JPH03236392A - 3-isooxazolidinylcepharosporin derivative for oral administration - Google Patents
3-isooxazolidinylcepharosporin derivative for oral administrationInfo
- Publication number
- JPH03236392A JPH03236392A JP3139090A JP3139090A JPH03236392A JP H03236392 A JPH03236392 A JP H03236392A JP 3139090 A JP3139090 A JP 3139090A JP 3139090 A JP3139090 A JP 3139090A JP H03236392 A JPH03236392 A JP H03236392A
- Authority
- JP
- Japan
- Prior art keywords
- group
- lower alkyl
- compound
- formula
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 239000003242 anti bacterial agent Substances 0.000 claims description 6
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 50
- -1 methoxyimino Chemical group 0.000 abstract description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 abstract description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 6
- 208000035143 Bacterial infection Diseases 0.000 abstract description 4
- 208000022362 bacterial infectious disease Diseases 0.000 abstract description 4
- 238000005886 esterification reaction Methods 0.000 abstract description 3
- 150000004820 halides Chemical class 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract description 2
- 150000007530 organic bases Chemical class 0.000 abstract description 2
- 239000002798 polar solvent Substances 0.000 abstract description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 229930186147 Cephalosporin Natural products 0.000 description 14
- 229940124587 cephalosporin Drugs 0.000 description 14
- 230000000844 anti-bacterial effect Effects 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 150000001780 cephalosporins Chemical class 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical class ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 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
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
- 238000007259 addition reaction Methods 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 150000001782 cephems Chemical group 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- CPQCSJYYDADLCZ-UHFFFAOYSA-N n-methylhydroxylamine Chemical compound CNO CPQCSJYYDADLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- PKPGSMOHYWOGJR-XAYXJRQQSA-N (2e)-2-methoxyimino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid Chemical compound CO\N=C(\C(O)=O)C1=CSC(NC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 PKPGSMOHYWOGJR-XAYXJRQQSA-N 0.000 description 1
- NSWHTWVHOBWFDQ-QMIKVBFTSA-N (2z)-2-[2-(tritylamino)-1,3-thiazol-4-yl]-2-trityloxyiminoacetic acid Chemical compound C=1SC(NC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=NC=1/C(C(=O)O)=N/OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NSWHTWVHOBWFDQ-QMIKVBFTSA-N 0.000 description 1
- AUYSXDWQQQCCMD-MRVPVSSYSA-N (6r)-3-ethenyl-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical class S1CC(C=C)=CN2C(=O)C[C@H]21 AUYSXDWQQQCCMD-MRVPVSSYSA-N 0.000 description 1
- IKWLIQXIPRUIDU-ZCFIWIBFSA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CCS[C@@H]2CC(=O)N12 IKWLIQXIPRUIDU-ZCFIWIBFSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SKNGHROBOKBHGJ-UHFFFAOYSA-N 2-methoxyiminoacetamide Chemical compound CON=CC(N)=O SKNGHROBOKBHGJ-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
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- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Natural products CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 1
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- 125000005131 dialkylammonium group Chemical group 0.000 description 1
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- 238000003113 dilution method Methods 0.000 description 1
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- 125000002541 furyl group Chemical group 0.000 description 1
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- 125000005842 heteroatom Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- RGZRSLKIOCHTSI-UHFFFAOYSA-N hydron;n-methylhydroxylamine;chloride Chemical compound Cl.CNO RGZRSLKIOCHTSI-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- PELJISAVHGXLAL-UHFFFAOYSA-N iodomethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCI PELJISAVHGXLAL-UHFFFAOYSA-N 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
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003017 phosphorus Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
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- 238000000746 purification Methods 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 235000017281 sodium acetate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- JPJKQVVKHIZICB-FYZOBXCZSA-M sodium;(6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[O-]C(=O)C1=CCS[C@@H]2CC(=O)N12 JPJKQVVKHIZICB-FYZOBXCZSA-M 0.000 description 1
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- 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
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Landscapes
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は経口投与用の新規セファロスポリン誘導体に関
し、更に詳しくは一般式(1)〔式中、R1は水素原子
または低級アルキル基を表わし、本印の炭素原子の立体
化学は、且、互、またはR5を示し、R2は一〇〇R”
0COR’基(式中、R3は水素原子または低級アル
キル基を表わし、R4は低級アルキル基、低級アルコキ
シ基またはシクロアルキルオキシ基を表わす)を示す〕
で示される新規な3−イソオキサゾリジニルセファロス
ポリン化合物およびそれらの薬理学上許容される酸付加
塩に関する。更に、本発明は一般式(1)の化合物およ
びその薬学的に許容しうる酸付加塩を有効成分として含
有する経口投与用の抗菌剤に関し、この抗菌剤は細菌感
染症治療剤として有用である。Detailed Description of the Invention [Industrial Field of Application] The present invention relates to a novel cephalosporin derivative for oral administration, and more particularly, it relates to a novel cephalosporin derivative for oral administration, and more specifically, a derivative of the general formula (1) [wherein R1 represents a hydrogen atom or a lower alkyl group] , the stereochemistry of the carbon atom in this mark is mutual or R5, and R2 is 100R"
0COR' group (in the formula, R3 represents a hydrogen atom or a lower alkyl group, and R4 represents a lower alkyl group, a lower alkoxy group, or a cycloalkyloxy group)]
The present invention relates to novel 3-isoxazolidinyl cephalosporin compounds represented by the following formulas and pharmacologically acceptable acid addition salts thereof. Furthermore, the present invention relates to an antibacterial agent for oral administration containing the compound of general formula (1) and its pharmaceutically acceptable acid addition salt as an active ingredient, and this antibacterial agent is useful as a therapeutic agent for bacterial infections. .
