0.000 claims description 25
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 24
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
• 229910052739 hydrogen Inorganic materials 0.000 claims description 24
• 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 24
• 239000001257 hydrogen Substances 0.000 claims description 21
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
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• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 17
• 125000003282 alkyl amino group Chemical group 0.000 claims description 15
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• 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
• HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 9
• 238000011321 prophylaxis Methods 0.000 claims description 8
• PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 7
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 6
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 6
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• 241000219198 Brassica Species 0.000 claims description 5
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 5
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 5
• DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 4
• AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 4
• PWPJWHXPIKDVAY-UHFFFAOYSA-N methyl 4-methylpiperazine-1-carboxylate Chemical compound COC(=O)N1CCN(C)CC1 PWPJWHXPIKDVAY-UHFFFAOYSA-N 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• NFYZJKOJCRMDRO-UHFFFAOYSA-N 1-(oxetan-3-yl)piperidine Chemical compound C1OCC1N1CCCCC1 NFYZJKOJCRMDRO-UHFFFAOYSA-N 0.000 claims description 2
• OVNUFQWRTFSQFU-UHFFFAOYSA-N 1-(oxetan-3-yl)pyrrolidine Chemical compound C1OCC1N1CCCC1 OVNUFQWRTFSQFU-UHFFFAOYSA-N 0.000 claims description 2
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• 239000004480 active ingredient Substances 0.000 claims description 2
• 150000001408 amides Chemical class 0.000 claims description 2
• JKIUUDJOCYHIGY-UHFFFAOYSA-N benzyl 4-hydroxypiperidine-1-carboxylate Chemical compound C1CC(O)CCN1C(=O)OCC1=CC=CC=C1 JKIUUDJOCYHIGY-UHFFFAOYSA-N 0.000 claims description 2
• LWZKZYOPPZAUQW-UHFFFAOYSA-N benzyl 4-methylpiperazine-1-carboxylate Chemical compound C1CN(C)CCN1C(=O)OCC1=CC=CC=C1 LWZKZYOPPZAUQW-UHFFFAOYSA-N 0.000 claims description 2
• 208000027096 gram-negative bacterial infections Diseases 0.000 claims description 2
• 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 2
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• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 175
• 239000000543 intermediate Substances 0.000 description 142
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• 238000006243 chemical reaction Methods 0.000 description 90
• 238000002953 preparative HPLC Methods 0.000 description 90
• 239000000203 mixture Substances 0.000 description 88
• 239000011541 reaction mixture Substances 0.000 description 78
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
• 206010057190 Respiratory tract infections Diseases 0.000 description 66
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 62
• 238000001704 evaporation Methods 0.000 description 61
• 230000008020 evaporation Effects 0.000 description 61
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 61
• 239000010410 layer Substances 0.000 description 55
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 49
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 41
• 239000003921 oil Substances 0.000 description 38
• 235000019198 oils Nutrition 0.000 description 38
• 238000004296 chiral HPLC Methods 0.000 description 32
• 239000012230 colorless oil Substances 0.000 description 32
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
• 239000002904 solvent Substances 0.000 description 30
• 208000015181 infectious disease Diseases 0.000 description 29
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• 241000894006 Bacteria Species 0.000 description 27
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
• 229910052740 iodine Inorganic materials 0.000 description 26
• 229920006395 saturated elastomer Polymers 0.000 description 26
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• 239000003480 eluent Substances 0.000 description 24
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• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 14
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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 13
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