CS212224B2 - Method of preparation of 7-(substituted benzoylureido) phenylacetamido derivatives of the cephalosporine - Google Patents
Method of preparation of 7-(substituted benzoylureido) phenylacetamido derivatives of the cephalosporine Download PDFInfo
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- CS212224B2 CS212224B2 CS802740A CS274080A CS212224B2 CS 212224 B2 CS212224 B2 CS 212224B2 CS 802740 A CS802740 A CS 802740A CS 274080 A CS274080 A CS 274080A CS 212224 B2 CS212224 B2 CS 212224B2
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- -1 benzoylureido Chemical group 0.000 title claims description 25
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 4
- HOKIDJSKDBPKTQ-UHFFFAOYSA-N 3-(acetyloxymethyl)-7-[(5-amino-5-carboxypentanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C(NC(=O)CCCC(N)C(O)=O)C12 HOKIDJSKDBPKTQ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 15
- 229940124587 cephalosporin Drugs 0.000 claims description 12
- 229930186147 Cephalosporin Natural products 0.000 claims description 11
- 150000001780 cephalosporins Chemical class 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 125000003831 tetrazolyl group Chemical group 0.000 claims 1
- 150000004867 thiadiazoles Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 7
- 125000004423 acyloxy group Chemical group 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- UNCACEGCFURZQB-UHFFFAOYSA-N (2-acetyloxy-4-carbonochloridoylphenyl) acetate Chemical compound CC(=O)OC1=CC=C(C(Cl)=O)C=C1OC(C)=O UNCACEGCFURZQB-UHFFFAOYSA-N 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical compound O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 description 2
- 229960003866 cefaloridine Drugs 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JWIRVWSAMLMXIV-UHFFFAOYSA-N (2-acetyloxy-3-carbonochloridoylphenyl) acetate Chemical compound CC(=O)OC1=CC=CC(C(Cl)=O)=C1OC(C)=O JWIRVWSAMLMXIV-UHFFFAOYSA-N 0.000 description 1
- PSAVXSZVPAYPEQ-HTCLMOQTSA-N (6R)-7-[[(2R)-2-amino-2-phenylacetyl]amino]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N[C@@H](C(=O)NC1[C@@H]2N(C(=C(CS2)CSC=2SC(=NN=2)C)C(=O)O)C1=O)C1=CC=CC=C1 PSAVXSZVPAYPEQ-HTCLMOQTSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OMAFFHIGWTVZOH-UHFFFAOYSA-N 1-methyltetrazole Chemical compound CN1C=NN=N1 OMAFFHIGWTVZOH-UHFFFAOYSA-N 0.000 description 1
- GIOUOHDKHHZWIQ-UHFFFAOYSA-N 2-(carbamoylamino)-2-phenylacetic acid Chemical class NC(=O)NC(C(O)=O)C1=CC=CC=C1 GIOUOHDKHHZWIQ-UHFFFAOYSA-N 0.000 description 1
- GRWKNBPOGBTZMN-UHFFFAOYSA-N 2-benzyl-3-phenylpropane-1,2-diamine Chemical compound C=1C=CC=CC=1CC(N)(CN)CC1=CC=CC=C1 GRWKNBPOGBTZMN-UHFFFAOYSA-N 0.000 description 1
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical class NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 241000588697 Enterobacter cloacae Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000191938 Micrococcus luteus Species 0.000 description 1
- 241000588772 Morganella morganii Species 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000531795 Salmonella enterica subsp. enterica serovar Paratyphi A Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 241000607715 Serratia marcescens Species 0.000 description 1
- 241000624602 Shigella flexneri 2b Species 0.000 description 1
- OKMHHBICYZAXBE-UHFFFAOYSA-N acetic acid;ethanol;ethyl acetate Chemical compound CCO.CC(O)=O.CCOC(C)=O OKMHHBICYZAXBE-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- ZGUNAGUHMKGQNY-UHFFFAOYSA-N alpha-phenylglycine Chemical compound OC(=O)C(N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-UHFFFAOYSA-N 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910001389 inorganic alkali salt Inorganic materials 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 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
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Description
Vynález se týká derivátů cefalosporinu, které mají široké antibakteriální spektrum a vykazují antibakteriální účinek vůči různým gramnegativním a grampozitivním bakteriím.The invention relates to cephalosporin derivatives having a broad antibacterial spectrum and exhibiting antibacterial activity against various gram-negative and gram-positive bacteria.
Přesněji se vynález týká 7-(alfa-substituovanýoh benzoylureido)fenylacetamidoderivátů cefalosporinu obecného vzorce I,More specifically, the invention relates to 7- (alpha-substituted benzoylureido) phenylacetamide derivatives of the cephalosporin of formula I,
kdewhere
R1 je atom vodíku nebo alkyl s 1 až 4 atomy uhlíku,R 1 is hydrogen or C 1 -C 4 alkyl,
R-j je alkanoyloxyskupína s 2 až 4 atomy uhlíku, n je 2 nebo 3, přičemž alespoň dva ze substituentů Rj jsou připojeny na sousední atomy uhlíku, poloha substituentu Rj je vybrána z poloh 2 až 6, je atom vodíku nebo methoxyl a je acetoxyl nebo -S-Rg, kde Rg je pětičlenný heterocyklický kruh včetně jednoho nebo více atomů dusíku a popřípadě atomu síry, který je popřípadě substituován alkylskupinou s 1 až 4 atomy uhlíku a jejich farmaceuticky vhodných solí.R 1 is C 2 -C 4 alkanoyloxy, n is 2 or 3, wherein at least two of R 1 are attached to adjacent carbon atoms, the position of R 1 is selected from positions 2 to 6, is hydrogen or methoxy and is acetoxyl; S-Rg, wherein Rg is a five-membered heterocyclic ring including one or more nitrogen and optionally sulfur atoms, optionally substituted with C1-C4 alkyl, and pharmaceutically acceptable salts thereof.