〔従来の技術および発明が解決しようとする課題3種々
のセファロスポリン抗生物質は、細菌感染症の治療に広
く使用されているが、従来公知のセファロスポリン類に
比べて抗菌力や抗菌スペクトルと同時に臨床的治療効果
が一層改善されて優れている新規なセファロスポリン誘
導体の発見が望まれている。更に経口投与によって良好
な生体内吸収を示すセファロスポリン誘導体の出現は、
化学療法の分野で多大な期待がかけられている。[Problems to be solved by the prior art and the invention 3 Various cephalosporin antibiotics are widely used for the treatment of bacterial infections, but they have lower antibacterial activity and antibacterial spectrum compared to conventionally known cephalosporins. At the same time, it is desired to discover new cephalosporin derivatives with improved clinical therapeutic effects. Furthermore, the emergence of cephalosporin derivatives that show good in vivo absorption when administered orally,
There are great expectations in the field of chemotherapy.
本発明者らは、先に鋭意研究を行ったが、その結果、2
−(2−アミノチアゾール−4−イル)−2−(置換又
は非置換ヒドロキシイミノ)−アセチル基を7−N−ア
シル基として有するセファロスポリン類であって、その
セフェム環の3位に、環集合へテロ環系の構造を形成す
るように炭素−炭素結合を介して結合する全く新規な種
類の側鎖基としてイソオキサゾリジニル基を導入するこ
とにより、ダラム陽性菌およびダラム陰性菌に対して強
い抗菌効力を有するものであり、それと共に更に7位の
側鎖基を種々に変換することにより緑膿菌に対してまで
も極めて強い抗菌効力を有することができる一連の新規
セファロスポリン誘導体を創製することに成功した。す
なわち、本発明者らは、次の一般式()
〔式中、R1は水素原子または低級アルキル基を表わし
、またはR1は同じ又は相異なる2個の低級アルキル基
を表わして式(1)中に示されたNR’がジアルキルア
ンモニウム基を表わし、本印の炭素原子の所の立体化学
は、且、主、または聾を示し、R2は水素原子、低級ア
ルキル基、またはカルボキシル基で置換された低級アル
キル基、あるいはモノハロ(低級)アルキル基、ジハロ
(低級)アルキル基、l−力ルボキシ−1−(ジヒドロ
キシフェニル)−メチル基、炭素数3〜6のシクロアル
キル基または低級アルケニル基を表わすか、もしくはR
8は、1〜3個の置換基を環上に有してもよいフェニル
基、フリル基、ピリジル基、ピリドニル基、イミダゾリ
ル基及びピリミジル基から選ばれる置換または非置換の
芳香族環基又は複素環式基で置換された低級アルキル基
を表わす〕で示される新規セファロスポリン誘導体およ
びそれらの薬理学上許容される塩類を発明した(本出願
人の出願に係る特願平2− 号;発明の名称「新規
な3−イソオキサゾリジニルセファロスポリン誘導体」
、平成2年2月7日出II)。The inventors previously conducted intensive research, and as a result, found that 2
Cephalosporins having a -(2-aminothiazol-4-yl)-2-(substituted or unsubstituted hydroxyimino)-acetyl group as a 7-N-acyl group, at the 3-position of the cephem ring, Durham-positive and Durham-negative bacteria by introducing isoxazolidinyl groups as an entirely new type of side chain group linked through carbon-carbon bonds to form a ring-assembly heterocyclic structure. A series of new cephalospores that have a strong antibacterial effect even against Pseudomonas aeruginosa by variously converting the side chain group at the 7-position. We succeeded in creating a phosphorus derivative. That is, the present inventors have proposed the following general formula () [wherein R1 represents a hydrogen atom or a lower alkyl group, or R1 represents the same or different two lower alkyl groups, and in formula (1) NR' shown in represents a dialkylammonium group, the stereochemistry at the carbon atom of this symbol is dominant or deaf, and R2 is substituted with a hydrogen atom, a lower alkyl group, or a carboxyl group. Does it represent a lower alkyl group, a monohalo (lower) alkyl group, a dihalo (lower) alkyl group, a l-ruboxy-1-(dihydroxyphenyl)-methyl group, a cycloalkyl group having 3 to 6 carbon atoms, or a lower alkenyl group? , or R
