MXPA00012391A - Derivatives of 3-(2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)-cephems - Google Patents
Derivatives of 3-(2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)-cephemsInfo
- Publication number
- MXPA00012391A MXPA00012391A MXPA/A/2000/012391A MXPA00012391A MXPA00012391A MX PA00012391 A MXPA00012391 A MX PA00012391A MX PA00012391 A MXPA00012391 A MX PA00012391A MX PA00012391 A MXPA00012391 A MX PA00012391A
- Authority
- MX
- Mexico
- Prior art keywords
- hydrogen
- compounds
- oxo
- ocor
- formula
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 41
- 239000001257 hydrogen Substances 0.000 claims abstract description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 40
- 239000011780 sodium chloride Substances 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 150000004677 hydrates Chemical class 0.000 claims abstract description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- -1 5-amino- [1,2,4] thiadiazol-3-yl Chemical group 0.000 claims description 52
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 19
- 159000000000 sodium salts Chemical class 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 239000000969 carrier Substances 0.000 claims description 2
- 230000001225 therapeutic Effects 0.000 claims description 2
- 230000000069 prophylaxis Effects 0.000 claims 4
- 239000000126 substance Substances 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 125000005348 fluorocycloalkyl group Chemical group 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 21
- 210000003702 immature single positive T cell Anatomy 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- DSIJXEVOJMBKAM-UHFFFAOYSA-M sodium;2-methyloct-2-enoate Chemical compound [Na+].CCCCCC=C(C)C([O-])=O DSIJXEVOJMBKAM-UHFFFAOYSA-M 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000875 corresponding Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000002194 synthesizing Effects 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000002844 melting Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 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 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal Effects 0.000 description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 150000003893 lactate salts Chemical class 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical class CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- GXYPITRJSPDNLU-UHFFFAOYSA-M (4-nitrophenyl)chloranuidylformate Chemical compound [O-]C(=O)[Cl-]C1=CC=C([N+]([O-])=O)C=C1 GXYPITRJSPDNLU-UHFFFAOYSA-M 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- AAMTXHVZOHPPQR-UHFFFAOYSA-N 2-(hydroxymethyl)prop-2-enoic acid Chemical compound OCC(=C)C(O)=O AAMTXHVZOHPPQR-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- QXNACHIBCYCZJG-UHFFFAOYSA-N 2-methylpropyl 2-[(4-nitrophenoxy)carbonyloxymethyl]pent-2-enoate Chemical compound CC(C)COC(=O)C(=CCC)COC(=O)OC1=CC=C([N+]([O-])=O)C=C1 QXNACHIBCYCZJG-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 229940100198 ALKYLATING AGENTS Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N Ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 102100000129 CHURC1 Human genes 0.000 description 1
- 101710014631 CHURC1 Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N Norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960001180 Norfloxacin Drugs 0.000 description 1
- 210000004940 Nucleus Anatomy 0.000 description 1
- 230000035536 Oral bioavailability Effects 0.000 description 1
- 102100013577 POU2F2 Human genes 0.000 description 1
- 101710006193 POU2F2 Proteins 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 229940055023 Pseudomonas aeruginosa Drugs 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 230000000844 anti-bacterial Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- HFGASVDZUAPXJQ-UHFFFAOYSA-N ethyl 2-[(4-nitrophenoxy)carbonyloxymethyl]prop-2-enoate Chemical compound CCOC(=O)C(=C)COC(=O)OC1=CC=C([N+]([O-])=O)C=C1 HFGASVDZUAPXJQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LKHYFCSSVZVVNF-UHFFFAOYSA-N ethyl hexanoate;sodium Chemical compound [Na].CCCCCC(=O)OCC LKHYFCSSVZVVNF-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000002319 fibrinogen receptor antagonist Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 230000036220 oral bioavailability Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrugs Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Abstract
The present invention is concerned with new compounds of formula (I) wherein R1 is hydrogen, C1-6-alkyl, optionally substituted by fluoro, or C3-6-cycloalkyl;R2 is hydrogen or a group selected from -CH2C(=CHR)-COOR, -CH2OCOR, -CH(R)OCOR, -CH(R)OCOOR, -CH(OCOR)OCOR, -CH2COCH2OCOR and (II);R3 is hydrogen or group selected from -CH2C(=CH2)-COOR, -COOCH2C(=CHR)-COOR, -COOCH2OCOR, -COOCH(R)OCOR, -CO CH(R)OCOOR, -COOCH(OCOR)OCOR, -COOCH2COCH2OCOR, and (III);with the proviso that one of R2 and R3 is hydrogen and the other of R2 and R3 is different from hydrogen, R is hydrogen or C1-6-alkyl;R4 is hydrogen or hydroxy, R5 is hydrogen or&ohgr;-hydroxyalkyl;and X is CH or N, as well as pharmaceutically acceptable salts of said compounds and hydrates of said compounds and of their salts, and with the use of compounds of formula (I) and of pharmaceutically acceptable salts of said compounds and hydrates of said compounds and of their salts for the manufacture of pharmaceutical preparations containing such compounds.
