CA2483538A1 - Bicyclic 6-alkylidene-penems as .szlig.-lactamases inhibitors - Google Patents

Info

Publication number

CA2483538A1

CA2483538A1 CA002483538A CA2483538A CA2483538A1 CA 2483538 A1 CA2483538 A1 CA 2483538A1 CA 002483538 A CA002483538 A CA 002483538A CA 2483538 A CA2483538 A CA 2483538A CA 2483538 A1 CA2483538 A1 CA 2483538A1

Authority

CA

Canada

Prior art keywords

optionally substituted

carboxylic acid

oxo

ene

thia

Prior art date

2002-05-01

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 125000002619 bicyclic group Chemical group 0.000 title claims description 19
• 239000003112 inhibitor Substances 0.000 title description 14
• 150000001875 compounds Chemical class 0.000 claims abstract description 164
• 208000035143 Bacterial infection Diseases 0.000 claims abstract description 6
• 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
• 239000000203 mixture Substances 0.000 claims description 225
• 229910052760 oxygen Inorganic materials 0.000 claims description 128
• 229910052799 carbon Inorganic materials 0.000 claims description 107
• 159000000000 sodium salts Chemical class 0.000 claims description 92
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 89
• -1 substituted Chemical class 0.000 claims description 76
• 229910052717 sulfur Inorganic materials 0.000 claims description 68
• 229910052757 nitrogen Inorganic materials 0.000 claims description 55
• 125000001072 heteroaryl group Chemical group 0.000 claims description 45
• 125000003118 aryl group Chemical group 0.000 claims description 40
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 36
• 229910052739 hydrogen Inorganic materials 0.000 claims description 33
• 238000000034 method Methods 0.000 claims description 32
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 24
• 125000005842 heteroatom Chemical group 0.000 claims description 20
• 239000001257 hydrogen Substances 0.000 claims description 19
• 230000003115 biocidal effect Effects 0.000 claims description 16
• 239000003782 beta lactam antibiotic agent Substances 0.000 claims description 15
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 14
• 125000004122 cyclic group Chemical group 0.000 claims description 14
• 150000001721 carbon Chemical group 0.000 claims description 13
• 125000004432 carbon atom Chemical group C* 0.000 claims description 13
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
• 150000002148 esters Chemical class 0.000 claims description 12
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
• 125000003107 substituted aryl group Chemical group 0.000 claims description 12
• 125000003342 alkenyl group Chemical group 0.000 claims description 11
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 11
• 125000000304 alkynyl group Chemical group 0.000 claims description 10
• 229910052736 halogen Inorganic materials 0.000 claims description 9
• 125000006239 protecting group Chemical group 0.000 claims description 9
• 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 8
• 125000005326 heteroaryloxy alkyl group Chemical group 0.000 claims description 8
• 229960002292 piperacillin Drugs 0.000 claims description 8
• WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 claims description 8
• 150000003839 salts Chemical class 0.000 claims description 8
• 125000003003 spiro group Chemical group 0.000 claims description 8
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 7
• 229960003022 amoxicillin Drugs 0.000 claims description 7
• LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin 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=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims description 7
• 150000002367 halogens Chemical class 0.000 claims description 7
• LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims description 7
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 7
• 229930186147 Cephalosporin Natural products 0.000 claims description 5
• 229930182555 Penicillin Natural products 0.000 claims description 5
