IE50333B1 - Antibacterial compositions comprising a beta-lactam-type compound and a 3-substituted propenoate - Google Patents
Antibacterial compositions comprising a beta-lactam-type compound and a 3-substituted propenoateInfo
- Publication number
- IE50333B1 IE50333B1 IE2249/80A IE224980A IE50333B1 IE 50333 B1 IE50333 B1 IE 50333B1 IE 2249/80 A IE2249/80 A IE 2249/80A IE 224980 A IE224980 A IE 224980A IE 50333 B1 IE50333 B1 IE 50333B1
- Authority
- IE
- Ireland
- Prior art keywords
- acid
- composition
- propenoate
- dimethylcyclopropanecarboxamido
- carbon atoms
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 64
- 150000001252 acrylic acid derivatives Chemical class 0.000 title claims abstract description 13
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 title description 30
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 27
- 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 abstract description 15
- 229960003866 cefaloridine Drugs 0.000 claims abstract description 15
- 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 abstract description 15
- 230000003115 biocidal effect Effects 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 claims abstract description 9
- 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 abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 4
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims abstract description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 3
- -1 N-guanyl Chemical compound 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 150000001408 amides Chemical class 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 230000003589 nefrotoxic effect Effects 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- WIESNNVNXBYTFK-FLIBITNWSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]oct-2-enoic acid Chemical group CCCCC\C=C(C(O)=O)/NC(=O)C1CC1(C)C WIESNNVNXBYTFK-FLIBITNWSA-N 0.000 claims description 3
- SWRDTUBIOYDACT-YVMONPNESA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]pent-2-enoic acid Chemical group CC\C=C(C(O)=O)/NC(=O)C1CC1(C)C SWRDTUBIOYDACT-YVMONPNESA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- CWMPPVPFLSZGCY-VOTSOKGWSA-N (2E)-oct-2-enoic acid Chemical compound CCCCC\C=C\C(O)=O CWMPPVPFLSZGCY-VOTSOKGWSA-N 0.000 claims description 2
- JGWBZZGFKONACH-JYRVWZFOSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-8-(1-phosphonoethylamino)oct-2-enoic acid Chemical group OP(=O)(O)C(C)NCCCCC\C=C(C(O)=O)/NC(=O)C1CC1(C)C JGWBZZGFKONACH-JYRVWZFOSA-N 0.000 claims description 2
- FXENFQRQJUHCSD-TWGQIWQCSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]hex-2-enoic acid Chemical group CCC\C=C(C(O)=O)/NC(=O)C1CC1(C)C FXENFQRQJUHCSD-TWGQIWQCSA-N 0.000 claims description 2
- ZBIISKDBQLYGPO-JYRVWZFOSA-N (z)-8-[carboxymethyl(methyl)amino]-2-[(2,2-dimethylcyclopropanecarbonyl)amino]oct-2-enoic acid Chemical group OC(=O)CN(C)CCCCC\C=C(C(O)=O)/NC(=O)C1CC1(C)C ZBIISKDBQLYGPO-JYRVWZFOSA-N 0.000 claims description 2
- CWMPPVPFLSZGCY-UHFFFAOYSA-N 2-Octenoic Acid Natural products CCCCCC=CC(O)=O CWMPPVPFLSZGCY-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000005518 carboxamido group Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002430 hydrocarbons Chemical group 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- JHEDEOKFVYJLEE-QPEQYQDCSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-7-(3-hydroxypyridin-2-yl)sulfanylhept-2-enoic acid Chemical group CC1(C)CC1C(=O)N\C(C(O)=O)=C/CCCCSC1=NC=CC=C1O JHEDEOKFVYJLEE-QPEQYQDCSA-N 0.000 claims 1
- GMTIJFPBZMNNII-GHXNOFRVSA-N (z)-8-(2-amino-2-oxoethyl)sulfanyl-2-[(2,2-dimethylcyclopropanecarbonyl)amino]oct-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(=C/CCCCCSCC(N)=O)C(O)=O GMTIJFPBZMNNII-GHXNOFRVSA-N 0.000 claims 1
- KXBBJEGOAWKPNB-ZSOIEALJSA-N 2-[(z)-6-carboxy-6-[(2,2-dimethylcyclopropanecarbonyl)amino]hex-5-enyl]sulfanylpyridine-3-carboxylic acid Chemical compound CC1(C)CC1C(=O)N\C(C(O)=O)=C/CCCCSC1=NC=CC=C1C(O)=O KXBBJEGOAWKPNB-ZSOIEALJSA-N 0.000 claims 1