Cefalosporinové deriváty mající benzoylureidoskupinu vázanou v alfa-poloze 7-acyiamidóvého postranního řetězce derivátů jsou známé například z USA patentů č. 3 925 368 a 4 06, 630, britských patentů č. 1 479 711, 1. 498 025, 1 505 885, 1 508 314,-jl 518 722 a 1 521 073 a DOS 2 653 621. Avšak žádný z těchto patentů neuvádí sloučeniny, které by měly hydroxyskupinu nebo nižší alkanoyloxyskupinu jako substituent na odpovídající benzoylskupině,Cephalosporin derivatives having a benzoylureido group attached at the alpha position of the 7-acyl amide side chain derivatives are known, for example, from U.S. Patent Nos. 3,925,368 and 4,066,630, British Patent Nos. 1,479,711, 1,498,025, 1,505,885, 1 508,314, i.e. 518,722 and 1,521,073 and DOS 2,653,621. However, none of these patents discloses compounds having a hydroxy or lower alkanoyloxy group as a substituent on the corresponding benzoyl group,
I když USA patent č. 3 687 949, britský patent č. 1 525 626 a japonský patent číslo 5787/77 uvádějí jako substituent nižší alkanoyloxyskupinu, neuvádějí hydroxylovou skupinu. Avšak výše uvedené tři odkazy uvádějí pouze obecný popis nižší alkanoyloxyskupiny jako jednoho z několika substituentů a nejsou nárokovány dvě nebo tři nižší alkanoyloxyskupiny, z nichž alespoň dvě jsou vázané na sousední atomy uhlíku. Déle nejsou uvedeny žádná konkrétní sloučeniny, která by měly nižší alkanoyloxyskupiny jako substituenty benzoylskupiny.Although U.S. Patent No. 3,687,949, British Patent No. 1,525,626 and Japanese Patent No. 5787/77 cite a lower alkanoyloxy group as substituents, they do not mention a hydroxyl group. However, the above three references provide only a general description of a lower alkanoyloxy group as one of several substituents, and two or three lower alkanoyloxy groups of which at least two are bonded to adjacent carbon atoms are not claimed. Further, no particular compounds having lower alkanoyloxy groups as benzoyl substituents are listed.
Jak je vysvětleno výše, jsou cefalosporinové deriváty podle vynálezu obecného vzorce I sloučeniny nová.As explained above, the cephalosporin derivatives of the invention of formula I are novel.
Deriváty podle vynálezu vykazují vysoký antibakteriální účinek, jak proti grampozitivním, tak proti gramnegativním bakteriím. Zejména jsou účinná proti bakteriím příslušejícím k Fseudomonas nebo Serratla a sloučeniny podle vynálezu vykazují značně vyšší antibakteriální účinek, než jaký mé cefazorin, cephaloridin nebo jiné běžně používané cefalosporinové antibiotika.The derivatives according to the invention show a high antibacterial effect against both Gram-positive and Gram-negative bacteria. In particular, they are effective against bacteria belonging to Fseudomonas or Serratla and the compounds of the invention show a significantly higher antibacterial effect than my cefazorin, cephaloridine or other commonly used cephalosporin antibiotics.
Sloučeniny podle vynálezu mají vynikající vlastnosti in vivo po aplikaci, jako je ebsorpce, vylučování, distribuce, metabolismus apod., a vykazují schopnost prevence před infekcí bakteriemi. Vzhledem k těmto vlastnostem jsou sloučeniny podle vynálezu použitelné jako antibakteriální činidla.The compounds of the invention have excellent in vivo properties after administration, such as ebsorption, excretion, distribution, metabolism and the like, and have the ability to prevent infection by bacteria. Because of these properties, the compounds of the invention are useful as antibacterial agents.
Ze sloučenin podle vynálezu jsou sloučeniny obecného vzorce I, kde R^ je alkanoyloxyskupina s 2 až 4 atomy uhlíku, nejen použitelná jako taková, ale používají se i jako meziprodukty, protože alkanoylskupina se odstraní a získá se sloučenina vzorce I, kde R-j je hydroxyl.Among the compounds of the invention, the compounds of formula I wherein R 1 is C 2 -C 4 alkanoyloxy are not only useful as such, but are also used as intermediates since the alkanoyl group is removed to give a compound of formula I wherein R 1 is hydroxyl.
