DE69030147T2 - 10-(1-Hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.0.3,8]undec-2-en-2-carbonsäure-Derivate - Google Patents
10-(1-Hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.0.3,8]undec-2-en-2-carbonsäure-DerivateInfo
- Publication number
- DE69030147T2 DE69030147T2 DE69030147T DE69030147T DE69030147T2 DE 69030147 T2 DE69030147 T2 DE 69030147T2 DE 69030147 T DE69030147 T DE 69030147T DE 69030147 T DE69030147 T DE 69030147T DE 69030147 T2 DE69030147 T2 DE 69030147T2
- Authority
- DE
- Germany
- Prior art keywords
- group
- solution
- compound
- mixture
- added
- Prior art date
- 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.)
- Expired - Fee Related
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- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 title 1
- LDCMOCGAIMMZPI-UHFFFAOYSA-N 2-methylundec-2-enoic acid Chemical class CCCCCCCCC=C(C)C(O)=O LDCMOCGAIMMZPI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 260
- -1 azidoethoxy group Chemical group 0.000 claims abstract description 53
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 40
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 32
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 10
- 125000000468 ketone group Chemical group 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 3
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 125000006239 protecting group Chemical group 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 150000002148 esters Chemical class 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 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 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 239000012453 solvate Substances 0.000 claims description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 230000000699 topical effect Effects 0.000 claims description 5
- 208000035143 Bacterial infection Diseases 0.000 claims description 4
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 4
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 230000009885 systemic effect Effects 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 101100533888 Hypocrea jecorina (strain QM6a) sor4 gene Proteins 0.000 claims description 2
- 101100533877 Hypocrea jecorina (strain QM6a) sor8 gene Proteins 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
- 229930194542 Keto Natural products 0.000 claims 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 13
- 125000003277 amino group Chemical group 0.000 abstract description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 abstract description 3
- 125000002947 alkylene group Chemical group 0.000 abstract description 2
- 101100276977 Caenorhabditis elegans dapk-1 gene Proteins 0.000 abstract 1
- 239000005864 Sulphur Chemical group 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 357
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 286
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 252
- 239000000243 solution Substances 0.000 description 246
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 236
- 239000000203 mixture Substances 0.000 description 169
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 158
- 239000000543 intermediate Substances 0.000 description 86
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 82
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 80
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 79
- 238000005160 1H NMR spectroscopy Methods 0.000 description 78
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 74
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 70
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 69
- 239000007787 solid Substances 0.000 description 64
- 239000012044 organic layer Substances 0.000 description 60
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 58
- 239000012267 brine Substances 0.000 description 58
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 58
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 58
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- 239000003921 oil Substances 0.000 description 52
- 239000011541 reaction mixture Substances 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 47
- 239000000741 silica gel Substances 0.000 description 47
- 229910002027 silica gel Inorganic materials 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 238000004809 thin layer chromatography Methods 0.000 description 45
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 42
- 239000003480 eluent Substances 0.000 description 41
- 239000002904 solvent Substances 0.000 description 40