- SYPHYEMZFUKSLW-UHFFFAOYSA-N C(C=CCCCCC)(=O)[O-].[NH4+] Chemical compound C(C=CCCCCC)(=O)[O-].[NH4+] SYPHYEMZFUKSLW-UHFFFAOYSA-N 0.000 claims 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 150000001768 cations Chemical class 0.000 claims 1
- 125000002883 imidazolyl group Chemical group 0.000 claims 1
- 206010029155 Nephropathy toxic Diseases 0.000 abstract description 5
- 231100000417 nephrotoxicity Toxicity 0.000 abstract description 5
- 230000007694 nephrotoxicity Effects 0.000 abstract description 5
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 229940088710 antibiotic agent Drugs 0.000 abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- 239000000243 solution Substances 0.000 description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- 229910001868 water Inorganic materials 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- 239000000047 product Substances 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 19
- 239000007787 solid Substances 0.000 description 18
- 238000004809 thin layer chromatography Methods 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 241000283973 Oryctolagus cuniculus Species 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- YBZQRYWKYBZZNT-UHFFFAOYSA-N 2,2-dimethylcyclopropane-1-carboxamide Chemical compound CC1(C)CC1C(N)=O YBZQRYWKYBZZNT-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 125000001246 bromo group Chemical group Br* 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- ATKJWBYYZNCOOO-DJWKRKHSSA-N (z)-2-[(2,2-dichlorocyclopropanecarbonyl)amino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1CC1(Cl)Cl ATKJWBYYZNCOOO-DJWKRKHSSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229910004373 HOAc Inorganic materials 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical group 0.000 description 4
- LSNKBVFMXFAUOF-UHFFFAOYSA-N benzyl methanimidate;hydrochloride Chemical compound Cl.N=COCC1=CC=CC=C1 LSNKBVFMXFAUOF-UHFFFAOYSA-N 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 4
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- NESNNVKHFUUNGQ-DAXSKMNVSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1CC1(C)C NESNNVKHFUUNGQ-DAXSKMNVSA-N 0.000 description 3
- WTVLQRGPKGVBFJ-XFFZJAGNSA-N (z)-8-bromo-2-[(2,2-dimethylcyclopropanecarbonyl)amino]oct-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(=C/CCCCCBr)C(O)=O WTVLQRGPKGVBFJ-XFFZJAGNSA-N 0.000 description 3
- SGRHVVLXEBNBDV-UHFFFAOYSA-N 1,6-dibromohexane Chemical compound BrCCCCCCBr SGRHVVLXEBNBDV-UHFFFAOYSA-N 0.000 description 3
- POUMCBWMYUEVKF-UHFFFAOYSA-N 2,2-dichlorocyclopropane-1-carboxamide Chemical compound NC(=O)C1CC1(Cl)Cl POUMCBWMYUEVKF-UHFFFAOYSA-N 0.000 description 3
- TYEYBOSBBBHJIV-UHFFFAOYSA-N 2-oxobutanoic acid Chemical compound CCC(=O)C(O)=O TYEYBOSBBBHJIV-UHFFFAOYSA-N 0.000 description 3
- MARYDOMJDFATPK-UHFFFAOYSA-N 3-hydroxy-1h-pyridine-2-thione Chemical compound OC1=CC=CN=C1S MARYDOMJDFATPK-UHFFFAOYSA-N 0.000 description 3
- WTVLQRGPKGVBFJ-UHFFFAOYSA-N 8-bromo-2-[(2,2-dimethylcyclopropanecarbonyl)amino]oct-2-enoic acid Chemical compound CC1(C)CC1C(=O)NC(=CCCCCCBr)C(O)=O WTVLQRGPKGVBFJ-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 3
- XMGZWGBXVLJOKE-UHFFFAOYSA-N acetic acid;toluene Chemical compound CC(O)=O.CC1=CC=CC=C1 XMGZWGBXVLJOKE-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000012223 aqueous fraction Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 3
- VUAOXPKYIYYINY-WCIBSUBMSA-N (z)-2-(nonanoylamino)but-2-enoic acid Chemical compound CCCCCCCCC(=O)N\C(=C/C)C(O)=O VUAOXPKYIYYINY-WCIBSUBMSA-N 0.000 description 2
- LALWXKAEURAMAW-TWGQIWQCSA-N (z)-2-[(2,2-dichlorocyclopropanecarbonyl)amino]oct-2-enoic acid Chemical compound CCCCC\C=C(C(O)=O)/NC(=O)C1CC1(Cl)Cl LALWXKAEURAMAW-TWGQIWQCSA-N 0.000 description 2
- 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
- CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