8 is a substituted or unsubstituted aromatic ring group or hetero group selected from a phenyl group, a furyl group, a pyridyl group, a pyridonyl group, an imidazolyl group, and a pyrimidyl group, which may have 1 to 3 substituents on the ring. represents a lower alkyl group substituted with a cyclic group] and their pharmacologically acceptable salts (Patent Application No. 1999 filed by the present applicant; Invention Name: "Novel 3-isoxazolidinyl cephalosporin derivative"
, February 7, 1990 II).
本発明者らが先に提案した上記の一般式(A)で示され
る、3−インオキサゾリジン−5−イル基を有する新規
セファロスポリン誘導体は優れた抗菌作用を有する化学
療法剤である。今回、本発明者らは、−数式(A)の化
合物のうちから選択して、次の一般式(I)
〔式中、R1は水素原子または低級アルキル基を表わし
1本印の炭素原子の所の立体化学は、1、互、または益
を示し R2は−CHR30COR’基(式中、R3は
水素原子または低級アルキル基を表わし、R4は低級ア
ルキル基、低級アルコキシ基またはシクロアルキルオキ
シ基を表わす)を示す〕で示される化合物の4位カルボ
キシル基におけるエステル誘導体が経口投与時に特に向
上された良好な生体内吸収性を有することを見出して本
発明を完成した。The novel cephalosporin derivative having a 3-ynoxazolidin-5-yl group, which is represented by the above general formula (A) and which was previously proposed by the present inventors, is a chemotherapeutic agent having excellent antibacterial activity. This time, the present inventors selected from compounds of the formula (A) and obtained the following general formula (I) [wherein R1 represents a hydrogen atom or a lower alkyl group and one carbon atom is where R2 represents a -CHR30COR' group (wherein R3 represents a hydrogen atom or a lower alkyl group, and R4 represents a lower alkyl group, a lower alkoxy group, or a cycloalkyloxy group); The present invention was completed based on the discovery that an ester derivative at the 4-position carboxyl group of the compound represented by the following formula has particularly improved in vivo absorption upon oral administration.
すなわち、第一の本発明によれば、一般式(1)〔式中
、R1は水素原子または低級アルキル基を表わし、本印
の炭素原子の立体化学は、且、互、または吐を示し、R
2は−CHR” 0COR’基(式中、R3は水素原子
または低級アルキル基を表わし、R4は低級アルキル基
、低級アルコキシ基またはシクロアルキルオキシ基を表
わす)を示す〕で示される七フェム化合物およびその薬
学的に許容できる酸付加塩が提供される。That is, according to the first invention, the general formula (1) [wherein R1 represents a hydrogen atom or a lower alkyl group, and the stereochemistry of the carbon atoms indicated by this symbol indicates mutual or mutual, R
2 represents a -CHR''0COR' group (in the formula, R3 represents a hydrogen atom or a lower alkyl group, and R4 represents a lower alkyl group, a lower alkoxy group, or a cycloalkyloxy group); Pharmaceutically acceptable acid addition salts thereof are provided.