Description
DERIVATIVES OF 3- (2-OXO- [1,3 '] BIPIRROLIDINIL-3-ILIDENMETIL) - CEFE S
Description of the invention. The present invention relates to the new compounds of formula I.
where R1 is a hydrogen, C? -6-alkyl, optionally substituted by fluorine, or the C3_6-cycloalkyl; R2 is a hydrogen or a group selected from -CH2C (= CHR) -C00R, -CH20C0R, -CH (R) OCOR, -CH (R) OCOOR, -CH (OCOR) OCOR, -CH2COCH2OCOR and
R3 is a hydrogen or a group selected from -CH2C (= CH2) -COOR, -COOCH2C (= CHR) -COOR, -COOCH2OCOR, -COOCH (R) OCOR, -COOCH (R) OCOOR, -COOCH (OCOR) OCOR , -COOCH2COCH2OCOR, and
Ref: 125347 with the proviso that R2 and R3 is a hydrogen and the other R2 or R3 is other than a hydrogen, R is a hydrogen or C? -6-alkyl; R4 is a hydrogen or hydroxy group, R5 is a hydrogen or a? -hydroxyalkyl; and X is CH or N as well as salts of the pharmaceutically acceptable compounds and hydrates of the compounds of formula I and their salts. The Vinylpyrrolidinone cefaslosporin derivatives are known to be useful antibiotic compounds, as described in EP-A-0 841 339, in addition to the compounds of formula A
wherein R1 and X are as defined above, and R5 is a hydrogen, and pharmaceutically acceptable salts thereof, in particular, (6R, 7R) -7- [(Z) - 2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylaminol-8-oxo-3- [(E) - (R) -2-oxo- [1, 3 '] bipyrrolidinyl-3-ylidene-methyl] -5-thia-1-aza-bicyclo [4. 2 .0] oct-2-en-2-carbixilico are potent antibacterial agents with methicillin-resistant staphylococcal activity, both in vi tro and in vi vo. However, these compounds have limited solubility, and do not allow bolus injections. Therefore, it is necessary to find derivatives of compounds A that give these compounds suitable for parenteral and intramuscular applications. From J. Med. Chem. (1996), 39 (2), 480-6 U.S. Pat. No. 5 466 811; Bioorganic and Medicinal Chem. Lett. 1997, 7.2909-2912; of U.S. Pat. No. 5,610,314 it is known that oxodioxolenylmethyl carbamates form amine derivatives, for example, for fibrinogen receptor antagonists, ampicillin, norfloxacin and other pharmaceuticals. In addition, 2- (alkyloxycarbonyl) -2-alkylidenethyl esters have been described as prodrugs of carboxylic acids for cephalosporins, J.
