WO2009141398A1 - Tricyclic nitrogen containing compounds and their use as antibacterials - Google Patents
Tricyclic nitrogen containing compounds and their use as antibacterials Download PDFInfo
- Publication number
- WO2009141398A1 WO2009141398A1 PCT/EP2009/056177 EP2009056177W WO2009141398A1 WO 2009141398 A1 WO2009141398 A1 WO 2009141398A1 EP 2009056177 W EP2009056177 W EP 2009056177W WO 2009141398 A1 WO2009141398 A1 WO 2009141398A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- dihydro
- amino
- dione
- piperidinyl
- Prior art date
Links
- 230000000844 anti-bacterial effect Effects 0.000 title description 8
- 229940088710 antibiotic agent Drugs 0.000 title description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 254
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 29
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 28
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 137
- 238000006243 chemical reaction Methods 0.000 claims description 93
- -1 4- { [(5 -chloro-6-methyl-3 -pyridinyl)methyl] amino } - 1 -piperidinyl Chemical group 0.000 claims description 79
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 61
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 21
- 241000124008 Mammalia Species 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- ARFDDHAJVWGEMX-QGZVFWFLSA-N (3R)-3-[[4-[(5-chloro-6-methylpyridin-3-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(Cl)C(C)=NC=C1CNC1CCN(C[C@H]2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 ARFDDHAJVWGEMX-QGZVFWFLSA-N 0.000 claims description 5
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- ARFDDHAJVWGEMX-UHFFFAOYSA-N 3-[[4-[(5-chloro-6-methylpyridin-3-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(Cl)C(C)=NC=C1CNC1CCN(CC2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 ARFDDHAJVWGEMX-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000005997 bromomethyl group Chemical group 0.000 claims description 3
- VHROMNADNJVTLT-MRXNPFEDSA-N (3R)-3-[[4-[(3,4-dichlorophenyl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(Cl)C(Cl)=CC=C1CNC1CCN(C[C@H]2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 VHROMNADNJVTLT-MRXNPFEDSA-N 0.000 claims description 2
- TXBCYJKNOJKGMF-QGZVFWFLSA-N (3R)-3-[[4-[(5-bromo-6-methylpyridin-3-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(Br)C(C)=NC=C1CNC1CCN(C[C@H]2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 TXBCYJKNOJKGMF-QGZVFWFLSA-N 0.000 claims description 2
- VHROMNADNJVTLT-INIZCTEOSA-N (3S)-3-[[4-[(3,4-dichlorophenyl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(Cl)C(Cl)=CC=C1CNC1CCN(C[C@@H]2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 VHROMNADNJVTLT-INIZCTEOSA-N 0.000 claims description 2
- ARFDDHAJVWGEMX-KRWDZBQOSA-N (3S)-3-[[4-[(5-chloro-6-methylpyridin-3-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(Cl)C(C)=NC=C1CNC1CCN(C[C@@H]2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 ARFDDHAJVWGEMX-KRWDZBQOSA-N 0.000 claims description 2
- QILXJQQOAXKFCI-UHFFFAOYSA-N 3-[[4-[(3,4-dimethylphenyl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(C)C(C)=CC=C1CNC1CCN(CC2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 QILXJQQOAXKFCI-UHFFFAOYSA-N 0.000 claims description 2
- QAZSCKZWWICDEV-UHFFFAOYSA-N 3-[[4-[(3-fluoro-4-methylphenyl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(F)C(C)=CC=C1CNC1CCN(CC2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 QAZSCKZWWICDEV-UHFFFAOYSA-N 0.000 claims description 2
- FROBZGZQIUQPIN-UHFFFAOYSA-N 3-[[4-[(3-methoxy-4-methylphenyl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(C)C(OC)=CC(CNC2CCN(CC3N4C=5N(C(C=CC=5N=CC4=O)=O)C3)CC2)=C1 FROBZGZQIUQPIN-UHFFFAOYSA-N 0.000 claims description 2
- QSQPOEISJDEMHK-UHFFFAOYSA-N 3-[[4-[(4-chloro-3-methylphenyl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(Cl)C(C)=CC(CNC2CCN(CC3N4C=5N(C(C=CC=5N=CC4=O)=O)C3)CC2)=C1 QSQPOEISJDEMHK-UHFFFAOYSA-N 0.000 claims description 2
- MNUOTOBVNWZFCO-UHFFFAOYSA-N 3-[[4-[(4-nitrophenyl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1CNC1CCN(CC2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 MNUOTOBVNWZFCO-UHFFFAOYSA-N 0.000 claims description 2
- QSYYEGFBIAQXPT-UHFFFAOYSA-N 3-[[4-[(5-bromo-4-methylthiophen-2-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound S1C(Br)=C(C)C=C1CNC1CCN(CC2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 QSYYEGFBIAQXPT-UHFFFAOYSA-N 0.000 claims description 2
- XIPQOHNZHUVMHV-UHFFFAOYSA-N 3-[[4-[(5-bromopyridin-3-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound BrC1=CN=CC(CNC2CCN(CC3N4C=5N(C(C=CC=5N=CC4=O)=O)C3)CC2)=C1 XIPQOHNZHUVMHV-UHFFFAOYSA-N 0.000 claims description 2
- YUIOIZNQSNPDJL-UHFFFAOYSA-N 3-[[4-[(5-chloropyridin-3-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound ClC1=CN=CC(CNC2CCN(CC3N4C=5N(C(C=CC=5N=CC4=O)=O)C3)CC2)=C1 YUIOIZNQSNPDJL-UHFFFAOYSA-N 0.000 claims description 2
- JRCJNVVDNZCLBN-UHFFFAOYSA-N 3-[[4-[(5-fluoro-6-methylpyridin-3-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(F)C(C)=NC=C1CNC1CCN(CC2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 JRCJNVVDNZCLBN-UHFFFAOYSA-N 0.000 claims description 2