- 235000017557 sodium bicarbonate Nutrition 0.000 description 39
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 39
- 239000013067 intermediate product Substances 0.000 description 37
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- 239000003208 petroleum Substances 0.000 description 31
- 150000003952 β-lactams Chemical class 0.000 description 31
- 229960000583 acetic acid Drugs 0.000 description 28
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 27
- 229910052700 potassium Inorganic materials 0.000 description 27
- 239000011591 potassium Substances 0.000 description 27
- 229960003975 potassium Drugs 0.000 description 27
- 238000003818 flash chromatography Methods 0.000 description 26
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 25
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 24
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 21
- 150000002576 ketones Chemical class 0.000 description 19
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 19
- 235000019441 ethanol Nutrition 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 16
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 15
- 235000019270 ammonium chloride Nutrition 0.000 description 15
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 239000008096 xylene Substances 0.000 description 15
- 239000002585 base Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- HNOLIWBAJVIBOU-UHFFFAOYSA-N prop-2-enyl 2-chloro-2-oxoacetate Chemical compound ClC(=O)C(=O)OCC=C HNOLIWBAJVIBOU-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 150000003951 lactams Chemical class 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 11
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 11
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 9
- 239000006260 foam Substances 0.000 description 9
- ZUFQCVZBBNZMKD-UHFFFAOYSA-M potassium 2-ethylhexanoate Chemical compound [K+].CCCCC(CC)C([O-])=O ZUFQCVZBBNZMKD-UHFFFAOYSA-M 0.000 description 9
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 150000002118 epoxides Chemical class 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- 150000007530 organic bases Chemical class 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 7
- 125000004414 alkyl thio group Chemical group 0.000 description 7
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 150000001768 cations Chemical class 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 150000002084 enol ethers Chemical class 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical class [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- 239000000010 aprotic solvent Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- 235000010265 sodium sulphite Nutrition 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 239000000370 acceptor Substances 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 150000004965 peroxy acids Chemical class 0.000 description 4
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000012047 saturated solution Substances 0.000 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 description 4
- 238000011200 topical administration Methods 0.000 description 4
- 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 3
- 241000282412 Homo Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 125000005002 aryl methyl group Chemical group 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000010779 crude oil Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000001925 cycloalkenes Chemical class 0.000 description 3
- SBEMOANGDSSPJY-UHFFFAOYSA-N cyclohexen-1-yloxy(trimethyl)silane Chemical compound C[Si](C)(C)OC1=CCCCC1 SBEMOANGDSSPJY-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 3
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- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002788 crimping Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- WPIRVUXAMPRMAY-UHFFFAOYSA-N cyclohexa-1,5-dien-1-yloxy(trimethyl)silane Chemical compound C[Si](C)(C)OC1=CCCC=C1 WPIRVUXAMPRMAY-UHFFFAOYSA-N 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- JHIVVAPYMSGYDF-PTQBSOBMSA-N cyclohexanone Chemical class O=[13C]1CCCCC1 JHIVVAPYMSGYDF-PTQBSOBMSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- PBGGNZZGJIKBMJ-UHFFFAOYSA-N di(propan-2-yl)azanide Chemical compound CC(C)[N-]C(C)C PBGGNZZGJIKBMJ-UHFFFAOYSA-N 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- SLFUXNFVAANERW-UHFFFAOYSA-N ethyl hexanoate;potassium Chemical compound [K].CCCCCC(=O)OCC SLFUXNFVAANERW-UHFFFAOYSA-N 0.000 description 1