- QIJRTFXNRTXDIP-JIZZDEOASA-N L-cysteine hydrochloride hydrate Chemical compound O.Cl.SC[C@H](N)C(O)=O QIJRTFXNRTXDIP-JIZZDEOASA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- OQAGVSWESNCJJT-UHFFFAOYSA-N Methyl 3-methylbutanoate Chemical compound COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 206010038540 Renal tubular necrosis Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 229940109239 creatinine Drugs 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 239000002178 crystalline material Substances 0.000 description 2
- 229960002433 cysteine Drugs 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 231100000381 nephrotoxic Toxicity 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000001223 reverse osmosis Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- ILYPJQIFUVDUAO-UHFFFAOYSA-N tert-butyl 2-[(2,2-dimethylcyclopropanecarbonyl)amino]hex-2-enoate Chemical compound CCCC=C(C(=O)OC(C)(C)C)NC(=O)C1CC1(C)C ILYPJQIFUVDUAO-UHFFFAOYSA-N 0.000 description 2
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 150000003573 thiols Chemical group 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000002132 β-lactam antibiotic Substances 0.000 description 2
- 229940124586 β-lactam antibiotics Drugs 0.000 description 2
- NIONDZDPPYHYKY-SNAWJCMRSA-N (2E)-hexenoic acid Chemical compound CCC\C=C\C(O)=O NIONDZDPPYHYKY-SNAWJCMRSA-N 0.000 description 1
- DQVNALUAZAIAIZ-TWGQIWQCSA-N (2z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]hexa-2,5-dienoic acid Chemical compound CC1(C)CC1C(=O)N\C(=C/CC=C)C(O)=O DQVNALUAZAIAIZ-TWGQIWQCSA-N 0.000 description 1
- 239000001096 (4-ethenyl-1-azabicyclo[2.2.2]octan-7-yl)-(6-methoxyquinolin-4-yl)methanol hydrochloride Substances 0.000 description 1
- NNKXWRRDHYTHFP-HZQSTTLBSA-N (r)-[(2s,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;hydron;dichloride Chemical compound Cl.Cl.C([C@H]([C@H](C1)C=C)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 NNKXWRRDHYTHFP-HZQSTTLBSA-N 0.000 description 1
- ILYMBAQVBJAPNQ-POHAHGRESA-N (z)-2-(2-ethylhexanoylamino)but-2-enoic acid Chemical compound CCCCC(CC)C(=O)N\C(=C/C)C(O)=O ILYMBAQVBJAPNQ-POHAHGRESA-N 0.000 description 1
- YWFULJGZDXBCCV-POHAHGRESA-N (z)-2-(3,5,5-trimethylhexanoylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CC(C)CC(C)(C)C YWFULJGZDXBCCV-POHAHGRESA-N 0.000 description 1
- BEKHLEOLEYWIMJ-FUQNDXKWSA-N (z)-2-(3-cyclohexylpropanoylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CCC1CCCCC1 BEKHLEOLEYWIMJ-FUQNDXKWSA-N 0.000 description 1
- SMEVVLDJQVBSIM-SGAXSIHGSA-N (z)-2-(3-cyclopentylpropanoylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CCC1CCCC1 SMEVVLDJQVBSIM-SGAXSIHGSA-N 0.000 description 1
- CJPNJOXVQSNEPB-DAXSKMNVSA-N (z)-2-(3-methylbut-2-enoylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C=C(C)C CJPNJOXVQSNEPB-DAXSKMNVSA-N 0.000 description 1
- ZIQJERGSQODYKF-DAXSKMNVSA-N (z)-2-(3-methylbutanoylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CC(C)C ZIQJERGSQODYKF-DAXSKMNVSA-N 0.000 description 1
- GGSPAUHFZIYFNI-YWEYNIOJSA-N (z)-2-(3-methylbutanoylamino)hex-2-enedioic acid Chemical compound CC(C)CC(=O)N\C(C(O)=O)=C/CCC(O)=O GGSPAUHFZIYFNI-YWEYNIOJSA-N 0.000 description 1
- AJVLMGINYDZYKX-YVMONPNESA-N (z)-2-(3-methylbutanoylamino)pent-2-enoic acid Chemical compound CC\C=C(C(O)=O)/NC(=O)CC(C)C AJVLMGINYDZYKX-YVMONPNESA-N 0.000 description 1
- ADPBQBFOYLFHLS-YVMONPNESA-N (z)-2-(3-methylpentanoylamino)but-2-enoic acid Chemical compound CCC(C)CC(=O)N\C(=C/C)C(O)=O ADPBQBFOYLFHLS-YVMONPNESA-N 0.000 description 1
- QYUGESGDZCNLES-OIXVIMQBSA-N (z)-2-(4-cyclohexylbutanoylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CCCC1CCCCC1 QYUGESGDZCNLES-OIXVIMQBSA-N 0.000 description 1
- DKIAAASBXDZLGU-YWEYNIOJSA-N (z)-2-(4-methylpentanoylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CCC(C)C DKIAAASBXDZLGU-YWEYNIOJSA-N 0.000 description 1
- KIUKBQIQQWESNM-SGAXSIHGSA-N (z)-2-(4-thiophen-2-ylbutanoylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CCCC1=CC=CS1 KIUKBQIQQWESNM-SGAXSIHGSA-N 0.000 description 1
- SWKAPDQINPDYKM-UQCOIBPSSA-N (z)-2-(5-chloropentanoylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CCCCCl SWKAPDQINPDYKM-UQCOIBPSSA-N 0.000 description 1
- PFNPOSYTIHCLIG-WAPJZHGLSA-N (z)-2-(6-bromohexanoylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CCCCCBr PFNPOSYTIHCLIG-WAPJZHGLSA-N 0.000 description 1