- NGKQPHFYALSDTK-UHFFFAOYSA-N 3-[[4-[(6-fluoro-5-methylpyridin-3-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound N1=C(F)C(C)=CC(CNC2CCN(CC3N4C=5N(C(C=CC=5N=CC4=O)=O)C3)CC2)=C1 NGKQPHFYALSDTK-UHFFFAOYSA-N 0.000 claims description 2
- ZQUNKXCOCPOTHO-UHFFFAOYSA-N 3-[[4-[[4-(trifluoromethoxy)phenyl]methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=CC(OC(F)(F)F)=CC=C1CNC1CCN(CC2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 ZQUNKXCOCPOTHO-UHFFFAOYSA-N 0.000 claims description 2
- VHROMNADNJVTLT-UHFFFAOYSA-N C1=C(Cl)C(Cl)=CC=C1CNC1CCN(CC2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 Chemical compound C1=C(Cl)C(Cl)=CC=C1CNC1CCN(CC2N3C=4N(C(C=CC=4N=CC3=O)=O)C2)CC1 VHROMNADNJVTLT-UHFFFAOYSA-N 0.000 claims description 2
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- OPQFKYZLJABARW-UHFFFAOYSA-N 1,4,7-triazatricyclo[6.3.1.04,12]dodeca-2,6,8(12),9-tetraene-5,11-dione Chemical compound N1=CC(=O)N2C=CN3C(=O)C=CC1=C32 OPQFKYZLJABARW-UHFFFAOYSA-N 0.000 claims 1
- AOWRPJQFMHXAQF-UHFFFAOYSA-N 3-[[4-[(5,6-dichloropyridin-3-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound N1=C(Cl)C(Cl)=CC(CNC2CCN(CC3N4C=5N(C(C=CC=5N=CC4=O)=O)C3)CC2)=C1 AOWRPJQFMHXAQF-UHFFFAOYSA-N 0.000 claims 1
- XWUQLGRONTZFEO-UHFFFAOYSA-N 3-[[4-[(5,6-dimethylpyridin-3-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound N1=C(C)C(C)=CC(CNC2CCN(CC3N4C=5N(C(C=CC=5N=CC4=O)=O)C3)CC2)=C1 XWUQLGRONTZFEO-UHFFFAOYSA-N 0.000 claims 1
- YXMCGYMHGLOAFE-UHFFFAOYSA-N 3-[[4-[[4-chloro-3-(trifluoromethyl)phenyl]methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=C(Cl)C(C(F)(F)F)=CC(CNC2CCN(CC3N4C=5N(C(C=CC=5N=CC4=O)=O)C3)CC2)=C1 YXMCGYMHGLOAFE-UHFFFAOYSA-N 0.000 claims 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 483
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 302
- 239000000203 mixture Substances 0.000 description 186
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 140
- 239000000243 solution Substances 0.000 description 140
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 115
- 239000007787 solid Substances 0.000 description 114
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 100
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 70
- 235000019439 ethyl acetate Nutrition 0.000 description 70
- 238000005160 1H NMR spectroscopy Methods 0.000 description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 50
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 50
- 239000000047 product Substances 0.000 description 49
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 48
- AYTAKQFHWFYBMA-UHFFFAOYSA-N chromium dioxide Chemical compound O=[Cr]=O AYTAKQFHWFYBMA-UHFFFAOYSA-N 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 44
- 230000002829 reductive effect Effects 0.000 description 43
- 239000003480 eluent Substances 0.000 description 42
- 238000002360 preparation method Methods 0.000 description 40
- 239000000741 silica gel Substances 0.000 description 40
- 229910002027 silica gel Inorganic materials 0.000 description 40
- 239000007858 starting material Substances 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 38
- 238000003818 flash chromatography Methods 0.000 description 35
- 238000000746 purification Methods 0.000 description 35
- 230000015572 biosynthetic process Effects 0.000 description 34
- 239000002904 solvent Substances 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 33
- 239000003921 oil Substances 0.000 description 32
- 235000019198 oils Nutrition 0.000 description 32
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 31
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
- 239000012074 organic phase Substances 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 229910052938 sodium sulfate Inorganic materials 0.000 description 27
- 239000000725 suspension Substances 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000007832 Na2SO4 Substances 0.000 description 25
- 229910052786 argon Inorganic materials 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 22
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- 239000000706 filtrate Substances 0.000 description 20
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 229910000027 potassium carbonate Inorganic materials 0.000 description 19
- 238000001914 filtration Methods 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 239000010410 layer Substances 0.000 description 15
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 15
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 239000012267 brine Substances 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- IAQWMWUKBQPOIY-UHFFFAOYSA-N chromium(4+);oxygen(2-) Chemical compound [O-2].[O-2].[Cr+4] IAQWMWUKBQPOIY-UHFFFAOYSA-N 0.000 description 12
