AU2012238374B2 - Isoxazole derivatives useful as antibacterial agents - Google Patents

Info

Publication number

AU2012238374B2

AU2012238374B2 AU2012238374A AU2012238374A AU2012238374B2 AU 2012238374 B2 AU2012238374 B2 AU 2012238374B2 AU 2012238374 A AU2012238374 A AU 2012238374A AU 2012238374 A AU2012238374 A AU 2012238374A AU 2012238374 B2 AU2012238374 B2 AU 2012238374B2

Authority

AU

Australia

Prior art keywords

methyl

alkyl

isoxazol

hydroxy

methylsulfonyl

Prior art date

2011-04-08

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

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• 239000003242 anti bacterial agent Substances 0.000 title description 5
• 150000002545 isoxazoles Chemical class 0.000 title description 2
• 125000000217 alkyl group Chemical group 0.000 claims description 122
• 150000001875 compounds Chemical class 0.000 claims description 121
• -1 methylenedioxy Chemical group 0.000 claims description 119
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 36
• 239000001257 hydrogen Substances 0.000 claims description 36
• 229910052739 hydrogen Inorganic materials 0.000 claims description 36
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
• 238000000034 method Methods 0.000 claims description 32
• 125000003118 aryl group Chemical group 0.000 claims description 27
• 125000001072 heteroaryl group Chemical group 0.000 claims description 26
• 125000000623 heterocyclic group Chemical group 0.000 claims description 26
• 150000003839 salts Chemical class 0.000 claims description 26
• DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 25
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 22
• 239000003814 drug Substances 0.000 claims description 17
• 229910052736 halogen Inorganic materials 0.000 claims description 15
• 150000002367 halogens Chemical class 0.000 claims description 15
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 13
• 125000001424 substituent group Chemical group 0.000 claims description 13
• 125000004104 aryloxy group Chemical group 0.000 claims description 11
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
• 125000004691 alkyl thio carbonyl group Chemical group 0.000 claims description 8
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 8
• 230000000694 effects Effects 0.000 claims description 7
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 7
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 6
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
• 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 6
• 125000005368 heteroarylthio group Chemical group 0.000 claims description 5
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
• 125000001544 thienyl group Chemical group 0.000 claims description 5
• 125000005110 aryl thio group Chemical group 0.000 claims description 4
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
• 125000005366 cycloalkylthio group Chemical group 0.000 claims description 4
• 208000027096 gram-negative bacterial infections Diseases 0.000 claims description 4
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• NXOTUZBMBWOEIM-MRXNPFEDSA-N (2r)-4-[3-(2-fluoro-3-methoxyphenyl)-1,2-oxazol-5-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical group COC1=CC=CC(C2=NOC(CC[C@](C)(C(=O)NO)S(C)(=O)=O)=C2)=C1F NXOTUZBMBWOEIM-MRXNPFEDSA-N 0.000 claims description 2
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
• 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
• 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 6
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 5