Antibiot. (1992), 45 (8), 1358-64. Both types of derivatives have been used to improve the oral bioavailability of the corresponding drugs. Currently, it has been found that the compounds of formula I have a better solubility in water and buffers even at physiological pH. They would easily be converted in vi tro and in vivo into compounds of formula A and therefore can be used for parenteral and intramuscular application forms. Accordingly, the invention relates to pharmaceutical preparations containing a compound of formula I and an inert carrier from a therapeutic point of view. As used herein the term "pharmaceutically acceptable salts" in this invention, this includes salts derived from metals, salts of amino acids and salts of mineral or organic acids. Examples of preferred metal salts are those derived from the alkali metals, for example, lithium (Li +), sodium (Na +) and potassium (K +). Sodium is especially preferred. Other salts are those derived from amino acids, such as, for example, salts with arginine or lysine. Examples of salts of mineral acids are, for example, hydrochlorides, sulfates or phosphates, and examples of salts of organic acids are mesylates (salts of methylsulfonic acid), napsylates (salts of naphthene-2-sulfonic acid), besylates (salts of benzenesulfonic acid), maleates, salicylates, tartrates, lactates, citrates, benzoates, succinates, acetates and the like. Chlorides, sulphates, phosphates, lactates and mesylates are especially preferred. In the formulas represented here, when the substituents linked to the nucleus are shown, a solid line (- ^ ßl), indicates that the substituent is in the β orientation, that is, on the plane of the molecule, a dashed line ('"' I), indicates that the substituent is in the orientation, that is, below the plane of the molecule, while the line (-N) indicates that the bond is possible in both orientations a and B. The term "C? -6-alkyl, optionally substituted by fluorine "refers to saturated hydrocarbon groups in both straight chain and branched chain having from 1 to 6 and preferably from 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like These groups can be substituted by one or more fluorine atoms such as, for example, fluoromethyl or trifluoromethyl As used herein, the term "? -hydroxyalkyl" refers to both saturated hydrocarbon groups both in straight chain and in branched chain, as defined above, carrying a hydroxy group in the terminal position, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, preferably hydroxymethyl. As for the term "C3_6-cycloalkyl" it is equivalent to a saturated carboxylic moiety of 3 to 6 members, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in particular cyclopentyl. Of the compounds of formula I, compounds of formula are especially preferred
I-a wherein R1, R2, R3 and X are defined above and R4 and R5 are hydrogen, as well as pharmaceutically acceptable salts of the compounds and hydrates of the compounds of formula I-a and their salts. Furthermore, the preferred compounds are the epimeros and diastereoisomers of formula I-a. Preferred compounds of formula I and formula Ia are the compounds wherein R 1 is hydrogen, X is N and R 2 is hydrogen and R 3 is a group selected from -CH 2 C (= CH 2) -COOCH 2 CH 3, -COO-CH 2 C (= CHCH 2 CH 3) - C00CH2CH (CH3) 2, and in particular
In addition to the preferred compounds of formula I, are the compounds wherein R1 and R3 are hydrogen, X is N and R2 is a group selected from -CH2C (= CHCH2CH3) -C00CH2CH (CH3) 2, -CH2C (= CH2) -COOCH2CH3 , -CH20COC (CH3) 3, -CH (CH3) 0C0CH3, -CH (CH3) OCOOCH2CH3, -CH (OCOCH3) OCOCH3, -CH2COCH20COCH3, and