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- 241000282414 Homo sapiens Species 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 239000013058 crude material Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 239000012458 free base Substances 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- QQBPIHBUCMDKFG-UHFFFAOYSA-N phenazopyridine hydrochloride Chemical compound Cl.NC1=NC(N)=CC=C1N=NC1=CC=CC=C1 QQBPIHBUCMDKFG-UHFFFAOYSA-N 0.000 description 1
- GDTFAKFYAPCTQE-ZDUSSCGKSA-N phenylmethyl (1s)-1-(hydroxymethyl)-3,8-dioxo-1,2,3,4-tetrahydro-5h,8h-2a,5,8a-triazaacenaphthylene-5-carboxylate Chemical compound C([C@H](N1C(=O)C=C2)CO)N(C(C3)=O)C1=C2N3C(=O)OCC1=CC=CC=C1 GDTFAKFYAPCTQE-ZDUSSCGKSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- YLHJACXHRQQNQR-UHFFFAOYSA-N pyridine;2,4,6-tris(ethenyl)-1,3,5,2,4,6-trioxatriborinane Chemical compound C1=CC=NC=C1.C=CB1OB(C=C)OB(C=C)O1 YLHJACXHRQQNQR-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DMSDBICNEXMFMS-UHFFFAOYSA-N tert-butyl 4-[(5-chloro-6-methylpyridin-3-yl)methylamino]piperidine-1-carboxylate Chemical compound C1=C(Cl)C(C)=NC=C1CNC1CCN(C(=O)OC(C)(C)C)CC1 DMSDBICNEXMFMS-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/16—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Definitions
- This invention relates to compounds, compositions containing them, their use in therapy, including their use as antibacterials, for example in the treatment of tuberculosis, and methods for the preparation of such compounds. Background of the invention
- the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or N-oxide thereof:
- one of Zl and Z ⁇ is CH or N and the other is CH;
- U represents a group selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, furanyl, imidazolyl and thiophenyl; n is 0 or 1 ;
- R 5 and R 6 are independently selected from: halo, CF 3 , OCF 3 , C 1-3 alkyl, NHR 7 , NR 7A R 7B , C 1-3 alkoxy, nitro and cyano; or R 5 may be a group -C m H2 m -A where m is 1-5 and the moiety -C m H2 m - may be straight or branched chain and A is selected from OH, OR 7 , OCOR 7 , OCO 2 R 7 , OCONR 7 , OPO 2 R 7 and NH 2 , where each R 7 , R 7A and R 7B is independently C 1-5 alkyl.
- a compound of Formula (I) may be a compound of Formula (IA) or a pharmaceutically acceptable salt or N-oxide thereof:
- one of Zl and Z ⁇ is CH or N and the other is CH;
- U represents a group selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, furanyl, imidazolyl and thiophenyl;
- R 5 and R 6 are independently selected from: halo, CF 3 , OCF 3 , C 1-3 alkyl, C 1-3 alkoxy, nitro and cyano, and n is O or 1.
- the invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents.
- the invention also provides a method of treatment of tuberculosis in mammals, particularly in man, which method comprises the administration to a mammal in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof.
- This invention further provides a method of treatment of bacterial infections in mammals, particularly in man, which method comprises the administration to a mammal in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof.
- the invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, for use in therapy.
- the invention yet further provides a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, for use in the treatment of tuberculosis in mammals, particularly in man.
- the invention yet further provides a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, for use in the treatment of bacterial infections in mammals, particularly in man.
- the invention still further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, in the manufacture of a medicament for use in the treatment of tuberculosis in mammals, particularly in man.
- the invention still further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, in the manufacture of a medicament for use in the treatment of bacterial infections in mammals, particularly in man.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents, for use in the treatment of tuberculosis in mammals, particularly in man.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents, for use in the treatment of bacterial infections in mammals, particularly in man.
- U represents a group selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, thienyl, thiazolyl, or thiophenyl. In another embodiment, U represents a group selected from: phenyl, pyridyl, pyridazinyl, thiazolyl, and thiophenyl.
- R 5 represents CF 3 , OCF 3 , Cl, Br, or NO 2 .
- n 1 and one of R 5 and R 6 represents Cl and the other represents Cl, CH 3 , C 2 H 5 , CN, CF 3 or OCF 3 .
- n 1 and one of R 5 and R 6 represents F and the other represents Cl, CF 3 , CN, CH 3 , or C 2 H 5 .
- n 1 and one of R 5 and R 6 represents CH 3 and the other represents Br, CH 3 , CF 3 , CN or NO 2 .
- n is O and R 5 represents CF 3 .
- n is 1 and R 5 and R 6 represent Cl and CH 3 .
- n is 1 and R 5 and R 6 represent CH 3 and CF 3 .
- n is 1 and R 5 and R 6 represent Cl and CN.
- m is 1 and A is -OH so R 5 represents -CH 2 - OH, n is 1 and R 6 is Cl.
- One or more of the above structural embodiments may be present in a compound of Formula (I).