Alkylskupina reprezentovaná symbolem R1 ve vzorci I je skupina s 1 až 4 atomy uhlíku, jako je například methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl a terč.butyl. Výhodnými příklády jsou methyl a ethylskupiny. Alkanoylskupina z alkanoyloxyskupiny reprezentovaná symbolem R-j je skupina obsahující 2 až 4 atomy uhlíku, které popřípadě mohou být rozvětvené a které zahrnuji například acetyl, propionyl, n-butyryl a isobutyrylskupiny. Výhodným příkladem je acetylskupina.The alkyl group represented by R 1 in formula I is C 1 -C 4, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. Preferred examples are methyl and ethyl. The alkanoyloxy group of alkanoyloxy represented by R1 is a group of 2 to 4 carbon atoms which may be branched, which may include, for example, acetyl, propionyl, n-butyryl and isobutyryl. A preferred example is acetyl.
Poloha substituentu Rj je buň 2 a 3 poloha, 3 a 4 poloha, 2, 3 a 4 poloha, 3, 4 a 5 poloha, 2, 4 a 5 poloha, 2, 3 a 5 poloha, nebo 2, 3 a 6 poloha. Výhodné jsou 2 a 3 poloha, 3 a 4 poloha nebo 3, 4 a 5 poloha.The position of substituent R1 is cell 2 and 3 position, 3 and 4 position, 2, 3 and 4 position, 3, 4 and 5 position, 2, 4 and 5 position, 2, 3 and 5 position, or 2, 3 and 6 position . Preferred are the 2 and 3 positions, the 3 and 4 positions or the 3, 4 and 5 positions.
Heterocyklické skupina s pěti členy v kruhu reprezentované symbolem Rg vzorce I zahrnuje například 1,3,4-thiadiazol, triazol a tetrazol, které popřípadě mohou být substituované jednou nebo více alkylskupinami s 1 až 4 atomy uhlíku. Alkyl je skupina s 1 až 4 atomy uhlíku, která mohou být popřípadě rozvětvené a které zahrnují například methyl, ethyl, n-propyl a isopropyl. Výhodným alkylem je methyl.The five-membered heterocyclic group represented by Rg of formula I includes, for example, 1,3,4-thiadiazole, triazole and tetrazole, which may optionally be substituted with one or more C 1 -C 4 alkyl groups. Alkyl is a group having 1 to 4 carbon atoms which may be optionally branched and include, for example, methyl, ethyl, n-propyl and isopropyl. Preferred alkyl is methyl.
Protože deriváty cefalosporinu podle vynálezu mají karboxylovou skupinu, jsou schopné tvořit soli s různými alkalickými sloučeninami. Veškeré tyto soli spadají rovněž do rozsahu vynálezu. Příklady solí sloučenin podle vynálezu jsou anorganické alkalické soli, například soli alkalických kovů, jako sodné a draselná soli, soli s kovy alkalických zemin, jako jsou vápenaté soli, a soli s organickými bázemi, jako například soli s prokainem nebo dibenzylethylendiaminem. Tyto soli se mohou připravit běžným způsobem, to jest reakcí volné karboxylové skupiny derivátu cefalosporinu s výše popsanou anorganickou nebo organickou bází.Since the cephalosporin derivatives of the invention have a carboxyl group, they are capable of forming salts with various alkaline compounds. All such salts are also within the scope of the invention. Examples of salts of the compounds of the invention are inorganic alkali salts such as alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salts, and salts with organic bases such as salts with procaine or dibenzylethylenediamine. These salts can be prepared in a conventional manner, i.e. by reacting the free carboxyl group of the cephalosporin derivative with the inorganic or organic base described above.
Vzhledem k asymetrickému uhlíku v 7-aeetamidoskupině jsou konečné produkty podle vynálezu optickými isomery, to je DL-, D- a L-isomery. VeSkeré tyto isomery spadají rovněž do rozsahu vynálezu.Due to the asymmetric carbon in the 7-acetamido group, the end products of the invention are optical isomers, i.e., DL-, D- and L-isomers. All such isomers are also within the scope of the invention.
Předmětem vynálezu je způsob přípravy derivátů cefalosporinu obecného vzorce I a jejich solí, který se vyznačuje tím, že se nechá reagovat alfa-ureidobenzylcefalosporin obecného vzorce VII,The present invention provides a process for the preparation of cephalosporin derivatives of the formula I and their salts, characterized in that the alpha-ureidobenzylcephalosporin of the formula VII is reacted,
HNCONH -CH -CONH f-fSHNCONH -CH -CONH f -S
R, X 0-^Νγ-™2-η*R, X 0 - ^ Ν γ- ™ 2 η *
COOY (VII) kde R, R^ a R^ mají význam uvedený výše a Y je atom vodíku nebo chránící skupina, nebo jeho reaktivní derivát s benzoylhalogenidem obecného vzorce VIIICOOY (VII) wherein R, R ^ and R ^ are as defined above and Y is hydrogen or a protecting group, or a reactive derivative thereof with a benzoyl halide of formula VIII
Ocox (Λ kde n a Hj mají význam uvedený výše a Xj je atom halogenu, a popřípadě se převede na atom vodíku a popřípadě se získané sloučenina vzorce I převede vhodnou sůl.O cox (Λ where Hj is as defined above and Xj is a halogen atom, and optionally is converted to a hydrogen atom, and optionally the compound of formula I obtained is converted into a suitable salt.