- GPLWHCWTPKRTOZ-XQRVVYSFSA-N (z)-2-(butanoylamino)but-2-enoic acid Chemical compound CCCC(=O)N\C(=C/C)C(O)=O GPLWHCWTPKRTOZ-XQRVVYSFSA-N 0.000 description 1
- ROPCBTFYZAIVAK-UQCOIBPSSA-N (z)-2-(cyclobutanecarbonylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1CCC1 ROPCBTFYZAIVAK-UQCOIBPSSA-N 0.000 description 1
- SCRGHZHCQJHEMG-MBXJOHMKSA-N (z)-2-(cyclohexanecarbonylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1CCCCC1 SCRGHZHCQJHEMG-MBXJOHMKSA-N 0.000 description 1
- KELGIWIIEOOTBV-WAPJZHGLSA-N (z)-2-(cyclopentanecarbonylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1CCCC1 KELGIWIIEOOTBV-WAPJZHGLSA-N 0.000 description 1
- GUKYSTRKIHDFKP-KXFIGUGUSA-N (z)-2-(cyclopropanecarbonylamino)but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1CC1 GUKYSTRKIHDFKP-KXFIGUGUSA-N 0.000 description 1
- LVNFBZHUWSSGPC-UQCOIBPSSA-N (z)-2-(cyclopropanecarbonylamino)hex-2-enedioic acid Chemical compound OC(=O)CC\C=C(C(O)=O)/NC(=O)C1CC1 LVNFBZHUWSSGPC-UQCOIBPSSA-N 0.000 description 1
- PVEZMMWIKQZRKT-CLTKARDFSA-N (z)-2-(cyclopropanecarbonylamino)pent-2-enoic acid Chemical compound CC\C=C(C(O)=O)/NC(=O)C1CC1 PVEZMMWIKQZRKT-CLTKARDFSA-N 0.000 description 1
- CQMLVAVRISQGIW-YWEYNIOJSA-N (z)-2-(hexanoylamino)but-2-enoic acid Chemical compound CCCCCC(=O)N\C(=C/C)C(O)=O CQMLVAVRISQGIW-YWEYNIOJSA-N 0.000 description 1
- OOXHCIOTUVKGOX-WMZJFQQLSA-N (z)-2-(octanoylamino)but-2-enoic acid Chemical compound CCCCCCCC(=O)N\C(=C/C)C(O)=O OOXHCIOTUVKGOX-WMZJFQQLSA-N 0.000 description 1
- OGXLMYKJGUACJB-DAXSKMNVSA-N (z)-2-(pentanoylamino)but-2-enoic acid Chemical compound CCCCC(=O)N\C(=C/C)C(O)=O OGXLMYKJGUACJB-DAXSKMNVSA-N 0.000 description 1
- WWGWPJJROPNASH-VURMDHGXSA-N (z)-2-(pentanoylamino)pent-2-enoic acid Chemical compound CCCCC(=O)N\C(C(O)=O)=C/CC WWGWPJJROPNASH-VURMDHGXSA-N 0.000 description 1
- AKZXZWGQZMFERG-WTKPLQERSA-N (z)-2-[(2,2-diethylcyclopropanecarbonyl)amino]but-2-enoic acid Chemical compound CCC1(CC)CC1C(=O)N\C(=C/C)C(O)=O AKZXZWGQZMFERG-WTKPLQERSA-N 0.000 description 1
- GZBPFDUSTMNJCK-YFHOEESVSA-N (z)-2-[(2,2-diethylcyclopropanecarbonyl)amino]pent-2-enoic acid Chemical compound CC\C=C(C(O)=O)/NC(=O)C1CC1(CC)CC GZBPFDUSTMNJCK-YFHOEESVSA-N 0.000 description 1
- QPIIFBCOGOOTLZ-XQRVVYSFSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-4,4,4-trifluorobut-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(=C/C(F)(F)F)C(O)=O QPIIFBCOGOOTLZ-XQRVVYSFSA-N 0.000 description 1
- STZDOHPMFRJVEG-LCYFTJDESA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-4-phenylbut-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(C(O)=O)=C/CC1=CC=CC=C1 STZDOHPMFRJVEG-LCYFTJDESA-N 0.000 description 1
- MNLVEBNHODBKKS-UITAMQMPSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-5-methoxypent-2-enoic acid Chemical compound COCC\C=C(C(O)=O)/NC(=O)C1CC1(C)C MNLVEBNHODBKKS-UITAMQMPSA-N 0.000 description 1
- JXEDSKSRJWLHSO-UITAMQMPSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-5-methylsulfonylpent-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(=C/CCS(C)(=O)=O)C(O)=O JXEDSKSRJWLHSO-UITAMQMPSA-N 0.000 description 1
- HCLNKFUQVLZXGS-YWEYNIOJSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-5-phosphonopent-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(=C/CCP(O)(O)=O)C(O)=O HCLNKFUQVLZXGS-YWEYNIOJSA-N 0.000 description 1
- LIPTWYHXNVWNCI-POHAHGRESA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-6-ethoxy-6-oxohex-2-enoic acid Chemical compound CCOC(=O)CC\C=C(C(O)=O)/NC(=O)C1CC1(C)C LIPTWYHXNVWNCI-POHAHGRESA-N 0.000 description 1
- GWBLSCPBZYDXDC-XFFZJAGNSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-6-methylhept-2-enoic acid Chemical compound CC(C)CC\C=C(C(O)=O)/NC(=O)C1CC1(C)C GWBLSCPBZYDXDC-XFFZJAGNSA-N 0.000 description 1
- FFTGIRQYFUHGNU-UITAMQMPSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-6-sulfanylhex-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(=C/CCCS)C(O)=O FFTGIRQYFUHGNU-UITAMQMPSA-N 0.000 description 1