- YLEAHEKEZRNPIM-UHFFFAOYSA-N ethyl-hydroxy-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound CCS(O)(=O)=S YLEAHEKEZRNPIM-UHFFFAOYSA-N 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004993 haloalkoxycarbonyl group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 150000002373 hemiacetals Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- BTNMPGBKDVTSJY-UHFFFAOYSA-M keto-phenylpyruvate Chemical compound [O-]C(=O)C(=O)CC1=CC=CC=C1 BTNMPGBKDVTSJY-UHFFFAOYSA-M 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 230000002475 laxative effect Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- WRUGWIBCXHJTDG-UHFFFAOYSA-L magnesium sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Mg+2].[O-]S([O-])(=O)=O WRUGWIBCXHJTDG-UHFFFAOYSA-L 0.000 description 1
- 229940061634 magnesium sulfate heptahydrate Drugs 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical group C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- GTWJETSWSUWSEJ-UHFFFAOYSA-N n-benzylaniline Chemical compound C=1C=CC=CC=1CNC1=CC=CC=C1 GTWJETSWSUWSEJ-UHFFFAOYSA-N 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- OGNBTAJODVCZQA-UHFFFAOYSA-N tetrabutylazanium;trihydrate Chemical compound O.O.O.CCCC[N+](CCCC)(CCCC)CCCC OGNBTAJODVCZQA-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Claims (16)
1. Verbindungen der allgemeinen Formel (I)
worin
R&sub1; für ein Wasserstoffatom oder eine
Hydroxylschutzgruppe steht;
R&sub2; für ein Wasserstoffatom oder eine
Carboxylschutzgruppe steht; und
R&sub3; für ein Wasserstoffatom, eine Hydroxylgruppe, eine
Hydroxymethylgruppe, eine C&sub1;&submin;&sub3;-Alkylgruppe oder eine Gruppe
XR&sub4; steht&sub1; worin X ein Sauerstoffatom oder die Gruppe S(O)n
bedeutet, worin n den Wert 0 hat oder die ganze Zahl 1 oder
2 ist, und R&sub4; für eine C&sub1;&submin;&sub5;-Alkyl-, C&sub3;&submin;&sub7;-Cycloalkyl- oder
Phenylgruppe steht, oder, wenn X ein Sauerstoff- oder
Schwefelatom ist, R&sub4; auch die Gruppe AlkNR&sub5;R&sub6; bedeuten kann,
worin Alk für eine gerade oder verzweigte C&sub2;&submin;&sub6;-Alkylenkette
steht, und R&sub5; und R&sub6; jeweils unabhängig voneinander für ein
Wasserstoffatom oder eine C&sub1;&submin;&sub4;-Alkylgruppe stehen oder R&sub5;
eine Formyl-, Acetyl- oder Iminomethylgruppe darstellt und
R&sub6; für ein Wasserstoffatom steht, oder worin R&sub5; und R&sub6;
zusammen mit dem Stickstoffatom, an das sie angefügt sind,
einen Pyrrolidino- oder Piperidinoring bilden, oder R&sub3; eine
Gruppe (CH&sub2;)mNR&sub7;R&sub8; darstellt, worin m den Wert 0 oder 1 hat
und R&sub7; und R&sub8; jeweils unabhängig voneinander für ein
Wasserstoffatom oder eine C&sub1;&submin;&sub4;-Alkylgruppe stehen oder R&sub7; eine
Formyl-, Acetyl- oder Iminomethylgruppe darstellt und R&sub8; für
ein Wasserstoffatom steht, oder R&sub3; und das Kohlenstoffatom,
an das es angefügt ist, eine Ketogruppe oder ein
Ketalderivat davon darstellen;
und Salze (mit Einschluß von inneren Salzen, wenn
passend) sowie metabolisch labile Ester und Solvate davon.
2. Verbindungen nach Anspruch 1, dadurch
gekennzeichnet, daß R&sub1; und R&sub2; Wasserstoffatome darstellen
sowie physiologisch annehmbare Salze (mit Einschluß innerer
Salze), metabolisch labile Ester und Solvate davon.
3, Verbindungen nach Anspruch 2, dadurch
gekennzeichnet, daß R&sub3; für eine Amino-, Aminomethyl-,
Methylamino-, Hydroxy-, Hydroxymethyl-, Methyl-, Methoxy-,
Ethoxy-, Isopropoxy-, Cyclopentoxy-, Aminoethoxy-,
Methylthio-, Phenylthio- oder Methylsulfinylgruppe steht oder
zusammen mit dem Kohlenstoffatom, an das es angefügt ist, eine
Keto- oder Dimethylketalgruppe bildet.
4. Verbindungen der allgemeinen Formel (Ie)
worin R&sub3; für eine Amino-, Aminomethyl-, Methylamino-,
Hydroxy-, Hydroxymethyl-, Methoxy-, Ethoxy-, Isopropoxy-,
Aminoethoxy-, Methylthio- oder Phenylthiogruppe steht,
und physiologisch annehmbare Salze, metabolisch labile
Ester und Solvate davon.
5. (45,8S,9R,10S,12R)-4-Methoxy-10-(1-hydroxyethyl)-11-
oxo-1-azatricyclo[7.2.0.03,8]undec-2-en-2-carbonsäure und
physiologisch annehmbare Salze, metabolisch labile Ester und
Solvate davon.
6. Die Verbindungen:
(45,85,9R,10S,12R)-4-Methylthio-10-(1-hydroxyethyl)-11-oxo-
1-azatricyclo[7.2.0.03,8]undec-2-en-2-carbonsäure,
(4S,8S,9R,10S,12R)-4-Methylsulfinyl-10-(1-hydroxyethyl)-11-
oxo-1-azatricyclo[7.2.0.03,8]undec-2-en-2-carbonsäure,
(4S,8S,9R,10S,12R)-4-Amino-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.03,8]undec-2-en-2-carbonsäure,
und physiologisch annehmbare Salze, metabolisch labile Ester
und Solvate davon.
