KR20160098503A - 항균성 1h-인다졸 및 1h-인돌 유도체 - Google Patents

Info

Publication number

KR20160098503A

KR20160098503A KR1020167019669A KR20167019669A KR20160098503A KR 20160098503 A KR20160098503 A KR 20160098503A KR 1020167019669 A KR1020167019669 A KR 1020167019669A KR 20167019669 A KR20167019669 A KR 20167019669A KR 20160098503 A KR20160098503 A KR 20160098503A

Authority

KR

South Korea

Prior art keywords

hydroxy

methyl

methylsulfonyl

butanamide

indazol

Prior art date

2013-12-19

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.)

Ceased

Links

• Espacenet
• Global Dossier
• Discuss

• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title description 3
• 230000000844 anti-bacterial effect Effects 0.000 title description 3
• BNIFVTPIXGUZCU-UHFFFAOYSA-N 1h-indazole Chemical compound C1=CC=C2C=NNC2=C1.C1=CC=C2C=NNC2=C1 BNIFVTPIXGUZCU-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 434
• -1 1-hydroxymethyl-cycloprop-1-yl Chemical group 0.000 claims abstract description 356
• 150000003839 salts Chemical class 0.000 claims abstract description 62
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 47
• 150000002367 halogens Chemical class 0.000 claims abstract description 47
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 27
• 125000005133 alkynyloxy group Chemical group 0.000 claims abstract description 16
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 13
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 56
• 238000011282 treatment Methods 0.000 claims description 40
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 26
• 208000035143 Bacterial infection Diseases 0.000 claims description 26
• 208000022362 bacterial infectious disease Diseases 0.000 claims description 26
• 125000000217 alkyl group Chemical group 0.000 claims description 23
• DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 23
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 22
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 21
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 21
• 239000011737 fluorine Substances 0.000 claims description 21
• 229910052731 fluorine Inorganic materials 0.000 claims description 21
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 16
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 238000011321 prophylaxis Methods 0.000 claims description 14
• 239000003814 drug Substances 0.000 claims description 13
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 11
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 8
• 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 8
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 5
• 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 5
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
• 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
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
• 229910019142 PO4 Inorganic materials 0.000 claims description 3
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 239000010452 phosphate Substances 0.000 claims description 3
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
• 239000004480 active ingredient Substances 0.000 claims description 2
• 208000027096 gram-negative bacterial infections Diseases 0.000 claims description 2
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 125000000335 thiazolyl group Chemical group 0.000 claims 9
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
• 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 14
• 230000000845 anti-microbial effect Effects 0.000 abstract description 12
• 125000002768 hydroxyalkyl group Chemical group 0.000 abstract description 9
• 125000004103 aminoalkyl group Chemical group 0.000 abstract description 6
• 125000004990 dihydroxyalkyl group Chemical group 0.000 abstract description 5
• 125000005505 thiomorpholino group Chemical group 0.000 abstract 1
• 238000005481 NMR spectroscopy Methods 0.000 description 133
• 238000002360 preparation method Methods 0.000 description 119
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 100
• 238000000034 method Methods 0.000 description 91
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 78
• 239000007787 solid Substances 0.000 description 78
• 239000000243 solution Substances 0.000 description 72
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
• 239000000543 intermediate Substances 0.000 description 60
• 239000000203 mixture Substances 0.000 description 60
• 238000006243 chemical reaction Methods 0.000 description 59
• 238000002953 preparative HPLC Methods 0.000 description 57
• 238000000746 purification Methods 0.000 description 56
• 239000011541 reaction mixture Substances 0.000 description 54
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
• 206010057190 Respiratory tract infections Diseases 0.000 description 38
• 239000012044 organic layer Substances 0.000 description 35
• 239000003921 oil Substances 0.000 description 33
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• 239000010410 layer Substances 0.000 description 32
• 208000015181 infectious disease Diseases 0.000 description 31
• 239000012267 brine Substances 0.000 description 28
• 125000004432 carbon atom Chemical group C* 0.000 description 28
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
• 238000004296 chiral HPLC Methods 0.000 description 23
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
• 229910052740 iodine Inorganic materials 0.000 description 22
• 239000006260 foam Substances 0.000 description 20
• 239000002904 solvent Substances 0.000 description 20
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 19
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
• 239000011630 iodine Substances 0.000 description 19
• 230000002829 reductive effect Effects 0.000 description 19
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
• 239000012071 phase Substances 0.000 description 16
• 241000589517 Pseudomonas aeruginosa Species 0.000 description 15
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 14
• 229910052794 bromium Inorganic materials 0.000 description 14
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 14
• 239000011734 sodium Substances 0.000 description 14
• 241000588747 Klebsiella pneumoniae Species 0.000 description 13
• 230000008878 coupling Effects 0.000 description 13
• 238000010168 coupling process Methods 0.000 description 13
• 238000005859 coupling reaction Methods 0.000 description 13
• 239000003480 eluent Substances 0.000 description 13
• 238000004519 manufacturing process Methods 0.000 description 13
• 241000588626 Acinetobacter baumannii Species 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 239000000047 product Substances 0.000 description 12
• 239000000725 suspension Substances 0.000 description 12
• 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 11
• LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 11
• 238000000926 separation method Methods 0.000 description 11
• 229910000104 sodium hydride Inorganic materials 0.000 description 11
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
• VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 10
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• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• 230000029936 alkylation Effects 0.000 description 9
• 238000005804 alkylation reaction Methods 0.000 description 9
• 239000003242 anti bacterial agent Substances 0.000 description 9
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• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 9
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• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 9
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 8
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