- FRWGPLBFRBOWGZ-RAXLEYEMSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]dec-2-enoic acid Chemical compound CCCCCCC\C=C(C(O)=O)/NC(=O)C1CC1(C)C FRWGPLBFRBOWGZ-RAXLEYEMSA-N 0.000 description 1
- GGMWYGMPRZBVBW-YFHOEESVSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]hept-2-enoic acid Chemical compound CCCC\C=C(C(O)=O)/NC(=O)C1CC1(C)C GGMWYGMPRZBVBW-YFHOEESVSA-N 0.000 description 1
- SYZURCIVHPUSDN-YWEYNIOJSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]hex-2-enedioic acid Chemical compound CC1(C)CC1C(=O)N\C(=C/CCC(O)=O)C(O)=O SYZURCIVHPUSDN-YWEYNIOJSA-N 0.000 description 1
- HFMLVRVBQDKHCL-XFXZXTDPSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]non-2-enoic acid Chemical compound CCCCCC\C=C(C(O)=O)/NC(=O)C1CC1(C)C HFMLVRVBQDKHCL-XFXZXTDPSA-N 0.000 description 1
- VGBJZPMVZKIKHB-SSZFMOIBSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]tridec-2-enoic acid Chemical compound CCCCCCCCCC\C=C(C(O)=O)/NC(=O)C1CC1(C)C VGBJZPMVZKIKHB-SSZFMOIBSA-N 0.000 description 1
- TVLRRKHAPPVNBS-DAXSKMNVSA-N (z)-2-[(2,3-dimethylcyclopropanecarbonyl)amino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1C(C)C1C TVLRRKHAPPVNBS-DAXSKMNVSA-N 0.000 description 1
- YHEDGIFKXKSRGG-MBXJOHMKSA-N (z)-2-[(2-chlorobenzoyl)amino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1=CC=CC=C1Cl YHEDGIFKXKSRGG-MBXJOHMKSA-N 0.000 description 1
- IVOTUVVRYIFRCY-WAPJZHGLSA-N (z)-2-[(2-cyclobutylacetyl)amino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CC1CCC1 IVOTUVVRYIFRCY-WAPJZHGLSA-N 0.000 description 1
- DRGKADGDMSSEKX-SGAXSIHGSA-N (z)-2-[(2-cyclohexylacetyl)amino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CC1CCCCC1 DRGKADGDMSSEKX-SGAXSIHGSA-N 0.000 description 1
- RSZGVXZPUJOGPM-UQCOIBPSSA-N (z)-2-[(2-cyclopropylacetyl)amino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CC1CC1 RSZGVXZPUJOGPM-UQCOIBPSSA-N 0.000 description 1
- QJAVSICABAQLGK-BAQGIRSFSA-N (z)-2-[(2-cyclopropylacetyl)amino]pent-2-enoic acid Chemical compound CC\C=C(C(O)=O)/NC(=O)CC1CC1 QJAVSICABAQLGK-BAQGIRSFSA-N 0.000 description 1
- XHZJVOBDWMCKNE-YWEYNIOJSA-N (z)-2-[(2-ethylcyclopropanecarbonyl)amino]but-2-enoic acid Chemical compound CCC1CC1C(=O)N\C(=C/C)C(O)=O XHZJVOBDWMCKNE-YWEYNIOJSA-N 0.000 description 1
- NYHJASRHKKCVKH-CLTKARDFSA-N (z)-2-[(2-methylcyclopropanecarbonyl)amino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1CC1C NYHJASRHKKCVKH-CLTKARDFSA-N 0.000 description 1
- FDOSKZGFRCHEDJ-OIXVIMQBSA-N (z)-2-[(2-phenylcyclopropanecarbonyl)amino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1CC1C1=CC=CC=C1 FDOSKZGFRCHEDJ-OIXVIMQBSA-N 0.000 description 1
- LBPKISKVVBVUHQ-YWEYNIOJSA-N (z)-2-[(3,3-dimethylcyclobutanecarbonyl)amino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1CC(C)(C)C1 LBPKISKVVBVUHQ-YWEYNIOJSA-N 0.000 description 1
- LYBRMCPKMYMELM-FPLPWBNLSA-N (z)-2-[(3-tert-butyl-2,2-dimethylcyclopropanecarbonyl)amino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1C(C(C)(C)C)C1(C)C LYBRMCPKMYMELM-FPLPWBNLSA-N 0.000 description 1
- JCAUQKQYXWAWQZ-WTKPLQERSA-N (z)-2-[(5-methoxy-3-methylpentanoyl)amino]but-2-enoic acid Chemical compound COCCC(C)CC(=O)N\C(=C/C)C(O)=O JCAUQKQYXWAWQZ-WTKPLQERSA-N 0.000 description 1
- KBLXLJAJIBJVIN-MBXJOHMKSA-N (z)-2-[3-(oxolan-2-yl)propanoylamino]but-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)CCC1CCCO1 KBLXLJAJIBJVIN-MBXJOHMKSA-N 0.000 description 1
- NXSXUKLRBZJPBR-FLIBITNWSA-N (z)-2-benzamido-5-methoxypent-2-enoic acid Chemical compound COCC\C=C(C(O)=O)/NC(=O)C1=CC=CC=C1 NXSXUKLRBZJPBR-FLIBITNWSA-N 0.000 description 1
- HTZJMFWSBMTOHG-MBXJOHMKSA-N (z)-2-benzamidobut-2-enoic acid Chemical compound C\C=C(C(O)=O)/NC(=O)C1=CC=CC=C1 HTZJMFWSBMTOHG-MBXJOHMKSA-N 0.000 description 1
- HCOHVICHSZCHPL-YFHOEESVSA-N (z)-2-benzamidohex-2-enedioic acid Chemical compound OC(=O)CC\C=C(C(O)=O)/NC(=O)C1=CC=CC=C1 HCOHVICHSZCHPL-YFHOEESVSA-N 0.000 description 1
- JINLEZYWEZETFZ-POHAHGRESA-N (z)-2-benzamidopent-2-enoic acid Chemical compound CC\C=C(C(O)=O)/NC(=O)C1=CC=CC=C1 JINLEZYWEZETFZ-POHAHGRESA-N 0.000 description 1
