WO2006081264A1 - Antibacterial agents - Google Patents
Antibacterial agents Download PDFInfo
- Publication number
- WO2006081264A1 WO2006081264A1 PCT/US2006/002537 US2006002537W WO2006081264A1 WO 2006081264 A1 WO2006081264 A1 WO 2006081264A1 US 2006002537 W US2006002537 W US 2006002537W WO 2006081264 A1 WO2006081264 A1 WO 2006081264A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- hydrogen
- compound according
- hydroxy
- dihydro
- Prior art date
Links
- 239000003242 anti bacterial agent Substances 0.000 title description 4
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 10
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 10
- 241000124008 Mammalia Species 0.000 claims abstract description 9
- -1 hydroxy, amino, piperidyl Chemical group 0.000 claims description 134
- 150000001875 compounds Chemical class 0.000 claims description 111
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 239000001257 hydrogen Substances 0.000 claims description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims description 61
- 125000003118 aryl group Chemical group 0.000 claims description 37
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- OJEYDZBIAYMFFD-UHFFFAOYSA-N cyclopentanecarboxamide Chemical compound NC(=O)C1C[CH]CC1 OJEYDZBIAYMFFD-UHFFFAOYSA-N 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000005035 acylthio group Chemical group 0.000 claims description 5
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 4
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical group C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 4
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 4
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 4
- 125000005647 linker group Chemical group 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 3
- 125000004468 heterocyclylthio group Chemical group 0.000 claims description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims 1
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 1
- 150000005054 naphthyridines Chemical class 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 80
- 239000000243 solution Substances 0.000 description 50
- 239000007787 solid Substances 0.000 description 40
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 238000002360 preparation method Methods 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- 239000000377 silicon dioxide Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- VEPGNAIYGRUSIA-UHFFFAOYSA-N 3-oxo-4h-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde Chemical compound S1CC(=O)NC2=NC(C=O)=CC=C21 VEPGNAIYGRUSIA-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- KBDDFKYRMCBPOT-UHFFFAOYSA-N 8-bromo-7-fluoro-2-methoxy-1,5-naphthyridine Chemical compound N1=CC(F)=C(Br)C2=NC(OC)=CC=C21 KBDDFKYRMCBPOT-UHFFFAOYSA-N 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 239000007819 coupling partner Substances 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- ZKAIYCQLABGZDR-UHFFFAOYSA-N 4-bromo-6-methoxy-1,5-naphthyridin-3-amine Chemical compound N1=CC(N)=C(Br)C2=NC(OC)=CC=C21 ZKAIYCQLABGZDR-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical compound CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 229960002317 succinimide Drugs 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- PPZNNZQHBXZAPS-UHFFFAOYSA-N (6-methoxy-1,5-naphthyridin-4-yl) trifluoromethanesulfonate Chemical compound N1=CC=C(OS(=O)(=O)C(F)(F)F)C2=NC(OC)=CC=C21 PPZNNZQHBXZAPS-UHFFFAOYSA-N 0.000 description 2
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 2
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 2
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- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
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- IWJLZADTSIIYBX-UHFFFAOYSA-N 5-(benzyloxy)-2-(hydroxymethyl)-1,4-dihydropyridin-4-one Chemical compound N1C(CO)=CC(=O)C(OCC=2C=CC=CC=2)=C1 IWJLZADTSIIYBX-UHFFFAOYSA-N 0.000 description 2
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- 150000007513 acids Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
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- 239000000010 aprotic solvent Substances 0.000 description 2
- 150000001499 aryl bromides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- IAQRGUVFOMOMEM-UHFFFAOYSA-N but-2-ene Chemical compound CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
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- 239000003638 chemical reducing agent Substances 0.000 description 2
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- 229940047650 haemophilus influenzae Drugs 0.000 description 1
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- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
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- 239000012535 impurity Substances 0.000 description 1
- 125000004130 indan-2-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])(*)C2([H])[H] 0.000 description 1
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 1
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 125000000686 lactone group Chemical group 0.000 description 1
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- 239000008176 lyophilized powder Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- OQUCMNQHZFOMPC-UHFFFAOYSA-N methyl 6-amino-5-bromopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(Br)C(N)=N1 OQUCMNQHZFOMPC-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
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- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 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
- 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
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
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- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 1
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- 244000052769 pathogen Species 0.000 description 1
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- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
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- 125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 description 1
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- 125000004260 quinazolin-2-yl group Chemical group [H]C1=NC(*)=NC2=C1C([H])=C([H])C([H])=C2[H] 0.000 description 1
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 1
- 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 description 1
- 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 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
- 238000001228 spectrum Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
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- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 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
- RXQLNMAPQLUGAA-UHFFFAOYSA-N tert-butyl cyclopent-3-ene-1-carboxylate Chemical compound CC(C)(C)OC(=O)C1CC=CC1 RXQLNMAPQLUGAA-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-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
- 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
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 238000009827 uniform distribution Methods 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
- C07D521/00—Heterocyclic compounds containing unspecified hetero rings
-
- 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
-
- 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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- This invention relates to novel compounds, compositions containing them, their use as antibacterials, and processes for their preparation.
- This invention comprises compounds of the formula (I), as described hereinafter, which are useful in the treatment of bacterial infections.
- This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier.
- This invention is also processes for the preparation of compounds of formula (I), as well as processes for the preparation of intermediates useful in the synthesis of compounds of formula (I).
- This invention is also novel intermediates useful in the preparation of antibacterial agents.
- This invention is also a method of treating bacterial infections in mammals, particularly in humans.
- This invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof:
- Z 1a , Z 3 , and Z 4 are independently N or CR ;
- Z 2 , Z 5 , and Z 6 are each CR 1a ;
- Ri and R 1a are independently at each occurrence hydrogen; cyano; halogen; hydroxy; (C-] _g)alkoxy unsubstituted or substituted by (C-
- W 1 , W 2 , and W 3 are each CR 3 R 4 ;
- R 3 , R 4 , R 6 , and R 7 are independently at each occurrence hydrogen; thiol; (C 1- 6 )alkylthio; halogen; trifluoromethyl; azido; (C 1-6 )alkyl; (C 2 - 6 )alkenyl; (C ⁇ alkoxycarbonyl; (d ⁇ alkylcarbonyl; (C 2 . 6 )alkenylcarbonyl; (C 2-6 )alkenyloxycarbonyl; aralkyl; aryl; heterocyclyl; heterocyclylalkyl; hydroxy; NR 1b R 1b '; (Ci- 6 )alkylsulphonyl; (C 2 .
- R 5 is hydrogen; halogen; hydroxyl; or (C 1-6 )alkyl;
- R 2 and R 8 are independently hydrogen, trifluoromethyl; (Ci -6 )alkyl; (C 2 . 6 )alkenyl; (C 1-6 )alkoxycarbonyl; (Cv 6 )alkylcarbonyl; (C 2-6 )alkenyloxycarbonyl; aryl; aralkyl; (C 3- 8 )cycloalkyl; heterocyclyl; or heterocyclylalkyl;
- R 1b and R 1b' are independently at each occurrence hydrogen; (C 1-6 )alkyl; aralkyl; aryl; heterocyclyl; heterocyclylalkyl; or together with the nitrogen that they are attached form an aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring (wherein said aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring are optionally substiuted with from 1 to 3 substituents selected from halogen, hydroxy; cyano; nitro; (C 1- 6 )alkyl; and aryl);
- R 10 is a substituted or unsubstituted bicyclic, carbocyclic, or heterocyclic ring system (A):
- X is C or N when part of an aromatic ring or CRn when part of a non aromatic ring;
- X is N, NR 12 , O, S(O) n , CO or CR 11 when part of an aromatic or non-aromatic ring or may in addition be CR 13 R 14 when part of a non aromatic ring;
- n is independently at each occurrence 0, 1 , or 2;
- X and X are independently N or C;
- Y is a 0 to 4 atom linker group each atom of which is independently selected from N, NR 12 , O, S(O) n , CO and CRn when part of an aromatic or non-aromatic ring or may additionally be CR 13 Ru when part of a non aromatic ring,
- Y is a 2 to 6 atom linker group, each atom of Y being independently selected from N, NR 12 , O, S(O) n , CO and CR 11 when part of an aromatic or non-aromatic ring or may additionally be CRi 3 R 14 when part of a non aromatic ring;
- R 11 , R 13 and R 14 are at each occurrence independently selected from: H; (C- ⁇
- R 12 is at each occurrence independently hydrogen; trifluoromethyl; (Ci _4)alkyl unsubstituted or substituted by hydroxy, carboxy, (C-
- this invention provides a compound of formula (I) wherein
- Z 1 and Z 4 are N; and Z 3 is CR 1a .
- this invention provides a compound of formula (I) wherein R 1 is OCH ⁇ .
- this invention provides a compound of formula (I) wherein
- R is at each occurrence independently hydrogen; halogen; or cyano.
- this invention provides a compound of formula (I) wherein R 2 is hydrogen.
- this invention provides a compound of formula (I) wherein R 3 and R 4 are each independently selected from hydrogen, hydroxyl, halogen, and (C 1- ⁇ )alkyl.
- this invention provides a compound of formula (I) wherein R 5 is hydrogen.
- this invention provides a compound of formula (I) wherein B is CH 2 . In some embodiments, this invention provides a compound of formula (I) wherein
- U is CH 2 .
- this invention provides a compound of formula (I) wherein R 10 is 4H-Pyrido[3,2-b][1 ,4]thiazin-3-oxo-6-yl; 4H-Pyrido[3,2-b][1 ,4]oxazin-3-oxo-6-yl; or
- this invention provides a compound of formula (I) wherein
- Z 1 and Z 4 are N; and Z 3 is CR 1a ; Ri is OCH 3 ; R is at each occurrence independently hydrogen; halogen; or cyano; R 2 is hydrogen; and R 3 and R 4 are each independently selected from hydrogen, hydroxyl, halogen, and (d. 6 )alkyl.
- this invention provides a compound of formula (I) wherein
- Z 1 and Z 4 are N; and Z 3 is CR 1a ; R 1 is OCH 3 ; R is at each occurrence independently hydrogen; halogen; or cyano; R 2 is hydrogen; R 3 and R 4 are each independently selected from hydrogen, hydroxyl, halogen, and (C 1-6 )alkyl; R 5 is hydrogen; B is CH 2 ; and U is CH 2 .
- this invention provides a compound of formula (I) wherein Z 1 and Z 4 are N; and Z 3 is CR 1a ; R 1 is OCH 3 ; R is at each occurrence independently hydrogen; halogen; or cyano; R 2 is hydrogen; and R 3 and R 4 are each independently selected from hydrogen, hydroxyl, halogen, and (C 1-6 )alkyl; R 5 is hydrogen; B is CH 2 ; U is
- R of Z 2 , Z 3 , and Z 5 is hydrogen; R 1a of Z 6 is fluorine; R 3 and R 4 of W 1 and W 2 are hydrogen; R 3 of W 3 is hydrogen; R 4 of W 3 is hydroxy; and R 2 and R 8 are independently hydrogen or (C 1-6 )alkyl.
- this invention provides a compound of formula (I) wherein
- Z 1 and Z 4 are N; and Z 3 is CR 1a ; R 1 is OCH 3 ; R is at each occurrence independently hydrogen; halogen; or cyano; R 2 is hydrogen; and R 3 and R 4 are each independently selected from hydrogen, hydroxyl, halogen, and (C 1-6 )alkyl; R 5 is hydrogen; B is CH 2 ; U is CH 2 ; R a of Z 2 , Z 3 , and Z 5 is hydrogen; R 1a of Z 6 is fluorine; R 3 and R 4 of W-i and W 2 are hydrogen; R 3 of W 3 is hydrogen; R 4 of W 3 is hydroxy; R 2 and R 8 are independently hydrogen or (C 1-6 )alkyl; and R 10 is 4H-Pyrido[3,2-b][1 ,4]thiazin-3-oxo-6-yl; 4H-Pyrido[3,2- b][ ⁇ ,4]oxazin-3-oxo-6-yl; or 2,3-Dihydro
- this invention provides a compound of formula (I) wherein the compound is (3/?,4/ : ?)-/V-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]-3-hydroxy-4- ( ⁇ [(3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]thiazin-6- yOmethyljaminoJmethyOcyclopentanecarboxamide; (3f?,4f?)-N-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]-3-hydroxy-4-( ⁇ [(3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]oxazin-6- yOmethyOaminoJmethyOcyclopentanecarboxamide; (3R,4R)-3- ⁇ [(2,3-fluoro-6
- this invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) or any other structural embodiment of the invention, and a pharmaceutically acceptable carrier
- this invention provides a method of treating bacterial infections in mammals which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) or any other structural embodiment of the invention.