(VIII) substituent Y na farmaceuticky(VIII) a substituent Y on a pharmaceutical
Reaktivní, derivát alfa-ureidobenzylcefalosporinu vzorce VII je derivát, ve Kterém uřeidoskupina acylskupiny v poloze 7 je aktivována na reaktivní formu.The reactive, alpha-ureidobenzylcephalosporin derivative of formula (VII) is a derivative in which the urido group of the acyl group at position 7 is activated to the reactive form.
Reakce se běžně provádí v rozpouštědle. Rozpouštědlo, které se používá při této reakci, je inertní organické rozpouštědlo, jako je chloroform, dichlormethan, tetrahydrofuran, ethylacetét, dioxán, aceton!trii apod. Reakce se běžně provádí při teplotě od -10 do 25 °C, s výhodou od 0 do 10 °C. I když reakční doba je různá a závisí na reakční teplotě a příslušných reakčních složkách a rozpouštědle, pohybuje se běžně od 1 do 46 hodin, s výhodou od 1 do 10 hodin.The reaction is conveniently carried out in a solvent. The solvent to be used in this reaction is an inert organic solvent such as chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, dioxane, acetonitrile and the like. The reaction is conveniently carried out at a temperature of from -10 to 25 ° C, preferably from 0 to Low: 14 ° C. Although the reaction time varies and depends on the reaction temperature and the respective reactants and solvent, it is normally from 1 to 46 hours, preferably from 1 to 10 hours.
Izolace sloučenin podle vynálezu z reakční směsi se může provádět jakýmkoliv běžným způsobem. Například extrakcí organickým rozpouštědlem, jako je dichlormethan, chloroform nebo ethylacetát, a chromatografif na silikagélu, iontoměničové pryskyřici, sílovaném dextranu, vysokoporézním polymeru styrenu nebo esteru akrylové kyseliny apod.Isolation of the compounds of the invention from the reaction mixture can be carried out by any conventional method. For example, extraction with an organic solvent such as dichloromethane, chloroform or ethyl acetate, and chromatography on silica gel, ion exchange resin, crosslinked dextran, high porosity styrene polymer or acrylic ester and the like.
Optické isomery, jako jsou D- nebo L-isomery sloučenin podle vynálezu, se mohou připravit použitím opticky aktivní výchozí sloučeniny, jako je alfa-aminofenyloctové kyselina nebo substituované ureidofenyloctové kyselina, které se připravuje běžným způsobem resolucí, například způsobem popsaným v J. P. Greenstein a M. Winitz v Chemistry of the Amino Aoids, sv. 1, str. 715 až 760, John Wiley and Sons, N, Y, (1961).Optical isomers, such as the D- or L-isomers of the compounds of the invention, can be prepared using an optically active starting compound, such as alpha-aminophenylacetic acid or substituted ureidophenylacetic acid, which is prepared by conventional resolution methods, for example as described in JP Greenstein and M. Winitz in Chemistry of the Amino Aoids, Vol. 1, pp. 715-760, John Wiley and Sons, N, Y (1961).
Sloučeniny podle vynálezu se mohou formulovat na různé farmaceutické přípravky připravené pro různé aplikační způsoby, způsobem popsaným pro jiné cefalosporinové sloučeniny. Vynélez se také týká farmaceutických směsí pro léčení lidí a zvířat. Příprava se provádí použitím běžných farmaceutických nosičů, ředidel a přísad.The compounds of the invention may be formulated into various pharmaceutical formulations prepared for various application routes, in the manner described for other cephalosporin compounds. The invention also relates to pharmaceutical compositions for the treatment of humans and animals. The preparation is carried out using conventional pharmaceutical carriers, diluents and additives.
Pro injekční aplikaci se mohou používat emulze, roztoky nebo suspenze ve vodném nebo olejovém nosiči. Čípky se připravují použitím běžných přísad pro čípky, jako jsou kokosový olej nebo glyceridy.Emulsions, solutions or suspensions in an aqueous or oily carrier may be employed for injection. Suppositories are prepared using conventional suppository ingredients such as coconut oil or glycerides.
212224 4 /212224 4 /
Obsah aktivní sloučeniny je různý a pohybuje se v závislosti na způsobu aplikace. Běžně se používá nad 0,1 jako je například 5 až 99 %, s výhodou 10 až 60 %.The content of active compound varies and varies depending on the mode of administration. It is commonly used above 0.1 such as 5 to 99%, preferably 10 to 60%.
Aplikované množství se pro dospělého člověka pohybuje v rozmezí 100 až 3 000 mg za den. S výhodou se používá množství v rozmezí 500 až 2 000 mg za den a závisí na tělesné hmotnosti věku, druhu onemocnění a způsobu aplikace a četnosti aplikace.The amount administered for an adult is between 100 and 3000 mg per day. Preferably, an amount in the range of 500 to 2000 mg per day is used and is dependent upon the body weight of the age, the type of disease and the mode of administration and the frequency of administration.
Způsob pro přípravu sloučenin podle vynélezu je déle blíže objasněn v následujících pří kladech.The process for preparing the compounds of the invention is explained in more detail in the following examples.