- Compounds of Formula (I) may exist in the form of salts, solvates or N-oxides, and Formula (I) encompasses these forms.
- compounds which are useful in the present invention include those mentioned in the Examples and their pharmaceutically acceptable salts, solvates or N- oxides.
- compounds which are useful in the present invention include:
- Certain of the compounds of Formula (I) may exist in the form of optical isomers, e.g. mixtures of isomers in all ratios, e.g. racemic mixtures.
- the invention includes all such forms, in particular the pure isomeric forms.
- the invention includes enantiomers.
- the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecif ⁇ c or asymmetric syntheses.
- C 1-3 alkyl refers to a straight or branched chain alkyl group having 1 to 3 carbon atoms. Examples Of C 1-3 alkyl groups include methyl, ethyl, n-propyl, iso-propyl.
- halo refers to fluoro, chloro, bromo and iodo groups. In one aspect, the term “halo” as used herein refers to fluoro, chloro and bromo groups.
- C 1-3 alkoxy refers to a straight or branched chain alkoxy group having 1 to 3 carbon atoms. Examples OfC 1-3 alkoxy groups include, methoxy, ethoxy, propoxy and isopropoxy.
- compounds of the invention as used herein means a compound of Formula (I) or a pharmaceutically acceptable salt or N-oxide thereof.
- a compound of the invention means any one of the compounds of the invention as defined above.
- phrases such as "a compound of Formula (I) or a pharmaceutically acceptable salt or N-oxide thereof or “compounds of the invention” are intended to encompass the compound of Formula (I), a pharmaceutically acceptable salt or N-oxide of the compound of Formula (I), or any pharmaceutically acceptable combination of these.
- a compound of Formula (I) or a pharmaceutically acceptable salt or N-oxide thereof encompasses a pharmaceutically acceptable salt of a compound of Formula (I) which is present as a solvate, or this phrase may include a mixture of a compound of Formula (I) and a salt of a compound of Formula (I).
- Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
- This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. Since the compounds of Formula (I) are intended for use in pharmaceutical compositions it will readily be understood that in particular embodiments they are provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and particularly at least 85%, especially at least 98% pure (% are on a weight for weight basis).
- Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and more particularly from 10 to 59% of a compound of Formula (I) or pharmaceutically acceptable salt or N-oxide thereof.
- salts of the compounds of Formula (I) include the acid addition or quaternary ammonium salts, for example their salts with mineral acids e.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, or organic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic, p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid or tartaric acids.
- the salt of a compound of Formula (I) is the hydrochloride salt.
- the salt of a compound of Formula (I) is the dihydrochloride salt.
- Compounds of Formula (I) may also be prepared as the N-oxide. The invention extends to all such salts and N-oxides.
- a suitable process comprises the reaction between an amine compound of Formula (HA) and a compound of Formula (HB):
- a reducing agent such as sodium borohydride
- W is a bromomethyl moiety -CH 2 .Br.
- Such reactions may be carried out in an organic solvent such as DCM/MeOH at ambient temperature.
- Compounds of Formula (HA) in a salt form may be used in this process to form compounds of Formula (I) in a salt form.
- Reaction with an aldehyde of Formula (HB) may be carried out in the presence of NaBH(O Ac)3 to yield the compound of Formula (I).
- Cyclisation of (6) can be effected with sodium hydride and then treatment with hydrogen over a palladium/charcoal catalyst gives intermediate (7).
- This intermediate can be deprotected with TFA to give (9) and reacted with methanesulfonic anhydride or benzenesulfonyl chloride to give (10) as an enantiomercally pure compound.
- the mesylate or benzenesulfonate (10) formed may then be converted to the amine of Formula (Ha) and finally to the target compound of Formula (I) as generally described herein.
- nitropyridine (1) Reaction of nitropyridine (1) with ammonia affords nitro-pyridine (2) which is reduced to bis-aniline (3).
- S-glycidyl nosylate ((2iS)-2-oxiranylmethyl 3-nitrobenzenesulfonate)
- step (a) trimethylacetamide may be reacted with 2-chloro-6- (methyloxy)pyridine.
- step (b) the product of step (a) may be treated with n-butyl lithium and 1,2-dibromoethane.
- the product from step (b) may be treated in step (c) with n-butyl acrylate. Hydrogenation in the presence of palladium on carbon in step (d) can yield the hydrogenated product.
- the product of step (d) may be cyclised in step (e) to yield the 3,4-dihydro-l,8-naphthyridin-2(lH)-one by treatment with hydrochloric acid.
- step (f) the oxirane may be formed by reaction with sodium hydride then with (2S)-2- oxiranylmethyl 3-nitrobenzenesulfonate. Cyclisation to the imidazonaphthyridine may be done by heating the oxirane, or microwave power. Step (h) to attach the 4-(N-tert- butoxycarbonylamino) piperidine moiety may be performed by formation of the methanesulfonate, then reaction with the corresponding amine. Aromatisation of the ring in step (i) may be done by treatment with DDQ followed by heating. The amine may then be deprotected using acid hydrolysis, step (j) to yield the amine (UA), which may then be reacted with a compound of Formula HB e.g. an aldehyde to form the compound of Formula (I).