- this invention describes compounds of formula I wherein the (a) and (b) rings of R-n are both aromatic as demonstrated by the following non-limiting examples: 1 H-pyrrolo[2,3-b]-pyridin-2-yl, 1 H-pyrrolo[3,2-b]-pyridin-2-yl, 3H-imidazo[4,5-b]- pyrid-2-yl, 3H-quinazolin-4-one-2-yl, benzimidazol-2-yl, benzo[1 ,2,3]-thiadiazol-5-yl, benzo[1 ,2,5]-oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl, benzo[b]thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl, imidazo[1 ,2-a]pyridin-2-yl, imidazo-[1 ,2-a]-pyrimidin- 2-yl,
- R 11 is defined by an aromatic (a) ring and a non aromatic (b) ring as illustrated by the following non-limiting examples: 1 ,1 ,3-trioxo-1 ,2,3,4-tetrahydro-1 P ⁇ benzo[ ⁇ ,4] thiazin-6-yl, benzo[1 ,3]dioxol-5-yl, 2,3-dihydro-benzo[1 ,4]dioxin-6-yl, 2-oxo- 2,3-dihydro-benzooxazol-6-yi, 4H-benzo[1 ,4]oxazin-3-one-6-yl (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl), 4H-benzo[1 ,4]thiazin-3-one-6-yl (3-oxo-3,4-dihydro-2H- benzo[1 ,4]thiazin-6-
- alkyl when used alone or when forming part of other groups (such as the 'alkoxy' group) includes substituted or unsubstituted, straight or branched chain alkyl groups containing the specified range of carbon atoms.
- (Ci -6 )alkyl include methyl, ethyl, propyl, butyl, iso-propyl, sec-butyl, tert-butyl, iso-pentyl, and the like.
- alkenyl means a substituted or unsubstituted alkyl group of the specified range of carbon atoms, wherein one carbon-carbon single bond is replaced by a carbon-carbon double bond.
- (C 2 6 )alkenyl include ethylene, 1 - propene, 2-propene, 1-butene, 2-butene, and isobutene, and the like. Both cis and trans isomers are included.
- cycloalkyl refers to substituted or unsubstituted carbocyclic system of the specifed range of carbon atoms, which may contain up to two unsaturated carbon- carbon bonds.
- (C. Jcycloalkyl) include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cycloheptyl.
- alkoxy refers to an O-alkyl radical where the alkyl group contains the specified range of carbon atoms and is as defined herein.
- the alkyl group contains 13 or less carbons; in some embodiments 10 or less carbon atoms; in some embodiments 6 or less carbon atoms; and is as otherwise defined.
- Aryl is as defined herein.
- alkylsulphonyl refers to a SO ⁇ alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.
- alkylthio refers to a Salkyl wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.
- aminosulphonyl refers to a SO 2 N radical wherein the nitrogen is substituted as specified.
- aminocarbonyl refers to a carboxamide radical wherein the nitrogen of the amide is substituted as defined.
- heterocyclylthio refers to a S-heterocyclyl radical wherein the heterocyclyl moiety is as defined herein.
- heterocyclyloxy refers to an O-heterocyclyl radical wherein heterocyclyl is as defined herein.
- arylthio refers to an S-aryl radical wherein aryl is as defined herein.
- aryloxy refers to an O-aryl radical wherein aryl is as defined herein.
- acylthio refers to a S-acyl radical wherein acyl is as defined herein.
- acyloxy refers to an O-acyl radical wherein acyl is as defined herein.
- alkoxycarbonyl refers to a CO 2 alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.
- alkenyloxycarbonyl refers to a CO 2 alkyl radical wherein the alkenyl group contains the specified range of carbon atoms and is as defined herein.
- alkylsulphonyloxy refers to an O-SO 2 alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.
- arylsulphonyl refers to a SO 2 aryl radical wherein aryl is as herein defined.
- arylsulphoxide refers to a SOaryl radical wherein aryl is as defined herein.
- suitable substituents for any alkyl, alkoxy, alkenyl, and cycloalkyl groups includes up to three substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, carboxy, amino, amidino, sulphonamido, unsubstituted (C-
- Halo or halogen includes fluoro, chloro, bromo and iodo.
- haloalkyl refers to an alkyl radical containing the specified range of carbon atoms and is as otherwise defined herein, which is further substituted with 1 -3 halogen atoms.
- haloalkoxy refers to an alkoxy radical of the specified range and as defined herein, which is further substituted with 1-3 halogen atoms.
- hydroxyalkyl refers to an alkyl group as defined herein, further substituted with a hydroxy group.
- heterocyclic or “heterocyclyl” as used herein includes optionally substituted aromatic and non-aromatic, single and fused, mono- or bicyclic rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or C-substituted by, for example, up to three groups selected from (C 1 4 )alkylthio; halo; (C 1 4 )haloalkoxy; (C 1
- Each heterocyclic ring suitably has from 3 to 7, preferably 5 or 6, ring atoms.
- a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
- suitable optional substituents in such substituted amino groups include hydrogen; trifluoromethyl; (C 1 4 )alkyl optionally substituted by hydroxy, (C 1
- heterocyclylalkyl refers to a (C 1-6 )alkyl radical which bears as a substituent a heterocyclyl group, wherein heterocyclyl and alkyl are as herein defined.
- the heterocyclyl group maybe joined to a primary, secondary or tertiary carbon of the (C 1- 6 )alkyl chain.
- aryl includes optionally substituted phenyl and naphthyl.
- Aryl groups may be optionally substituted with up to five, preferably up to three, groups selected from (C 1 4 )alkylthio; halo; (C 1 4 )haloalkoxy; (C 1 4 )haloalkyl; (C 1 4 )alkyi; (C 2 4 )alkenyl; hydroxy; (C ⁇ hydroxyalkyl; (C 1 4 )alkylthio; (C 1 4 )alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally substituted by (C 1 4 )alkyl; (C 1 4 )alkylsulphonyl; (C 2 4 )alkenylsulphonyl.
- aralkyl refers to a (Ci. 6 )alkyl radical which bears as a substituent an aryl group, wherein aryl and alkyl are as herein defined.
- the aryl group maybe joined to a primary, secondary or tertiary carbon of the (C ⁇ alkyl chain.
- Solvates maybe produced from crystallization from a given solvent or mixture of solvents, inorganic or organic. Solvates may also be produced upon contact or exposure to solvent vapors, such as water. This invention includes within its scope stoichiometric and non-stoichiometric solvates including hydrates.
- phrases such as "a compound of Formula I or a pharmaceutically acceptable salt, solvate or derivative thereof” are intended to encompass the compound of Formula I, a derivative of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), a solvate of formula (I), or any pharmaceutically acceptable combination of these.
- a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof may include a pharmaceutically acceptable salt of a compound of formula (I) that is further present as a solvate.
- the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably 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 preferably from 10 to 59% of a compound of the formula (I) or pharmaceutically acceptable derivative thereof.
- salts of the above-mentioned compounds of formula (I) include the free base form or their 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.
- Compounds of formula (I) may also be prepared as the N-oxide.
- compositions of formula (I) that have been covalently modifed with a group that undergoes at least some in vivo cleavage to a compound of formula (I).
- Suitable pharmaceutically acceptable in vivo hydrolysable ester- forming groups include those forming esters which break down readily in the human body to leave the parent acid or its salt.
- Suitable groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v):
- R is hydrogen, (C 1 6 ) alkyl, (C 3 7 ) cycloalkyl, methyl, or phenyl
- R is (C 1 6 ) alkyl, (C 1 6 )alkoxy, phenyl, benzyl, (C 37 )cycloalkyl, (C 37 )cycloalkyloxy, (C 1 6 )alkyl(C 3 7 ) cycloalkyl, 1 -amino ⁇ 6 )aikyl, or a b
- R and R together form a 1 ,2-phenylene group optionally substituted by one or two methoxy groups;
- R° represents (C 1 6 )alkylene d e optionally substituted with a methyl or ethyl group and
- R and R independently represent f g
- R represents (C 1-6 ) alkyl; R represents (C 1-6 ) alkyl; R represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C 1 6 ) alkyl, or (C 1-6 ) alkoxy; Q is oxygen or NH; R is hydrogen or
- (C 1 6 ) alkyl is hydrogen, (C 1 6 ) alkyl optionally substituted by halogen, (C 2 6 ) alkenyl, (C 1 6 )alkoxycarbonyl, aryl or heteroaryl; or R and R together form (C 1 6 ) alkylene; R represents hydrogen, (C 1 6 ) alkyl or (C 1 6 )alkoxycarbonyl; k and R represents (C 1 8 )alkyl, (C 1 8 )alkoxy, (C 1 ⁇ aIkOXy(C 1 6 )alkoxy or aryl.
- suitable in vivo hydrolysable ester groups include, for example, 8CyIoXy(C 1 6 )alkyl groups such as acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, and (i-aminoethyl)carbonyloxymethyl; (C 1 6 )alkoxycarbonyloxy(C 1 6 )alkyl groups, such as ethoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; Ui(C 1- 6 )alkylamino(C 1 6 )alkyl especially di(C 1 4 )alkylamino(C 1 4 )alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-(Cy
- R is hydrogen, C 1 6 alkyl or phenyl.
- R is preferably hydrogen.
- Compounds of formula (I) may also be prepared as the corresponding N-oxides.
- Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
- the invention includes all such form, including pure isomeric forms.
- 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 stereospecific or asymmetric syntheses.
- reaction parameters such as reaction time, temperature, energy source, pressure, light, pressure, solvent or solvents used, co-reagents, catalysts, and the like.
- Protective groups wherever found herein maybe designated by their specific formula or alternatively, maybe referred to generically by P or P n (wherein n is an integer). It is to be appreciated that where generic descriptors are used, that such descriptors are at each occurrence independent from each other. Thus, a compound with more than one of the same generic descriptors (e.g. P) does not indicate that each P is the same protective group, they maybe the same or different, so long as the group is suitable to the chemistry being employed. Where protection or deprotection is generically referred to, one of ordinary skill in the art will understand this to mean that suitable conditions are employed that will allow for the removal of the protecting group to be removed while minimizing reaction at other positions of the molecule, unless otherwise indicated.
- P generic descriptors
- a carboxylic acid maybe reacted with a coupling reagent such as DCC, CDI, EDCI, isobutyl chloroformate, etc, and the corresponding reative intermediate thus formed is further reacted with the nucleophilic coupling partner.
- a coupling reagent such as DCC, CDI, EDCI, isobutyl chloroformate, etc
- the activation step maybe performed before the introduction of the nucleophilic coupling partner, or in some cases, even in the presence of the nucleophilic coupling partner (depending upon the identity of the particular activating agent, carboxylic acid and nuclephilic coupling partner used).
- leaving groups generally refer to atoms or groups which can be eliminated, substituted or otherwise dissociate during the course of the reaction.
- antibacterial 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.
- 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 in mammals including humans.
- compositions may be formulated for administration by any route.
- 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.
- Tablets and capsules for oral administration may be 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.
- Oral liquid preparations may be in the form of, for example, 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 />hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
- 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 the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 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. Such a dosage corresponds to 1.5 to 50 mg/kg per day.
- the dosage is from 5 to 20 mg/kg per day.
- the compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibacterials. If the other antibacterial is a ⁇ -lactam then a ⁇ -lactamase inhibitor may also be employed.
- Compounds of formula (I) are active against a wide range of organisms including both Gram-negative and Gram-positive organisms.
- the compounds of this invention may also be used in the manufacture of medicaments useful in treating bacterial infections in humans or other mammals.
- Reagents and conditions (a) isobutylene, Et2 ⁇ , H2SO4, -78°C to RT; (b) /V-hydroxy benzylamine-HCI, (CH 2 O)n, Et 3 N, toluene, EtOH, 85 0 C; (c) Pd(OH) 2 , H 2 (50 psi), MeOH; (d) ⁇ /-(benzyloxycarbonyloxy)-succinimide, DCM, RT; (e) TFA, DCM, RT; (f) NH4HCO3, (BoC) 2 O, pyridine, THF, RT; (g) Pd 2 (dba)3, rac-BINAP, 8-bromo-7-fluoro-2-(methyloxy)- 1 ,5-naphthyridine, dioxane, 10O 0 C, 36h; (h) Pd(OH) 2 , H 2 (1 atm), MeOH, RT;
- Ester I-2 Carboxylic acid 1-1 was reacted with isobutylene and sulfuric acid to give ester I-2.
- the unsaturated ester I-2 was heated with a hydroxylamine and paraformaldehyde to give cycloaddition product 1-3.
- Hydrogenation of I-3 cleaved the N-O bond and concommitantly removed the benzyl functionality yielding amino alcohol I-4.
- Protection of the primary amine with a benzyl carbamate followed by hydrolysis of the ester with TFA provided acid I-6.
- protecting groups to mask reactive functionality is well-known to those of skill in the art, and other protecting groups are listed in standard reference volumes, such as Greene, "Protective Groups in Organic Synthesis" (published by Wiley-lnterscience).
- an added base such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used.