- VIKGWTDIJWLHQJ-GHXNOFRVSA-N (z)-3-(2-chlorophenyl)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]prop-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(C(O)=O)=C/C1=CC=CC=C1Cl VIKGWTDIJWLHQJ-GHXNOFRVSA-N 0.000 description 1
- SXSHMTNDCWWKOW-LCYFTJDESA-N (z)-4-cyclohexyl-2-[(2,2-dimethylcyclopropanecarbonyl)amino]but-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(C(O)=O)=C/CC1CCCCC1 SXSHMTNDCWWKOW-LCYFTJDESA-N 0.000 description 1
- OSWAFNAYCVWDEC-POHAHGRESA-N (z)-6-(dimethylamino)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-6-oxohex-2-enoic acid Chemical compound CN(C)C(=O)CC\C=C(C(O)=O)/NC(=O)C1CC1(C)C OSWAFNAYCVWDEC-POHAHGRESA-N 0.000 description 1
- KLJKHKZVZUGXOD-YWEYNIOJSA-N (z)-6-amino-2-[(2,2-dimethylcyclopropanecarbonyl)amino]-6-iminohex-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(=C/CCC(N)=N)C(O)=O KLJKHKZVZUGXOD-YWEYNIOJSA-N 0.000 description 1
- WDZFCTJHCKFLEH-XFFZJAGNSA-N (z)-8-(diaminomethylideneamino)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]oct-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(=C/CCCCCNC(N)=N)C(O)=O WDZFCTJHCKFLEH-XFFZJAGNSA-N 0.000 description 1
- HNBBJXPIRUDAKP-XFFZJAGNSA-N (z)-8-amino-2-[(2,2-dimethylcyclopropanecarbonyl)amino]oct-2-enoic acid Chemical compound CC1(C)CC1C(=O)N\C(=C/CCCCCN)C(O)=O HNBBJXPIRUDAKP-XFFZJAGNSA-N 0.000 description 1
- NXFBJNIZJZYWAC-UHFFFAOYSA-N 1-bromo-1-chloropentane Chemical compound CCCCC(Cl)Br NXFBJNIZJZYWAC-UHFFFAOYSA-N 0.000 description 1
- OJJYTODFFFMXNA-UHFFFAOYSA-N 2,2-dichlorocyclopropane-1-carbonyl chloride Chemical compound ClC(=O)C1CC1(Cl)Cl OJJYTODFFFMXNA-UHFFFAOYSA-N 0.000 description 1
- QQNQOWHUBGUGQI-UHFFFAOYSA-N 2,2-dimethylcyclopropane-1-carbonyl chloride Chemical compound CC1(C)CC1C(Cl)=O QQNQOWHUBGUGQI-UHFFFAOYSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- XPKAIZFKHGPXAI-UHFFFAOYSA-N 2-(butanethioylamino)but-2-enoic acid Chemical compound C(C)CC(=S)NC(C(=O)O)=CC XPKAIZFKHGPXAI-UHFFFAOYSA-N 0.000 description 1
- FXENFQRQJUHCSD-UHFFFAOYSA-N 2-[(2,2-dimethylcyclopropanecarbonyl)amino]hex-2-enoic acid Chemical compound CCCC=C(C(O)=O)NC(=O)C1CC1(C)C FXENFQRQJUHCSD-UHFFFAOYSA-N 0.000 description 1
- QEESFGJMQBONPV-UHFFFAOYSA-N 2-[(2,2-dimethylcyclopropanecarbonyl)amino]prop-2-enoic acid Chemical compound CC1(C)CC1C(=O)NC(=C)C(O)=O QEESFGJMQBONPV-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 description 1
- GPPUPQFYDYLTIY-UHFFFAOYSA-N 2-oxooctanoic acid Chemical compound CCCCCCC(=O)C(O)=O GPPUPQFYDYLTIY-UHFFFAOYSA-N 0.000 description 1
- KDVFRMMRZOCFLS-UHFFFAOYSA-N 2-oxopentanoic acid Chemical compound CCCC(=O)C(O)=O KDVFRMMRZOCFLS-UHFFFAOYSA-N 0.000 description 1
- QMMPIAPFEICUFE-UHFFFAOYSA-N 2-phenylpent-2-enoic acid Chemical compound CCC=C(C(O)=O)C1=CC=CC=C1 QMMPIAPFEICUFE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZPLCXHWYPWVJDL-UHFFFAOYSA-N 4-[(4-hydroxyphenyl)methyl]-1,3-oxazolidin-2-one Chemical compound C1=CC(O)=CC=C1CC1NC(=O)OC1 ZPLCXHWYPWVJDL-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- CBTBJLURHXVTPX-UHFFFAOYSA-N 5-methoxypent-2-enoic acid Chemical compound COCCC=CC(O)=O CBTBJLURHXVTPX-UHFFFAOYSA-N 0.000 description 1
- PJGORSICMYLNNE-UHFFFAOYSA-N C(C=CCCCC)(=O)O.CC1(C(C1)C(=O)N)C Chemical compound C(C=CCCCC)(=O)O.CC1(C(C1)C(=O)N)C PJGORSICMYLNNE-UHFFFAOYSA-N 0.000 description 1
- SDDNNKJNVSYGNJ-XGICHPGQSA-N C\C=C(C(O)=O)/NC(=O)CC(C)CCC=C(C)C Chemical compound C\C=C(C(O)=O)/NC(=O)CC(C)CCC=C(C)C SDDNNKJNVSYGNJ-XGICHPGQSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 1
- 102000020897 Formins Human genes 0.000 description 1
- 108091022623 Formins Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- NIONDZDPPYHYKY-UHFFFAOYSA-N Z-hexenoic acid Natural products CCCC=CC(O)=O NIONDZDPPYHYKY-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- ZZTURJAZCMUWEP-UHFFFAOYSA-N diaminomethylideneazanium;hydrogen sulfate Chemical compound NC(N)=N.OS(O)(=O)=O ZZTURJAZCMUWEP-UHFFFAOYSA-N 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- ARPJZLLWCWXWJQ-UHFFFAOYSA-N dihydrogen phosphate;ethylazanium Chemical compound CCN.OP(O)(O)=O ARPJZLLWCWXWJQ-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- ANEDZEVDORCLPM-UHFFFAOYSA-N ethyl 1,3-dithiane-2-carboxylate Chemical compound CCOC(=O)C1SCCCS1 ANEDZEVDORCLPM-UHFFFAOYSA-N 0.000 description 1