- a compound of Formula HB e.g. an aldehyde to form the compound of Formula (I).
- a suitable process for making compounds of Formula (I) comprises the reaction between a compound of Formula (HC) and a compound of Formula (HD):
- Salt forms of compounds of Formula (I) and (IA), e.g. hydrochlorides may be formed by treatment of the corresponding free bases with an acid such as hydrochloric acid, or formation of the compounds in the presence of such an acid.
- reagents of Formula (HB) containing the required R ⁇ and optional R 6 group are known compounds (see for example the commercial sources listed in Table 1) or may be prepared analogously to known compounds. See for example WO02/08224, WO02/50061, WO02/56882, WO02/96907, WO2003087098, WO2003010138, WO2003064421, WO2003064431, WO2004002992, WO2004002490, WO2004014361, WO2004041210,WO2004096982, WO2002050036, WO2004058144, WO2004087145, WO06002047, WO06014580, WO06010040, WO06017326, WO06012396, WO06137485, WO06017468, WO06020561 and EP0559285.
- antibacterial and/or antitubercular compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibacterials or antitubercular compounds.
- compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection or infection with Mycobacterium tuberculosis in mammals including humans.
- the composition may be formulated for administration by any route appropriate to antibacterial and/or antitubercular therapy.
- the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
- topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
- the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
- suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
- Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
- Formulations for oral administration may for example comprise tablets or capsules in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
- the tablets may be coated according to methods well known in normal pharmaceutical practice.
- Formulations for oral administration may also be in liquid form, for example in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p -hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
- suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate,
- Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
- fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
- the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
- the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
- agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum.
- the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
- Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
- the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
- compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of a compound of the invention.
- each unit will preferably contain from 50-1000 mg of the active ingredient.
- the dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Suitably the dosage is from 5 to 30 mg/kg per day.
- the compound of Formula (I), or a pharmaceutically acceptable pharmaceutically acceptable salt or N-oxide thereof may be the sole therapeutic agent in the compositions of the invention, or it may be present in the formulation in combination with one or more additional therapeutic agents.
- the invention thus provides, in a further aspect, a combination comprising a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof together with one or more additional therapeutic agents.
- the one or more additional therapeutic agent is, for example, an agent useful for the treatment of tuberculosis in a mammal.
- therapeutic agents include isoniazid, ethambutol, rifampin, pirazinamide, streptomycin, capreomycin, ciprofloxacin and clofazimine.
- a compound of Formula (I), or a pharmaceutically acceptable pharmaceutically acceptable salt or N-oxide thereof is used in combination with one or more additional therapeutic agents, the dose of the compound or agent may differ from that when the compound or agent is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention and the one or more additional therapeutic agents required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
- the combinations may conveniently be presented for use in the form of a pharmaceutical formulation.
- a pharmaceutical combination comprising a compound of Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, together with one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers, excipients or diluents.
- the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
- either the compound of the present invention or one or more additional therapeutic agent may be administered first.
- the combination may be administered either in the same or different pharmaceutical composition.
- the compound and agents must be stable and compatible with each other and the other components of the formulation.
- they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
- the compound of Formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with one or more other antibacterial and/or antitubercular compound. If the other antibacterial is a ⁇ -lactam then a ⁇ - lactamase inhibitor may also be employed.
- Compounds of Formula (I) may also be used in the treatment of bacterial infections caused by a wide range of organisms including both Gram-negative and Gram- positive organisms. Some compounds of Formula (I) may be active against more than one organism. This may be determined by the methods described herein. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
- references to preparations carried out in a similar manner to, or by the general method of, other preparations may encompass variations in routine parameters such as time, temperature, workup conditions, minor changes in reagent amounts etc.
- Reactions involving metal hydrides including lithium hydride, lithium aluminium hydride, di-isobutylaluminium hydride, sodium hydride, sodium borohydride and sodium triacetoxyborohydride are carried out under argon.
- Example 1 Compound: Synthesis of (1R )-l-[(4- ⁇ [(5-chloro-6-methyl-3- pyridinyl)methyl] amino ⁇ - l-piperidinyl)methyl] - 1 ,2-dihydro-4H,9H-imidazo [ 1 ,2,3- //]-l,8-naphthyridine-4,9-dione hydrochloride, using Preparative Scheme (3)
- reaction mixture was then heated at 80 oC for 4 h and then at 120 oC for 3 h.
- the reaction was then evaporated and water (1000 ml) was added and the mixture was extracted with Et 2 O (3 x 500 ml).
- the combined organic solvents were then dried (MgSO 4 , filtered, evaporated to give the crude product. This was then dissolved in DCM (300 ml) and chromatographed (10-30% EtOAc :40-60 petroleum ether) and then dried in vacuo to give product as a white solid (87.412 g, 95%).
- reaction can be heated with microwave power at 16OoC for 40 mins.
- reaction mixture was then evaporated, treated with saturated aqueous NaHCO (200 ml) was then added and the mixture was extracted with DCM (3 x 200ml). The combined organic solvents were then dried (MgSO 4 , filtered, evaporated to give the crude product as a brown solid.
- reaction mixture was treated with saturated aqueous K 2 CO 3 (5%, 1000 ml) and extracted with DCM (3 x 500 ml). The combined organic solvents were then dried (MgSC 4 ), filtered, evaporated to give the crude product as a brown solid.