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 5
• 125000005018 aryl alkenyl group Chemical group 0.000 claims description 5
• 125000005325 aryloxy aryl group Chemical group 0.000 claims description 5
• 229940124587 cephalosporin Drugs 0.000 claims description 5
• 150000001780 cephalosporins Chemical class 0.000 claims description 5
• 125000002950 monocyclic group Chemical group 0.000 claims description 5
• 238000006894 reductive elimination reaction Methods 0.000 claims description 5
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
• 125000004104 aryloxy group Chemical group 0.000 claims description 4
• 238000006664 bond formation reaction Methods 0.000 claims description 4
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 4
• 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 4
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 4
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
• QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 3
• JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-N 0.000 claims description 3
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 3
• 150000003973 alkyl amines Chemical class 0.000 claims description 3
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 3
• 125000005133 alkynyloxy group Chemical group 0.000 claims description 3
• 229960000723 ampicillin Drugs 0.000 claims description 3
• 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 3
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 3
• 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 claims description 3
• 229960000433 latamoxef Drugs 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 claims description 3
• 125000006574 non-aromatic ring group Chemical group 0.000 claims description 3
• OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 claims description 3
• 229960004659 ticarcillin Drugs 0.000 claims description 3
• JETQIUPBHQNHNZ-NJBDSQKTSA-N (2s,5r,6r)-3,3-dimethyl-7-oxo-6-[[(2r)-2-phenyl-2-sulfoacetyl]amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound C1([C@H](C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)S(O)(=O)=O)=CC=CC=C1 JETQIUPBHQNHNZ-NJBDSQKTSA-N 0.000 claims description 2
• XTADYNGCKRLHLU-AGEOTTOMSA-N (5r,6z)-7-oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-ylmethylidene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1=C2CCCCN2N=C1/C=C1/C(=O)N2[C@@H]1SC=C2C(=O)O XTADYNGCKRLHLU-AGEOTTOMSA-N 0.000 claims description 2
• VAEBCNPDQMGFNE-UHFFFAOYSA-N 6-(6,7-dihydro-4h-thieno[3,2-c]pyran-2-ylmethylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1OCCC(S2)=C1C=C2C=C1C(=O)N2C1SC=C2C(=O)O VAEBCNPDQMGFNE-UHFFFAOYSA-N 0.000 claims description 2
• 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 claims description 2
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
• SNAJDOSOLZFUIK-UHFFFAOYSA-N CC1(CCC(NC1)=O)C.[Na] Chemical compound CC1(CCC(NC1)=O)C.[Na] SNAJDOSOLZFUIK-UHFFFAOYSA-N 0.000 claims description 2
• JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 2
• 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 claims description 2
• 229960003644 aztreonam Drugs 0.000 claims description 2
• CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical compound O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 claims description 2
• 229960003866 cefaloridine Drugs 0.000 claims description 2
• 229960000603 cefalotin Drugs 0.000 claims description 2
• 229960002420 cefatrizine Drugs 0.000 claims description 2
• 229960001139 cefazolin Drugs 0.000 claims description 2
• MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 claims description 2
• 229960002588 cefradine Drugs 0.000 claims description 2
• 229940106164 cephalexin Drugs 0.000 claims description 2
• ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 claims description 2
• VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 claims description 2
• RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 claims description 2
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 2