• AXLOCHLTNQDFFS-BESJYZOMSA-N azastene Chemical compound C([C@H]1[C@@H]2CC[C@@]([C@]2(CC[C@@H]1[C@@]1(C)C2)C)(O)C)C=C1C(C)(C)C1=C2C=NO1 AXLOCHLTNQDFFS-BESJYZOMSA-N 0.000 claims 4
• 125000001475 halogen functional group Chemical group 0.000 claims 2
• HCERQTLDRDZHNO-MRXNPFEDSA-N (2r)-4-[5-(2-fluoro-3-methoxyphenyl)-1,2-oxazol-3-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound COC1=CC=CC(C=2ON=C(CC[C@](C)(C(=O)NO)S(C)(=O)=O)C=2)=C1F HCERQTLDRDZHNO-MRXNPFEDSA-N 0.000 claims 1
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
• 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims 1
• 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims 1
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
• FHSUWVXCKYWKQC-UHFFFAOYSA-N 4-[3-(2,4-difluorophenyl)-1,2-oxazol-5-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound O1C(CCC(C)(C(=O)NO)S(C)(=O)=O)=CC(C=2C(=CC(F)=CC=2)F)=N1 FHSUWVXCKYWKQC-UHFFFAOYSA-N 0.000 claims 1
• PBABRFLCYVRPGQ-UHFFFAOYSA-N 4-[3-(2-ethoxypropan-2-yl)-1,2-oxazol-5-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound CCOC(C)(C)C=1C=C(CCC(C)(C(=O)NO)S(C)(=O)=O)ON=1 PBABRFLCYVRPGQ-UHFFFAOYSA-N 0.000 claims 1
• VXTCDBXHICHZMI-UHFFFAOYSA-N 4-[3-(3,4-difluorophenyl)-1,2-oxazol-5-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound O1C(CCC(C)(C(=O)NO)S(C)(=O)=O)=CC(C=2C=C(F)C(F)=CC=2)=N1 VXTCDBXHICHZMI-UHFFFAOYSA-N 0.000 claims 1
• WURMAIUGSVDXNQ-UHFFFAOYSA-N 4-[3-(3,4-dimethoxyphenyl)-1,2-oxazol-5-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound C1=C(OC)C(OC)=CC=C1C1=NOC(CCC(C)(C(=O)NO)S(C)(=O)=O)=C1 WURMAIUGSVDXNQ-UHFFFAOYSA-N 0.000 claims 1
• BLYGFQFTPVQVEJ-UHFFFAOYSA-N 4-[3-(3-fluoro-4-morpholin-4-ylphenyl)-1,2-oxazol-5-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound O1C(CCC(C)(C(=O)NO)S(C)(=O)=O)=CC(C=2C=C(F)C(N3CCOCC3)=CC=2)=N1 BLYGFQFTPVQVEJ-UHFFFAOYSA-N 0.000 claims 1
• PYDSRUSDMQVQJD-UHFFFAOYSA-N 4-[3-(3-fluorophenyl)-1,2-oxazol-5-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound O1C(CCC(C)(C(=O)NO)S(C)(=O)=O)=CC(C=2C=C(F)C=CC=2)=N1 PYDSRUSDMQVQJD-UHFFFAOYSA-N 0.000 claims 1
• FQLMYDRKOBWRFB-UHFFFAOYSA-N 4-[3-(3-fluoropyridin-2-yl)-1,2-oxazol-5-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound O1C(CCC(C)(C(=O)NO)S(C)(=O)=O)=CC(C=2C(=CC=CN=2)F)=N1 FQLMYDRKOBWRFB-UHFFFAOYSA-N 0.000 claims 1
• VNMAFOGPKMKWCF-UHFFFAOYSA-N 4-[3-(3-fluoropyridin-4-yl)-1,2-oxazol-5-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound O1C(CCC(C)(C(=O)NO)S(C)(=O)=O)=CC(C=2C(=CN=CC=2)F)=N1 VNMAFOGPKMKWCF-UHFFFAOYSA-N 0.000 claims 1
• UOSUVHHPJJREPU-UHFFFAOYSA-N 4-[3-(4-fluorophenyl)-1,2-oxazol-5-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound O1C(CCC(C)(C(=O)NO)S(C)(=O)=O)=CC(C=2C=CC(F)=CC=2)=N1 UOSUVHHPJJREPU-UHFFFAOYSA-N 0.000 claims 1
• QQNMJEMOLKXMFB-UHFFFAOYSA-N 4-[3-(5-ethylthiophen-2-yl)-1,2-oxazol-5-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical group S1C(CC)=CC=C1C1=NOC(CCC(C)(C(=O)NO)S(C)(=O)=O)=C1 QQNMJEMOLKXMFB-UHFFFAOYSA-N 0.000 claims 1
• VRUGEGDNLIATDC-UHFFFAOYSA-N 4-[5-(2,6-dichlorophenyl)-1,2-oxazol-3-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound O1N=C(CCC(C)(C(=O)NO)S(C)(=O)=O)C=C1C1=C(Cl)C=CC=C1Cl VRUGEGDNLIATDC-UHFFFAOYSA-N 0.000 claims 1
• SIUYFAFARGZKKQ-UHFFFAOYSA-N 4-[5-(2-fluorophenyl)-1,2-oxazol-3-yl]-n-hydroxy-2-methyl-2-methylsulfonylbutanamide Chemical compound O1N=C(CCC(C)(C(=O)NO)S(C)(=O)=O)C=C1C1=CC=CC=C1F SIUYFAFARGZKKQ-UHFFFAOYSA-N 0.000 claims 1
• OIQRWKYGJHKCKL-UHFFFAOYSA-N [3-[4-(hydroxyamino)-3-methyl-3-methylsulfonyl-4-oxobutyl]-1,2-oxazol-5-yl]methyl n-butylcarbamate Chemical compound CCCCNC(=O)OCC1=CC(CCC(C)(C(=O)NO)S(C)(=O)=O)=NO1 OIQRWKYGJHKCKL-UHFFFAOYSA-N 0.000 claims 1
