NO323007B1 - Cefalosporin antibiotika, deres anvendelse samt antibakterielt preparat - Google Patents

Info

Publication number

NO323007B1

NO323007B1 NO19981653A NO981653A NO323007B1 NO 323007 B1 NO323007 B1 NO 323007B1 NO 19981653 A NO19981653 A NO 19981653A NO 981653 A NO981653 A NO 981653A NO 323007 B1 NO323007 B1 NO 323007B1

Authority

NO

Norway

Prior art keywords

amino

alkyl

salt

substituted

cephem

Prior art date

1995-10-12

Links

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• 238000002360 preparation method Methods 0.000 title claims description 27
• 230000000844 anti-bacterial effect Effects 0.000 title claims description 10
• 239000003242 anti bacterial agent Substances 0.000 title description 16
• 229940088710 antibiotic agent Drugs 0.000 title description 14
• 229930186147 Cephalosporin Natural products 0.000 title description 13
• 229940124587 cephalosporin Drugs 0.000 title description 13
• 150000001780 cephalosporins Chemical class 0.000 title description 13
• -1 iodo, mercapto Chemical class 0.000 claims description 193
• 150000001875 compounds Chemical class 0.000 claims description 125
• 125000000217 alkyl group Chemical group 0.000 claims description 77
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 67
• 150000003839 salts Chemical class 0.000 claims description 50
• 125000000623 heterocyclic group Chemical group 0.000 claims description 40
• 229910052739 hydrogen Inorganic materials 0.000 claims description 40
• 239000001257 hydrogen Substances 0.000 claims description 40
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
• 125000003118 aryl group Chemical group 0.000 claims description 28
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 27
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 26
• 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 25
• 150000002431 hydrogen Chemical class 0.000 claims description 24
• 125000001424 substituent group Chemical group 0.000 claims description 23
• 239000003814 drug Substances 0.000 claims description 21
• RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims description 20
• 229960003085 meticillin Drugs 0.000 claims description 20
• 241000894006 Bacteria Species 0.000 claims description 19
• 125000002252 acyl group Chemical group 0.000 claims description 19
• 125000001072 heteroaryl group Chemical group 0.000 claims description 19
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 125000001544 thienyl group Chemical group 0.000 claims description 17
• 125000003342 alkenyl group Chemical group 0.000 claims description 16
• 125000003368 amide group Chemical group 0.000 claims description 16
• AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 16
• 229960000723 ampicillin Drugs 0.000 claims description 16
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 15
• 208000035143 Bacterial infection Diseases 0.000 claims description 15
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 15
• 208000022362 bacterial infectious disease Diseases 0.000 claims description 15
• 239000000460 chlorine Substances 0.000 claims description 15
• 229910052801 chlorine Inorganic materials 0.000 claims description 15
• 125000002541 furyl group Chemical group 0.000 claims description 15
• 125000002883 imidazolyl group Chemical group 0.000 claims description 15
• 125000004193 piperazinyl group Chemical group 0.000 claims description 15
• 125000004076 pyridyl group Chemical group 0.000 claims description 15
• 229910052717 sulfur Chemical group 0.000 claims description 15
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 15
• 125000000335 thiazolyl group Chemical group 0.000 claims description 15
• 241000124008 Mammalia Species 0.000 claims description 13
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
• 108010059993 Vancomycin Proteins 0.000 claims description 13
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
• 125000004414 alkyl thio group Chemical group 0.000 claims description 13
• 125000001041 indolyl group Chemical group 0.000 claims description 13
• 229910052757 nitrogen Inorganic materials 0.000 claims description 13
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• 239000001301 oxygen Substances 0.000 claims description 12
• 239000011593 sulfur Chemical group 0.000 claims description 12
• 229960003165 vancomycin Drugs 0.000 claims description 12
• MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
• 125000003545 alkoxy group Chemical group 0.000 claims description 11
• 229910052736 halogen Inorganic materials 0.000 claims description 10
• 150000002367 halogens Chemical class 0.000 claims description 10
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 8
• 230000002401 inhibitory effect Effects 0.000 claims description 8
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
• WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims description 7
• MZJUGRUTVANEDW-UHFFFAOYSA-N bromine fluoride Chemical compound BrF MZJUGRUTVANEDW-UHFFFAOYSA-N 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 7
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 7
• ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 claims description 7
• 229960002182 imipenem Drugs 0.000 claims description 7
• 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 6
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
• 229960004261 cefotaxime Drugs 0.000 claims description 6
• AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 claims description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 5
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
• 150000003857 carboxamides Chemical class 0.000 claims description 5
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 239000011737 fluorine Substances 0.000 claims description 5
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 5
• 125000004665 trialkylsilyl group Chemical group 0.000 claims description 5
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
• 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 4
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
• 229910052794 bromium Inorganic materials 0.000 claims description 4
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000000524 functional group Chemical group 0.000 claims description 4
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 4
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 4
• 239000007924 injection Substances 0.000 claims description 4
• 238000002347 injection Methods 0.000 claims description 4
• 125000004043 oxo group Chemical group O=* 0.000 claims description 4
• LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 4
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
• 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 2
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
• MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 claims 6
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 5
• 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims 2
• SOILGIPMTQLPMJ-SSKZIVTRSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2-fluoroethoxyimino)acetyl]amino]-3-[3-(2-azaniumylethylsulfanylmethyl)pyridin-4-yl]sulfanyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1C(N)=NC(C(=N\OCCF)\C(=O)N[C@@H]2C(N3C(=C(SC=4C(=CN=CC=4)CSCC[NH3+])CS[C@@H]32)C([O-])=O)=O)=C1 SOILGIPMTQLPMJ-SSKZIVTRSA-N 0.000 claims 1
• PWMVUTRMTFMHKU-DWVKKRMSSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-hydroxyiminoacetyl]amino]-3-[3-(2-azaniumylethylsulfanylmethyl)pyridin-4-yl]sulfanyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(SC=4C(=CN=CC=4)CSCC[NH3+])CS[C@@H]32)C([O-])=O)=O)=C1 PWMVUTRMTFMHKU-DWVKKRMSSA-N 0.000 claims 1
• CAZTUTWNIILQNT-QDECCPLTSA-N (6r,7r)-7-[[(2z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-hydroxyiminoacetyl]amino]-3-[3-(2-azaniumylethylsulfanyl)pyridin-4-yl]sulfanyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1C(N)=NC(\C(=N\O)C(=O)N[C@@H]2C(N3C(=C(SC=4C(=CN=CC=4)SCC[NH3+])CS[C@@H]32)C([O-])=O)=O)=C1Cl CAZTUTWNIILQNT-QDECCPLTSA-N 0.000 claims 1
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
• 101100490437 Mus musculus Acvrl1 gene Proteins 0.000 claims 1
• 239000005864 Sulphur Substances 0.000 claims 1
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 1
• 125000001246 bromo group Chemical group Br* 0.000 claims 1
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
• VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 90
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
• 239000000243 solution Substances 0.000 description 56
• 238000005160 1H NMR spectroscopy Methods 0.000 description 45
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• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
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• 238000006243 chemical reaction Methods 0.000 description 20
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• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 14
• 239000002904 solvent Substances 0.000 description 14
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
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• 239000003782 beta lactam antibiotic agent Substances 0.000 description 10
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