- Et3N triethylamine
- i-Pr2NEt diisopropylethylamine
- K2CO3 K2CO3
- Reagents and conditions (a) CH3OH, H2SO4, 6O 0 C; (b) ⁇ /-hydroxy benzylamine-HCI, (CH 2 O) n , Et 3 N, toluene, EtOH, 85 0 C; (c) NH 3 , MeOH, 55°C, 72h; (d) Pd 2 (CHDa) 3 , rac- BINAP, 8-bromo-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine, dioxane, 100 0 C, 36h; (e) Pd(OH) 2 , H 2 (50 psi), MeOH; (f) ⁇ /-(benzyloxycarbonyloxy)-succinimide, DCM, RT; (g) Pd(OH) 2 , H 2 (1 atm), MeOH, RT; (h) 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]
- Carboxylic acid 1-1 was esterified with methanol and sulfuric acid to give ester 11-1.
- the unsaturated ester 11-1 was heated with a hydroxylamine and paraformaldehyde to give cycloaddition product H-2.
- Conversion of the ester functionality to primary amide II-3 was achieved with ammonia in methanol using a sealed system.
- the amide was then coupled to an aryl bromide or triflate using standard Buchwald coupling conditions to give amide 11-4. Hydrogenation of 11-4 results in cleavage of the N-O bond and concommitant removal of the benzyl functionality. Protection of the primary amine with was achieved using a benzyl carbamate affording 1-8.
- protecting groups to mask reactive functionality is well-known to those of skill in the art, and other protecting groups are listed in standard reference volumes, such as Greene, "Protective Groups in Organic Synthesis” (published by Wiley-lnterscience).
- Removal of the benzyl carbamate was accomplished using Pd/C and hydrogen gas in methanol.
- the free amine is converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH2CI2, EtOH or CH3CN.
- the imine is subsequently or simultaneously reacted with a suitable reducing agent such as NaBH ⁇ ., NaBH(OAc)3 or NaBH ⁇ CN in solvent to give the secondary amine
- an added base such as triethylamine (Et ⁇ N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used.
- Et ⁇ N triethylamine
- i-Pr2NEt diisopropylethylamine
- K2CO3 K2CO3
- Mass spectra were obtained using electrospray (ES) ionization techniques. Elemental analyses were performed by Quantitative Technologies Inc., Whitehouse, NJ. Melting points were obtained on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius.
- E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Flash chromatography was carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Analytical HPLC was performed on Beckman chromatography systems. Preparative HPLC was performed using Gilson chromatography systems. ODS refers to an octadecylsilyl derivatized silica gel chromatographic support.
- YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan.
- PRP- 1 ® is a polymeric (styrene-divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada.
- Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colorado.
- this mixture was dissolved in CH2CI2 (150 mL) and treated with trifluoroacetic acid (100 mL). The reaction was stirred for 3 hr then was concentrated to dryness. The residue was partitioned between CHCI3 and saturated sodium bicarbonate solution and the layers were separated. The aqueous phase was extracted with CHCI3, and the combined organics were dried (MgS ⁇ 4) and concentrated to low volume. The solid was collected by suction filtration, washed with a small volume of CHCI3 and dried under vacuum to afford a first crop of the title compound (31.14 g).
- NCCLS National Committee for Clinical Laboratory Standards
- the compounds were tested in serial two-fold dilutions ranging from 0.016 to 16 mcg/mL.
- Compounds were evaluated against a panel of Gram-positive organisms, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Enterococcus faecalis.
- 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.
Abstract
Naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
Description
TITLE ANTIBACTERIAL AGENTS
FIELD OF THE INVENTION
This invention relates to novel compounds, compositions containing them, their use as antibacterials, and processes for their preparation.
BACKGROUND OF THE INVENTION The emergence of pathogens resistant to known antibiotic therapy is becoming a serious global healthcare problem (Chu, et al., (1996) J. Med. Chem., 39: 3853-3874). Thus, there is a need to discover new broad spectrum antibiotics useful in combating multidrug-resistant organisms. Importantly, it has now been discovered that certain compounds have antibacterial activity, and, therefore, may be useful for the treatment of bacterial infections in mammals, particularly in humans. WO0125227, WO0240474, WO0207572, WO04024712, WO04024713, WO9937635, WO0021948, WO0021952, WO0043383, WO0078748, WO0107433, WO0107432, WO0208224, WO0224684, WO0250061 , WO0250040, WO0256882, WO0296907, WO03087098, WO03010138, WO03064431 , WO03064421 , WO04002992, and WO0400249 disclose quinoline and/or naphthyridine derivatives having antibacterial activity.
SUMMARY OF THE INVENTION
This invention comprises compounds of the formula (I), as described hereinafter, which are useful in the treatment of bacterial infections. This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier. This invention is also processes for the preparation of compounds of formula (I), as well as processes for the preparation of intermediates useful in the synthesis of compounds of formula (I). This invention is also novel intermediates useful in the preparation of antibacterial agents. This invention is also a method of treating bacterial infections in mammals, particularly in humans.
DETAILED DESCRIPTION OF THE INVENTION This invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof:
1a Z1, Z3, and Z4 are independently N or CR ;
Z2, Z5, and Z6 are each CR1a;
Ri and R1a are independently at each occurrence hydrogen; cyano; halogen; hydroxy; (C-] _g)alkoxy unsubstituted or substituted by (C-| _g)alkoxy, hydroxy, amino, piperidyl, guanidino or amidino any of which is unsubstituted or N-substituted by one or two (C-|.Q)alkyl, acyl, (Ci_g)alkylsulphonyl, CONH2, hydroxy, (C^ _g)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C-) . 6)a!kylsulphonyloxy; (C-|_g)alkyl; (C-j _g)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio; (C-| _g)alkylsulphonyl; (C-] _g)alkylsulphoxide; arylsulphonyl; arylsulphoxide; or an amino, piperidyl, guanidino or amidino group unsubstituted or N- substituted by one or two (C-| _g)alkyl, acyl or (C-] .g)alkylsulphonyl groups; or R-i and R1a of
Z2 together form ethylenedioxy;
W1 , W2, and W3 are each CR3R4;
B is CR6R7or C=O;
R3, R4, R6, and R7 are independently at each occurrence hydrogen; thiol; (C1- 6)alkylthio; halogen; trifluoromethyl; azido; (C1-6)alkyl; (C2-6)alkenyl; (C^alkoxycarbonyl; (d^alkylcarbonyl; (C2.6)alkenylcarbonyl; (C2-6)alkenyloxycarbonyl; aralkyl; aryl; heterocyclyl; heterocyclylalkyl; hydroxy; NR1bR1b'; (Ci-6)alkylsulphonyl; (C2.
6)alkenylsulphonyl; or (C-j.δ)aminosulphonyl wherein the amino group is optionally and independently substituted by hydrogen, (C1-6)alkyl, (C2.6)alkenyl or aralkyl;
R5 is hydrogen; halogen; hydroxyl; or (C1-6 )alkyl;
R2 and R8 are independently hydrogen, trifluoromethyl; (Ci-6)alkyl; (C2.6)alkenyl; (C1-6)alkoxycarbonyl; (Cv6)alkylcarbonyl; (C2-6)alkenyloxycarbonyl; aryl; aralkyl; (C3- 8)cycloalkyl; heterocyclyl; or heterocyclylalkyl;
R1b and R1b' are independently at each occurrence hydrogen; (C1-6)alkyl; aralkyl; aryl; heterocyclyl; heterocyclylalkyl; or together with the nitrogen that they are attached form an aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring (wherein said aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring are optionally substiuted with from 1 to 3 substituents selected from halogen, hydroxy; cyano; nitro; (C1- 6)alkyl; and aryl);
U is CH2; C(=O); or SO2;
R10 is a substituted or unsubstituted bicyclic, carbocyclic, or heterocyclic ring system (A):
containing up to four heteroatoms in each ring in which at least one of rings (a) and (b) is aromatic;
X is C or N when part of an aromatic ring or CRn when part of a non aromatic ring; X is N, NR12, O, S(O)n , CO or CR11 when part of an aromatic or non-aromatic ring or may in addition be CR13R14 when part of a non aromatic ring; n is independently at each occurrence 0, 1 , or 2;
3 5
X and X are independently N or C;
Y is a 0 to 4 atom linker group each atom of which is independently selected from N, NR12, O, S(O)n , CO and CRn when part of an aromatic or non-aromatic ring or may additionally be CR13Ru when part of a non aromatic ring,
Y is a 2 to 6 atom linker group, each atom of Y being independently selected from N, NR12, O, S(O)n , CO and CR11 when part of an aromatic or non-aromatic ring or may additionally be CRi3R14 when part of a non aromatic ring;
R11, R13 and R14 are at each occurrence independently selected from: H; (C-μ
4)alkylthio; halo; (C-|_4)alkyl; (C2-4)alkenyl; hydroxy; hydroxy(C-)-4)alkyl; mercapto(Ci_ 4)alkyl; (C-| _4)alkoxy; trifluoromethoxy; nitro; cyano; carboxy; amino or aminocarbonyl unsubstituted or substituted by (C-j _4)alkyl;
R12 is at each occurrence independently hydrogen; trifluoromethyl; (Ci _4)alkyl unsubstituted or substituted by hydroxy, carboxy, (C-| _4)alkoxy, (C^_e)alkylthio, halo or trifluoromethyl; (C2-4)alkenyl; or aminocarbonyl wherein the amino group is optionally substituted with (C^_4)alkyl; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, this invention provides a compound of formula (I) wherein
Z1 and Z4 are N; and Z3 is CR1a.
In some embodiments, this invention provides a compound of formula (I) wherein R1 is OCH ό .
In some embodiments, this invention provides a compound of formula (I) wherein
1a R is at each occurrence independently hydrogen; halogen; or cyano.
In some embodiments, this invention provides a compound of formula (I) wherein R2 is hydrogen.
In some embodiments, this invention provides a compound of formula (I) wherein R3 and R4 are each independently selected from hydrogen, hydroxyl, halogen, and (C1- β)alkyl.
In some embodiments, this invention provides a compound of formula (I) wherein R5 is hydrogen.
In some embodiments, this invention provides a compound of formula (I) wherein B is CH2. In some embodiments, this invention provides a compound of formula (I) wherein
U is CH2.
In some embodiments, this invention provides a compound of formula (I) wherein R10 is 4H-Pyrido[3,2-b][1 ,4]thiazin-3-oxo-6-yl; 4H-Pyrido[3,2-b][1 ,4]oxazin-3-oxo-6-yl; or
2,3-Dihydro-[1 ,4]dioxino[2,3-c]-pyridin-6-yl.
In some embodiments, this invention provides a compound of formula (I) wherein
Z1 and Z4 are N; and Z3 is CR1a; Ri is OCH3; R is at each occurrence independently hydrogen; halogen; or cyano; R2 is hydrogen; and R3 and R4 are each independently selected from hydrogen, hydroxyl, halogen, and (d.6)alkyl. In some embodiments, this invention provides a compound of formula (I) wherein
Z1 and Z4 are N; and Z3 is CR1a; R1 is OCH3; R is at each occurrence independently hydrogen; halogen; or cyano; R2 is hydrogen; R3 and R4 are each independently selected from hydrogen, hydroxyl, halogen, and (C1-6)alkyl; R5 is hydrogen; B is CH2; and U is CH2. In some embodiments, this invention provides a compound of formula (I) wherein Z1 and Z4 are N; and Z3 is CR1a; R1 is OCH3; R is at each occurrence independently hydrogen; halogen; or cyano; R2 is hydrogen; and R3 and R4 are each independently selected from hydrogen, hydroxyl, halogen, and (C1-6)alkyl; R5 is hydrogen; B is CH2; U is
CH2; R of Z2, Z3, and Z5 is hydrogen; R1a of Z6 is fluorine; R3 and R4 of W1 and W2 are hydrogen; R3 of W3 is hydrogen; R4 of W3 is hydroxy; and R2 and R8 are independently hydrogen or (C1-6)alkyl.
In some embodiments, this invention provides a compound of formula (I) wherein
Z1 and Z4 are N; and Z3 is CR1a; R1 is OCH3; R is at each occurrence independently hydrogen; halogen; or cyano; R2 is hydrogen; and R3 and R4 are each independently selected from hydrogen, hydroxyl, halogen, and (C1-6)alkyl; R5 is hydrogen; B is CH2; U is CH2; R a of Z2, Z3, and Z5 is hydrogen; R1a of Z6 is fluorine; R3 and R4 of W-i and W2 are hydrogen; R3 of W3 is hydrogen; R4 of W3 is hydroxy; R2 and R8 are independently hydrogen or (C1-6)alkyl; and R10 is 4H-Pyrido[3,2-b][1 ,4]thiazin-3-oxo-6-yl; 4H-Pyrido[3,2- b][\ ,4]oxazin-3-oxo-6-yl; or 2,3-Dihydro-[1 ,4]dioxino[2,3-c]-pyridin-6-yl.