7. Verfahren zur Herstellung der Verbindungen nach
Anspruch 1, umfassend die Cyclisierung einer Verbindung der
Formel (II)
(worin R1a eine Hydroxylschutzgruppe darstellt, R2a eine
Carboxylschutzgruppe darstellt und R3a die Definition für R&sub3;
hat oder eine Gruppe bedeutet, die in diese umwandelbar ist,
und Y für ein Sauerstoffatom oder eine Phosphingruppe steht)
und danach erforderlichenfalls oder gewünschtenfalls die
Unterwerfung der resultierenden Verbindung entweder vor oder
nach irgendeiner Auftrennung in ihre stereochemischen
Isomeren einer oder mehreren der folgenden Maßnahmen:
a) Umwandlung einer Gruppe R3a in die gewünschte
Gruppe R&sub3;,
b) Entfernung einer oder mehrerer Schutzgruppen, oder
c) Umwandlung einer Verbindung, bei der R&sub2; ein
Wasserstoffatom oder eine Carboxylschutzgruppe ist, in ein
entsprechendes Salz, einen metabolisch labilen Ester oder ein
Solvat.
8. Verfahren nach Anspruch 7, dadurch
gekennzeichnet, daß man die cyclisierung einer Verbindung
der Formel (II), bei der Y ein Sauerstoffatom ist, durch
Erhitzen in Gegenwart eines organischen Phosphits bewirkt.
9. Verfahren nach Anspruch 7 oder 8, dadurch
gekennzeichnet, daß man eine Verbindung (1), bei
der R&sub2; eine Carboxylschutzgruppe ist und R&sub3; eine Gruppe SR&sub4;
ist (wobei R&sub4; wie in Anspruch 1 definiert ist) oxidiert, um
eine Verbindung (I) zu erhalten, bei der R&sub3; eine Gruppe SOR&sub4;
ist.
10. Verfahren nach Anspruch 7 oder 8, dadurch
gekennzeichnet, daß man eine Verbindung (I), bei
der R&sub2; eine Carboxylschutzgruppe ist und R&sub3; zusammen mit dem
Kohlenstoffatom, an das es angefügt ist, eine Ketalgruppe
darstellt, hydrolysiert, um eine Verbindung (1) zu erhalten,
bei der die Gruppe R&sub3; zusammen mit dem Kohlenstoffatom, an
das sie angefügt ist, eine Ketogruppe darstellt.
11. Verfahren nach Anspruch 7 oder 8, dadurch
gekennzeichnet, daß man eine Verbindung (I), bei
der R&sub2; eine Carboxylschutzgruppe ist und R&sub3; zusammen mit dem
Kohlenstoffatom, an das es angefügt ist, eine Ketogruppe
darstellt, reduziert, um eine Verbindung (I) zu erhalten,
bei der R&sub3; eine Hydroxylgruppe ist.
12. Verfahren nach Anspruch 7 oder 8, dadurch
gekennzeichnet, daß man eine Verbindung (I), bei
der R&sub1; eine Hydroxylschutzgruppe ist, R&sub2; für eine
Carboxylschutzgruppe steht und R&sub3; eine Hydroxylgruppe ist,
O-alkyliert, um eine Verbindung (1) zu erhalten, bei der R&sub3; eine
Alkoxygruppe ist.
13, Verbindungen nach einem der Ansprüche 2 bis 6 zur
Verwendung bei der Therapie oder Prophylaxe von systemischen
oder topischen bakteriellen Infektionen beim Menschen oder
Tier.
14. Verwendung einer Verbindung nach einem der Ansprüche 2
bis 6 zur Herstellung eines Arzneimittels zur Behandlung
oder Prophylaxe von systemischen oder topischen bakteriellen
Infektionen beim Menschen oder Tier.
15. Pharmazeutische Präparate, umfassend eine Verbindung
nach einem der Ansprüche 2 bis 6, im Gemisch mit einem oder
mehreren physiologisch annehmbaren Trägern oder
Exzipientien.
16.