更に詳しく説明するに、一般式(I)の本発明化合物に
おいて、R1は水素原子またはメチル基、エチル基、プ
ロピル基、ブチル基などの炭素数1〜4の低級アルキル
基を表わし、またR2は本化合物を投与後に生体内に吸
収される際、または吸収された後に加水分解を受けて遊
離のカルボキシル基(R”=Hの場合)を与える加水分
解により脱離し易いエステル形成基である。例えば、基
R2を示す式−CHR” 0COR’の基において、R
3は水素原子またはメチル、エチルなどの低級アルキル
基を挙げることができる。また、R4が低級アルキル基
である場合には、それの例としてメチル、エチル、プロ
ピル、イソプロピル、ブチル、イソブチル、5ec−ブ
チル、tert−ブチルなどの炭素数1〜4のアルキル
基であることができ、またR4が低級アルコキシ基であ
る場合には、それの例としてメトキシ、エトキシ、1−
メチルエトキシなどの炭素数1〜4のアルコキシ基であ
ることができ、更にR4がシクロアルキルオキシ基であ
る場合にはそれの例として、シクロペンチルオキシ、シ
クロヘキシルオキシなどの炭素数3〜6のシクロアルキ
ルオキシ基を挙げることができる。To explain in more detail, in the compound of the present invention of general formula (I), R1 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, and R2 represents It is an ester-forming group that is easily eliminated by hydrolysis to give a free carboxyl group (in the case of R''=H) when the present compound is absorbed into the body after administration or after being absorbed.For example, , in the group of the formula -CHR''0COR' representing the group R2, R
3 can be a hydrogen atom or a lower alkyl group such as methyl or ethyl. Further, when R4 is a lower alkyl group, examples thereof include an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, and tert-butyl. and when R4 is a lower alkoxy group, examples thereof include methoxy, ethoxy, 1-
It can be an alkoxy group having 1 to 4 carbon atoms such as methylethoxy, and when R4 is a cycloalkyloxy group, examples thereof include cycloalkyl having 3 to 6 carbon atoms such as cyclopentyloxy and cyclohexyloxy. Mention may be made of oxy groups.
ル基、1−アセトキシエチル基などの1−アシルオキシ
−低級アルキル基、あるいは1−エトキシカルボニルオ
キシエチル基、1−イソプロポキシカルボニルオキシエ
チル基などの1−アルコキシカルボニルオキシ−低級ア
ルキル基などが挙げられる。Examples include 1-acyloxy-lower alkyl groups such as 1-acetoxyethyl group, 1-acetoxyethyl group, and 1-alkoxycarbonyloxy-lower alkyl groups such as 1-ethoxycarbonyloxyethyl group and 1-isopropoxycarbonyloxyethyl group. .
本発明による一般式(I)の化合物の薬理学上許容され
る酸付加塩とは、一般式(I)の化合物のアミノ基また
はイミノ基に薬理学上許容される公知の無機酸、例えば
塩酸、硫酸、硝酸、リン酸など。The pharmacologically acceptable acid addition salt of the compound of general formula (I) according to the present invention refers to the addition salt of the compound of general formula (I) with a known pharmacologically acceptable inorganic acid, such as hydrochloric acid, to the amino group or imino group of the compound of general formula (I). , sulfuric acid, nitric acid, phosphoric acid, etc.
あるいは公知の有機酸1例えば酢酸、プロピオン酸、マ
レイン酸、リンゴ酸などが付加している塩であることが
できる。Alternatively, it can be a salt added with a known organic acid such as acetic acid, propionic acid, maleic acid, malic acid, etc.
本発明化合物を示す一般式(1)における木印の炭素原
子の所の立体化学の絶対配置は又と主の形態が可能であ
るが、本発明化合物はその両者の何れか一方、あるいは
脛混成体を包含する。The absolute configuration of the stereochemistry at the carbon atom of the wood stamp in the general formula (1) showing the compound of the present invention can be in either of the two main forms, but the compound of the present invention may be in either one of the two forms or in the hybrid form. Includes the body.
本発明の一般式(1)の化合物の具体例としては、以下
の例示の化合物に限定されるものではないが、以下に示
す化合物が挙げられる。Specific examples of the compound of general formula (1) of the present invention include, but are not limited to, the compounds shown below.
(1) (6R,7R)−7−((Z)−2−(2−ア
ミノチアゾール−4−イル)−2−(メトキシイミノ)
アセトアミド)−3−((S)−2−メチルイソオキサ
ゾリジン−5−イルツー3−セフェム−4−カルボン酸
ピバロイルオキシメチルエステル(後記の実施例工の
化合物)。(1) (6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)
acetamido)-3-((S)-2-methylisoxazolidin-5-yl2-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (compound in Examples below).
(2) (6R,7幻−7−((Z)−2−(2−アミ
ノチアゾール−4−イル)−2−(メトキシイミノ)ア
セトアミド〕−3−((fi) −2−メチルイソオキ
サゾリジン−5−イルツー3−セフェム−4−カルボン
酸 ピバロイルオキシメチルエステル(後記の実施例2
の化合物)。(2) (6R,7-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamide)-3-((fi)-2-methylisoxazolidine -5-yl2-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (Example 2 below)
compounds).