In some embodiments, this invention provides a compound of formula (I) wherein the compound is (3/?,4/:?)-/V-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]-3-hydroxy-4- ({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]thiazin-6- yOmethyljaminoJmethyOcyclopentanecarboxamide; (3f?,4f?)-N-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]-3-hydroxy-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]oxazin-6- yOmethyOaminoJmethyOcyclopentanecarboxamide; (3R,4R)-3-{[(2,3- dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-Λ/-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]-4-hydroxycyclopentanecarboxamide; (1
(methyloxy)-1 ,5-naphthyridin-4-yl]-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]thiazin-6- yl)methyl]amino}methyl)cyclopentanecarboxamide; (1 S,3H,4/?)-3-hydroxy-Λ/-[6- (methyloxy)-1 ,5-naphthyridin-4-yl]-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-£>][1 ,4]oxazin-6- yOmethyOaminoJmethyOcyclopentanecarboxamide; or (1 S,3R,4/:?)-3-{[(2,3-
dιΗydro[1 ,4]dioxino[2,3-c]pyriclin-7-ylmethyl)amino]methyl}-4-hyclroxy-Λ/-[6-(mθthyloxy)- 1.δ-naphthyridin^-yllcyclopentanecarboxamide; or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, this invention provides a pharmaceutical composition comprising a compound of formula (I) or any other structural embodiment of the invention, and a pharmaceutically acceptable carrier
In some embodiments, this invention provides a method of treating bacterial infections in mammals which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) or any other structural embodiment of the invention.
In some embodiments, this invention describes compounds of formula I wherein the (a) and (b) rings of R-n are both aromatic as demonstrated by the following non-limiting examples: 1 H-pyrrolo[2,3-b]-pyridin-2-yl, 1 H-pyrrolo[3,2-b]-pyridin-2-yl, 3H-imidazo[4,5-b]- pyrid-2-yl, 3H-quinazolin-4-one-2-yl, benzimidazol-2-yl, benzo[1 ,2,3]-thiadiazol-5-yl, benzo[1 ,2,5]-oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl, benzo[b]thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl, imidazo[1 ,2-a]pyridin-2-yl, imidazo-[1 ,2-a]-pyrimidin- 2-yl, indol-2-yl, indol-6-yl, isoquinolin-3-yl, [1 ,8]-naphthyridine-3-yl, oxazolo[4,5-b]-pyridin- 2-yl, quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, indan-2-yl, naphthalen-2-yl, 1 ,3-dioxo- isoindol-2yl, benzimidazol-2-yl, benzothiophen-2-yl, 1 H-benzotriazol-5-yl, 1 H-indol-5-yl, 3H-benzooxazol-2-one-6-yl, 3H-benzooxazol-2-thione-6-yl, 3H-benzothiazol-2-one-5-yl, 3H-quinazolin-4-one-2-yl, 3H-quinazolin-4-one-6-yl, 4-oxo-4H-pyrido[1 ,2-a]pyrimidin-3-yl, benzo[1 ,2,3]thiadiazol-6-yl, benzo[1 ,2,5]thiadiazol-5-yl, benzo[1 ,4]oxazin-2-one-3-yl, benzothiazol-5-yl, benzothiazol-6-yl, cinnolin-3-yl, imidazo[1 ,2-a]pyridazin-2-yl, imidazo[1 ,2-b]pyridazin-2-yl, pyrazolo[1 ,5-a]pyrazin-2-yl, pyrazolo[1 ,5-a]pyridin-2-yl, pyrazolo[1 ,5-a]pyrimidin-6-yl, pyrazolo[5,1 -c][1 ,2,4]triazin-3-yl, pyrido[1 ,2-a]pyrimdin-4- one-2-yl, pyrido[1 ,2-a]pyrimidin-4-one-3-yl, quinazolin-2-yl, quinoxalin-6-yl, thiazolo[3,2- a]pyrimidin-5-one-7-yl, thiazolo[5,4-b]pyridin-2-yl, thieno[3,2-b]pyridin-6-yl, thiazolo[5,4- b]pyridin-6-yl, 4-oxo-4H-pyrido[1 ,2-a]pyrimidin-2-yl, 1-oxo-1 ,2-dihydro-isoquinolin-3-yl, thiazolo[4,5-b]pyridin-5-yl, [1 ,2,3]thiadiazolo[5,4-b]pyridin-6-yl, 2H-isoquinolin-1 -one-3-yl. In yet other embodiments, R-n is defined by a non-aromatic (a) ring and aromatic
(b) ring as illustrated by the following non-limiting examples:_(2S)-2,3-dihydro-1 H-indol-2- yl, (2S)-2,3-dihydro-benzo[1 ,4]dioxine-2-yl, 3-(R,S)-3,4-dihydro-2H-benzo[1 ,4]thiazin-3-yl, 3-(R)-2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-3-yl, 3-(S)-2,3-dihydro-[1 ,4]dioxino[2,3- b]pyridin-3-yl, 2,3-dihydro-benzo[1 ,4]dioxan-2-yl, 3-substituted-3H-quinazolin-4-one-2-yl, 2,3-dihydro-benzo[1 ,4]dioxan-2-yl, 1 -oxo-1 ,3,4,5-tetrahydrobenzo[c]azepin-2-yl.
In still other embodiments, R11 is defined by an aromatic (a) ring and a non aromatic (b) ring as illustrated by the following non-limiting examples: 1 ,1 ,3-trioxo-1 ,2,3,4-tetrahydro-1 P~benzo[\ ,4] thiazin-6-yl, benzo[1 ,3]dioxol-5-yl, 2,3-dihydro-benzo[1 ,4]dioxin-6-yl, 2-oxo- 2,3-dihydro-benzooxazol-6-yi, 4H-benzo[1 ,4]oxazin-3-one-6-yl (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl), 4H-benzo[1 ,4]thiazin-3-one-6-yl (3-oxo-3,4-dihydro-2H- benzo[1 ,4]thiazin-6-yl), 4H-benzo[1 ,4]oxazin-3-one-7-yl, 4-oxo-2,3,4,5-tetrahydro- benzo[b][1 ,4]thiazepine-7-yl, 5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl, benzo[1 ,3]dioxol-5-yl, 2-oxo-2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]thiazin-7-yl, 2-oxo-2,3- dihydro-1 H-pyrido[3,4-b][1 ,4]thiazin-7-yl, 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]thiazin-6- yl, 2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1 ,4]dioxino[2,3-c]pyridin-7-yl, 2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-7-yl, 6,7-dihydro-[1 ,4]dioxino[2,3-d]pyrimidin-2-yl, 3- oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazin-6-yl, 2-oxo-2,3-dihydro-1 H-pyrido[3,4- b][1 ,4]oxazin-7-yl, 2~oxo-2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]oxazin-7-yl, 6-oxo-6,7-dihydro- 5H-8-thia-1 ,2,5-triaza-naphthalen-3-yl, 3,4-dihydro-2H-benzo[1 ,4]oxazin-6-yl, 3- substituted-3H-benzooxazol-2-one-6-yl, 3-substituted-3H-benzooxazole-2-thione-6-yl, 3- substituted-3H-benzothiazol-2-one-6-yl, 2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]thiazin-7-yl, 3,4- dihydro-2H-benzo[1 ,4]thiazin-6-yl, 3,4-dihydro-1 H-quinolin-2-one-7-yl, 3,4-dihydro-1 H- quinoxalin-2-one-7-yl, 6,7-dihydro-4H-pyrazolo[1 ,5-a]pyrimidin-5-one-2-yl, 5,6,7,8- . tetrahydro-[1 ,8]naphthyridin-2-yl, 2-oxo-3,4-dihydro-1 H-[1 ,8]naphthyridin-6-yl, 3,4-dihydro- 2H-pyrido[3,2-b][1 ,4]thiazin-6-yl.
Unless otherwise defined, the term "alkyl" when used alone or when forming part of other groups (such as the 'alkoxy' group) includes substituted or unsubstituted, straight or branched chain alkyl groups containing the specified range of carbon atoms. For example, the term "(Ci-6)alkyl" include methyl, ethyl, propyl, butyl, iso-propyl, sec-butyl, tert-butyl, iso-pentyl, and the like.
The term "alkenyl" means a substituted or unsubstituted alkyl group of the specified range of carbon atoms, wherein one carbon-carbon single bond is replaced by a carbon-carbon double bond. For example, the term "(C2 6)alkenyl" include ethylene, 1 - propene, 2-propene, 1-butene, 2-butene, and isobutene, and the like. Both cis and trans isomers are included.
The term "cycloalkyl" refers to substituted or unsubstituted carbocyclic system of the specifed range of carbon atoms, which may contain up to two unsaturated carbon- carbon bonds. For example, the term "(C. Jcycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cycloheptyl.
The term "alkoxy" refers to an O-alkyl radical where the alkyl group contains the specified range of carbon atoms and is as defined herein.
The term "acyl" refers to a C(=O)alkyl or a C(=O)aryl radical. In some embodiments, the alkyl group contains 13 or less carbons; in some embodiments 10 or less carbon atoms; in some embodiments 6 or less carbon atoms; and is as otherwise defined. Aryl is as defined herein.
The term "alkylcarbonyl" refers to a (Ci.6)alkyl(C=O)(Ci.6)alkyl group wherein alkyl is as otherwise defined herein.
The term "alkylsulphonyl" refers to a SO≥alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.
The term "alkylthio" refers to a Salkyl wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.
The term "aminosulphonyl" refers to a SO2N radical wherein the nitrogen is substituted as specified. The term "aminocarbonyl" refers to a carboxamide radical wherein the nitrogen of the amide is substituted as defined.
The term "heterocyclylthio" refers to a S-heterocyclyl radical wherein the heterocyclyl moiety is as defined herein.
The term "heterocyclyloxy" refers to an O-heterocyclyl radical wherein heterocyclyl is as defined herein.
The term "arylthio" refers to an S-aryl radical wherein aryl is as defined herein. The term "aryloxy" refers to an O-aryl radical wherein aryl is as defined herein. The term "acylthio" refers to a S-acyl radical wherein acyl is as defined herein. The term "acyloxy" refers to an O-acyl radical wherein acyl is as defined herein. The term "alkoxycarbonyl" refers to a CO2alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.
The term "alkenyloxycarbonyl" refers to a CO2alkyl radical wherein the alkenyl group contains the specified range of carbon atoms and is as defined herein.
The term "alkylsulphonyloxy" refers to an O-SO2alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.
The term "arylsulphonyl" refers to a SO2aryl radical wherein aryl is as herein defined.
The term "arylsulphoxide" refers to a SOaryl radical wherein aryl is as defined herein. Unless otherwise defined, suitable substituents for any alkyl, alkoxy, alkenyl, and cycloalkyl groups includes up to three substituents selected from the group consisting of
hydroxy, halogen, nitro, cyano, carboxy, amino, amidino, sulphonamido, unsubstituted (C-| _3)alkoxy, trif luromethyl, and acyloxy.
Halo or halogen includes fluoro, chloro, bromo and iodo. The term "haloalkyl" refers to an alkyl radical containing the specified range of carbon atoms and is as otherwise defined herein, which is further substituted with 1 -3 halogen atoms.
The term "haloalkoxy" refers to an alkoxy radical of the specified range and as defined herein, which is further substituted with 1-3 halogen atoms.
The term "hydroxyalkyl" refers to an alkyl group as defined herein, further substituted with a hydroxy group.
Unless otherwise defined, the term "heterocyclic" or "heterocyclyl" as used herein includes optionally substituted aromatic and non-aromatic, single and fused, mono- or bicyclic rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or C-substituted by, for example, up to three groups selected from (C1 4)alkylthio; halo; (C1 4)haloalkoxy; (C1
4)haloalkyl; (C1 4)alkyl; (C2 4)alkenyl; hydroxy; hydroxy, (C1 Jalkyl; (C-|_4)thioalkyl; (C1 4)alkoxy; nitro; cyano, carboxy; (C1 4)alkylsulphonyl; (C24)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (C1 4)alkyl or (C2 4)alkenyl. Each heterocyclic ring suitably has from 3 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention.
Where an amino group forms part of a single or fused non-aromatic heterocyclic ring as defined above suitable optional substituents in such substituted amino groups include hydrogen; trifluoromethyl; (C1 4)alkyl optionally substituted by hydroxy, (C1
4)alkoxy, (C1 4)alkylthio, halo or trifluoromethyl; and (C24)alkenyl. The term "heterocyclylalkyl" refers to a (C1-6)alkyl radical which bears as a substituent a heterocyclyl group, wherein heterocyclyl and alkyl are as herein defined. The heterocyclyl group maybe joined to a primary, secondary or tertiary carbon of the (C1- 6)alkyl chain.
When used herein the term "aryl", includes optionally substituted phenyl and naphthyl.
Aryl groups may be optionally substituted with up to five, preferably up to three, groups selected from (C1 4)alkylthio; halo; (C1 4)haloalkoxy; (C1 4)haloalkyl; (C1 4)alkyi; (C2 4)alkenyl; hydroxy; (C^hydroxyalkyl; (C1 4)alkylthio; (C1 4)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally substituted by (C1 4)alkyl; (C1 4)alkylsulphonyl; (C2 4)alkenylsulphonyl.
The term "aralkyl" refers to a (Ci.6)alkyl radical which bears as a substituent an aryl group, wherein aryl and alkyl are as herein defined. The aryl group maybe joined to a primary, secondary or tertiary carbon of the (C^alkyl chain.