Natrium-(45,85,9R,10S,12R)-4-methoxy-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.03,8]undec-2-en-2-
carboxylat.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB898920337A GB8920337D0 (en) | 1989-09-08 | 1989-09-08 | Heterocyclic compounds |
| GB909015484A GB9015484D0 (en) | 1990-07-13 | 1990-07-13 | Heterocyclic compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69030147D1 DE69030147D1 (de) | 1997-04-17 |
| DE69030147T2 true DE69030147T2 (de) | 1997-07-10 |
Family
ID=26295887
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69029627T Expired - Fee Related DE69029627T2 (de) | 1989-09-08 | 1990-09-07 | 4-(1'-Oxocyclohex-2'-yl)azetidin-2-on-Derivate |
| DE69030147T Expired - Fee Related DE69030147T2 (de) | 1989-09-08 | 1990-09-07 | 10-(1-Hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.0.3,8]undec-2-en-2-carbonsäure-Derivate |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69029627T Expired - Fee Related DE69029627T2 (de) | 1989-09-08 | 1990-09-07 | 4-(1'-Oxocyclohex-2'-yl)azetidin-2-on-Derivate |
Country Status (28)
| Country | Link |
|---|---|
| US (2) | US5138048A (de) |
| EP (2) | EP0416952B1 (de) |
| JP (2) | JP3018442B2 (de) |
| KR (1) | KR100188175B1 (de) |
| AT (2) | ATE147394T1 (de) |
| AU (1) | AU632163B2 (de) |
| CA (1) | CA2024880C (de) |
| CZ (1) | CZ285778B6 (de) |
| DD (1) | DD298102A5 (de) |
| DE (2) | DE69029627T2 (de) |
| DK (1) | DK0416953T3 (de) |
| ES (2) | ES2100872T3 (de) |
| FI (1) | FI93450C (de) |
| GR (1) | GR3023647T3 (de) |
| HR (1) | HRP940559B1 (de) |
| HU (1) | HU218222B (de) |
| IE (1) | IE903257A1 (de) |
| IL (1) | IL95609A (de) |
| MY (1) | MY106980A (de) |
| NO (1) | NO175479C (de) |
| NZ (1) | NZ235223A (de) |
| PL (1) | PL166197B1 (de) |
| PT (1) | PT95247B (de) |
| RU (1) | RU2054006C1 (de) |
| SG (1) | SG73399A1 (de) |
| SI (1) | SI9011699A (de) |
| SK (1) | SK278688B6 (de) |
| YU (1) | YU48073B (de) |
Families Citing this family (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU636913B2 (en) * | 1989-10-11 | 1993-05-13 | Takeda Chemical Industries Ltd. | Tricyclic carbapenem compounds |
| GB9015485D0 (en) * | 1990-07-13 | 1990-08-29 | Glaxo Spa | Heterocyclic derivatives |
| NZ239474A (en) * | 1990-08-21 | 1994-06-27 | Glaxo Spa | Azatricyclic derivatives and pharmaceutical compositions |
| GB9104769D0 (en) * | 1991-03-07 | 1991-04-17 | Glaxo Spa | Heterocyclic compounds |
| GB9104838D0 (en) * | 1991-03-07 | 1991-04-17 | Glaxo Spa | Heterocyclic compounds |
| AP198A (en) * | 1991-03-07 | 1992-06-30 | Glaxo Spa | Heterocyclic compounds. |
| GB9104833D0 (en) * | 1991-03-07 | 1991-04-17 | Glaxo Spa | Heterocyclic compounds |
| GB9104832D0 (en) * | 1991-03-07 | 1991-04-17 | Glaxo Spa | Heterocyclic compounds |
| CA2065079C (en) * | 1991-04-05 | 2003-03-18 | Michiyuki Sendai | Polycyclic carbapenem compounds, their production and use |
| TW198035B (de) * | 1991-05-29 | 1993-01-11 | Hoechst Ag | |
| GB9218240D0 (en) * | 1992-08-27 | 1992-10-14 | Glaxo Spa | Heterocyclic compounds |
| GB9218781D0 (en) * | 1992-09-04 | 1992-10-21 | Glaxo Spa | Heterocyclic derivatives |
| GB9305806D0 (en) * | 1993-03-20 | 1993-05-05 | Glaxo Spa | Chemical compounds |
| GB9305853D0 (en) * | 1993-03-20 | 1993-05-05 | Glaxo Spa | Chemical compounds |