Chromatografie na tenké vrstvě se v příkladech provédí na silikagélu 60 P254 (hotové desky vyráběné firmou E. Merck, Darmstadt) v následujících směsích:Thin layer chromatography is carried out on silica gel 60 P 254 (finished plates manufactured by E. Merck, Darmstadt) in the following mixtures in the examples:
1. ethylacetát-ethanol-kyselina octová (25:5:1, objemově),1. Ethyl acetate-ethanol-acetic acid (25: 5: 1, v / v);
IX. ethylaeetát-ethanol-kyselina ootové-voda (10:4:2:1, objemově).IX ethyl acetate-ethanol-oic acid-water (10: 4: 2: 1, v / v).
Příklad 1Example 1
7-[D-(-)-alfa-(3-methyl-1-ureido)-alfa-:fenylacetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cefem-4-karboxylové kyselina (4 g) připravené reakcí jednomolérního ekvivalentu 7-(D-(-)-alfa-amino-fenylacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cefem-4-karboxylová kyseliny s 1,2 molérním ekvivalentem methylisokyanétu se suspenduje v dichlormethanu (80 mil N,O-bis(trlmethylsilyl)acetamid (7,5 ml) se přikape k suspenzi při teplotě 5 až 10 °C a reakční směs se míchá při teplotě 5 až 10 °C až do vzniku roztoku.7- [D - (-) - alpha - (3-methyl-1-ureido) -alpha-phenylacetamido] -3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem -4-carboxylic acid (4 g) prepared by reacting one molar equivalent of 7- (D - (-) - alpha-amino-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3 -cephem-4-carboxylic acid with 1.2 molar equivalent of methyl isocyanate was suspended in dichloromethane (80 ml of N, O-bis (trimethylsilyl) acetamide (7.5 ml) was added dropwise to the suspension at 5-10 ° C and the reaction mixture The mixture is stirred at 5-10 ° C until a solution is formed.
Ke směsi se přidá roztok (10 ml) 3,4-diacetoxybenzoylohloridu (1,9 g) v bezvodém dichlormethanu a směs se míchá 5 hodin při teplotě místnosti. Reakční směs se pak odpaří pří teplotě místnosti za sníženého tlaku k suchu a po přidání bezvodého methanolu k odparku se směs znovu odpaří za sníženého tlaku k suchu. Pak se přidá směs ethylaoetétu (150 ml) a studeného nasyceného vodného roztoku hydrogenuhličitanu sodného (200 ml) a směs se dokonale smísí za chlazení ledovou vodou, Po odstranění nerozpustných podílů se vodná fáze oddělí a pH se upraví na hodnotu 1 přidáním studené 2N kyseliny chlorovodíkové. Sraženina se odfiltruje, promyje vodou (100 ml) a rozpustí v acetonu (100 ml). Roztok se zpracuje s aktivním uhlím a odpařením za sníženého tlaku se odstraní použité rozpouštědlo. Odparek se rozpustí ve směsi methanolu a chloroformu, chromatografuje se na koloně silikagélu a pak se eluuje stejnou směsí rozpouštědel. Eluované frakce se jímají a destilací za sníženého tlaku se odstraní rozpouštědlo. Odparek se zpracuje s diethyletherem (50 ml) a získá se 3,5 g 7-[D-(-)-alfa3-(3,4-di ac etoxybenzoyl)-3-methyl-1-urei do)-alfa-fenylaoetamido J-3-(5-methyl-1,3,4-thi adiazol-2-ylthiomethyl)-3-oefem-4-karboxylové kyseliny (uváděné jako sloučenina P níže) ve formě světle žlutého prášku.To the mixture was added a solution (10 mL) of 3,4-diacetoxybenzoyl chloride (1.9 g) in anhydrous dichloromethane, and the mixture was stirred at room temperature for 5 hours. The reaction mixture is then evaporated to dryness at room temperature under reduced pressure and, after adding anhydrous methanol to the residue, the mixture is again evaporated to dryness under reduced pressure. A mixture of ethyl acetate (150 ml) and cold saturated aqueous sodium bicarbonate solution (200 ml) was added and the mixture was thoroughly mixed under cooling with ice water. After the insolubles were removed, the aqueous phase was separated and the pH adjusted to 1 by adding cold 2N hydrochloric acid. . The precipitate was filtered off, washed with water (100 ml) and dissolved in acetone (100 ml). The solution is treated with activated carbon and the solvent is evaporated off under reduced pressure. The residue is dissolved in a mixture of methanol and chloroform, chromatographed on a silica gel column, and then eluted with the same mixture of solvents. The eluted fractions were collected and the solvent removed by distillation under reduced pressure. The residue was treated with diethyl ether (50 mL) to give 3.5 g of 7- [D - (-) - alpha3- (3,4-di-acetoxybenzoyl) -3-methyl-1-urido) -alpha-phenylaoetamido N -3- (5-methyl-1,3,4-thiazadol-2-ylthiomethyl) -3-oephem-4-carboxylic acid (referred to as compound P below) as a pale yellow powder.
Chromatografie na tenké vrstvě: Rf 0,50, soustava II.Thin Layer Chromatography: Rf 0.50, System II.
iC spektrum: v (om-1) 3 700 až 2 300, 1 775, 1 690, 1 510.iC spectrum:? (? -1 ) 3700-2300, 1775, 1690, 1510.