This invention also contemplates that some of its structural embodiments maybe present as a solvate. Solvates maybe produced from crystallization from a given solvent or mixture of solvents, inorganic or organic. Solvates may also be produced upon contact or exposure to solvent vapors, such as water. This invention includes within its scope stoichiometric and non-stoichiometric solvates including hydrates.
Furthermore, it will be understood that phrases such as "a compound of Formula I or a pharmaceutically acceptable salt, solvate or derivative thereof" are intended to encompass the compound of Formula I, a derivative of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), a solvate of formula (I), or any pharmaceutically acceptable combination of these. Thus by way of non-limiting example used here for illustrative purpose, "a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof" may include a pharmaceutically acceptable salt of a compound of formula (I) that is further present as a solvate.
Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably 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 preferably from 10 to 59% of a compound of the formula (I) or pharmaceutically acceptable derivative thereof.
Pharmaceutically acceptable salts of the above-mentioned compounds of formula (I) include the free base form or their 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. Compounds of formula (I) may also be prepared as the N-oxide. Compounds of formula (I) having a free carboxy group may also be prepared as an in vivo hydrolysable ester. The invention extends to all such derivatives. One of skill in the art will recognize that where compounds of the invention contain multiple basic sites, a compound of the invention maybe present as a salt complexed with more than one equivalent of a corresponding acid or mixture of acids.
Pharmaceutically acceptable derivatives refers to compounds of formula (I) that have been covalently modifed with a group that undergoes at least some in vivo cleavage to a compound of formula (I).
Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester- forming groups include those forming esters which break down readily in the human body to leave the parent acid or its salt.
Suitable groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v):
RC- N< Re
CH,- ORf
a b wherein R is hydrogen, (C1 6) alkyl, (C3 7) cycloalkyl, methyl, or phenyl, R is (C1 6) alkyl, (C1 6)alkoxy, phenyl, benzyl, (C37)cycloalkyl, (C37)cycloalkyloxy, (C1 6)alkyl(C3 7) cycloalkyl, 1 -amino^ 6)aikyl, or
a b
1 -(C1 6 alkyOaminotC, 6) alkyl; or R and R together form a 1 ,2-phenylene group optionally substituted by one or two methoxy groups; R° represents (C1 6)alkylene d e optionally substituted with a methyl or ethyl group and R and R independently represent f g
(C1-6) alkyl; R represents (C1-6) alkyl; R represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C1 6) alkyl, or (C1-6) alkoxy; Q is oxygen or NH; R is hydrogen or
(C1 6) alkyl; R is hydrogen, (C1 6) alkyl optionally substituted by halogen, (C2 6) alkenyl, (C1 6)alkoxycarbonyl, aryl or heteroaryl; or R and R together form (C1 6) alkylene; R represents hydrogen, (C1 6) alkyl or (C1 6)alkoxycarbonyl; k and R represents (C1 8)alkyl, (C1 8)alkoxy, (C1 ^aIkOXy(C1 6)alkoxy or aryl.
Examples of suitable in vivo hydrolysable ester groups include, for example, 8CyIoXy(C1 6)alkyl groups such as acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, and (i-aminoethyl)carbonyloxymethyl; (C1 6)alkoxycarbonyloxy(C1 6)alkyl groups, such as ethoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; Ui(C1- 6)alkylamino(C1 6)alkyl especially di(C1 4)alkylamino(C1 4)alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-(C1 6)alkoxycarbonyl)-2-(C2 6)alkenyl groups such as 2-(isobutoxycarbonyl)pent-2-enyl and
2-(ethoxycarbonyl)but-2-enyl; lactone groups such as phthalidyl and dimethoxyphthalidyl. A further suitable pharmaceutically acceptable in vivo hydrolysable ester-forming group is that of the formula:
wherein R is hydrogen, C1 6 alkyl or phenyl. R is preferably hydrogen.
Compounds of formula (I) may also be prepared as the corresponding N-oxides. Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such form, including pure isomeric forms. 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 stereospecific or asymmetric syntheses.
One of skill in the readily appreciates that optimization for a given reaction may require some routine variation in reaction parameters such as reaction time, temperature, energy source, pressure, light, pressure, solvent or solvents used, co-reagents, catalysts, and the like.
Protective groups wherever found herein maybe designated by their specific formula or alternatively, maybe referred to generically by P or Pn (wherein n is an integer). It is to be appreciated that where generic descriptors are used, that such descriptors are at each occurrence independent from each other. Thus, a compound with more than one of the same generic descriptors (e.g. P) does not indicate that each P is the same protective group, they maybe the same or different, so long as the group is suitable to the chemistry being employed. Where protection or deprotection is generically referred to, one of ordinary skill in the art will understand this to mean that suitable conditions are employed that will allow for the removal of the protecting group to be removed while minimizing reaction at other positions of the molecule, unless otherwise indicated. Many protective groups and protective group strategies are known to those of skill in the art in maybe found in numerous references including, Greene, et al. "Protective Groups in Organic Synthesis" (Published by Wiley-lnterscience), which is herein incorporated by reference in its entirety.
Leaving groups wherever found herein maybe designated by a specific chemical formula, or alternatively, maybe generically referred to as L or Ln (wherein n is an integer). It is to be appreciated that where a generic descriptor is used, that such descriptors are at each occurrence independent from each other. Leaving groups can be single atoms such as Cl, Br, or I, or maybe a group such as OSO2CH3, OC(=O)CH3, 0(C=O)CF3, OSO2CF3, and the like. . Leaving groups may be formed during the course of a reaction and thus a compound containing a leaving group may not always be an isolated material but rather as a reactive intermediate. By way of non-limiting example, a carboxylic acid maybe reacted with a coupling reagent such as DCC, CDI, EDCI, isobutyl chloroformate, etc, and the corresponding reative intermediate thus formed is further reacted with the nucleophilic coupling partner. In such cases, one of skill in the art appreciates that the activation step maybe performed before the introduction of the nucleophilic coupling partner, or in some cases, even in the presence of the nucleophilic coupling partner (depending upon the identity of the particular activating agent, carboxylic acid and nuclephilic coupling partner used). One skilled in the art readily ascertains that leaving groups generally refer to
atoms or groups which can be eliminated, substituted or otherwise dissociate during the course of the reaction.
The antibacterial 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.
The pharmaceutical 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 in mammals including humans.
The composition may be formulated for administration by any route. 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.
The 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. 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. Tablets and capsules for oral administration may be 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. Oral liquid preparations may be in the form of, for example, 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 />hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
For parenteral administration, 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. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 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. Such a dosage corresponds to 1.5 to 50 mg/kg per day.
Suitably the dosage is from 5 to 20 mg/kg per day. The compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibacterials. If the other antibacterial is a β-lactam then a β-lactamase inhibitor may also be employed.
Compounds of formula (I) are active against a wide range of organisms including both Gram-negative and Gram-positive organisms. The compounds of this invention may also be used in the manufacture of medicaments useful in treating bacterial infections in humans or other mammals.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference (whether specifically stated to be so or not) as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
It is to be understood that the present invention covers all combinations of particular and preferred groups described herein above.
The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form, for example, of product, composition, process, or use claims.
The following examples illustrate the preparation of certain compounds of formula (I) and the activity of certain compounds of formula (I) against various bacterial organisms. Although specific examples are described in the schemes, one of skill in the art appreciates that the methods are more generally applicable.
One of skill in the art readily appreciates that although the following schemes describe specific examples, they maybe more generally applied to produce additional embodiments of this invention. Furthermore, the examples set forth below are illustrative of the present invention and are not intended to limit, in any way, the scope of the present invention.
The compounds of the present invention were prepared by the methods illustrated in Schemes I and II.
Scheme I
1-1 I-2
I-3 I-4
I-5
I-6
Reagents and conditions: (a) isobutylene, Et2θ, H2SO4, -78°C to RT; (b) /V-hydroxy benzylamine-HCI, (CH2O)n, Et3N, toluene, EtOH, 85 0C; (c) Pd(OH)2, H2 (50 psi), MeOH; (d) Λ/-(benzyloxycarbonyloxy)-succinimide, DCM, RT; (e) TFA, DCM, RT; (f) NH4HCO3, (BoC)2O, pyridine, THF, RT; (g) Pd2(dba)3, rac-BINAP, 8-bromo-7-fluoro-2-(methyloxy)- 1 ,5-naphthyridine, dioxane, 10O0C, 36h; (h) Pd(OH)2, H2 (1 atm), MeOH, RT; (i) 3-oxo- 3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, CH2CI2, EtOH; then NaBH(OAc)3.
Carboxylic acid 1-1 was reacted with isobutylene and sulfuric acid to give ester I-2. The unsaturated ester I-2 was heated with a hydroxylamine and paraformaldehyde to give cycloaddition product 1-3. Hydrogenation of I-3 cleaved the N-O bond and concommitantly removed the benzyl functionality yielding amino alcohol I-4. Protection of the primary amine with a benzyl carbamate followed by hydrolysis of the ester with TFA provided acid I-6. The use of protecting groups to mask reactive functionality is well-known to those of skill in the art, and other protecting groups are listed in standard reference volumes, such as Greene, "Protective Groups in Organic Synthesis" (published by Wiley-lnterscience). Conversion of the carboxylic acid functionality to primary amide 1-7 was achieved with Boc anhydride and NH4HCO3. The amide was then coupled to the aryl bromide or triflate using standard Buchwald coupling conditions. Removal of the benzyl carbamate was accomplished using Pd/C and hydrogen gas in methanol. The free amine is converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH2CI2, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBHφ NaBH(0Ac)3 or NaB^CN in solvent to give the secondary amine 1-9. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used. Many additional methods for reductive aminations are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - Vl (published by Wiley-lnterscience).
Scheme Il
11-3 11-4
Reagents and conditions: (a) CH3OH, H2SO4, 6O0C; (b) Λ/-hydroxy benzylamine-HCI, (CH2O)n, Et3N, toluene, EtOH, 85 0C; (c) NH3, MeOH, 55°C, 72h; (d) Pd2(CHDa)3, rac- BINAP, 8-bromo-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine, dioxane, 1000C, 36h; (e) Pd(OH)2, H2 (50 psi), MeOH; (f) Λ/-(benzyloxycarbonyloxy)-succinimide, DCM, RT; (g) Pd(OH)2, H2 (1 atm), MeOH, RT; (h) 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6- carboxaldehyde, CH2CI2, EtOH; then NaBH(OAc)3, EtOH.
Carboxylic acid 1-1 was esterified with methanol and sulfuric acid to give ester 11-1. The unsaturated ester 11-1 was heated with a hydroxylamine and paraformaldehyde to give cycloaddition product H-2. Conversion of the ester functionality to primary amide II-3 was achieved with ammonia in methanol using a sealed system. The amide was then
coupled to an aryl bromide or triflate using standard Buchwald coupling conditions to give amide 11-4. Hydrogenation of 11-4 results in cleavage of the N-O bond and concommitant removal of the benzyl functionality. Protection of the primary amine with was achieved using a benzyl carbamate affording 1-8. The use of protecting groups to mask reactive functionality is well-known to those of skill in the art, and other protecting groups are listed in standard reference volumes, such as Greene, "Protective Groups in Organic Synthesis" (published by Wiley-lnterscience). Removal of the benzyl carbamate was accomplished using Pd/C and hydrogen gas in methanol. The free amine is converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH2CI2, EtOH or CH3CN. The imine is subsequently or simultaneously reacted with a suitable reducing agent such as NaBH^., NaBH(OAc)3 or NaBHβCN in solvent to give the secondary amine
1-9. Depending on whether acid neutralization is required, an added base, such as triethylamine (EtβN), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used. Many additional methods for reductive aminations are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - Vl (published by Wiley-lnterscience).
General
Proton nuclear magnetic resonance (1 H NMR) spectra were recorded at 300 MHz, and chemical shifts are reported in parts per million (δ) downfield from the internal standard tetramethylsilane (TMS). Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz. CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, and CD3OD is tetradeuteriomethanol. Mass spectra were obtained using electrospray (ES) ionization techniques. Elemental analyses were performed by Quantitative Technologies Inc., Whitehouse, NJ. Melting points were obtained on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius. E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Flash chromatography was carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Analytical HPLC was performed on Beckman chromatography systems. Preparative HPLC was performed using Gilson chromatography systems. ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan.
PRP- 1 ® is a polymeric (styrene-divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada. Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colorado.
Stereochemical designations in the Examples are relative only.