Especially preferred compounds of formula I and formula Ia are (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino ] -3- [(E) - (R) -1 '- (5-methyl-2-oxo- [1,3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1,3'] bipyrrolidinyl-3 -ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid Sodium salt (1: 1) of (6R, 7R) -7- [( Z) -2- (5-Amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) -1 '- (5-ethyl- 2-oxo- [1,3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0 ] oct-2-en-2-carboxylic acid Sodium salt (1: 1) of (6R, 7R) -7- [(Z) -2- (5-Amino- [1, 2, 4] thiadiazole-3-acid] il) -2-hydroxyimino-acetylamino] -3- [(E) - (R) -l '- (2-oxo-5-propyl- [1,3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [ 1, 3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [.2.0] oct-2-en-2-carboxylic acid Sodium salt (1: 1) of (6R, 7R) -7- [(Z) -2- (5-Amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) -l '- (5-isopropyl-2-oxo- [1,3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1, 3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid Sodium salt (1: 1) of the acid (6R, 7R ) -7- [(Z) -2- (5-Amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) -1 ' - (5-tert-Butyl-2-oxo- [1,3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-1 -aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid Sodium salt (1: 1) of (6R, 7R) -7- [(Z) -2- (5-Amino- [1, 2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) -1 '- (E-2-isobutoxycarbonyl-pent-2-enyloxycarbonyl) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid Sodium salt (1: 1) ( 6R, 7R) -7- [(Z) -2- (5-Amino- [1,2,] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) - 1 '- (2-ethoxycarbonyl-allyl) -2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl] -8-ox o-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid Sodium salt (1: 1) of (6R, 7R) -7- [(Z) -2- ( 5-Amino- [1,2, 4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -5'-hydroxymethyl-1 '- (5-methyl-2-oxo- [ 1,3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2- en-2-carboxylic Sodium salt (1: 1) of (6R, 7R) -7- [(Z) -2- (5-Amino- [1,2,] thiadiazol-3-yl) -2-hydroxyimino acid -acetylamino] -3- [(E) - (3'S, 4'S) -y- (3'R, 4'R) -4'-hydroxy-1- (5-methyl-2-oxo- [1, 3 ] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2 carboxylic The compounds of formula I and Ia as well as their salts can be hydrated. The hydration may be carried out during the manufacturing process or may occur gradually as a result of the hygroscopic properties of an initially anhydrous product. The compounds of the present invention are useful as antibiotics because of their potent and broad antibacterial activity; in particular, against methicillin-resistant staphylococci (MRSA) and Pseudomonas aeruginosa. The products according to the invention can be used as medicaments, for example, in the form of pharmaceutical preparations for parenteral administration, and for this purpose are prepared as lyophilizates or dry powders for dilution with usual means, such as water or isotonic common salt or carbohydrate solution (eg, glucose) . Depending on the nature of the pharmacologically active compound, the pharmaceutical preparations may contain the compound to prevent and treat infectious diseases in mammals, humans and non-humans. A daily dose of approx. 10 mg to approx. 4000 mg, especially about 50 mg up to approx. 3000 mg, is usual, with people skilled in the art who appreciate that the dose also depends on the age, the conditions of the mammals and the kind of diseases to be prevented or treated. The daily dose can be administered in a single dose or it can be divided into several doses. An average individual dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg can be contemplated. The compounds of formula I and Ia according to the invention, as well as their pharmaceutically acceptable salts, hydrates or easily hydrolysable esters can be prepared, for example, following the procedures shown below: Compounds of formula I and Ia where R2 is a hydrogen and R3 is a group -COOCH2C (= CHR) -COOR, -COOCH2OCOR, -COOCH (R) OCOR, -COOCH (R) OCOOR, -COOCH (OCOR) OCOR, -COOCH2COCH2OCOR or
it can be prepared according to Reaction Scheme 1 by acylation of compounds of formula A with the corresponding 4-nitrophenyl ester of carbonic acid. Reaction scheme 1
where R1 and R are as defined above and Y is a group - CH2C (= CHR) -COOR, - CH2OCOR, -CH (R) OCOR, -CH (R) OCOOR,
-CH (OCOR) OCOR, -CH2CO CH2OCOR, or
For the preparation of compounds of formula I and I-a wherein R3 is -CH2C (= CH2) -COOR a compound of formula A which is reacted with the ethyl ester of 2- (4-nitrophenoxycarbonyloxymethyl) -acrylic acid. This reaction takes place with loss of carbon dioxide, see the reaction scheme 2. Reaction scheme 2
