ES2592403T3 - Compuestos beta-lactámicos sustituidos con amidina, su preparación y uso como agentes antibacterianos - Google Patents
Compuestos beta-lactámicos sustituidos con amidina, su preparación y uso como agentes antibacterianos Download PDFInfo
- Publication number
- ES2592403T3 ES2592403T3 ES13701246.4T ES13701246T ES2592403T3 ES 2592403 T3 ES2592403 T3 ES 2592403T3 ES 13701246 T ES13701246 T ES 13701246T ES 2592403 T3 ES2592403 T3 ES 2592403T3
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- Prior art keywords
- alkyl
- amino
- substituted
- group
- hydroxy
- Prior art date
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- -1 Beta-lactam compounds Chemical group 0.000 title claims abstract description 92
- 150000001409 amidines Chemical group 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 5
- 239000003242 anti bacterial agent Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 168
- 125000001424 substituent group Chemical group 0.000 claims abstract description 54
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 50
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 40
- 239000001257 hydrogen Substances 0.000 claims abstract description 40
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 33
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 28
- 229910052736 halogen Chemical group 0.000 claims abstract description 21
- 150000002367 halogens Chemical group 0.000 claims abstract description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 21
- 125000003118 aryl group Chemical group 0.000 claims abstract description 16
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 12
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 5
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical group C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- 208000035143 Bacterial infection Diseases 0.000 claims 3
- 208000022362 bacterial infectious disease Diseases 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 241001465754 Metazoa Species 0.000 claims 1
- 239000003781 beta lactamase inhibitor Substances 0.000 claims 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 claims 1
- HIIBYEWJDPOSHF-UHFFFAOYSA-N diethyl-methyl-[2-oxo-2-(9h-xanthen-9-ylamino)ethyl]azanium;bromide Chemical group [Br-].C1=CC=C2C(NC(=O)C[N+](C)(CC)CC)C3=CC=CC=C3OC2=C1 HIIBYEWJDPOSHF-UHFFFAOYSA-N 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 claims 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- 239000000203 mixture Substances 0.000 description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- 239000000243 solution Substances 0.000 description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 239000007787 solid Substances 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 16
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- 125000002344 aminooxy group Chemical group [H]N([H])O[*] 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 11
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 229960001701 chloroform Drugs 0.000 description 10
- 235000019253 formic acid Nutrition 0.000 description 10
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000003643 water by type Substances 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000003586 protic polar solvent Substances 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 229940041009 monobactams Drugs 0.000 description 6
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 5
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 4
- 229960003644 aztreonam Drugs 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 description 4
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 150000003952 β-lactams Chemical class 0.000 description 4
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 3
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 108020004256 Beta-lactamase Proteins 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 102000006635 beta-lactamase Human genes 0.000 description 3
- 229940041011 carbapenems Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- NWCBOWOTHFLANG-UHFFFAOYSA-N propan-2-yl methanimidate;hydrochloride Chemical compound Cl.CC(C)OC=N NWCBOWOTHFLANG-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- CMIBWIAICVBURI-ZETCQYMHSA-N tert-butyl (3s)-3-aminopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](N)C1 CMIBWIAICVBURI-ZETCQYMHSA-N 0.000 description 1