Preparation 1
Preparation of 4-Bromo-3-f luoro-6-methoxy-f 1 ,51naphthyridine
a) (2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester
A solution of 5-amino-2-methoxypyridine (Aldrich, 10Og, 0.806 mole) and diethyl ethoxymethylenemalonate (Aldrich, 163 ml_, 0.806 mole) in EtOH (1 L) was heated at reflux for 4 hours, then was cooled to RT. Concentration to dryness gave the title compound (238 g, quantitative).
b) 6-Methoxy-4-oxo-1 ,4-dihvdro-π ,51naphthyridine-3-carboxylic acid ethyl ester
b) _Dowthemn A (Fluka, 500 ml_) was brought to boiling (250 0C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distill over. The resulting solution was cooled to RT and diluted with hexanes (750 ml_). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72g, 73%).
c) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester
A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmole) in dry DMF (260 ml_) under argon was stirred efficiently*
in a water bath (to maintain approximately RT - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmole) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).
d) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid
2 N NaOH (300 mL, 600 mmole) was added dropwise over 30 min to a stirred solution of 4-bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (83.56 g, 268 mmole) in THF (835 mL). Stirring was continued overnight, at which time LC/MS showed that the saponification was complete. 2 N HCI was added to pH 6 and the THF was removed in vacuo. 2 N HCI was added to pH 2, then water (250 mL) was added, and the mixture was cooled thoroughly in ice. The solid was collected by suction filtration, washed with water and dried (first using a rotary evaporator at 50 0C and then under high vacuum at 50 0C overnight) to give the title compound (76.7 g, slightly over quantitative). This material was used without further purification.
e) 4-Bromo-6-methoxy-[1 ,5]naphthyridin-3-ylamine A suspension of 4-bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid (50 g,
177 mmole) in dry DMF (600 mL) was treated with triethylamine (222.5 mL, 1.60 mole), tert-butanol (265 mL, 2.77 mole), and diphenylphosphoryl azide (41.75 mL, 194 mmole). The reaction was stirred under argon at 100 0C for 1 hr, then was cooled to RT and concentrated to low volume. Ethyl acetate and excess aqueous sodium bicarbonate solution were added, the mixture was shaken, and some insoluble solid was filtered off. The layers were separated and the organic phase was washed with water (2x) and dried (MgSθ4). Concentration to dryness gave a crude mixture of 4-bromo-6-methoxy-
[1 ,5]naphthyridin-3-ylamine (minor product) and (4-bromo-6-methoxy-[1 ,5]naphthyridin-3- ylamine)carbamic acid tørt-butyl ester (major product) along with impurities.
Without further purification, this mixture was dissolved in CH2CI2 (150 mL) and treated with trifluoroacetic acid (100 mL). The reaction was stirred for 3 hr then was concentrated to dryness. The residue was partitioned between CHCI3 and saturated sodium bicarbonate solution and the layers were separated. The aqueous phase was
extracted with CHCI3, and the combined organics were dried (MgSθ4) and concentrated to low volume. The solid was collected by suction filtration, washed with a small volume of CHCI3 and dried under vacuum to afford a first crop of the title compound (31.14 g). The filtrate was purified by flash chromatography on silica gel (30% EtOAc/CHCl3) to afford further material (2.93 g, total = 34.07 g, 76%). Alternatively, the filtrate was left at RT overnight and then filtered to give a second crop of the title compound (2.5 g).
f) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-diazonium tetrafluoroborate
A solution of 4-bromo-6-methoxy-[1 ,5]naphthyridin-3-ylamine (25.2 g, 99.2 mmole) in dry THF (400 ml_) was maintained at -5 0C while nitrosonium tetrafluoroborate (12.9 g, 110 mmole) was added portionwise over 30 min (approximately 2 g portions). The reaction was continued for an additional 1 hr at -5 0C, at which time TLC* and LC/MS indicated that the reaction was complete. The orange solid was collected by suction filtration, washed with ice-cold THF and dried under vacuum to provide the title compound (31.42 g, 90%).
g) 4-Bromo-3-fluoro-6-methoxy-[1 ,5]naphthyridine
A suspension of 4-bromo-6-methoxy-[1 ,5]naphthyridine-3-diazonium tetrafluoroborate (31.42 g, 89.0 mmole) in decalin (mixed isomers, 500 ml_) in a 2 L flask* was heated to 180 0C and held at this temperature for 5 min. The mixture was cooled and diluted with CHCI3 (500 mL, to keep the product in solution), and the resulting mixture was stirred vigorously for 30 min to break up a black solid byproduct. The mixture was then poured onto a column of silica gel and the column was eluted with CHCI3 to remove decalin and then with 3% EtOAc/CHCl3 to afford the title compound (9.16 g, 40%).
Preparation 2
a) 4-Hydroxy-6-methoxy-[1 ,5]-naphthyridine
5-Amino-2-methoxypyridine (55g, 0.44mol) in methanol (1000ml) with methyl propiolate (40ml, 0.44mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6g, 48%).
The unsaturated ester (10.5g, O.Oδmol) in warm Dowtherm A (50ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give the title compound (6.26g, 70%).
b) 6-(methyloxy)-1 ,5-naphthyridin-4-yl trifluoromethanesulfonate
4-Hydroxy-6-methoxy-[1 ,5]-naphthyridine (10g, 0.057mol) in dichloromethane (200ml) containing 2,6-lutidine (9.94ml, 0.086mol) and 4-dimethylaminopyridine (0.07g,
0.0057mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5ml,
0.063mol). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica (dichloromethane).
Preparation 3
Preparation of 3-Oxo-3.4-dihydro-2H-pyrido[3,2-biπ ,41oxazine-6-carboxaldehyde
a) 2-Bromo-5-hydroxy-6-nitropyridine
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml_) and a solution of 25% sodium methoxide in methanol (33 ml_, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C, and bromine (7.2 ml_, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 ml_). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification.
MS (ES) m/z219.0 (M + H)+.
b) Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate
2-Bromo-5-hydroxy-6-nitropyridine (30 g, 0.14 mole) was suspended in acetone (200 ml), and potassium carbonate (39 g, 0.28 mole) was added, followed by ethyl bromoacetate (15.7 ml, 0.14 mmole). The reaction was heated at reflux for 10 hr, then was cooled to room temperature and diluted with Et2θ. The precipitate was removed by suction filtration, and the filtrate was concentrated in vacuo to afford material (38 g, 89%), which was used without further purification; MS (ES) m/z 305.0 (M + H)+.
c) 6-Bromo-4H-pyrido[3,2-b][1 ,4]oxazin-3-one
Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 0C for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g,
52%); MS (ES) m/z 229.0 (M + H)+.
d) 6-((£)-Styryl)-4H-pyrido[3,2-b][1 ,4]oxazin-3-one 6-Bromo-4H-pyrido[3,2-b][1 ,4]oxazin-3-one (6.0 g, 26.3 mmole) and frans-2- phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in 1 ,4-dioxane (150 mL) and the solution was degassed with argon. (Ph3P)4Pd (230 mg, 0.2 mmole) was added, followed by a solution of potassium carbonate (6.9 g, 50 mmole) in H2O (20 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with EtOAc (200 mL). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The solid residue was purified by flash chromatography on silica gel (5-10% EtOAc/CHCl3) to afford a solid (2.5 g, 38%).
MS (ES) m/z 253.0 (M + H)+.
e) 3-Oxo-3,4-dihydro-2/-/-pyrido[3,2-ιb][1 ,4]oxazine-6-carboxaldehyde
6-((£)-Styryl)-4H-pyrido[3,2-b][1 ,4]oxazin-3-one (1.2 g, 4.8 mmole) was dissolved in CH2CI2 (200 mL) and the solution was cooled to -78 0C. Ozone was bubbled through the solution with stirring until a pale blue color appeared, then the excess ozone was
removed by bubbling oxygen through the solution for 15 min. Dimethylsulfide (1.76 mL, 24 mmole) was added to the solution, and the reaction was stirred at -78 0C for 3 hr, then at room temperature overnight. The solvent was removed in vacuo, and the residue was triturated with Et2θ (50 mL). The collected solid was washed with additional Et2θ and dried to afford a solid (700 mg, 82%). MS (ES) m/z 179.0 (M + H)+.
Preparation 4
Preparation of 2,3-Dihydro-π .41dioxinor2,3-clpyridine-7-carboxaldehyde
a) 5-Benzyloxy-2-hydroxymethyl-1 H-pyridin-4-one
A mixture of 5-benzyloxy-2-hydroxymethyl-4-pyrone (prepared from Kojic acid by the method of D. Erol, J. Med. Chem., 1994, 29, 893) (9.7 g, 40 mmol), concentrated aqueous (880) ammonia (100 mL), and ethanol (20 mL) was heated to reflux overnight. The mixture was allowed to cool to room temperature then filtered. The resultant solid was washed with ether and dried in vacuo (5.9 g); MS (APCI+) m/z 232 (MH+).
b) (2,3-Dihydro-[1 ,4jdioxino[2,3-c]pyridin-7-yl)-methanol
A solution of 5-Benzyloxy-2-hydroxymethyl-1 H-pyridin-4-one (2 g, 8.7 mmol) in water (220 mL) containing sodium hydroxide (17 mmol) was hydrogenated over 10% palladium on charcoal (1 g) for 4 hours. The mixture was filtered and evaporated to give a white solid. This solid was dissolved in N,N-dimethylformamide (8 mL) then treated with potassium carbonate (2.9 g) and 1 ,2-dibromoethane (0.6 mL, 7 mmol). The mixture was heated at 850C overnight. The cooled mixture was evaporated onto silica and chromatographed eluting with 10-30% methanol in ethyl acetate affording a white solid (250 mg, 21 %); MS (APCI+) m/z 168 (MH+).
c) 2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridine-7-carboxaldehyde
A solution of (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61 %); MS (APCI+) m/z 166 (MH+).
Preparation 5
Preparation of 3-Oxo-3.4-dihvdro-2/-/-pyridor3,2-/7l[1 ,41thiazine-6-carboxaldehyde
a) Methyl 3-oxo-3,4-dihydro-2W-pyrido[3,2-#][1 ,4]thiazine-6-carboxylate
A solution of ethyl 2-mercaptoacetate (1.473 mL) in DMF (48 mL) was ice-cooled and treated with sodium hydride (540 mg of a 60% dispersion in oil). After 1 hour methyl 6-amino-5-bromopyridine-2-carboxylate (3 g) (T.R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was added and the mixture stirred for 16 hours at room temperature. The solution was diluted with EtOAc (1 litre), washed with water (3 x 300 mL), dried and evaporated to about 10 mL. The white solid was filtered off and washed with a little EtOAc to give the ester (0.95g); MS (APCI") m/z 223 ([M-H]", 100%).
b) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]thiazine-6-carboxylic acid
A solution of Methyl 3-oxo-3,4-dihydro-2W-pyrido[3,2-/?][1 ,4]thiazine-6-carboxylate (788 mg) in dioxan (120 ml)/water (30 mL) was treated dropwise over 2 hours with 0.5M NaOH solution (8 mL) and stirred overnight. After evaporation to approx. 3 ml, water (5 mL) was added and 2M HCI to pH4. The precipitated solid was filtered off, washed with a small volume of water and dried under vacuum to give a solid (636 mg); MS (APCI") m/z 209 ([M-H]", 5%), 165([M-COOH]-, 100%).
c) 6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-ib][1 ,4]thiazine
A solution of 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]thiazine-6-carboxylic acid (500mg) in THF (24 mL) with triethylamine (0.396 mL) was cooled to -1O0C and isobutyl chloroformate (0.339ml) added. After 20 minutes the suspension was filtered through kieselguhr into an ice-cooled solution of sodium borohydride (272 mg) in water (8 mL), the mixture stirred 30 minutes and the pH reduced to 7 with dilute HCI. The solvent was evaporated and the residue triturated under water. The product was filtered and dried under vacuum to give a white solid (346mg); MS (APCI") m/z 195 ([M-H]-, 50%), 165(100%).
d) 3-Oxo-3,4-dihydro-2/-/-pyrido[3,2-jb][1 ,4]thiazine-6-carboxaldehyde
A solution of 6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-/?][1 ,4]thiazine (330 mg) in dichloromethane (30 mL)/THF (30 mL) was treated with manganese dioxide (730 mg) and stirred at room temperature. Further manganese dioxide was added after 1 hour (730 mg) and 16 hours (300 mg). After a total of 20 hours the mixture was filtered through kieselguhr and the filtrate evaporated. The product was triturated with EtOAc/hexane (1 :1) and collected to give a solid (180mg); MS (APCI") m/z 195 ([M-H]", 95%), 165 (100%).