| GB9305805D0 (en) * | 1993-03-20 | 1993-05-05 | Glaxo Spa | Chemical process |
| GB9305813D0 (en) * | 1993-03-20 | 1993-05-05 | Glaxo Spa | Chemical process |
| US5849907A (en) * | 1993-03-20 | 1998-12-15 | Glaxo Wellcome Spa | Chemical process |
| US5374630A (en) * | 1993-06-10 | 1994-12-20 | Merck & Co., Inc. | Bridged carbapenem antibacterial compounds |
| US5372993A (en) * | 1993-06-10 | 1994-12-13 | Merck & Co., Inc. | Bridged carbapenem compounds, compositions containing such compounds and methods of use |
| US5401735A (en) * | 1993-08-02 | 1995-03-28 | Merck & Co., Inc. | Bridged biphenyl carbapenem antibacterial compounds |
| US5384317A (en) * | 1993-08-02 | 1995-01-24 | Merck & Co., Inc. | Bridged biphenyl carbapenem compounds, compositions containing such compounds and methods of use |
| GB9323137D0 (en) * | 1993-11-10 | 1994-01-05 | Glaxo Spa | Chemical compounds |
| GB9403729D0 (en) * | 1994-02-26 | 1994-04-13 | Glaxo Spa | Amine derivatives |
| GB9406074D0 (en) * | 1994-03-26 | 1994-05-18 | Glaxo Spa | Chemical process |
| GB2287709A (en) * | 1994-03-26 | 1995-09-27 | Glaxo Spa | Silylated azetidinone intermediates |
| US5688786A (en) * | 1994-04-01 | 1997-11-18 | Microcide Pharmaceuticals, Inc. | β-lactam antibiotics |
| US5698547A (en) * | 1994-04-01 | 1997-12-16 | Microcide Pharmaceuticals, Inc. | Cephalosporin antibiotics |
| GB9516118D0 (en) * | 1995-08-05 | 1995-10-04 | Glaxo Spa | Chemical process |
| US6531466B2 (en) | 1996-11-14 | 2003-03-11 | Glaxosmithkline Spa | Tricyclic carbapenem compounds |
| GB9623684D0 (en) * | 1996-11-14 | 1997-01-08 | Glaxo Wellcome Spa | Chemical compounds |
| JPH10168057A (ja) * | 1996-12-12 | 1998-06-23 | Takasago Internatl Corp | シクロヘキシルアゼチジノン誘導体の製造法 |
| AU5781498A (en) * | 1997-02-10 | 1998-08-26 | Sankyo Company Limited | Tricyclic heterocyclic compounds |
| US5994343A (en) * | 1997-10-02 | 1999-11-30 | Merck & Co., Inc. | Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment |
| US6207823B1 (en) * | 1997-10-23 | 2001-03-27 | Merck & Co., Inc. | Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment |
| JP2001520192A (ja) * | 1997-10-23 | 2001-10-30 | メルク エンド カムパニー インコーポレーテッド | カルバペネム抗菌性化合物、組成物及び治療方法 |
| US6271222B1 (en) | 1998-05-28 | 2001-08-07 | Merck & Co., Inc. | Penem antibacterial compounds, compositions and methods of treatment |
| CN101367817B (zh) * | 2007-06-26 | 2011-01-12 | 山东轩竹医药科技有限公司 | 含有环己烯酮甲酰氨基的碳青霉烯化合物 |
| EP2085084A1 (de) * | 2008-01-29 | 2009-08-05 | LEK Pharmaceuticals D.D. | Verwendung eines Hemmers von Beta-Lactamasen und dessen Kombination mit Beta-Lactam-Antibiotika |
| EP2135871A1 (de) * | 2008-06-18 | 2009-12-23 | LEK Pharmaceuticals D.D. | Neuartige Trinemantibiotika und Hemmer von Beta-Lactamasen |
| BR112019023322B1 (pt) | 2017-05-08 | 2023-11-14 | Glaxosmithkline Intellectual Property Development Limited | Uso do sanfetrinem, sanfetrinem sódico ou sanfetrinem cilexetila para a produção de um medicamento para o tratamento de tuberculose e combinação de sanfetrinem |
| KR102471353B1 (ko) * | 2020-07-03 | 2022-11-28 | 한국공학대학교산학협력단 | 바이메탈을 이용한 복원 기능을 포함하는 퓨즈 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4260627A (en) * | 1978-10-24 | 1981-04-07 | Merck & Co., Inc. | 1-, 6- And 2-substituted-1-carba-2-penem-3-carboxylic acids |