本発明の一般式(I)の化合物の製造は、後記に製法を
説明する新規化合物である下記の一般式()
〔式中、R1は前述と同じ意味を表わす〕で示される(
6R,7R)−7−[(Z)−2−(2−7ミノチアゾ
ー/I/−4−1’ル)−2−(置換又は非置換イミノ
)アセトアミド]−3−(2−メチルイソオキサゾリジ
ン−5−イル)−3−セフェム−4−カルボン酸を出発
化合物として用い、一般式(n)の化合物とトリエチル
アミンなどの有機塩基との付加塩あるいは一般式(1)
の化合物のカルボキシル基におけるナトリウム、カリウ
ムなどのアルカリ金属の塩(カルボキシレート)を、一
般式()
〔式中、Xはハロゲン原子、R2およびR4は前述と同
じ意味を持つ〕で示されるハライド誘導体と反応するこ
とにより行なわれる0本エステル化反応は一り0℃〜室
温で行なうのが好ましくジメチルホルムアミド、ジメチ
ルスルホキシドなどの極性溶媒あるいは水あるいはこれ
らの混合溶液中で行なわれる。The production of the compound of general formula (I) of the present invention is a new compound represented by the following general formula () [wherein R1 represents the same meaning as above] (
6R,7R)-7-[(Z)-2-(2-7minothiazole/I/-4-1'l)-2-(substituted or unsubstituted imino)acetamide]-3-(2-methylisoxazolidine -5-yl)-3-cephem-4-carboxylic acid as a starting compound, an addition salt of a compound of general formula (n) and an organic base such as triethylamine or a compound of general formula (1)
A salt (carboxylate) of an alkali metal such as sodium or potassium in the carboxyl group of the compound is a halide derivative represented by the general formula () [wherein, X is a halogen atom, and R2 and R4 have the same meanings as above] The esterification reaction carried out by reacting with is preferably carried out at 0 DEG C. to room temperature, and is preferably carried out in a polar solvent such as dimethylformamide or dimethyl sulfoxide, water, or a mixed solution thereof.
前述の如く、本発明による一般式(I)のエステル型化
合物は経口投与すると、一般式(1)におけるR2で示
されるエステル基が生体内で式(I)の化合物から脱離
して遊離のカルボキシル基となり、これにより生成した
遊離カルボン酸の形に転化した式(1)の化合物が生体
内で優れた抗菌力を発揮する。一般式(1)による本発
明化合物の優れた生物学的性状を次に示す。As mentioned above, when the ester type compound of the general formula (I) according to the present invention is orally administered, the ester group represented by R2 in the general formula (1) is detached from the compound of the formula (I) in vivo to form a free carboxyl group. The compound of formula (1), which is converted into a free carboxylic acid form, exhibits excellent antibacterial activity in vivo. The excellent biological properties of the compound of the present invention according to general formula (1) are shown below.
(1)経口投与時の生体内吸収試験
本発明による一般式(I)で示される3−イソオキサゾ
リジニルセファロスポリン化合物として、後記の実施例
1の化合物または実施例2の化合物をICRマウス(雌
、4週令)に経口投与(投与量、300■/マウス)シ
、投与後O〜5時間の尿を集め枯草菌(PCI219)
を試験菌として尿中に***された遊離カルボン酸型の抗
生物質〔一般式(I)においてR2=Hの場合に相当す
る化合物)の抗菌活性を測定し、この抗生物質の尿中回
収率を計算した。その結果は第1表の通りである。(1) In vivo absorption test during oral administration As a 3-isoxazolidinyl cephalosporin compound represented by general formula (I) according to the present invention, the compound of Example 1 or Example 2 described later was administered to ICR mice. (female, 4 weeks old) was orally administered (dose: 300 μ/mouse), and urine was collected from 0 to 5 hours after administration to collect Bacillus subtilis (PCI219).
The antibacterial activity of the free carboxylic acid type antibiotic (compound corresponding to the case where R2=H in general formula (I)) excreted in the urine was measured using the test bacteria, and the urinary recovery rate of this antibiotic was determined. I calculated it. The results are shown in Table 1.