- the reaction was repeated using a further portion of carbamate (2.889 g, 7.18 mmol) in 1,4-dioxane (50 ml) with DDQ (2.444 g, 10.77 mmol).
- the reaction was performed and worked up as above and the combined residues were chromato graphed (0-100% EtOAc:40-60 Petroleum ether then 0-20% MeO ⁇ :EtOAc) to give the product as a brown solid (1.532 g, 18%).
- Example IA Synthesis of Example 1 Compound (lR)-l-[(4- ⁇ [(5-chloro-6-methyl-3- pyridinyl)methyl] amino ⁇ - l-piperidinyl)methyl] - 1 ,2-dihydro-4H,9H-imidazo [1 ,2,3- //]-l,8-naphthyridine-4,9-dione hydrochloride, proceeding via a salt form of a compound of Formula (HA).
- 6-Methoxy-2-chloro-3-nitropyridine (36.94 g, 195.9 mmol) and 2-aminopropane- 1.3-diol (35.65 g, 391.3 mmol) were stirred in ethanol (500 ml) at reflux under argon for 3 h. The mixture was allowed to cool to room temperature and left overnight. The solvent was partially removed under reduced pressure (to ca. 150 ml) and the resulting bright yellow slurry was poured into ice-water (1.5 L) with vigorous stirring. The mixture was stirred for 1 h then filtered with suction while cold.
- N-(2,2-Dimethyl-l,3-dioxan-5-yl)-6-(methyloxy)-3-nitro-2-pyridinamine (35.00 g, 123.6 mmol) was divided into 2 aliquots, each of which was taken up in 1,4-dioxane (500 ml) and hydrogenated over 10% Pd on carbon (paste, 1 : 1 w:w with water, 4.00 g) under 1 atmosphere hydrogen pressure, at room temperature for 18 h. The mixtures were filtered with suction though Celite, using argon blanket and taking care to minimise contact of the product with air.
- the racemic dihydrochloride (10.42 g) was resolved into its two enantiomers by preparative chiral ⁇ PLC using a 4 inch Chiralpak AD (20 microns) preparative column with 50:50:0.1 C ⁇ 3CN:MeO ⁇ :isopropylamine as the mobile phase.
- the alpha value was 3.1 and baseline resolution was observed for all 3 runs. There was no overlap fraction and both enantiomers (as the free bases) were isolated in >99.8 ee each.
- reaction was quenched by the addition of saturated aqueous NH 4 Cl (610 ml) and the mixture was stirred for 10 min. Na 2 SO 4 (1 kg) was added and the mixture was stirred for 10 min before being filtered through celite. The filter cake was washed with EtOAc (5 L).
- the reaction was allowed to cooled to room temperature and then to OoC in an ice bath.
- the precipitated solid was filtrated under vacuum and washed with CH 3 CN, to give a first filtrate. Then, the isolated solid was washed again with H 2 O and TBME to give a second filtrate.
- the first filtrate was concentrated under vacuum and dissolved in DCM. 2N HCl was added until p ⁇ 1-2 and the organic phase was extracted and discarded. 10% NaHCO 3 was added to the aqueous phase until pH 9, and the organic phase was extracted with DCM, washed with NaCl, dried (MgSO 4 ), filtered and concentrated.
- Example 9 Compound: Synthesis of (1R)-l- ⁇ [4-( ⁇ [6-(Trifluoromethyl)-3- pyridinyl]methyl ⁇ amino)-l-piperidinyl]methyl ⁇ -l,2-dihydro-4H,9H-imidazo[l,2,3- ij] - 1 ,8-naphthyridine-4,9-dione hydrochloride.
- Example 11 Compound: Synthesis of (1R )-l- ⁇ [4-( ⁇ [6-(trifluoromethyl)-3- pyridinyl]methyl ⁇ amino)-l-piperidinyl]methyl ⁇ -l,2-dihydro-3H,8H-2a,5,8a- triazaacenaphthylene-3,8-dione, using Preparative Scheme (2)
- 6-(Methyloxy)-3-nitro-2-pyridinamine (26 g, 129 mmol) was suspended in EtOH (500 ml) at room temperature under argon and then treated with palladium on carbon (15 g, 14.10 mmol) (10% paste). The reaction was stirred under 1 atmosphere of hydrogen overnight. The reaction was filtered through a Celite pad and the pad washed with EtOH (500ml). EtOH was evaporated to afford the product as a purple oil (20.68 g, slightly impure). [ES MS] m/z 140 (MH + ).
- 6-(Methyloxy)-2,3-pyridinediamine (21.7 g, estimated 87% purity, 136 mmol) was dissolved in CH3CN (500 ml) at room temperature under argon and then treated with K2CO3 (24.38 g, 176 mmol) and ethyl bromoacetate (18.13 ml, 163 mmol). The reaction was stirred at room temperature overnight. The CH3CN was then removed in vacuo.
- Phenylmethyl 6-(methyloxy)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-l(2H)- carboxylate (11 g, 35.1 mmol) was dissolved in DMF (300 ml) at room temperature under argon to give a yellow solution. The solution was then cooled with an ice bath and treated with sodium hydride (1.685 g, 42.1 mmol). The solution was allowed to warm to room temperature. After 20 minutes (2S)-2-oxiranylmethyl 3-nitrobenzenesulfonate (9.56 g, 36.9 mmol) was added.
