AU2010278779B2 - Nitroimidazooxazine and nitroimidazooxazole analogues and their uses - Google Patents

Info

Publication number

AU2010278779B2

AU2010278779B2 AU2010278779A AU2010278779A AU2010278779B2 AU 2010278779 B2 AU2010278779 B2 AU 2010278779B2 AU 2010278779 A AU2010278779 A AU 2010278779A AU 2010278779 A AU2010278779 A AU 2010278779A AU 2010278779 B2 AU2010278779 B2 AU 2010278779B2

Authority

AU

Australia

Prior art keywords

methyl

nitro

oxazine

imidazo

dihydro

Prior art date

2009-07-31

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

• YVMGQODAKAHLHB-UHFFFAOYSA-N 3-nitroimidazo[4,5-e]oxazine Chemical compound O1N=C([N+](=O)[O-])C=C2N=CN=C21 YVMGQODAKAHLHB-UHFFFAOYSA-N 0.000 title abstract description 10
• RJLPZNLNSQCJHV-UHFFFAOYSA-N 2-nitro-2h-imidazo[4,5-d][1,3]oxazole Chemical class C1=NC2=NC([N+](=O)[O-])OC2=N1 RJLPZNLNSQCJHV-UHFFFAOYSA-N 0.000 title abstract description 9
• 150000001875 compounds Chemical class 0.000 claims abstract description 106
• 238000000034 method Methods 0.000 claims abstract description 87
• 238000011282 treatment Methods 0.000 claims abstract description 17
• 239000000203 mixture Substances 0.000 claims description 105
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 55
• 229910052740 iodine Inorganic materials 0.000 claims description 44
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 40
• -1 carrier Substances 0.000 claims description 34
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 24
• 241000222727 Leishmania donovani Species 0.000 claims description 14
• 125000001424 substituent group Chemical group 0.000 claims description 14
• 235000010290 biphenyl Nutrition 0.000 claims description 12
• 208000015181 infectious disease Diseases 0.000 claims description 12
• 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 10
• 241000223109 Trypanosoma cruzi Species 0.000 claims description 10
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
• 230000000813 microbial effect Effects 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 7
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
• 150000003839 salts Chemical class 0.000 claims description 7
• GCQFLMSHYSWNIZ-UHFFFAOYSA-N 6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine Chemical compound C1CCOC2=NC=CN21 GCQFLMSHYSWNIZ-UHFFFAOYSA-N 0.000 claims description 6
• 239000002671 adjuvant Substances 0.000 claims description 4
• 239000004305 biphenyl Substances 0.000 claims description 4
• 239000000872 buffer Substances 0.000 claims description 4
• 239000003381 stabilizer Substances 0.000 claims description 4
• 230000002924 anti-infective effect Effects 0.000 claims description 3
• 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• YCDRNIZCGKVAJS-UHFFFAOYSA-N 6-[[5-(4-fluorophenyl)pyridin-2-yl]oxymethyl]-2-nitro-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine Chemical compound C1OC2=NC([N+](=O)[O-])=CN2CC1COC(N=C1)=CC=C1C1=CC=C(F)C=C1 YCDRNIZCGKVAJS-UHFFFAOYSA-N 0.000 claims description 2
• NBORUIOPRKKLHI-UHFFFAOYSA-N 6-[[6-(4-fluorophenyl)pyridin-3-yl]oxymethyl]-2-nitro-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine Chemical compound C1OC2=NC([N+](=O)[O-])=CN2CC1COC(C=N1)=CC=C1C1=CC=C(F)C=C1 NBORUIOPRKKLHI-UHFFFAOYSA-N 0.000 claims description 2
• IQJFYFAKNUOHAE-UHFFFAOYSA-N 7-[[4-(4-fluorophenyl)phenoxy]methyl]-7-methyl-2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine Chemical compound C1CN2C=C([N+]([O-])=O)N=C2OC1(C)COC(C=C1)=CC=C1C1=CC=C(F)C=C1 IQJFYFAKNUOHAE-UHFFFAOYSA-N 0.000 claims description 2
• ALHDHSLKVWVIHN-UHFFFAOYSA-N 7-methyl-2-nitro-7-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methoxymethyl]-5,6-dihydroimidazo[2,1-b][1,3]oxazine Chemical compound C1CN2C=C([N+]([O-])=O)N=C2OC1(C)COCC(C=1)=CC=CC=1C1=CC=C(OC(F)(F)F)C=C1 ALHDHSLKVWVIHN-UHFFFAOYSA-N 0.000 claims description 2