NMR spektrum: (aceton-dg, 60 MHz) delta (ppm) 2,28 (6H, s), 2,67 (3H, s), 3,15 (3H, s),NMR Spectrum: (acetone-d6, 60 MHz) .delta. (Ppm) 2.28 (6H, s), 2.67 (3H, s), 3.15 (3H, s),
3,74 (2H, brs), 4,44 (2H, ABq), 5,12 (1H, d, J=5Hz), 5,6 až 6,0 (2H, m), 7,2 až 7,7 (8H, m).3.74 (2H, brs), 4.44 (2H, ABq), 5.12 (1H, d, J = 5Hz), 5.6-6.0 (2H, m), 7.2-7, Δ (8H, m).
(a) Postupem popsaným výše v tomto příkladu se nechá reagovat 2,3-diacetoxybenzoylohlo rid a 7-[D-(-)-alfa-ureido-alfa-fenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cefem-4-karboxylové kyselina a získá sa 7-[D-(-)-alfa-{3-(2,3-diacetoxybenzoyl)-1-ureido}-alfa-fenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-oefem-4-karboxylové kyselina (uváděné jako sloučenina M níže) ve formě světle žlutého préšku.(a) 2,3-Diacetoxybenzoyl chloride and 7- [D - (-) - alpha-ureido-alpha-phenylacetamido] -3- (1-methyl-1H-tetrazole-5-) were reacted as described above in this example. ylthiomethyl) -3-cephem-4-carboxylic acid to give 7- [D - (-) - alpha - {3- (2,3-diacetoxybenzoyl) -1-ureido} -alpha-phenylacetamido] -3- (1) methyl-1H-tetrazol-5-ylthiomethyl) -3-oephem-4-carboxylic acid (referred to as compound M below) as a pale yellow powder.
IC spektrum: v (cm-1) 3 700 až 2 300, 1 775, 1 690, 1 530, 1 490.IC spectrum: v (cm -1 ) 3700-2300, 1775, 1690, 1530, 1490.
UlcAXUlcAX
NMR spektrum: (aceton-dg, 60MHz), delta (ppm) 2,28 ($H, s), 3,75 (2H, brs), 3,95 (3H, s), 4,4 (2H, brs), 5,07 (1H, d, J=5Hz), 5,6 až 6,0 (2H, m), 7,2 až 8,0 (8H, m).NMR Spectrum: (acetone-d6, 60MHz), .delta. (Ppm) 2.28 ($ H, s), 3.75 (2H, brs), 3.95 (3H, s), 4.4 (2H, brs) 5.07 (1H, d, J = 5 Hz), 5.6-6.0 (2H, m), 7.2-8.0 (8H, m).
(b) Postupem uvedeným výše se nechá reagovat 3,4-diacetoxybenzoylchlorid a 7—[3>—C—) — -alfa-(3-methyl-1 -ureido)-alfa-fenylaeetamido]-3-acetoxymethyl-3-cefem-4-karboxylové kyselina a získá se 7-[D-(-)-alfe-{3-(3,4-diacetoxybenzoyl)-3-methyl-1-ureidoj-alfa-fenylacetamido]-3-acetoxymethyl-3-cefem-4-karboxylová kyselina (uváděná déle jako sloučenina N) ve formě bílého prášku.(b) 3,4-Diacetoxybenzoyl chloride and 7- [3- (C) -alpha- (3-methyl-1 -ureido) -alpha-phenylaeetamido] -3-acetoxymethyl-3-cephem are reacted as described above. -4-carboxylic acid to give 7- [D - (-) - alpha- {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido] alpha-phenylacetamido] -3-acetoxymethyl-3-cephem -4-carboxylic acid (hereinafter referred to as compound N) in the form of a white powder.
Chromatografie na tenké vrstvě: Rf 0,62, soustava II.Thin Layer Chromatography: Rf 0.62, System II.
IČ spektrum: v 3 700 ež 2 300, 1 780, 1 745, 1 695, 1 510.IR: v 3,700, e , 2,300, 1,780, 1,745, 1,695, 1,510.
NMR spektrum: (aceton-dg, 60 MHz), delta (ppm) 2,00 (3H, s), 2,28 (6H, s), 3,15 (3H, s),NMR Spectrum: (acetone-d6, 60 MHz), .delta. (Ppm) 2.00 (3H, s), 2.28 (6H, s), 3.15 (3H, s),
3,5 (2H, široký s), 4,6 až 5,3 <3H, m), 5,5 až 6,0 (2H, m), 7,2 až 7,7 (8H, o (c) Postupem popsaným výše se nechá reagovat 7-[D-(-)-alfa-(3-methyl-1-ureido)-alfa-fenylaoetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cefem-4-karboxylová kyselina a 3,4-diacetoxybenzoylchlorid a získá se 7-[D-(-)-alfa-{3-(3,4-diacetoxybenzoyl)-3-methyl-1-ureido}-alfa-fenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-eefem-4-karboxylové kyselina (uváděná jako sloučenina R níže) ve formě bílého prášku.3.5 (2H, broad s), 4.6-5.3 (3H, m), 5.5-6.0 (2H, m), 7.2-7.7 (8H, o (c) 7- [D - (-) - alpha - (3-Methyl-1-ureido) -alpha-phenylaoetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3- was reacted as described above. cefem-4-carboxylic acid and 3,4-diacetoxybenzoyl chloride to give 7- [D - (-) - alpha - {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -alpha-phenylacetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-eephem-4-carboxylic acid (referred to as compound R below) as a white powder.