• 229940049954 penicillin Drugs 0.000 claims description 2
• 235000019371 penicillin G benzathine Nutrition 0.000 claims description 2
• 229910052698 phosphorus Inorganic materials 0.000 claims description 2
• 229960004932 sulbenicillin Drugs 0.000 claims description 2
• 239000002132 β-lactam antibiotic Substances 0.000 claims 7
• 229940124586 β-lactam antibiotics Drugs 0.000 claims 7
• PIQJFYXOGLAPEL-GPWUBDCCSA-N (5r,6z)-6-(4,6-dihydropyrazolo[1,5-c][1,3]thiazol-2-ylmethylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1=C2CSCN2N=C1/C=C1/C(=O)N2[C@@H]1SC=C2C(=O)O PIQJFYXOGLAPEL-GPWUBDCCSA-N 0.000 claims 2
• HUGCXBGSKYVVDN-JTMRULEUSA-N (5R,6Z)-6-[(5,5-dimethyl-4,6-dihydropyrrolo[1,2-b]pyrazol-2-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound S([C@@H]1\2)C=C(C(O)=O)N1C(=O)C/2=C/C1=NN(CC(C)(C)C2)C2=C1 HUGCXBGSKYVVDN-JTMRULEUSA-N 0.000 claims 1
• WCZPETISIDPRLB-KGHNQEBZSA-N (5r,6z)-6-(2,3-dihydropyrazolo[5,1-b][1,3]oxazol-6-ylmethylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1=C2OCCN2N=C1/C=C1/C(=O)N2[C@@H]1SC=C2C(=O)O WCZPETISIDPRLB-KGHNQEBZSA-N 0.000 claims 1
• BHGUWNPCJQAETH-KGHNQEBZSA-N (5r,6z)-6-(2,3-dihydropyrazolo[5,1-b][1,3]thiazol-6-ylmethylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1=C2SCCN2N=C1/C=C1/C(=O)N2[C@@H]1SC=C2C(=O)O BHGUWNPCJQAETH-KGHNQEBZSA-N 0.000 claims 1
• IKNPDLCLBOGEQM-TWLAMCEISA-N (5r,6z)-6-(5,7-dihydro-4h-pyrazolo[1,5-c][1,3]thiazin-2-ylmethylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1=C2CCSCN2N=C1/C=C1/C(=O)N2[C@@H]1SC=C2C(=O)O IKNPDLCLBOGEQM-TWLAMCEISA-N 0.000 claims 1
• DWYDARUUOLMALM-TWLAMCEISA-N (5r,6z)-6-(6,7-dihydro-4h-pyrazolo[5,1-c][1,4]oxazin-2-ylmethylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1=C2COCCN2N=C1/C=C1/C(=O)N2[C@@H]1SC=C2C(=O)O DWYDARUUOLMALM-TWLAMCEISA-N 0.000 claims 1
• QQDDJIUJAPMCCX-SIBGDRKGSA-N (5r,6z)-6-[(5-benzyl-6,7-dihydro-4h-thieno[3,2-c]pyridin-2-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound N1([C@@H]2SC=C1C(=O)O)C(=O)\C2=C\C(SC=1CC2)=CC=1CN2CC1=CC=CC=C1 QQDDJIUJAPMCCX-SIBGDRKGSA-N 0.000 claims 1
• TZHYRIOYHMAWIJ-KGHNQEBZSA-N (5r,6z)-7-oxo-6-[(4-oxo-6,7-dihydropyrazolo[5,1-c][1,4]oxazin-2-yl)methylidene]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1=C2C(=O)OCCN2N=C1/C=C1/C(=O)N2[C@@H]1SC=C2C(=O)O TZHYRIOYHMAWIJ-KGHNQEBZSA-N 0.000 claims 1
• 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims 1
• FYZUENZXIZCLAZ-UHFFFAOYSA-N 2-methylhept-2-enoic acid Chemical compound CCCCC=C(C)C(O)=O FYZUENZXIZCLAZ-UHFFFAOYSA-N 0.000 claims 1
• VLVRGEYTLMKACY-UHFFFAOYSA-N 7-oxo-6-(6,7,8,9-tetrahydro-5h-imidazo[1,2-a]azepin-2-ylmethylidene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1CCCCC2=NC(C=C3C(=O)N4C3SC=C4C(=O)O)=CN21 VLVRGEYTLMKACY-UHFFFAOYSA-N 0.000 claims 1
• UOCJDOLVGGIYIQ-PBFPGSCMSA-N cefatrizine Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](N)C=2C=CC(O)=CC=2)CC=1CSC=1C=NNN=1 UOCJDOLVGGIYIQ-PBFPGSCMSA-N 0.000 claims 1
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• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
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• 239000000243 solution Substances 0.000 description 276
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• 239000011541 reaction mixture Substances 0.000 description 207
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 179
• 230000002829 reductive effect Effects 0.000 description 135
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 130
• 229910001868 water Inorganic materials 0.000 description 128
• 239000007787 solid Substances 0.000 description 127
• 229940093499 ethyl acetate Drugs 0.000 description 120
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• 239000000706 filtrate Substances 0.000 description 111
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• 238000004440 column chromatography Methods 0.000 description 38
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• OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 30
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