Preparation 6
Preparation of (±)-phenylmethyl {[(1 f?,2f?,45)-4-(aminocarbonvO-2- hydroxycvclopentylimethvDcarbamate
a) (±)-1 ,1-dimethylethyl (3aH,5S,6a/:?)-2-(phenylmethyl)hexahydro-2H- cyclopenta[d|isoxazole-5-carboxylate
To a solution of 1 ,1-dimethylethyl 3-cyclopentene-i-carboxylate (8.4 g, 50.0 mmole) [JACS, 1983, 105, 2435-2439] in toluene (150 mL) and EtOH (75 mL) was added paraformaldehyde (11.0 g, 250 mmole), Λ/-hydroxybenzylamine hydrochloride (11.8 g, 75 mmole) and triethylamine (10.4 mL, 75 mmole). After 24 hours at 800C, the reaction solution was concentrated under vacuum and redissolved in hexanes/EtOAc, 4:1 (200 mL) and filtered. The organic solution was concentrated and then purified on silica (hexanes/EtOAc, 4:1) to give the title compound (13.0 g, 86%) as a light yellow oil: LC-MS
(ES) m/e 304 (M+H)+.
b) (±)-1 ,1 -dimethylethyl (1 S,3/:?,4/:?)-3-(aminomethyl)-4-hydroxycyclopentanecarboxylate
To a solution of (±)- 1 ,1 -dimethylethyl (3a/?,5S,6a/:?)-2-(phenylmethyl)hexahydro- 2H-cyclopenta[c/|isoxazole-5-carboxylate (13.0 g, 42.9 mmole) in EtOH (100 mL) in a Parr flask was added Pd(OH)2 (~ 400 mg). The reaction contents were shaken under 50 psi of
H2 overnight at RT. The reaction contents were filtered through Celite® (MeOH) and concentrated to give the title compound (7.87, 99%) as a white solid: LC-MS (ES) m/e 216 (M+H)+.
c) (±)-1 ,1 -dimethylethyl (1 S,3fi,4fl)-3-hydroxy-4-
[({[(phenylmethyl)oxy]carbonyl}amino)methyl]cyclopentanecarboxylate
To a solution of (±)-1 ,1 -dimethylethyl (1 S,3R,AR)-3-{am\uome\hy\)-4- hydroxycyclopentanecarboxylate (7.9 g, 37.0 mmole) in DCM (100 mL) at RT was added Et3N (6.7 mL, 48.4 mmole) and Λ/-(benzyloxycarbonyloxy)succinimide (12.1 g, 48.4 mmole). After 18 h, the DCM was removed under vacuum and the residue purified on
silica (1 :1 , hexanes/EtOAc) to give the title compound (11.6 g, 89%) as a white solid: LC- MS (ES) m/e 350 (M+H)+.
d) (±)-phenylmethyl {[(1 fi,2fi,4S)-4-(aminocarbonyl)-2- hydroxycyclopentyljmethyljcarbamate
To a solution of (±)-1 ,1-dimethylethyl (1 S.Sfi^/^-S-hydroxy^- [({[(phenylmethyl)oxy]carbonyl}amino)methyl]cyclopentanecarboxylate (11.4 g, 32.7 mmole) in DCM (75 ml_) was added HCI (50 mL, 4M in dioxane). After stirring 6 h at RT, the reaction solution was concentrated under vacuum to give a white solid: LC-MS (ES) m/e 294 (M+H)+.
To the solid in THF (100 mL) at RT was added pyridine (2.1 mL, 25.6 mmole) and NH4HCO3 (6.8 g, 85.3 mmole). Di-fert-butyl dicarbonate (4.84 g, 22.2 mmole) was then added to the solution with continued stirring for 5 hours. The reaction solution was filtered and concentrated under vacuum. The residue was purified on silica [MeOH (w/ 5% NH4OH)/CHCl3, 1 :9] to afford the title compound (3.0 g, 60%) as a white solid: LC-MS
(ES) m/e 293 (M+H)+.
Preparation 7
Preparation of (±)-(1 S,3R4fl)-3-(aminomethylVN-[3-fluoro-6-(methyloxyV1 ,5-naphthyridin- 4-yl1-4-hvdroxycvclopentanecarboxamide
To a solution of methyl-S-cyclopentene-i-carboxylate (6.1 g, 48.4 mmole) in toluene (150 imL) and EtOH (75 ml_) was added paraformaldehyde (10.6 g, 242 mmole), Λ/-hydroxybenzylamine hydrochloride (11.4 g, 72.6 mmole) and triethylamine (10.1 ml_, 72.6 mmole). After 24 hours at 800C, the reaction solution was concentrated under vacuum and redissolved in hexanes/EtOAc, 4:1 (200 mL) and filtered. The organic solution was concentrated and then purified on silica (hexanes/EtOAc, 4:1) to give the title compound (10.7 g, 85%) as a light yellow oil containing mixture of diastereoisomers in the ratio of 6 (trans) to 1 (cis): LC-MS (ES) m/e 262 (M+H)+.
The title compound was separated into pure diastereomers via reverse phase HPLC (see below).
b) (±)-(3aH,5S,6a/?)-2-(phenylmethyl)hexahydro-2/-/-cyclopenta[d]isoxazole-5- carboxamide
To a solution of (±)-trans-methyl (3a/r?,5S,6af?)-2-(phenylmethyl)hexahydro-2/-/- cyclopenta[αflisoxazole-5-carboxylate (10.0 g, 38.2 mmole) in MeOH (10 mL) in a pressure tube was added NH3 (50 mL, 7M in CH3OH). The contents were heated to 55°C for 72h and then concentrated under vacuum. The residue was purified on silica (CHCl3/MeOH,
9:1) to afford the title compound (8.77 g, 93%) as a light orange solid: LC-MS (ES) m/e 247 (M+H)+.
c) (±)-trans-(3aR,5S,6af?)-/V-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]-2- (phenylmethyl)hexahydro-2H-cyclopenta[d]isoxazole-5-carboxamide
To a solution of (±)-(3a/:?,5S,6aR)-2-(phenylmethyl)hexahydro-2H- cyclopenta[d]isoxazole-5-carboxamide (5.0 g, 20.33 mmole) in dioxane (75 ml_) was added rac-BINAP (0.76 g, 1.22 mmole), cesium carbonate (8.28 g, 25.41 mmole), 4- bromo-3-fluoro-6-methoxy-[1 ,5]naphthyridine (5.20 g, 20.33 mmole) and Pd2(dba)3 (0.42 g, 0.41 mmole). After heating to 95°C for 48h under N2, the reaction contents were concentrated in vacuo and purified on silica (CHCl3/MeOH/NH4θH, 90:9:1 ) to give the title compound (4.2 g, 49%) as a tan solid: LC-MS (ES) m/e 423 (M+H)+.
d) (±)-trans-phenylmethyl {[(1 R,2/:?,4S)-4-({[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]amino}carbonyl)-2-hydroxycyclopentyl]methyl}carbamate
To a solution of (±)-(3aF?,5S,6a/:?)-Λ/-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]- 2-(phenylmethyl)hexahydro-2H-cyclopenta[c/jisoxazole-5-carboxamide (3.7 g, 8.77 mmole) in MeOH (100 mL) in a Parr flask was added Pd(OH)2 (~ 400 mg). The reaction contents were shaken under 50 psi of H2 for 72h at RT. The reaction contents were filtered through Celite® (MeOH) and concentrated to give the title compound (2.75, 94%) as a white solid: LC-MS (ES) m/e 335 (M+H)+.
To the amine (2.5 g, 7.48 mmole) dissolved in DCM/DMF (100mL/25mL) was added N-(benzyloxycarbonyloxy)succinimide (2.42 g, 9.73 mmole) and triethylamine (1.36 mL, 9.73 mmole). After stirring for 24 h at RT, the reaction solution was concentrated and purified on silica (CHCIs/MeOH/Nh^OH, 90:9:1) to give the title compound (2.5 g, 71%) as an off-white solid: LC-MS (ES) m/e 423 (M+H)+.
e) (±)-trans-(1 S,3fi,4fl)-3-(aminomethyl)~Λ/-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]- 4-hydroxycyclopentanecarboxamide
To a solution of (±)-phenylmethyl {[(1 R,2R,4S)-4-({[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]amino}carbonyl)-2-hydroxycyclopentyl]methyl}carbamate (2.2 g, 4.70 mmole) in MeOH (100 mL) was added Pd(OH)2 (~ 400 mg). The reaction contents were stirred under a balloon of H2 overnight at RT. The reaction contents were filtered through
Celite® (MeOH) and concentrated to give the title compound (1.3 g, 83%) as an off- white solid: LC-MS (ES) m/e 335 (M+H)+.
Preparation 8
Preparation of (±)-trans-(15,3ff,4/?)-3-(aminomethyl)-4-hvdroxy-Λ/-[6-(methyloxy)-1 ,5- naphthyridin^-ylicvclopentanecarboxamide
Prepared according to the procedure of Preparation 7, except substituting 6- (methyloxy)-i ,5-naphthyridin-4-yl trif luoromethanesulfonate for 4-bromo-3-fluoro-6-
methoxy-[1 ,5]naphthyridine, to give the title compound as an off- white solid: LC-MS (ES) m/e 318 (M+H)+.
Example 1
Preparation of (+)- (1 S,3f?,4ffl-/V-r3-fluoro-6-(methyloxyV1 ,5-naphthyridin-4-yll-3-hvdroxy-
4-((r(3-oxo-3.4-dihvdro-2H-pyridor3.2-ibiri .41thiazin-6- yl)methvπamino)methyl)cyclopentanecarboxamide
To a stirred solution of (+)- (1 S,3F?,4ft)-3-(aminomethyl)-Λ/-[3-fluoro-6-(methyloxy)- 1.δ-naphthyridin^-ylH-hydroxycyclopentanecarboxamide (0.43 g, 1.29 mmole) in dry CH2CI2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H- pyrido[1 ,4]thiazine-6-carboxaldehyde (0.25 g, 1.29 mmole). After 24h, at RT was added NaBH(OAc)3 (0-41 9> 1 -93 rnmole). After 4h, the reaction solution was concentrated under vacuum to a solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.12 g, 18%) as light yellow solid: 1 H NMR (400 MHz, OQ- dioxane) δ 8.75 (s, 1 H), 8.27 (d, J = 9.0 Hz, 1 H), 7.64 (d, J = 7.8 Hz1 1 H), 7.15 (d, J = 9.0 Hz, 1 H), 7.02 (d, J = 7.8 Hz, 1 H), 4.35 (m, 1 H), 4.10 (s, 3H), 3.78 (s, 2H), 3.49 (s, 2H), 3.36 (m, 1 H), 2.81 (m, 1 H), 2.73 (m, 1 H), 2.20 (m, 3H), 2.04 (m, 1 H), 1.87 (m, 1 H). LC-MS
(ES) m/e 513 (M + H)+.
Example 2
Preparation of (±V (1 S,3f?,4ffl-Λ/-r3-fluoro-6-(methyloxy)-1.5-naphthyridin-4-vπ-3-hvdroxy- 4-(JF(3-oxo-3.4-dihvdro-2H-pyridof3.2-fo1f1.41oxazin-6- vDmethvπaminolmethvDcvclopentanecarboxamide
According to the procedure of Example 1 except substituting 3-oxo-3,4-dihydro- 2H-pyrido[1 ,4]oxazine-6-carboxaldehyde (0.23 g, 1.29 mmole) for 3-oxo-3,4-dihydro-2H- pyrido[1 ,4]thiazine-6-carboxaldehyde, the title compound (90 mg, 14%) was prepared as an off-white solid: 1 H NMR (400 MHz, CD3OD) δ 8.90 (s, 1 H), 8.30 (d, J = 9.1 Hz, 1 H),
7.40 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.1 1 (d, J = 7.9 Hz, 1H), 4.71 (s, 2H), 4.48 (m, 1 H)1 4.29 (s, 2H), 4.16 (s, 3H), 3.60 (m, 1 H), 3.47 (m, 1 H), 3.21 (m, 1 H), 2.50 (m,
1 H), 2.27 (m, 3H), 2.03 (m, 1 H). LC-MS (ES) m/e 497 (M + H)+.
Example 3
Preparation of (±)- (1 S.3R4ffl-3-(r(2,3-dihvdrof1 ,41dioxinof2.3-c1pyridin-7- ylmethvπamino1methyl)-Λ/-f3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vn-4- hydroxycvclopentanecarboxamide
According to the procedure of Example 1 except substituting 2,3- dihydro[1 ,4]dioxino[2,3-φyridine-7-carbaldehyde (0.21 g, 1.29 mmole) for 3-oxo-3,4- dihydro-2H-pyrido[1 ,4]thiazine-6-carboxa(dehyde, the title compound (170 mg, 27%) was prepared as an off-white solid: 1 H NMR (400 MHz, CDCI3) δ 8.70 (m, 1 H), 8.21 (d, J = 9.0
Hz, 1 H), 8.12 (s, 1 H), 7.12 (d, J= 9.0 Hz, 1 H), 6.75 (s, 1 H), 4.59 (m, 1 H), 4.38 (m, 2H), 4.34 (m, 2H), 4.12 (s, 3H), 3.89 (m, 1 H), 3.77 (m, 1 H), 3.44 (m, 1 H), 2.90 (m, 2H), 2.35
(m, 1 H), 2.28 (m, 3H), 1.91 (m, 1 H). LC-MS (ES) m/e 484 (M + H)+.