- SVPLPHKLJAGCIF-UHFFFAOYSA-N ethyl 7-chloro-2-oxohept-3-enoate Chemical compound CCOC(=O)C(=O)C=CCCCCl SVPLPHKLJAGCIF-UHFFFAOYSA-N 0.000 description 1
- YJJLIIMRHGRCFM-UHFFFAOYSA-N ethyl 7-chloro-2-oxoheptanoate Chemical compound CCOC(=O)C(=O)CCCCCCl YJJLIIMRHGRCFM-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- HHQJWDKIRXRTLS-UHFFFAOYSA-N n'-bromobutanediamide Chemical compound NC(=O)CCC(=O)NBr HHQJWDKIRXRTLS-UHFFFAOYSA-N 0.000 description 1
- ZWFJZRUFKJFTSR-UHFFFAOYSA-N n,n,n',n'-tetramethyldodeca-2,10-diyne-1,12-diamine Chemical compound CN(C)CC#CCCCCCCC#CCN(C)C ZWFJZRUFKJFTSR-UHFFFAOYSA-N 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 229960001811 quinine hydrochloride Drugs 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- GJGWTNQVGRBQLG-UHFFFAOYSA-N tert-butyl 2-[(2,2-dimethylcyclopropanecarbonyl)amino]-2-methoxyhexanoate Chemical compound CCCCC(C(=O)OC(C)(C)C)(OC)NC(=O)C1CC1(C)C GJGWTNQVGRBQLG-UHFFFAOYSA-N 0.000 description 1
- DZHRYRHFJWSUFE-UHFFFAOYSA-N tert-butyl 2-[(2,2-dimethylcyclopropanecarbonyl)amino]hexanoate Chemical compound CCCCC(C(=O)OC(C)(C)C)NC(=O)C1CC1(C)C DZHRYRHFJWSUFE-UHFFFAOYSA-N 0.000 description 1
- CZROWHOGJRLBIE-UHFFFAOYSA-N tert-butyl 2-aminohexanoate Chemical compound CCCCC(N)C(=O)OC(C)(C)C CZROWHOGJRLBIE-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Reproductive Health (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cephalosporin Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9079379A | 1979-11-02 | 1979-11-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE802249L IE802249L (en) | 1981-05-02 |
| IE50333B1 true IE50333B1 (en) | 1986-04-02 |
Family
ID=22224340
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2249/80A IE50333B1 (en) | 1979-11-02 | 1980-10-30 | Antibacterial compositions comprising a beta-lactam-type compound and a 3-substituted propenoate |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0028778B1 (en:Method) |
| JP (1) | JPS5681518A (en:Method) |
| AT (1) | ATE11221T1 (en:Method) |
| DE (1) | DE3069986D1 (en:Method) |
| DK (1) | DK462580A (en:Method) |
| ES (2) | ES496446A0 (en:Method) |
| GR (1) | GR70784B (en:Method) |
| IE (1) | IE50333B1 (en:Method) |
| PT (1) | PT72006B (en:Method) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880793A (en) * | 1978-07-24 | 1989-11-14 | Merck & Co., Inc. | Combination of thienamycin-type antibiotics with dipeptidase inhibitors |
| US5071843A (en) * | 1978-07-24 | 1991-12-10 | Merck & Co., Inc. | Combination of 2-substituted carbapenems with dipeptidase inhibitors |
| DE3173503D1 (en) * | 1980-09-17 | 1986-02-27 | Merck & Co Inc | Antibacterial composition of thienamycin type compound and a dipeptidase inhibitor |
| EP0086590A1 (en) * | 1982-02-17 | 1983-08-24 | Beecham Group Plc | Antibacterial agents, their preparation and use |
| DE3569725D1 (en) * | 1984-02-28 | 1989-06-01 | Sumitomo Chemical Co | A method for the optical purification of an optically active 2,2-dimethylcyclopropanecarboxylic acid amide |
| EP0161546B1 (en) * | 1984-04-30 | 1989-12-13 | Merck & Co. Inc. | Combination of 2-substituted carbapenems with dipeptidase inhibitors |
| FR2601946B1 (fr) * | 1986-07-25 | 1988-10-21 | Rhone Poulenc Chimie | Procede de preparation de perfluoroalkylcetones |
| JPS63290860A (ja) * | 1987-05-22 | 1988-11-28 | Sanraku Inc | アミノエチルシステイン誘導体 |
| ATE217195T1 (de) * | 1991-02-01 | 2002-05-15 | Suntory Ltd | Verwendung von cilastatin, glutathione und n- acetyl-l-cysteine zur herstellung eines arzneimittels zur verbesserung der resorption von carbapenem oder penem antibiotika im magen-darm- trakt |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3498979A (en) * | 1967-04-03 | 1970-03-03 | Glaxo Lab Ltd | Recovery of n-(7-2'-thienylacetamidoceph-3-em-3-ylmethyl) pyridinium - 4-carboxylate from an acid addition salt thereof |