Chromatografie na tenké vrstvě: Rf 0,55, soustava II.TLC: Rf 0.55, System II.
IČ spektrum: v ™r 3 700 až 2 300, 1 775, 1 690, 1 510.IR spectrum: R3 ™ 700-2 300 1775, 1690 1 510th
ifloXifloX
NMR spektrum: (aceton-dg, 60 MHz) delta (ppm) 2,27 (6H, s), 3,13 (3H, s), 3,75 (2H, brs), 3,93 (3H, s), 4,37 (2H, široký s), 5,11 (1H, d, J=5Hz), 5,6 až 5,9 (2H, m), 7,2 až 7,7 (8H, m).NMR Spectrum: (acetone-d6, 60 MHz) .delta. (Ppm) 2.27 (6H, s), 3.13 (3H, s), 3.75 (2H, brs), 3.93 (3H, s) 4.37 (2H, broad s), 5.11 (1H, d, J = 5 Hz), 5.6-5.9 (2H, m), 7.2-7.7 (8H, m).
(d) Postupem uvedeným výše se nechá reagovat 3,4-diacetoxybenzoylchlorid a 7beta-[D-(-)(d) Reaction of 3,4-diacetoxybenzoyl chloride and 7beta- [D - (-)
-alfa-(3-methyl-1-ureido)-alfa-fenylacetamido]-7alfa-methoxy-3-acetoxymethyl-3-eefem-4-kerbq xylové kyselina a získá se 7beta-[D-(-)-alfa-^3-(3,4-diacetoxybenzoyl)-3-methyl-1-ureido}-alfa-fenylacetamidoJ-7alfa-methoxy-3-acetoxymethyl-3-cefem-4-karboxylová kyselina (uváděné jako sloučenina Z níže) ve formě světle žlutého prášku.-alpha- (3-methyl-1-ureido) -alpha-phenylacetamido] -7alpha-methoxy-3-acetoxymethyl-3-eephem-4-carbonic acid affords 7beta- [D - (-) - alpha -? 3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -alpha-phenylacetamido-7alpha-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid (referred to as compound Z below) as a pale yellow powder.
Chromatografie na tenké vrstvě: Rf 0,60, soustava II.Thin Layer Chromatography: Rf 0.60, System II.
IČ spektrum: v (cm-1) 3 700 až 2 300, 1 775, 1 740 až 1 680, 1 505.IR: v (cm -1 ) 3700-2300, 1775, 1740-167, 1550.
ιπηχιπηχ
NMR spektrum: (aceton-dg, 60 MHz), delta (ppm) 2,01 (3H, s), 2,28 (6H, s), 3,17 (3H, s),NMR Spectrum: (acetone-d6, 60 MHz), .delta. (Ppm) 2.01 (3H, s), 2.28 (6H, s), 3.17 (3H, s),
3,2 (2H, brs), 3,50 (3H, s), 4,91 (2H, ABq), 5,09 (1H, s), 5,72 (1H, d, J=7Hz), 7,2 až 7,7 (8H, m), 8,60 (1H, s), 9,85 (1H, d, J=7Hz).3.2 (2H, brs), 3.50 (3H, s), 4.91 (2H, ABq), 5.09 (1H, s), 5.72 (1H, d, J = 7 Hz), 7 2 to 7.7 (8H, m), 8.60 (1H, s), 9.85 (1H, d, J = 7Hz).
(e) Postupem popsaným výše se nechá reagovat 3,4-diacetoxybenzoylchlorid a 7beta-|jD-(-)(e) 3,4-Diacetoxybenzoyl chloride and 7beta-1D - (-) were reacted as described above.
-alfa-(3-methyl-1 -ureido)-alfa-fenylacetamido]-7 alfa-methoxy-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cefem-4-karboxylové kyselina a získá se 7beta-[D-(-)-alfa-{3-(3,4-diacetoxybenzoyl)-3-methyl-1-ureido}-alfa-fenylacetamido]-7alfa-methoxy-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cefem-4-karboxylová kyselina (uváděná jako sloučenina AA níže) ve formě světle žlutého prášku.-alpha- (3-methyl-1 -ureido) -alpha-phenylacetamido] -7 alpha-methoxy-3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid afforded 7beta- [D - (-) - alpha - {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -alpha-phenylacetamido] -7alpha-methoxy-3- (1-methyl-1H-tetrazole) -5-ylthiomethyl) -3-cephem-4-carboxylic acid (referred to as Compound AA below) as a pale yellow powder.
Chromatografie na tenké vrstvě: Rf 0,54, soustava II.Thin Layer Chromatography: Rf 0.54, System II.
IČ spektrum: v (cm-1) 3 700 až 2 300, 1 775, 1 720 až 1 680, 1 510.IR: v (cm -1 ) 3700-2300, 1775, 1720-167, 1510.