• UOHVERHTRSLFEH-UHFFFAOYSA-N 7-methyl-2-nitro-7-[[4-(trifluoromethoxy)phenyl]methoxymethyl]-5,6-dihydroimidazo[2,1-b][1,3]oxazine Chemical compound C1CN2C=C([N+]([O-])=O)N=C2OC1(C)COCC1=CC=C(OC(F)(F)F)C=C1 UOHVERHTRSLFEH-UHFFFAOYSA-N 0.000 claims description 2
• NTTCBTHLOZNZJK-UHFFFAOYSA-N 7-methyl-2-nitro-7-[[4-[4-(trifluoromethoxy)phenyl]phenyl]methoxymethyl]-5,6-dihydroimidazo[2,1-b][1,3]oxazine Chemical compound C1CN2C=C([N+]([O-])=O)N=C2OC1(C)COCC(C=C1)=CC=C1C1=CC=C(OC(F)(F)F)C=C1 NTTCBTHLOZNZJK-UHFFFAOYSA-N 0.000 claims description 2
• KEPDMMNFWQRFEA-UHFFFAOYSA-N 2-nitro-7-[[3-(trifluoromethoxy)phenyl]methoxymethyl]-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine Chemical compound O1C2=NC([N+](=O)[O-])=CN2CCC1COCC1=CC=CC(OC(F)(F)F)=C1 KEPDMMNFWQRFEA-UHFFFAOYSA-N 0.000 claims 1
• FIWDQXOEOCUBND-UHFFFAOYSA-N 2-nitro-7-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methoxymethyl]-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine Chemical compound O1C2=NC([N+](=O)[O-])=CN2CCC1COCC(C=1)=CC=CC=1C1=CC=C(OC(F)(F)F)C=C1 FIWDQXOEOCUBND-UHFFFAOYSA-N 0.000 claims 1
• AKYSJCGKQJLIEI-UHFFFAOYSA-N 2-nitro-7-[[4-(trifluoromethoxy)phenyl]methoxymethyl]-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine Chemical compound O1C2=NC([N+](=O)[O-])=CN2CCC1COCC1=CC=C(OC(F)(F)F)C=C1 AKYSJCGKQJLIEI-UHFFFAOYSA-N 0.000 claims 1
• YXWALFWDXOZXLM-UHFFFAOYSA-N 2-nitro-7-[[4-[4-(trifluoromethoxy)phenyl]phenyl]methoxymethyl]-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine Chemical compound O1C2=NC([N+](=O)[O-])=CN2CCC1COCC(C=C1)=CC=C1C1=CC=C(OC(F)(F)F)C=C1 YXWALFWDXOZXLM-UHFFFAOYSA-N 0.000 claims 1
• VCENEFJSXTYRJF-UHFFFAOYSA-N 6-[[4-(4-fluorophenyl)phenoxy]methyl]-2-nitro-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine Chemical compound C1OC2=NC([N+](=O)[O-])=CN2CC1COC(C=C1)=CC=C1C1=CC=C(F)C=C1 VCENEFJSXTYRJF-UHFFFAOYSA-N 0.000 claims 1
• QACAURHEZMYCGU-UHFFFAOYSA-N 7-[[4-(4-fluorophenyl)phenoxy]methyl]-2-nitro-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine Chemical compound O1C2=NC([N+](=O)[O-])=CN2CCC1COC(C=C1)=CC=C1C1=CC=C(F)C=C1 QACAURHEZMYCGU-UHFFFAOYSA-N 0.000 claims 1
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
• 230000003287 optical effect Effects 0.000 claims 1
• 238000002360 preparation method Methods 0.000 abstract description 6
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 490
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 312
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 264
• 235000019439 ethyl acetate Nutrition 0.000 description 245
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 225
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 181
• 239000000741 silica gel Substances 0.000 description 181
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• 238000005481 NMR spectroscopy Methods 0.000 description 166
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• 238000010828 elution Methods 0.000 description 154
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 148
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 142
• 239000003208 petroleum Substances 0.000 description 129
• 239000000047 product Substances 0.000 description 104
• 238000004587 chromatography analysis Methods 0.000 description 103
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 99
• 229920000728 polyester Polymers 0.000 description 87
• 239000006071 cream Substances 0.000 description 83
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 75
• 230000015572 biosynthetic process Effects 0.000 description 75
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• 230000029936 alkylation Effects 0.000 description 42
• 238000005804 alkylation reaction Methods 0.000 description 42
• BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 40
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 36
• 239000011734 sodium Substances 0.000 description 36
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 34
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