(2)遊離カルボン酸型になった本発明セファロスポリ
ン化合物〔一般式(I)においてR”=Hの場合の化合
物〕の抗菌活性
一般式(1)の本発明化合物の抗菌活性を示すために、
本発明化合物からエステル形成基(R2)を脱離して誘
導される遊離カルボン酸型の誘導体、すなわち後記の実
施例1及び2で用いられた出発化合物を供試化合物とし
て用い、これら供試化合物について、標準の倍数希釈法
で評価した各種の細菌に対する最低生長阻止濃度(MI
C,wcg/i+R)を測定した。(2) Antibacterial activity of the cephalosporin compound of the present invention in the free carboxylic acid form [compound where R''=H in general formula (I)] To demonstrate the antibacterial activity of the compound of the present invention of general formula (1) To,
Free carboxylic acid type derivatives derived from the compound of the present invention by removing the ester-forming group (R2), that is, the starting compounds used in Examples 1 and 2 described later, were used as test compounds, and regarding these test compounds. , Minimum Inhibitory Concentration (MI) for various bacteria evaluated by standard multiple dilution method
C, wcg/i+R) was measured.
供試化合物(a)ニー
(吐、釧)−7−[(孟)−2−(2−アミノチアゾー
ル−4−イル)−2−(メトキシイミノ)アセトアミド
]−3−((S)−2−メチルイソオキサゾリジン−5
−イルゴー3−セフェム−4−カルボン酸
供試化合物(b) : −
(吐、 7R)−7−((Z)−2−(2−アミノチア
ゾール−4−イル)−2−(メトキシイミノ)アセトア
ミド)−3−((且)−2−メチルイソオキサゾリジン
−5−イル〕−3−セフェム=4−カルボン酸
得られた結果を次の第2表に示す。Test Compound (a) Ni(釧)-7-[(Meng)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamide]-3-((S)-2 -Methyl isoxazolidine-5
-Ilgo 3-cephem-4-carboxylic acid test compound (b): - (7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino) Acetamide)-3-((and)-2-methylisoxazolidin-5-yl]-3-cephem=4-carboxylic acid The results obtained are shown in Table 2 below.
本発明による一般式(I)のセフェム化合物又はその酸
付加塩は、これを有効成分として用いて、これに種々の
公知の薬理学的に許容できる固体又は液体状の担体と混
合することによって常法で抗菌剤組成物の形に調製でき
る。The cephem compound of general formula (I) or its acid addition salt according to the present invention can be prepared by using it as an active ingredient and mixing it with various known pharmacologically acceptable solid or liquid carriers. It can be prepared in the form of an antibacterial composition by a method.
従って、第二の本発明によると、第一の本発明による一
般式(I)のセフェム化合物またはこれの薬理学上許容
される酸付加塩を有効成分として含有する経口投与用抗
菌剤組成物が提供される。Therefore, according to the second invention, there is provided an orally administered antibacterial composition containing as an active ingredient the cephem compound of general formula (I) or a pharmacologically acceptable acid addition salt thereof according to the first invention. provided.
第二の本発明に係る抗菌剤に有効成分として含有される
一般式(I)の本発明化合物は優れた経口吸収性と抗菌
力を有しているので経口投与用細菌感染症治療剤として
一有用である0本発明化合物の投与量は、年令、体重、
症状などによって異なるが、通常成人に対し1日100
■ないし2gを1回ないし数回に分けて投与することが
できる。The compound of the present invention of the general formula (I) contained as an active ingredient in the second antibacterial agent of the present invention has excellent oral absorbability and antibacterial activity, so it is suitable as an orally administered bacterial infection treatment agent. The useful dosage of the compound of the present invention depends on age, body weight,
It varies depending on the symptoms, etc., but it is usually 100% per day for adults.
2 to 2 g can be administered once or in divided doses.
−数式(1)で示される本発明化合物やその酸付加塩を
有効成分として含有する抗菌剤は、従来既知のセファロ
スポリン類と同様に、適当な液体状担体又は固体状担体
を配合することによって、通常の経口投与処方に従って
、カプセル剤、散剤、顆粒剤、錠剤などの経口剤、もし
くは腸内投与処方に従って、直腸投与剤、油脂性座剤、
水溶性座剤などの種々の剤形に調製される。これらの各
種製剤は通常用いられている賦形剤、増量剤、結合剤、
湿潤化剤、崩壊剤、表面活性剤、滑沢剤、分散剤、緩衝
剤、保存剤、溶解補助剤、防腐剤、矯味矯臭剤、無痛化
剤などを配合して常法により調製することができる。-An antibacterial agent containing the compound of the present invention represented by formula (1) or its acid addition salt as an active ingredient may be formulated with an appropriate liquid carrier or solid carrier, similar to conventionally known cephalosporins. According to the usual oral administration formulation, oral preparations such as capsules, powders, granules, tablets, etc., or rectal administration formulations, oily suppositories, etc. according to the intestinal administration formulation.