NMR spektrum: (aceton-dg, 60 MHz), delta (ppm) 2,28 (6H, s),'3,16 (3H, s), 3,48 (3H, s),NMR Spectrum: (acetone-d6, 60 MHz), .delta. (Ppm) 2.28 (6H, s), 3.16 (3H, s), 3.48 (3H, s),
3,8 (2H, široký s), 3,94 (3H, s), 4,36 (2H, ABq), 4,03 (1H, s), 5,70 (TH, d, J=7Hz), 7,2 až 7,6 (8H, m), 8,6 (1H, s), 9,82 (1H, d, J=7Hz).3.8 (2H, broad s), 3.94 (3H, s), 4.36 (2H, ABq), 4.03 (1H, s), 5.70 (TH, d, J = 7 Hz), 7.2-7.6 (8H, m), 8.6 (1H, s), 9.82 (1H, d, J = 7Hz).
Minimální inhibiční koncentrace (MIC v^ug/ml) pro některé druhy bakterií je stanovena pro sloučeniny podle vynálezu připravené podle příkladů 1 a výsledky jsou shrnuty v následující tabulce. V tabulce jsou bakterie očíslovány podle následujících údajů:The minimum inhibitory concentration (MIC in µg / ml) for some bacterial species is determined for the compounds of the invention prepared according to Examples 1 and the results are summarized in the following table. In the table, the bacteria are numbered according to the following information:
1. Bacillus subtilis PCI-219Bacillus subtilis PCI-219
2. Staphylococcus aureus 209 P2. Staphylococcus aureus 209 P
3. Staphylococcus aureus JU-5Staphylococcus aureus JU-5
4. Sarcina lutea B4. Sarcina lutea B
5. Escherichia coli NIHJ5. Escherichia coli NIHJ
6. Shigella flexneri 2b6. Shigella flexneri 2b
7. Salmonella paratyphi A7. Salmonella paratyphi A
8. Klebsiella pneumoniae 15CKlebsiella pneumoniae 15C
9. Próteus mirabilis 12879. Proteus mirabilis 1287
10. Próteus morgani JU-22410. Proteus morgani JU-224
11. Pseudomonas aeruginosa J-27211. Pseudomonas aeruginosa J-272
12. Pseudomonas aeruginosa J-16912. Pseudomonas aeruginosa J-169
13. Pseudomonas aeruginosa J-169-CM222Pseudomonas aeruginosa J-169-CM222
14. Pseudomonas aeruginosa GNB-7514. Pseudomonas aeruginosa GNB-75
15. Pseudomonas aeruginosa GNB-75-M57740Pseudomonas aeruginosa GNB-75-M57740
16. Pseudomonas aeruginosa KAN-216. Pseudomonas aeruginosa KAN-2
17. Pseudomonas aeruginosa Ps-6Pseudomonas aeruginosa Ps-6
18. Serratia márcescens Ser-25b18. Serratia Marcescens Ser-25b
19. Serratia márcescens FU-10419. Serratia márcescens FU-104
20. Enterobacter cloacae FU-25020. Enterobacter cloacae FU-250
TabulkaTable
PŘEDMĚT VYNÁLEZUSUBJECT OF THE INVENTION
Claims (4)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11062778A JPS5538304A (en) | 1978-09-11 | 1978-09-11 | Cephalosporin derivative and its preparation |
| JP5084179A JPS55143995A (en) | 1979-04-26 | 1979-04-26 | Cephalosporin derivative and its preparation |
| CS794208A CS212222B2 (en) | 1978-06-22 | 1979-06-19 | Method of preparation of the 7-(substituted benzoylureido)-phenyl acetamido derivatives of the cephalosporine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS212224B2 true CS212224B2 (en) | 1982-03-26 |
Family
ID=27179453
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS802742A CS212226B2 (en) | 1978-09-11 | 1980-04-18 | Method of preparation of 7-(substituted benzoylureido)- phenyl-acetoamido derivatives of the cephalosporine |
| CS802739A CS212223B2 (en) | 1978-09-11 | 1980-04-18 | Method of preparation of 7-( substituted benzolureido) phenyl-acetamido derivatives of the cephalosporine |
| CS802740A CS212224B2 (en) | 1978-09-11 | 1980-04-18 | Method of preparation of 7-(substituted benzoylureido) phenylacetamido derivatives of the cephalosporine |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS802742A CS212226B2 (en) | 1978-09-11 | 1980-04-18 | Method of preparation of 7-(substituted benzoylureido)- phenyl-acetoamido derivatives of the cephalosporine |
| CS802739A CS212223B2 (en) | 1978-09-11 | 1980-04-18 | Method of preparation of 7-( substituted benzolureido) phenyl-acetamido derivatives of the cephalosporine |
Country Status (1)
| Country | Link |
|---|---|
| CS (3) | CS212226B2 (en) |
-
1980
- 1980-04-18 CS CS802742A patent/CS212226B2/en unknown
- 1980-04-18 CS CS802739A patent/CS212223B2/en unknown
- 1980-04-18 CS CS802740A patent/CS212224B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS212226B2 (en) | 1982-03-26 |
| CS212223B2 (en) | 1982-03-26 |
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