2. Ethylcaproate sodium in DMSO
The synthesis of the compounds of formula I and I-a, wherein R 3 is a hydrogen, (Reaction scheme 3) is carried out by the alkylation of the carboxylate, preferably in the step of the compound of formula A completely protected. The protecting groups for R1 are preferably trityl and in position R3, tert-butyloxycarbonyl (BOC). The separation of the tert.-butyloxycarbonyl and the trityl protecting groups is carried out by conventional methods and the desired compounds of formula I and I-a are isolated as the hydrochloride salts by precipitation of the dioxane. Reaction scheme 3
where R1 is the group C? _6-alkyl, substituted dimethylsulfoxide, 20.0 g of (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3) acid -yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) -1 '- (5-methyl-2-oxo- [1, 3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1, 3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid. The mixture is stirred under argon at room temperature for 4 hours and 1000 ml of acetone are added. The slightly cloudy solution is clarified by filtration through a fluted filter. To the liquids or clear mother liquors, 34.0 ml (34 mmol) of an IN solution of sodium 2-ethylcapronate in acetone is added at room temperature for 20 minutes. The slightly yellow suspension is stirred for 10 minutes at room temperature, the solid is collected by filtration, washed with 1000 ml of acetone and 1000 ml of n-pentane and removed in a high vacuum. The product is suspended in 600 ml of acetone and stirred at room temperature for 2 hours. The product is collected by filtration and dried in a high vacuum to give 23.94 g of the main compound as an off-white powder. MS (ISP): M + H + = 691.3; M + NH 4 + = 708.2; M + Na + = 713.1 In a similar way, the following carbamates are prepared from the corresponding mixed carbamates: 1.2.Sodium salt (1: 1) of the acid (6R, 7R) -7- [(Z) -2- ( 5-Amino-optionally by fluorine, or C3_6-cycloalkyl or a protective group, preferably trityl, and BOC is tert-butyloxycarbonyl The compounds of formula A are known compounds and can be prepared according to the methods described in EP-A-0 849 269. Alkylating agents, ie the compounds R2Br or R2C1 are known compounds, some of which are commercially available The following examples illustrate the invention, however, they do not limit its scope Examples 1.1 Synthesis of (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] iadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) -1 '- (5-methyl-2-oxo- [1,3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5 -thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic or
They are added to a solution of 13.2 g (44.72 mmol) of 4-nitrophenyl ester of the 5-methyl-2-oxo- (1, 3) dioxol-4-ylmethyl ester of carbonic acid in 200 ml of [1 , 2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) 1 '- (5-ethyl-2-oxo- [1, 3] dioxol-4 illmethoxycarbonyl) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
MS (ISP): M + H + = 705.2, M + NH4 + = 722.3, M + Na + = 727.2 1.3 Sodium salt (1: 1) of the acid (6R, 7R) -7- [(Z) -2- (5- Amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) -1 '- (2-oxo-5-propyl- [1,3-Jiox -4-ylmethoxycarbonyl) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
MS (ISP): M + H + = 719.3, M + NH4 + = 736.2, M + Na + = 741.2 1.4. Sodium salt (1: 1) of (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] - 3- [(E) - (R) -1 '- (5-isopropyl-2-oxo- [1,3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl ] -8- oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic
MS (ISP): M + H + = 719.3, M + NH4 + = 736.2, M + Na + = 741.2 1.5. Sodium salt (1: 1) of the acid (6R, 7R) -7- [(Z) -2- (5-A- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) -1 '- (5-tert-butyl-2-oxo- [1,3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1,3'] bipyrrolidinyl- 3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
MS (ISP): M + H + = 733.2, M + NH4 + = 750.4 1.6 Sodium salt (1: 1) of the acid (6R, 7R) -7- [(Z) -2- (5-A ino- [1, 2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) -1 '- (E-2-isobutoxycarbonyl-pent-2-enyloxycarbonyl) -2-oxo- [1, 3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