It is prepared in various dosage forms such as water-soluble suppositories. These various preparations contain commonly used excipients, fillers, binders,
It can be prepared by conventional methods by adding wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizing agents, preservatives, flavoring agents, soothing agents, etc. can.
次に、本発明による一般式(1)の化合物の製造に出発
化合物として用いられる前出の一般式(n)の化合物を
調製する方法について説明する。Next, a method for preparing the above-mentioned compound of general formula (n) used as a starting compound in the production of the compound of general formula (1) according to the present invention will be explained.
−数式(n)の出発化合物の製造には、先づ、セフェム
環の3位に炭素−炭素結合で結合して環集合へテロ環系
の構造を形成するように導入された3−イソオキサゾリ
ジニル基を有する7−保護アミノ−3−イソオキサゾリ
ジニル−3−セフェム−4−カルボン酸化合物を調製す
るのが便利である。このために、−数式(IV)
〔式中、R’は一般的な通常のカルボキシル保護基、例
えば4−メトキシベンジル基の如き加水分解で脱離し易
いエステル形成基を意味し、Rbは一般的な通常のアミ
ノ保護基、例えばフェニルアセチル基を意味することが
できる〕で表わされる3−ビニルセフェム誘導体〔「ジ
ャーナル・オブ・アンチビオチフス」38巻、1738
〜1751頁、(1985年)参照〕と、−数式(V)
で表わされる両極性のニトロン誘導体とを環の形成を伴
って付加反応させることにより一般式(VI)〔式中、
−Rb、Hbおよび*印は前述と同じ意味を持つ〕で表
わされる化合物を生成する。本付加反応は中性付近で行
なうのが好ましく、メタノール、エタノール、ジオキサ
ン、ジメチルホルムアミド、ジメチルスルホキシド、ア
セトン、アセトニトリル、テトラヒドロフランなどの極
性有機溶媒あるいは水、あるいはこれらの混合溶液中で
行なわれる0本反応は通常、室温から100℃の温度で
行なうのが適している。また本反応に要する時間は通常
3〜6時間である(後記の参考例1(a)参照)。- For the production of the starting compound of formula (n), first, 3-isoxane is introduced so as to be bonded to the 3-position of the cephem ring with a carbon-carbon bond to form a structure of a ring assembly heterocyclic system. It is convenient to prepare 7-protected amino-3-isoxazolidinyl-3-cephem-4-carboxylic acid compounds having a zolidinyl group. For this purpose, - formula (IV) [wherein R' means a common conventional carboxyl protecting group, for example, an ester-forming group that is easily eliminated by hydrolysis such as 4-methoxybenzyl group, and Rb means a common conventional carboxyl protecting group, 3-vinylcephem derivatives [Journal of Antibiotyphoid Fever], Vol. 38, 1738
- p. 1751, (1985)] and a bipolar nitrone derivative represented by the formula (V) with the formation of a ring, the general formula (VI) [in the formula,
-Rb, Hb and * have the same meanings as above] is produced. This addition reaction is preferably carried out near neutrality, and is preferably carried out in a polar organic solvent such as methanol, ethanol, dioxane, dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, tetrahydrofuran, water, or a mixed solution thereof. Usually, it is suitable to carry out at a temperature of room temperature to 100°C. Further, the time required for this reaction is usually 3 to 6 hours (see Reference Example 1(a) below).
本付加反応で得られる一般式(Vl)の化合物は、本印
の炭素原子の所の立体化学が1体と基体の混合物(経混
成体)として得られるが、この混合物を選ばれた特定の
種類の有機溶媒例えばジクロロメタンに溶解して可溶性
生成物と不溶性生成物に分けることにより、本印の炭素
原子の所の立体化学が純粋な単一の立体異性体化合物を
それぞれ単離することができる。またシリカゲルカラム
クロマトグラフィーによっても1体と1体を分離するこ
とができる(後記の参考例1(a)の参照)。The compound of general formula (Vl) obtained by this addition reaction is obtained as a mixture (stereohybrid) of one stereochemistry at the carbon atom indicated by this symbol and the substrate, but this mixture is By dissolving the soluble and insoluble products in different organic solvents, such as dichloromethane, each single stereoisomeric compound can be isolated, stereochemically pure at the carbon atom of this symbol. . Furthermore, 1-body and 1-body can be separated by silica gel column chromatography (see Reference Example 1(a) below).