Example 4
Preparation of (+)- (1 S,3ff.4ffl-3-hvdroxy-/V-r6-(methyloxy)-1 ,5-naphthyridin-4-yll-4-((r(3- oxo-3.4-dihvdro-2H-pyridor3.2-/3in .41thiazin-6- vOmethyllaminoImethyDcvclopentanecarboxamide
To a stirred solution of (±)- (1 S,3fl,4/:?)-3-(aminomethyl)-4-hydroxy-Λ/-[6- (methyloxy)-1 ,5-naphthyridin-4-yl]cyclopentanecarboxamide (0.48 g, 1.51 mmole) in dry CH2CI2 (50 ml_) and dry EtOH (20 ml_) at RT was added 3-oxo-3,4-dihydro-2H- pyrido[1 ,4]thiazine-6-carboxaldehyde (0.29 g, 1.51 mmole). After 24h, at RT was added NaBH4 (0.063 g, 1.66 mmole). After 4h, the reaction solution was concentrated under vacuum to a solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.13 g, 17%) as light yellow solid: 1 H NMR (400 MHz, CDCI3) δ 9.44 (s, 1 H), 8.68 (d, J= 5.1 Hz, 1 H), 8.49 (d, J= 5.1 Hz, 1 H), 8.22 (d, J= 9.0 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.16 (d, J = 9.0 Hz, 1 H), 6.96 (d, J = 7.8 Hz, 1 H), 4.12 (s, 3H), 3.92 (m, 3H), 3.49 (s, 2H), 3.38 (m, 1 H), 2.95 (m, 2H), 2.39 (m, 1 H), 2.50 (m, 4H), 1.91
(m, 1 H). LC-MS (ES) m/e 495 (M + H)+.
Example 5
Preparation of (±)- (15.3fl.4ffl-3-hvdroxy-Λ/-r6-(methyloxy)-1 ,5-naphthyridin-4-yll-4-((r(3- oxo-3.4-dihvdro-2/-/-pyridor3.2-biπ .41oxazin-6- vDmethvHaminolmethvDcyclopentanecarboxamide
According to the procedure of Example 4 except substituting 3-oxo-3,4-dihydro- 2/-/-pyrido[1 ,4]oxazine-6-carboxaldehyde (0.27 g, 1.51 mmole) for 3-oxo-3,4-dihydro-2H- pyrido[1 ,4]thiazine-6-carboxaldehyde, the title compound (110 mg, 15%) was prepared as an off-white solid: 1 H NMR (400 MHz, CDCI3) δ 9.44 (s, 1 H), 8.71 (d, J = 5.1 Hz, 1 H),
8.53 (d, J= 5.1 Hz, 1 H), 8.22 (d, J= 9.0 Hz, 1 H), 7.32 (d, J= 7.8 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1 H), 6.95 (d, J = 7.8 Hz, 1 H), 4.65 (s, 3H), 4.13 (s, 2H), 3.86 (m, 1 H), 3.70 (s, 2H),
2.92 (m, 2H), 2.61 (m, 1H), 2.32 (m, 4H), 2.05 (m, 1 H). LC-MS (ES) m/e 479 (M + H)+.
Example 6
Preparation of (±M1 S,3RΛR)-3-{\(2.3-ό\hydro\1 ,41dioxinor2.3-clPyridin-7- ylmethyl)aminolmethyl|-4-hvdroxy-Λ/-r6-(methyloxy)-1 ,5-naphthyridin-4- yl]cyclopentanecarboxamide
According to the procedure of Example 4 except substituting 2,3- dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.25 g, 1.51 mmole) for 3-oxo-3,4- dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, the title compound (57 mg, 8%) was prepared as an off-white solid: 1 H NMR (400 MHz, CDCI3) δ 9.43 (m, 1H), 8.68 (d, J= 5.1
Hz, 1 H), 8.50 (d, J = 5.1 Hz, 1 H), 8.20 (d, J = 9.0 Hz, 1 H), 8.11 (s, 1 H), 7.16 (d, J= 9.1 Hz, 1 H), 6.61 (s, 1 H), 4.61 (m, 1H), 4.38 (m, 2H), 4.31 (m, 2H), 4.12 (s, 3H), 3.89 (m, 2H),
3.38 (m, 1 H), 2.92 (m, 2H), 2.36 (m, 1 H), 2.24 (m, 3H), 1.92 (m, 1 H). LC-MS (ES) m/e 466 (M + H)+.
Example 7
Antimicrobial Activity Assay:
Whole-cell antimicrobial activity was determined by broth microdilution using the
National Committee for Clinical Laboratory Standards (NCCLS) recommended procedure,
Document M7-A6, "Methods for Dilution Susceptibility Tests for Bacteria that Grow
Aerobically". The compounds were tested in serial two-fold dilutions ranging from 0.016 to 16 mcg/mL.
Compounds were evaluated against a panel of Gram-positive organisms, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Enterococcus faecalis.
In addition, compounds were evaluated against a panel of Gram-negative strains including Haemophilus influenzae, Moraxella catarrhalis and Escherichia coli.
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.
One skilled in the art would consider any compound with a MIC of less than 20 mg/mL to be a potential lead compound. For instance, each of the listed Examples (1 to 6), as identified in the present application, had a MIC <20 mg/ml against at least one of the organisms listed above.
Claims
1. A compound of formula (I)
(I) wherein:
13
Z1, Z3, and Z4 are independently N or CR ;
Z2, Z5, and Z6 are each CR1a;
R1 and R1a are independently at each occurrence hydrogen; cyano; halogen; hydroxy; (C-| _g)alkoxy unsubstituted or substituted by (C-| .β)alkoxy, hydroxy, amino, piperidyl, guanidino or amidino any of which is unsubstitued or N-substituted by one or two (Ci_Q)alkyl, acyl, (C-|_6)alkylsulphonyl, CONH2, hydroxy, (C-|.g)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C-| _6)alkylsulphonyloxy; (C-j_ρ)alkyl; (Ci _6)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio; (C-] . g)alkylsulphonyl; (C-] _g)alkylsulphoxide; arylsulphonyl; arylsulphoxide; or an amino, piperidyl, guanidino or amidino group unsubstituted or N-substituted by one or two (C-μ 6)alkyl, acyl or (C-|_6)alkylsulphonyl groups; or R1 and R1a of Z2 together form ethylenedioxy;
W1, W2, and W3 are each CR3R4;
B is CR6R7or C=O; Re, R4, R6, and R7 are independently at each occurrence hydrogen; thiol; (C1. 6)alkylthio; halogen; trifluoromethyl; azido; (C1-6)alkyl; (C2-6)alkenyl; (C^alkoxycarbonyl; (C1-6)alkylcarbonyl; (C2.6)alkenylcarbonyl; (C2.6)alkenyloxycarbonyl; aralkyl; aryl; heterocyclyl; heterocyclylalkyl; hydroxy; NR1bR1b'; (C1.6)alkylsulphonyl; (C2. 6)alkenylsulphonyl; or (C1-6)aminosulphonyl wherein the amino group is optionally and independently substituted by hydrogen, (Ci-6)alkyl, (C2.6)alkenyl or aralkyl;
R5 is hydrogen; halogen; hydroxyl; or (C1-6 )alkyl;
R2 and R8 are independently hydrogen, trifluoromethyl; (C1-6)alkyl; (C2-6)alkenyl; (C1.6)alkylcarbonyl; (C2.6)alkenyloxycarbonyl; aryl; aralkyl; (C3- 8)cycloalkyl; heterocyclyl; or heterocyclylalkyl;
R1b and R1b' are independently at each occurrence hydrogen; (d.6)alkyl; aralkyl; aryl; heterocyclyl; heterocyclylalkyl; or together with the nitrogen that they are attached torn an aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring (wherein said aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring are optionally substiuted with from 1 to 3 substituents selected from halogen, hydroxy; cyano; nitro; (C1- 6)alkyl; and aryl);
R9 is UR10;
U is CH2; C(=O); or SO2;
R10 is a substituted or unsubstituted bicyclic carbocyclic or heterocyclic ring system (A):
containing up to four heteroatoms in each ring in which at least one of rings (a) and (b) is aromatic;
X is C or N when part of an aromatic ring or CR11 when part of a non aromatic ring; 2
X is N, NR12, O, S(O)n , CO or CRn when part of an aromatic or non-aromatic ring or may in addition be CR13R14 when part of a non aromatic ring; n is independently at each occurrence 0, 1 or 2;
3 5 X and X are independently N or C;
Y is a 0 to 4 atom linker group each atom of which is independently selected from N, NR12, O, S(O)n , CO and CR11 when part of an aromatic or non-aromatic ring or may additionally be CR13R14 when part of a non aromatic ring,
Y is a 2 to 6 atom linker group, each atom of Y being independently selected from N, NR12, O, S(O)n , CO and CR11 when part of an aromatic or non-aromatic ring or may additionally be CR13R14 when part of a non aromatic ring;
R11, R13 and R14 are at each occurrence independently selected from: H; (C-μ
4)alkylthio; halo; (C-j_4)alkyl; (C2_4)alkenyl; hydroxy; hydroxy(C-]_4)alkyl; mercapto(Ci_ 4)alkyl; (C-j _4)alkoxy; trif luoromethoxy; nitro; cyano; carboxy; amino or aminocarbonyl unsubstituted or substituted by (C-] _4)alkyl;
R12 is at each occurrence independently hydrogen; trifluoromethyl; (C-|_4)alkyl unsubstituted or substituted by hydroxy, carboxy, (C-| _4)alkoxy, (Ci _g)alkylthio, halo or trifluoromethyl; (C2-4)alkenyl; or aminocarbonyl wherein the amino group is optionally substituted with (C^ _4)alkyl;
or a pharmaceutically acceptable salt or solvate thereof.
2. A compound according to claim 1 , wherein Z1 and Z4 are N; and
Z3 is CR1a.
3. A compound according to claim 1 , wherein: R1 is OCK.
1a
4. A compound according to claim 1 , wherein R is at each occurrence independently hydrogen; halogen; or cyano.
5. A compound according to claim 1 , wherein: R2 is hydrogen.
6. A compound according to claim 1 , wherein:
R3 and R4 are each independently selected from hydrogen, hydroxyl, halogen, and (C1-6)alkyl.
7. A compound according to claim 1 , wherein: R5 is hydrogen.
8. A compound according to claim 1 , wherein: B is CH2.
9. A compound according to claim 1 , wherein: U is CH2.
10. A compound according to claim 1 , wherein Ri0 is: 4H-Pyrido[3,2-b][1 ,4]thiazin-3-oxo-6-yl; 4/-/-Pyrido[3,2-b][1 ,4]oxazin-3-oxo-6-yl; or 2,3-Dihydro-[1 ,4]dioxino[2,3-c]-pyridin-6-yl.
11. A compound according to claim 2, wherein: R1 is OCH3;
1a
R is at each occurrence independently hydrogen; halogen; or cyano; R2 is hydrogen; and
R3 and R4 are each independently selected from hydrogen, hydroxyl, halogen, and (C^alkyl.
12. A compound according to claim 11 , wherein: R5 is hydrogen;
B is CH2; and U is CH2.
13. A compound according to claim 12, wherein:
R a of Z2, Z3, and Z5 is hydrogen; R1a of Z6 is fluorine; R3 and R4 of W1 and W2 are hydrogen;
R3 of W3 is hydrogen and R4 of W3 is hydroxy; and
R2 and R8 are independently hydrogen or (Ci.6)alkyl.
14. A compound according to claim 13, wherein Ri0 is: 4H-Pyrido[3,2-b][1 ,4]thiazin-3-oxo-6-yl; 4/-/-Pyrido[3,2-b][1 ,4]oxazin-3-oxo-6-yl; or 2,3-Dihydro-[1 ,4]dioxino[2,3-c]-pyridin-6-yl.
15. A compound according to claim 1 , wherein the compound is:
a) (3R,4R)-Λ/-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]-3-hydroxy-4-({[(3- oxo-3,4-dihydro-2/-/-pyrido[3,2-fa][1 ,4]thiazin-6- yl)methyl]amino}methyl)cyclopentanecarboxamide;
b) (3f?J4f?)-Λ/-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]-3-hydroxy-4-({[(3- oxo-3,4-dihydro-2H-pyrido[3,2-£>][1 ,4]oxazin-6- yl)methyl]amino}methyl)cyclopentanecarboxamide;
c) (3R,4/:f)-3-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}- Λ/-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]-4-hydroxycyclopentanecarboxamide;
d) (1 S,3fi,4fi)-3-hydroxy-Λ/-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]-4-({[(3-oxo- 3,4-dihydro-2/-/-pyrido[3,2-ib][1 ,4]thiazin-6- yl)methyl]amino}methyl)cyclopentanecarboxamide;
e) (1 S,3R,4R)-3-hydroxy-Λ/-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]-4-({[(3-oxo- 3,4-dihydro-2/-/-pyrido[3,2-jb][1 ,4]oxazin-6- yOmethyllaminoJmethyOcyclopentanecarboxamide; or
f) (1 S,3R,4f?)-3-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]methyl}-4-hydroxy-Λ/-[6-(methyloxy)-1 ,5-naphthyridin-4- yl]cyclopentanecarboxamide; or
a pharmaceutically acceptable salt or solvate thereof.
16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier.
17. A method of treating bacterial infections in mammals which comprises administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1 to 15.
18. A compound according to any one of claims 1 to 15 for use in treating bacterial infections.
19. Use of a compound according to any one of claims 1 to 15 in the manufacture of a medicament for use in the treatment of bacterial infections.
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Also Published As
Publication number | Publication date |
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US7605169B2 (en) | 2009-10-20 |
EP1846417A4 (en) | 2009-12-23 |
EP1846417A1 (en) | 2007-10-24 |
JP2008528598A (en) | 2008-07-31 |
US20080009483A1 (en) | 2008-01-10 |
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