MS (ISP): M + H + = 747.4, M + NH4 + = 764.3, M + Na + = 769.3 1.7 Sodium salt (1: 1) of the acid (6R, 7R) -7- [(Z) -2- (5- Amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (R) -1 '- (2-ethoxycarbonyl-allyl) -2-oxo- [ 1, 3 '] bi? Irolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
MS (ISP): M + H + = 647.4 1.8 Sodium salt (1: 1) of (6R, 7R) -7- [(Z) -2- (5-Amino- [1,2,4] thiadiazole-3) acid -yl) -2-hydroxy iminoacetylamino] -3- [(E) - (3'R, 5 'S) -5' -hydroxymethyl-1 '- (5-methyl-2-oxo- [1,3] ] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2 -carboxylic
MS (ISP): M + H + = 721.3, M + NH4 + = 738.2, M + Na + = 743.2 1.9 Mixture (1: 1) of the sodium salt (1: 1) of the acid (6R, 7R) -7- [( Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) - (3 'S, 4' S) -y- (3 'R, 4' R) -4 '-hydroxy-1' - (5-methyl-2-oxo- [1,3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1,3 '] bipyrrolidinyl -3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
MS (ISN): M-H + = 705.3 Preparation of starting materials for examples 1.7. and 1.6 .: a) 2- (4-nitro-phenoxycarbonyloxymethyl) -acrylic acid ethyl ester
A mixture of 2.60 g of ethyl ester of 2-hydroxymethyl-acrylic acid (0.020 mol) and 4.0 g of 4-nitrophenyl-chloroformate (0.020 mol) in 70 ml of dichloromethane is treated with a solution of 5.5 ml (0.030 mol) of Ethyl diisopropylamine in 55 ml of dichloromethane at 0 ° C for two hours. The mixture is hydrolysed with 10% potassium bicarbonate, the phases are separated and the product contained in the organic phase is purified by chromatography on silica gel using a 4: 1 mixture of n-hexane and ethyl acetate as eluent. The product fractions are collected and evaporated and 3.5 g (60%) of the main compound is obtained as a white crystalline solid with a melting point of 42-43 ° C after the crystallization of the t-butylmethyl ether and the n- Hexane b) 2- (4-nitro-phenoxycarbonyloxymethyl) -pent-2-enoic acid isobutyl ester
It is prepared according to the procedure described above. A yellowish oil is obtained. MS (El): M + H + = 352 M-C4H7O = 278 Example 2 2.1.a) Synthesis of the acid (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4 ] thiadiazol-3-yl) -2-trityloxyimino-acetylamino] -3- [(E) - (R) -1 '- (5-tert-b-toxicarbonyl-2-oxo- [1,3] dioxol-4-) illmethoxycarbonyl) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
They are added to a solution of 1.67 g (1865 mmol) of salt (1: 2) of (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4]] hydrochloride. thiadiazol-3-yl) -2-trityloxyimino-acetylamino] -8-oxo-3- [(E) - (R) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -5-thia- l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid in 20.0 ml of dimethylformamide, 0.56 ml (4.00 mmol) of triethylamine and 0.554 g of di-tert-butyldicarbonate and the mixture is stirred at room temperature for 1.5 hours. The mixture is diluted with 500 ml of ethyl acetate and 100 ml of water. The pH is adjusted to 2 by adding IN hydrochloric acid. The phases are separated and the organic phase is washed twice with 100 ml of water, it is clarified by filtration through a fluted filter and concentrated. 100 ml of diethyl ether are added and the resulting suspension is stirred at room temperature for 1 hour. The solid is collected by filtration, washed with diethyl ether and dried, yielding 1.31 g (76%) of the main compound as a beige powder. MS (ISP): M + H + = 877.4, (M + NH4) + = 894.4, (M + Na) + = 899.4
b) Synthesis of the hydrochloride (1: 1.6) of the (E) -2-isobutoxycarbonyl-pent-2-enyl ester of (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo-3- [(E) - (R) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] - 5-thia-1-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