| FR2272684A1 (en) * | 1975-01-07 | 1975-12-26 | Ito Shojiro | Antibiotic-unsaturated acid compsns. - having a synergistic effect against gram positive and negative bacteria |
| DK153486C (da) * | 1978-07-03 | 1988-11-28 | Merck & Co Inc | Analogifremgangsmaade til fremstilling af krystallinsk n-formimidoyl-thienamycin-monohydrat |
| AR244550A1 (es) * | 1978-07-24 | 1993-11-30 | Merck & Co Inc | Procedimiento para obtener una composicion de antibioticos del tipo de la tienamicina con inhibidores de la dipeptidasa |
-
1980
- 1980-10-30 GR GR63250A patent/GR70784B/el unknown
- 1980-10-30 IE IE2249/80A patent/IE50333B1/en unknown
- 1980-10-31 EP EP80106704A patent/EP0028778B1/en not_active Expired
- 1980-10-31 DK DK462580A patent/DK462580A/da not_active Application Discontinuation
- 1980-10-31 DE DE8080106704T patent/DE3069986D1/de not_active Expired
- 1980-10-31 AT AT80106704T patent/ATE11221T1/de not_active IP Right Cessation
- 1980-10-31 PT PT72006A patent/PT72006B/pt unknown
- 1980-10-31 ES ES496446A patent/ES496446A0/es active Granted
- 1980-11-04 JP JP15394880A patent/JPS5681518A/ja active Pending
-
1981
- 1981-11-05 ES ES506895A patent/ES8207130A1/es not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES8201954A1 (es) | 1982-01-16 |
| GR70784B (en:Method) | 1983-03-23 |
| ES496446A0 (es) | 1982-01-16 |
| ES506895A0 (es) | 1982-09-01 |
| PT72006B (en) | 1984-05-29 |
| DK462580A (da) | 1981-05-03 |
| PT72006A (en) | 1980-11-01 |
| EP0028778B1 (en) | 1985-01-16 |
| ES8207130A1 (es) | 1982-09-01 |
| JPS5681518A (en) | 1981-07-03 |
| DE3069986D1 (en) | 1985-02-28 |
| ATE11221T1 (de) | 1985-02-15 |
| EP0028778A1 (en) | 1981-05-20 |
| IE802249L (en) | 1981-05-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0007614B1 (en) | An antibacterial composition of thienamycin-type compound and a dipeptidase inhibitor | |
| EP0072014B1 (en) | Combination of 2-substituted penems with dipeptidase inhibitors | |
| US5147868A (en) | Thienamycin renal peptidase inhibitors | |
| US4539208A (en) | Combination of thienamycin-type antibiotics with dipeptidase inhibitors | |
| US4668504A (en) | Use of substituted propenoates to prevent nephrotoxicity of certain antibiotics | |
| EP0010573B1 (en) | Novel z-2-acylamino-3-monosubstituted propenic acids and their esters and salts, and processes for preparing them | |
| EP0161546B1 (en) | Combination of 2-substituted carbapenems with dipeptidase inhibitors | |
| EP0028778B1 (en) | Antibacterial compositions comprising a beta-lactam-type compound and a 3-substituted propenoate | |
| US4988728A (en) | Suprofen esters and amides as ophthalmic anti-inflammatory agents | |
| EP0048301A1 (en) | 2-(Cyclopropane-carboxamido)-2-alkenoic acids, their esters and salts, and antibacterial compositions comprising the same and a thienamycin-type compound | |
| US4616038A (en) | Combination of thienamycin-type antibiotics with dipeptidase inhibitors | |
| US5071843A (en) | Combination of 2-substituted carbapenems with dipeptidase inhibitors | |
| US4880793A (en) | Combination of thienamycin-type antibiotics with dipeptidase inhibitors | |
| EP0049389B1 (en) | Z-omega-substituted thio-2-(2,2-dimethylcyclopropanecarboxamido)-2-alkenoic acids, a process for preparing and an antibacterial composition containing the same | |
| US4406902A (en) | Dipeptidase inhibitors | |
| EP0048025A1 (en) | Antibacterial composition of thienamycin type compound and a dipeptidase inhibitor | |
| US4739113A (en) | Bis(cyclopropanecarboxamido)alkadienedioic acids as renal dipeptidase inhibitors | |
| JPS6160816B2 (en:Method) | ||
| HU211143A9 (hu) | Tienamicin renális peptidáz inhibitorok Az átmeneti oltalom az 1-23. igénypontokra vonatkozik. | |
| DD145099A5 (de) | Verfahren zur herstellung von z-2- cylamino-3-monosubst.-propionaten | |
| NO783132L (no) | Fremgangsmaate for fremstilling av clavulansyreaminoetere | |
| NO150602B (no) | Analogifremgangmaate ved fremstilling av nye kjemiske forbindelser som selektivt inhiberer metabolisme av dipeptidase | |
| SI8310101A8 (sl) | Postopek za pridobivanje z 2-acilamino-3-monosubstituiranih propenoatov |