• OUZUKKAIQOQIAS-UHFFFAOYSA-N ethyl n-[[3-[4-(hydroxyamino)-3-methyl-3-methylsulfonyl-4-oxobutyl]-1,2-oxazol-5-yl]methyl]-n-propan-2-ylcarbamate Chemical compound CCOC(=O)N(C(C)C)CC1=CC(CCC(C)(C(=O)NO)S(C)(=O)=O)=NO1 OUZUKKAIQOQIAS-UHFFFAOYSA-N 0.000 claims 1
• ROURQWCQAQJLLS-UHFFFAOYSA-N n-cyclohexyl-5-[4-(hydroxyamino)-3-methyl-3-methylsulfonyl-4-oxobutyl]-1,2-oxazole-3-carboxamide Chemical compound O1C(CCC(C)(C(=O)NO)S(C)(=O)=O)=CC(C(=O)NC2CCCCC2)=N1 ROURQWCQAQJLLS-UHFFFAOYSA-N 0.000 claims 1
• ZDOBONUVBLDFGC-UHFFFAOYSA-N n-hydroxy-2-methyl-2-methylsulfonyl-4-[5-(phenylmethoxymethyl)-1,2-oxazol-3-yl]butanamide Chemical compound O1N=C(CCC(C)(C(=O)NO)S(C)(=O)=O)C=C1COCC1=CC=CC=C1 ZDOBONUVBLDFGC-UHFFFAOYSA-N 0.000 claims 1
• OMCCRZYPUNCTEJ-UHFFFAOYSA-N n-hydroxy-2-methyl-4-[3-(4-methylphenyl)-1,2-oxazol-5-yl]-2-methylsulfonylbutanamide Chemical compound C1=CC(C)=CC=C1C1=NOC(CCC(C)(C(=O)NO)S(C)(=O)=O)=C1 OMCCRZYPUNCTEJ-UHFFFAOYSA-N 0.000 claims 1
• WDMWLDLIXNEGSQ-UHFFFAOYSA-N n-hydroxy-4-[5-(9-hydroxynonyl)-1,2-oxazol-3-yl]-2-methyl-2-methylsulfonylbutanamide Chemical compound ONC(=O)C(S(C)(=O)=O)(C)CCC=1C=C(CCCCCCCCCO)ON=1 WDMWLDLIXNEGSQ-UHFFFAOYSA-N 0.000 claims 1
• ZXZYFWXNOKFWOD-UHFFFAOYSA-N n-hydroxy-4-[5-[(1-hydroxycyclohexyl)methyl]-1,2-oxazol-3-yl]-2-methyl-2-methylsulfonylbutanamide Chemical compound O1N=C(CCC(C)(C(=O)NO)S(C)(=O)=O)C=C1CC1(O)CCCCC1 ZXZYFWXNOKFWOD-UHFFFAOYSA-N 0.000 claims 1
• AERPGCYOXMZKJB-UHFFFAOYSA-N n-hydroxy-4-[5-[(2-methoxyphenoxy)methyl]-1,2-oxazol-3-yl]-2-methyl-2-methylsulfonylbutanamide Chemical compound COC1=CC=CC=C1OCC1=CC(CCC(C)(C(=O)NO)S(C)(=O)=O)=NO1 AERPGCYOXMZKJB-UHFFFAOYSA-N 0.000 claims 1
• DGTDBTFFMVHEFK-UHFFFAOYSA-N s-butyl n-[[3-[4-(hydroxyamino)-3-methyl-3-methylsulfonyl-4-oxobutyl]-1,2-oxazol-5-yl]methyl]-n-methylcarbamothioate Chemical group CCCCSC(=O)N(C)CC1=CC(CCC(C)(C(=O)NO)S(C)(=O)=O)=NO1 DGTDBTFFMVHEFK-UHFFFAOYSA-N 0.000 claims 1
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
• 239000002253 acid Substances 0.000 abstract description 12
• 208000035143 Bacterial infection Diseases 0.000 abstract description 7
• 208000022362 bacterial infectious disease Diseases 0.000 abstract description 7
• NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 abstract description 5
• 239000003112 inhibitor Substances 0.000 abstract description 4
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
• 125000003545 alkoxy group Chemical group 0.000 description 32
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• 238000006243 chemical reaction Methods 0.000 description 26
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• 125000005843 halogen group Chemical group 0.000 description 18
• 238000002360 preparation method Methods 0.000 description 18
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 18
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• 125000004453 alkoxycarbonyl group Chemical group 0.000 description 15
• 208000015181 infectious disease Diseases 0.000 description 15
• 125000004414 alkyl thio group Chemical group 0.000 description 14
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• 125000004448 alkyl carbonyl group Chemical group 0.000 description 13
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• 229910052717 sulfur Inorganic materials 0.000 description 11
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• 238000003786 synthesis reaction Methods 0.000 description 10
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• PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 7
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
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