- PSJQQTSUTZXYNK-UHFFFAOYSA-N tert-butyl 4-[(4-hydroxybenzenecarboximidoyl)-[(2-methylpropan-2-yl)oxycarbonyl]amino]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N(C1CCN(CC1)C(=O)OC(C)(C)C)C(=N)c1ccc(O)cc1 PSJQQTSUTZXYNK-UHFFFAOYSA-N 0.000 description 1
- FFCXTFAZMDAIIX-UHFFFAOYSA-N tert-butyl n-(1,3-diaminopropan-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC(CN)CN FFCXTFAZMDAIIX-UHFFFAOYSA-N 0.000 description 1
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
- UYNSYFDLTSSUNI-UHFFFAOYSA-N tert-butyl n-(2-aminopropyl)carbamate Chemical compound CC(N)CNC(=O)OC(C)(C)C UYNSYFDLTSSUNI-UHFFFAOYSA-N 0.000 description 1
- QYVFEFFJTQKDTK-UHFFFAOYSA-N tert-butyl n-[2-amino-3-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC(N)CNC(=O)OC(C)(C)C QYVFEFFJTQKDTK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VAMSVIZLXJOLHZ-QWFSEIHXSA-N tigemonam Chemical compound O=C1N(OS(O)(=O)=O)C(C)(C)[C@@H]1NC(=O)C(=N/OCC(O)=O)\C1=CSC(N)=N1 VAMSVIZLXJOLHZ-QWFSEIHXSA-N 0.000 description 1
- 229950010206 tigemonam Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- A61K31/4164—1,3-Diazoles
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| EP12152279 | 2012-01-24 | ||
| EP12152279 | 2012-01-24 | ||
| PCT/EP2013/051217 WO2013110643A1 (en) | 2012-01-24 | 2013-01-23 | Amidine substituted beta - lactam compounds, their preparation and use as antibacterial agents |
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| ES2592403T3 true ES2592403T3 (es) | 2016-11-30 |
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| US20160326157A1 (en) * | 2014-01-06 | 2016-11-10 | President And Fellows Of Harvard College | Monobactams and methods of their synthesis and use |
| KR101733441B1 (ko) | 2014-03-24 | 2017-05-10 | 노파르티스 아게 | 박테리아 감염의 치료를 위한 모노박탐 유기 화합물 |
| CN105175335B (zh) * | 2015-08-13 | 2017-11-03 | 南阳师范学院 | 一种3‑(3,3‑二氯烯丙氧基)‑1‑甲基吡唑‑5‑甲酰胺衍生物及其制备方法 |
| JP6837480B2 (ja) * | 2015-09-23 | 2021-03-03 | ノバルティス アーゲー | モノバクタム抗生物質の塩および固体形態 |
| EP3390357B1 (en) | 2015-12-15 | 2021-11-10 | Merck Sharp & Dohme Corp. | Biaryl monobactam compounds for the treatment of bacterial infections |
| RU2733402C2 (ru) * | 2016-03-07 | 2020-10-01 | Мерк Шарп И Доум Корп. | Бициклические арильные монобактамовые соединения и способы их применения для лечения бактериальных инфекций |
| CN107641119B (zh) | 2016-07-21 | 2019-11-08 | 中国科学院上海药物研究所 | 单环β-内酰胺-铁载体轭合物及其制备方法和用途 |
| SG11201900669WA (en) | 2016-08-26 | 2019-03-28 | Codexis Inc | Engineered imine reductases and methods for the reductive amination of ketone and amine compounds |
| WO2018091668A1 (en) | 2016-11-18 | 2018-05-24 | Aicuris Anti-Infective Cures Gmbh | Novel formulations of amidine substituted beta-lactam compounds on the basis of modified cyclodextrins and acidifying agents, their preparation and use as antimicrobial pharmaceutical compositions |
| WO2018091671A1 (en) | 2016-11-18 | 2018-05-24 | Aicuris Anti-Infective Cures Gmbh | Liposomal formulations of amidine substituted beta-lactam compounds for use in the treatment of bacterial infections |
| WO2018065636A1 (en) * | 2016-12-21 | 2018-04-12 | Aicuris Anti-Infective Cures Gmbh | COMBINATION THERAPY WITH AMIDINE SUBSTITUTED ß-LACTAM COMPOUNDS AND ß-LACTAMASE INHIBITORS FOR INFECTIONS WITH ANTIBIOTIC RESISTANT BACTERIAL STRAINS |
| EP3655402A1 (de) | 2017-07-18 | 2020-05-27 | Bayer CropScience Aktiengesellschaft | Substituierte 3-heteroaryloxy-1h-pyrazole sowie deren salze und ihre verwendung als herbizide wirkstoffe |
| UY37824A (es) | 2017-07-28 | 2019-02-28 | Aicuris Anti Infective Cures Gmbh | Forma cristalina de ácido (2s)-2-[[(z)-[1-(2-amino-4-tiazolil)-2-[[(3s)-2,2-dimetil-4-oxo-1-(sulfoxi)-3-azetidinil]amino]-2-oxoetiliden]amino]oxi]-3-[4-[imino[(3r)-3-piperidinilamino]metil]fenoxi]-propanoico |
| CN111094281B (zh) | 2017-08-02 | 2023-08-29 | 诺华股份有限公司 | 用于制备单内酰胺抗生素的化学方法及其中间体 |
| GEAP202215303A (en) | 2017-10-02 | 2022-04-11 | Merck Sharp & Dohme | Chromane monobactam compounds for the treatment of bacterial infections |
| US10280161B2 (en) * | 2017-10-02 | 2019-05-07 | Arixa Pharmaceuticals, Inc. | Aztreonam derivatives and uses thereof |