To a solution of 0.150 g (0.171 mmol) of (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiadiazol-3-yl) -2-trityloxyimino- acetylamino] -3- [(E) - (R) -1'-tert-butoxycarbonyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-1-aza- bicyclo [4.2.0] oct-2-en-2-carboxylic acid in one ml of dimethylsulfoxide are added 18.7 mg of (0.163 mmol) 1,1-3,3-tetramethylguanidine and 64 mg (0.257 mmol) of (Z) - 2- (bromomethyl) -2-isobutyl pentenoate, and the mixture is stirred at room temperature for 20 minutes. The solvent is evaporated in a high vacuum and the residue is purified by MCI gel chromatography using a gradient of 40 to 100% acetonitrile in water as eluent. The product fractions are collected and the organic solvent is removed by evaporation. The product is extracted from the remaining aqueous phase with dichloromethane. The combined organic phases are dried over magnesium sulfate, evaporated to dryness and triturated with tert-butyl methyl ether to give 130 mg (0.125 mmol) of beige crystals with a melting point of 158-159 ° C, which are dissolved in 1.2 ml of dichloromethane. To this solution is added 0.0366 ml (0.23 mmol) of triethylsilane and 0.38 ml of trifluoroacetic acid at 0 ° C and the mixture is stirred for one hour. To the resulting clear solution, 2.0 ml of dioxane are added and the mixture is concentrated in vacuo. The residue is dissolved in 2.0 ml of dioxane and 0.182 ml of a 1.9 N solution of hydrochloric acid in dioxane is added, stirring at room temperature. The precipitate is collected by filtration, washed with dioxane and acetone and dried to give 85 mg of main compound in the form of beige crystals with a melting point of 139-140 ° C (dec.) HPLC: 99% (area) MS: M + H + = 703.3
In a similar manner, the following prodrug-ester compounds are prepared, from the corresponding alkyl halides: 2.2. Hydrochloride of the acid (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -2-dimethylpropionyloxymethyl ester] -8-oxo-3- [(E) - (R) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2 -in-2-carboxylic
MS (ISP): M + H + = 649.3 2.3. Hydrochloride (1: 1.5) of the 5-methyl-2-oxo- (1,3) dioxol-4-ylmethyl ester of (6R, 7R) -7- [(Z) -2- (5-amino- [1 , 2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo-3- [(E) - (R) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenmethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
MS (ISP): M + H + = 647.3 2.4. 1: 1 mixture of the hydrochloride (1: 1.2) of the ester (R) and (S) -1-acetoxyethyl of the acid (6R, 7R) -7- [(Z) -2- (5-amino- [1,2 , 4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo-3- [(E) - (R) -2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl] -5 -thia-1-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
MS (ISP): M + H + = 621.3 2.5. 1: 1 mixture of the hydrochloride (1: 1.4) of the ester (R) and (S) -1-ethoxycarbonyloxy-ethyl acid (6R, 7R) -7- [(Z) -2- (5-amino- [1 , 2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -8-0x0-3- [(E) - (R) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenmethyl] -5-thia-1-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
MS (ISP): M + H + = 651.2 2.6. 1: 1 mixture of the hydrochloride (1: 1.4) of the ester (R) and (S) -l-acetoxy-2-oxo-ropylic acid (6R, 7R) -7- [(Z) -2- (5 -amino- [1,2,4] thiadiazol-3-yl) -2-hydroxy-n-acetylamino] -8-OXO-3- [(E) - (R) -2-oxo- [1,3 '] bi? irolidinyl-3-ylidenemethyl] -5-thia-1-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
MS (ISP): M + H + = 649 2.7. Hydrochloride (1: 1.65) of (3R, 7R) -7- [(Z) -2- (5-Amino- [1,2,4] thiadiazole-3-acetoxy-2-oxo-propyl) ester il) -2- hydroxyiminoacetylamino.no] -8-oxo-3- [(E) - (R) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l- aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid MS (ISP): M + H + = 649. 2
It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (9)
1. Compounds of formula I, characterized in that R1 is a hydrogen, C6-6-alkyl, optionally substituted by fluorine, or the C3-6-cycloalkyl; R2 is a hydrogen or a group selected from -CH2C (= CHR) -COOR, -CH2OCOR, -CH (R) OCOR, -CH (R) OCOOR, -CH (OCOR) OCOR, -CH2COCH2OCOR and R3 is a hydrogen or a group selected from -CH2C (= CH2) -COOR, -COOCH2C (= CHR) -COOR, -COOCH2OCOR, -COOCH (R) OCOR, -COOCH (R) OCOOR, -COOCH (OCOR) OCOR , -COOCH2COCH2OCOR, and -COOCH VS) L ° with the proviso that R2 and R3 is a hydrogen and the other R2 or R3 is other than hydrogen, R is a hydrogen or C? -6-alkyl; R4 is a hydrogen or hydroxy group, R5 is a hydrogen or a? -hydroxyalkyl; and X is CH or N as well as salts of the pharmaceutically acceptable compounds and hydrates of the compounds of formula I and their salts.