- Phenylmethyl 6-(methyloxy)-4-[(2R )-2-oxiranylmethyl]-3-oxo-3,4- dihydropyrido[2,3-b]pyrazine-l(2H)-carboxylate was dissolved in DMF (250 ml) at room temperature and heated at 130oC for 2 nights and at 120oC for one night. The reaction was complete so DMF was evaporated and the residue treated with water/brine(350/50ml) and DCM (500 ml).The layers were separated and the aqueous layer was extracted once more with DCM (500 ml).
- Example 12 Compound: Synthesis of (lR)-l-[(4- ⁇ [(5-bromo-6-methyl-3- pyridinyl)methyl] amino ⁇ - l-piperidinyl)methyl] - 1 ,2-dihydro-4H,9H-imidazo [1 ,2,3- //]-l,8-naphthyridine-4,9-dione hydrochloride, using Preparative Scheme (3)
- Example 17 Compound: Synthesis of 2- ⁇ [4-( ⁇ [6-(trifluoromethyl)-3- pyridazinyl]methyl ⁇ amino)-l-piperidinyl]methyl ⁇ -l,2-dihydro-3H,8H-2a,5,8a- triazaacenaphthylene-3,8-dione, using Preparative Scheme (1)
- Example 51 Compound: Synthesis of (2R)-2-[(4- ⁇ [(5-bromo-6-methyl-3- pyridinyl)methyl] amino ⁇ - l-piperidinyl)methyl] - 1 ,2-dihydro-3H,8H-2a,5,8a- triazaacenaphthylene-3,8-dione hydrochloride, using Preparative Scheme (1)
- Example 60 Compound: Synthesis of (lR)-l- ⁇ [4-( ⁇ [5-methyl-6-(trifluoromethyl) -3- pyridinyl] methyl ⁇ amino)-l-piperidinyl] methyl ⁇ - l,2-dihydro-4H,9H-imidazo[ 1,2,3- ij ] -1 ,8-naphthyridine-4,9-dione
- (lR)-l-[(4-amino-l-piperidinyl)methyl]-l,2-dihydro-4H,9H-imidazo[l,2,3- ij]-l,8-naphthyridine-4,9-dione (Example 1 sep (j): 70.5 mg, 0.235 mmol), 5-methyl-6- (trifluoromethyl)-3-pyridinecarbaldehyde (Preparation 12: 37 mg, 0.196 mmol) and magnesium sulphate (anhydrous) (58
- Example 71 Compound: Synthesis of (2-chloro-4- ⁇ [(l- ⁇ [(lR)-4,9-dioxo-l,2-dihydro- 4H,9H-imidazo[l,2,3-ij]-l,8-naphthyridin-l-yl]methyl ⁇ -4-piperidinyl) amino] methyl ⁇ phenyl) methyl acetate (last step).
- This example illustrates the use of a compound of Formula (HB) in which W is a bromomethyl moiety.
- Example 75 Compound: Synthesis of (2R)-2- ⁇ [4-( ⁇ [5-methyl-6-(trifluoromethyl)-3- pyridinyl]methyl ⁇ amino)-l-piperidinyl]methyl ⁇ -l,2-dihydro-3H,8H-2a,5,8a- triazaacenaphthylene-3,8-dione hydrochloride.
- Example 1 the source of the compound of Formula HB used in the preparation of the Example compounds is indicated. Where these are not known compounds their preparation is described below.
- the other Example compounds listed above were prepared using an analogous procedure with minor modifications and were isolated either as the parent compound or as the hydrochloride.
- Trifluoroacetic anhydride (231 ⁇ l, 1.635 mmol) was added to a solution of 3- chloro-5-(l,3-dioxolan-2-yl)-2-methylpyridine 1 -oxide (225 mg, 1.043 mmol) in DCM (4 ml) at 0 oC and the mixture was stirred at room temperature for 48 h. Full conversion was observed by HPLC. MeOH (0.5 ml, 12.36 mmol) was added and, after stirring for 10 min, DCM and 10% Na 2 CO 3 solution were added. Extraction, drying (MgSO 4 ), and filtration afforded 223.2 mg of crude material.
- Oxalic acid (415 mg, 3.29 mmol) was added to a mixture of [3-chloro-5-(l,3- dioxolan-2-yl)-2-pyridinyl]methanol (142 mg, 0.659 mmol), acetone (7.5 ml), and water (7.5 ml) at room temperature and heated under reflux. After 2.5 h, HPLC showed full conversion. Cooled to rt, basified with IM NaOH, extracted with TBME, dried (MgSO 4 ), filtered and concentrated to give 139 mg of crude material. Purification by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of DCM and MeOH as eluent afforded impure product.
- DIBAL-H (3.37 ml, 3.37 mmol) was slowly added to a solution of ethyl 5-chloro- 6-iodo-3-pyridinecarboxylate (500 mg, 1.605 mmol) in THF (10 ml) at -78 oC.
- the solution turned yellow and was stirred at that temperature for 3 h and then still in the dry- ice bath allowed to slowly attain room temperature overnight. Next morning, TLC showed starting material remaining.