| EP3747883A4 (en) * | 2018-01-29 | 2020-12-16 | Medshine Discovery Inc. | B-LACTAM MONOCYCLIC COMPOUND FOR TREATMENT OF BACTERIAL INFECTION |
| EP3882246A4 (en) * | 2018-11-13 | 2021-12-29 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Monobactam compounds and use therefor |
| CN113227088B (zh) | 2018-12-18 | 2022-05-31 | 南京明德新药研发有限公司 | 单环β-内酰胺化合物在制药中的应用 |
| CN111303144B (zh) * | 2019-12-13 | 2020-11-27 | 苏州信诺维医药科技有限公司 | 一种治疗细菌感染的化合物 |
| US12491180B2 (en) | 2019-12-19 | 2025-12-09 | Shenzhen Optimum Biological Technology Co., Ltd | Application of compound in treating pneumonia |
| CN111253405B (zh) * | 2020-03-20 | 2022-12-16 | 南京安伦化工科技有限公司 | 一种比阿培南中间体的制备方法 |
| CN113754651B (zh) | 2020-06-02 | 2023-04-18 | 中国医学科学院医药生物技术研究所 | 一种β-内酰胺化合物、其用途及其制备方法 |
| CN111675641B (zh) * | 2020-06-04 | 2023-09-08 | 宁夏农林科学院农业资源与环境研究所（宁夏土壤与植物营养重点实验室） | 单环β-内酰胺类化合物、单环内酰胺类化合物盐及其制备方法 |
| CN111592536B (zh) * | 2020-06-04 | 2023-11-03 | 宁夏农林科学院农业资源与环境研究所（宁夏土壤与植物营养重点实验室） | 单环β-内酰胺化合物及其制备方法和应用 |
| WO2022011626A1 (en) * | 2020-07-16 | 2022-01-20 | Ningxia Academy Of Agriculture And Forestry Sciences | Novel monobactam compounds, their preparation and use as antibacterial agents |
| EP4007759A4 (en) * | 2020-08-06 | 2024-04-10 | Ningxia Academy of Agriculture and Forestry Sciences | BETA-LACTAM COMPOUNDS, THEIR PRODUCTION AND USE AS ANTIBACTERIAL AGENTS |
| CN112079791A (zh) * | 2020-08-21 | 2020-12-15 | 宁夏农林科学院农业资源与环境研究所（宁夏土壤与植物营养重点实验室） | 单环β-内酰胺类抗生素侧链酸及其酯、其制备方法和应用 |
| CN111909067B (zh) * | 2020-08-28 | 2022-03-15 | 浙江凯普化工有限公司 | 一种d-青霉胺的有机全合成方法 |
| US20240390335A1 (en) * | 2021-11-09 | 2024-11-28 | Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences | Pharmaceutical composition containing beta-lactam compound and use thereof |
| JP7671398B2 (ja) * | 2021-11-18 | 2025-05-01 | メルク・シャープ・アンド・ドーム・エルエルシー | クロマンアミジンモノバクタム抗生物質 |
| EP4433476A1 (en) * | 2021-11-18 | 2024-09-25 | Merck Sharp & Dohme LLC | Chromane amidine monobactam antibiotics |
| CN118255695B (zh) * | 2024-02-26 | 2025-03-14 | 广州艾奇西医药科技有限公司 | 一种β-内酰胺类化合物的中间体的纯化方法和制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE2458973A1 (de) * | 1974-12-13 | 1976-06-16 | Hoechst Ag | Acylaminopenicillansaeuren und verfahren zu ihrer herstellung |
| DE2749265A1 (de) | 1977-11-03 | 1979-05-10 | Linde Ag | Verfahren zur biologischen reinigung von abwasser |
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| JPS58210061A (ja) * | 1982-05-31 | 1983-12-07 | Takeda Chem Ind Ltd | １−スルホ−２−オキソアゼチジン誘導体、その製造法および用途 |
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| EP0336667A3 (en) | 1988-04-04 | 1991-04-10 | E.R. Squibb & Sons, Inc. | [3S(Z)]-3-[[(2-amino-4-thiazolyl)[[2-(hydroxyamino)-2-oxoethoxy]imino]acetyl]-amino]-2,2-dimethyl-4-oxo-1-azetidinyl sulfate |
| US5112968A (en) | 1989-07-28 | 1992-05-12 | E. R. Squibb & Sons, Inc. | Monobactam hydrazide derivatives |
| CA2024282A1 (en) | 1989-09-21 | 1991-03-22 | Peter H. Ermann | Heterocyclic hydrazide derivatives of monocyclic beta-lactam antibiotics |
| ZA918014B (en) | 1990-11-05 | 1992-07-29 | Squibb & Sons Inc | Heteroaroyl derivatives of monocyclic beta-lactam antibiotics |
| US5250691A (en) | 1991-09-09 | 1993-10-05 | E. R. Squibb & Sons, Inc. | Heteroaryl derivatives of monocyclic beta-lactam antibiotics |
| US5994340A (en) * | 1997-08-29 | 1999-11-30 | Synphar Laboratories, Inc. | Azetidinone derivatives as β-lactamase inhibitors |
| BR0113861A (pt) * | 2000-09-14 | 2004-01-27 | Pantherix Ltd | Derivados de ácidos 3-(heteroaril acetamido)-2-oxo-azetidina-1-sulfÈnicos como agentes antibacterianos |
| JP2007520484A (ja) | 2004-01-27 | 2007-07-26 | メルク フロスト カンパニー | シクロオキシゲナーゼ−２インヒビターとしてのジアリール−２−（５ｈ）−フラノンの一酸化窒素放出プロドラッグ |
| NZ567629A (en) | 2005-09-23 | 2011-08-26 | Ms Science Corp | Piperazine derivatives useful in the treatment of discorders of the central nervous system |
| DK2484680T3 (da) | 2005-12-07 | 2013-09-08 | Basilea Pharmaceutica Ag | Nyttige kombinationer af monolactam-antibiotika med beta-lactamase-inhibitorer |
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| CA2744756C (en) | 2008-12-19 | 2013-05-28 | Pfizer Inc. | Monocarbams and their use as antibacterial agent |
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