| US4600713A (en) * | 1979-12-03 | 1986-07-15 | Merck & Co., Inc. | 1-, 6- and 2-substituted-1-carba-2-penem-3-carboxylic acids |
| US4374848A (en) * | 1981-09-14 | 1983-02-22 | Merck & Co., Inc. | 6-(1-Hydroxyethyl)cyclonocardicin |
| US4374849A (en) * | 1981-09-14 | 1983-02-22 | Merck & Co., Inc. | 6-Amidocyclonocardicins |
| JPS61236785A (ja) * | 1985-04-15 | 1986-10-22 | Sankyo Co Ltd | アゼチジノン誘導体 |
| GB8607921D0 (en) | 1986-04-01 | 1986-05-08 | Fujisawa Pharmaceutical Co | 3,4-disubstituted-2-azetidinone derivatives |
| AU636913B2 (en) * | 1989-10-11 | 1993-05-13 | Takeda Chemical Industries Ltd. | Tricyclic carbapenem compounds |
-
1990
- 1990-09-04 CZ CS904359A patent/CZ285778B6/cs not_active IP Right Cessation
- 1990-09-06 DD DD90343863A patent/DD298102A5/de not_active IP Right Cessation
- 1990-09-06 YU YU169990A patent/YU48073B/sh unknown
- 1990-09-06 SI SI9011699A patent/SI9011699A/sl unknown
- 1990-09-07 NZ NZ235223A patent/NZ235223A/xx unknown
- 1990-09-07 AU AU62265/90A patent/AU632163B2/en not_active Ceased
- 1990-09-07 MY MYPI90001540A patent/MY106980A/en unknown
- 1990-09-07 IL IL9560990A patent/IL95609A/en not_active IP Right Cessation
- 1990-09-07 JP JP2235976A patent/JP3018442B2/ja not_active Expired - Lifetime
- 1990-09-07 US US07/578,949 patent/US5138048A/en not_active Expired - Fee Related
- 1990-09-07 US US07/578,948 patent/US5407931A/en not_active Expired - Fee Related
- 1990-09-07 ES ES90309848T patent/ES2100872T3/es not_active Expired - Lifetime
- 1990-09-07 FI FI904423A patent/FI93450C/fi not_active IP Right Cessation
- 1990-09-07 NO NO903914A patent/NO175479C/no unknown
- 1990-09-07 SG SG1996006269A patent/SG73399A1/en unknown
- 1990-09-07 SK SK4359-90A patent/SK278688B6/sk unknown
- 1990-09-07 KR KR1019900014226A patent/KR100188175B1/ko not_active IP Right Cessation
- 1990-09-07 ES ES90309847T patent/ES2095860T3/es not_active Expired - Lifetime
- 1990-09-07 PT PT95247A patent/PT95247B/pt not_active IP Right Cessation
- 1990-09-07 EP EP90309847A patent/EP0416952B1/de not_active Expired - Lifetime
- 1990-09-07 IE IE325790A patent/IE903257A1/en not_active IP Right Cessation
- 1990-09-07 DE DE69029627T patent/DE69029627T2/de not_active Expired - Fee Related
- 1990-09-07 DE DE69030147T patent/DE69030147T2/de not_active Expired - Fee Related
- 1990-09-07 PL PL90286796A patent/PL166197B1/pl unknown
- 1990-09-07 AT AT90309847T patent/ATE147394T1/de active
- 1990-09-07 DK DK90309848.1T patent/DK0416953T3/da active
- 1990-09-07 JP JP2235975A patent/JP3035325B2/ja not_active Expired - Fee Related
- 1990-09-07 CA CA002024880A patent/CA2024880C/en not_active Expired - Fee Related
- 1990-09-07 HU HU826/90A patent/HU218222B/hu not_active IP Right Cessation
- 1990-09-07 EP EP90309848A patent/EP0416953B1/de not_active Expired - Lifetime
- 1990-09-07 AT AT90309848T patent/ATE150022T1/de not_active IP Right Cessation
-
1992
- 1992-06-04 RU SU5011726/04A patent/RU2054006C1/ru not_active IP Right Cessation
-
1994
- 1994-09-16 HR HRP-1699/90A patent/HRP940559B1/xx not_active IP Right Cessation
-
1997
- 1997-05-09 GR GR970401017T patent/GR3023647T3/el unknown
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