2. The components of the formula I-a according to claim 1, IAa characterized in that R1, R2, R3 and X as defined in claim 1 and R4 and R5 are hydrogen, as well as the salts of the compounds which are accept- able from the chain, and the hydrates of the compounds of the formula I-a and their salts.
3. The compounds according to claim 1 or 2, characterized in that R1 is a hydrogen, X is N, R2 is a hydrogen and R3 is a group -COO-CH2C (= CHCH2CH3) -COOCH2CH (CH3) 2, -CH2C (= CH2) -COOCH2CH3, or
4. The compounds according to claim 1 or 2, characterized in that R1 and R3 are hydrogen, X is N and R2 is -CH2C (= CHCH2CH3) -COOCH2CH (CH3) 2, -CH2C (= CH2) -COOCH2CH3, -CH2OCOC ( CH3) 3, -CH (CH3) OCOCH3, -CH (CH3) OCOOCH2CH3, -CH (OCOCH3) OCOCH3, -CH2COCH2OCOCH3, or
5. The compound according to claims 1 and 2, characterized in that it comprises an acid (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) - 2-hydroxyimino-acetylamino] -3- [(E) - (R) -1 '- (5-methyl-2-oxo- [1, 3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1, 3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
6. The compound according to claims 1 and 2, characterized because it comprises a sodium salt (1: 1) of the acid (6R, 7R) -7- [(Z) -2- (5-Amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino- acetylamino] -3- [(E) - (R) -1 '- (5-ethyl-2-oxo- [1,3] dioxol-4-ylmethoxycarbonyl) -2-oxo- [1,3'] bipyrrolidinyl- 3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
7. The compounds according to any one of claims 1 to 6, characterized in that they are used as active pharmaceutical substances, in particular for the treatment and prophylaxis of infectious diseases.
8. A pharmaceutical preparation according to any of claims 1 to 6, characterized in that it contains a compound and an inert carrier from a therapeutic point of view, in particular for the treatment and prophylaxis of infectious diseases.
9. The compounds according to any of claims 1 to 6, characterized in that they are used in the treatment and prophylaxis of infectious diseases or for the manufacture of medicaments for the treatment and prophylaxis of infectious diseases. Summary of the Invention The present invention relates to the compounds of formula I R1 is a hydrogen, C6-6-alkyl, optionally substituted by fluorine, or else C3_6-cycloalkyl; R2 is a hydrogen or a group selected from -CH2C (= CHR) -COOR, -CH2OCOR, -CH (R) OCOR, -CH (R) OCOOR, -CH (OCOR) OCOR, -CH2COCH2OCOR and R3 is a hydrogen or a group selected from -CH2C (= CH2) -COOR, -COOCH2C (= CHR) -COOR, -COOCH2OCOR, -COOCH (R) OCOR, -COOCH (R) OCOOR, -COOCH (OCOR) OCOR, -COOCH2COCH2OCOR, and with the proviso that R2 and R3 is a hydrogen and the other R2 or R3 is other than hydrogen, R is a hydrogen or C? -6-alkyl; R4 is a hydrogen or hydroxy group, R5 is a hydrogen or a? -hydroxyalkyl; and X is CH or N as well as salts of the pharmaceutically acceptable compounds and hydrates of the compounds of formula I and their salts, and with the use of compounds of formula I and of the pharmaceutically acceptable compounds and hydrates of the compounds and their salts for the manufacture of pharmaceutical preparations containing the compounds.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98110888.9 | 1998-06-15 | ||
| EP98117099.6 | 1998-09-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00012391A true MXPA00012391A (en) | 2001-11-21 |
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