- the solution was cooled to -78 oC and DIBAL-H (3.37 ml, 3.37 mmol) was added. 3 h later it was allowed to warm to room temperature and after 2 h starting material was still observed.
- Acetaldehyde (47 ⁇ l, 0.841 mmol) was added and the mixture stirred at -20 oC for 10 min. Partial conversion was observed by LCMS and no evolution was observed after 1 h. Excess acetaldehyde was added but no changes were observed after 30 min by LCMS. Then, it was quenched with saturated NH 4 Cl, extracted with EtOAc, dried (MgSO 4 ), filtered, and concentrated to afford 177.4 mg of crude material as a brown oil.
- the minimum inhibitory concentration (MIC) was determined as the lowest concentration of compound that inhibited visible growth. A mirror reader was used to assist in determining the MIC endpoint.
- MIC minimum inhibitory concentration
- Isoniazid starting at 160 ⁇ gml -1 was prepared and 5 ⁇ l of this control curve was added to 95 ⁇ l of Middlebrook 7H9 medium (Difco catalogue ref. 271310). (Row 11, lines A-H). Five ⁇ l of neat DMSO were added to row 12 (growth and Blank controls).
- the inoculum was standardised to approximately 1x10 ' cfu/ml and diluted 1 in 100 in Middlebrook 7H9 broth (Middlebrook ADC enrichment, a dehydrated culture media which supports growth of mycobacterial species available from Becton Dickinson Catalogue Ref. 211887), to produce the final inoculum of H37Rv strain (ATCC25618).
- Middlebrook ADC enrichment a dehydrated culture media which supports growth of mycobacterial species available from Becton Dickinson Catalogue Ref. 211887), to produce the final inoculum of H37Rv strain (ATCC25618).
- One hundred ⁇ l of this inoculum was added to the entire plate but G- 12 and H- 12 wells (Blank controls). All plates were placed in a sealed box to prevent drying out of the peripheral wells and they were incubated at 37 0 C without shaking for six days.
- a resazurin solution was prepared by dissolving one tablet of resazurin (Resazurin Tablets for Milk Testing; Ref 330884Y VWR International Ltd) in 30 ml sterile PBS (phosphate buffered saline). 25 ⁇ l of this solution was added to each well. Fluorescence was measured (Spectramax M5 Molecular Devices, Excitation 530nm, Emission 590nm) after 48 h to determine the MIC value.
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WO2010043714A1 (en) | 2008-10-17 | 2010-04-22 | Glaxo Group Limited | Tricyclic nitrogen compounds used as antibacterials |
US8273882B2 (en) | 2008-05-23 | 2012-09-25 | Novartis Ag | Quinoxaline carboxamide derivatives as protein tyrosine kinase inhibitors |
WO2013164769A1 (en) | 2012-05-02 | 2013-11-07 | Lupin Limited | Substituted pyridine compounds as crac modulators |
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WO2017211759A1 (en) | 2016-06-08 | 2017-12-14 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. | New antibacterial compounds |
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WO2021198981A1 (en) | 2020-04-01 | 2021-10-07 | Janssen Biopharma, Inc. | Antiviral compounds and uses thereof |
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WO2017211759A1 (en) | 2016-06-08 | 2017-12-14 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. | New antibacterial compounds |
WO2017211760A1 (en) | 2016-06-08 | 2017-12-14 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. | New antibacterial compounds |
US10633366B2 (en) | 2016-06-08 | 2020-04-28 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. | Antibacterial compounds |
US10640488B2 (en) | 2016-06-08 | 2020-05-05 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. | Antibacterial compounds |
Also Published As
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TW201008941A (en) | 2010-03-01 |
NZ589062A (en) | 2012-06-29 |
IL209270A (en) | 2013-09-30 |
AU2009248786A1 (en) | 2009-11-26 |
CR11838A (en) | 2011-03-25 |
EA018817B1 (en) | 2013-10-30 |
DOP2010000342A (en) | 2010-11-30 |
JP5474941B2 (en) | 2014-04-16 |
PE20091927A1 (en) | 2010-01-21 |
MA32406B1 (en) | 2011-06-01 |
CA2725726A1 (en) | 2009-11-26 |
IL209270A0 (en) | 2011-01-31 |
ES2455496T3 (en) | 2014-04-15 |
JP2011520943A (en) | 2011-07-21 |
MX2010012732A (en) | 2010-12-07 |
AU2009248786B2 (en) | 2013-04-04 |
EP2300476A1 (en) | 2011-03-30 |
BRPI0912995A2 (en) | 2015-10-13 |
CN102105473B (en) | 2013-05-08 |
EP2300476B1 (en) | 2014-01-08 |
CL2009001267A1 (en) | 2010-12-31 |
UY31839A (en) | 2009-12-14 |
CN102105473A (en) | 2011-06-22 |
US20090306089A1 (en) | 2009-12-10 |
CO6321284A2 (en) | 2011-09-20 |
EA201071352A1 (en) | 2011-06-30 |
KR20110016947A (en) | 2011-02-18 |
US8097628B2 (en) | 2012-01-17 |
ZA201007945B (en) | 2011-08-31 |
AR071869A1 (en) | 2010-07-21 |
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