なお、前記の式(V)のニトロン誘導体は、次式H,C
−NH−OH
で示されるN−メチルヒドロキシアミンの塩酸塩をジオ
キサン中でホルムアルデヒドと反応させることによって
調製できる(後記の参考例1(a)参照)。In addition, the nitrone derivative of the above formula (V) has the following formula H,C
It can be prepared by reacting the hydrochloride of N-methylhydroxyamine represented by -NH-OH with formaldehyde in dioxane (see Reference Example 1(a) below).
式(VI)の化合物において、Rhは一般的な通常のア
ミノ基の保護基であるが、このアミノ保護基(Rh)は
、セファロスポリン化合物で通常用いられる脱保護方法
により7位のアミノ基から脱離することができ、これに
より、一般式(■)で表わされるセフェム化合物を得る
ことができる(後記の参考例1(b)参照)、続いて一
般式(■)のセフェム化合物の7位アミノ基を一般式(
■)〔式中、R1は前述の式(I)の化合物における基
R1と同じ水素又はアルキル基を意味し、R’は水素原
子またはアミノ保護基例えばトリチル基を表わす〕で示
される化合物、またはそのカルボン酸基の反応性誘導体
とセファロスポリン類の合成上で公知の要領で反応(即
ち7−N−アシル化)せしめることによって、一般式(
IK)
〔式中、R1,R’、R6、および木印は前述と同じ意
味を持つ〕で示される化合物を得る(後記の参考例2(
a)及び参考例3参照)。In the compound of formula (VI), Rh is a general protecting group for an amino group, and this amino protecting group (Rh) can be removed from the amino group at the 7-position by a deprotection method commonly used for cephalosporin compounds. By this, the cephem compound represented by the general formula (■) can be obtained (see Reference Example 1(b) below), and then the cephem compound 7 of the general formula (■) can be obtained. The amino group in position is defined by the general formula (
(2) A compound represented by [wherein R1 means the same hydrogen or alkyl group as the group R1 in the compound of formula (I) above, and R' represents a hydrogen atom or an amino protecting group such as a trityl group], or The general formula (
IK) [In the formula, R1, R', R6, and the wooden seal have the same meanings as above] to obtain a compound (Reference Example 2 (described later)).
a) and Reference Example 3).
最後に、式(IX)の化合物は、これから既知の脱保護
方法で保護基R″及びR’を除去することにより、一般
式(II)で示される新規なセフェム化合物を製造する
ことができる(後記の参考例2(a)参照)。Finally, by removing the protecting groups R'' and R' from the compound of formula (IX) using known deprotection methods, a novel cephem compound of general formula (II) can be produced ( (See Reference Example 2(a) below).
上記のようにして得られた一般式(n)の化合物は、こ
のカルボン酸化合物をアルカリ金属又はアルカリ土類金
属の水酸化物、炭酸塩又は水素炭酸酸塩と水溶液中で反
応させることによって、一般式(n)の化合物の金属塩
(カルボキシレート)を形成することができる。The compound of general formula (n) obtained as described above can be obtained by reacting this carboxylic acid compound with an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate in an aqueous solution. Metal salts (carboxylates) of compounds of general formula (n) can be formed.
次に実施例及び参考例をあげて本発明の化合物を具体的
に説明するが、本発明はこれによって限定されるもので
はない。Next, the compounds of the present invention will be specifically explained with reference to Examples and Reference Examples, but the present invention is not limited thereto.
失凰量よ
(6R,7幻−7−((Z)−2−(2−アミノチアゾ
ール−4−イル)−2−(メトキシイミノ)アセトアミ
ド)−3−((S)−2−メチルイソオキサゾリジン−
5−イル〕−3−セフェムー4−カルボン酸 ピバロイ
ルオキシメチルエステルの製造。The amount of loss (6R,7 phantom-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamide)-3-((S)-2-methyliso Oxazolidine
Preparation of 5-yl]-3-cephemu-4-carboxylic acid pivaloyloxymethyl ester.
後記の参考例2で得られた(6R,7隻)−7−((Z
)−2−(2−アミノチアゾール−4−イル)−2−(
メトキシイミノ)アセトアミド)−3−((S)−2−
メチルイソオキサゾリジン−5−イルツー3−セフェム
−4−カルボン酸ナトリウム塩65■をジメチルホルム
アミド0.4raQに溶かし、その溶液へ一15℃にて
ヨウ化ピバロイルオキシメチル40■を加え、同温度で
30分間撹拌してエステル化反応を行った。その後に、
反応液に酢酸エチルを加え水10%チオ硫酸ナトリウム
水溶液および飽和食塩水で洗浄した。洗浄された溶液か
ら溶媒を減圧留去し、得られた残留物を調製用シリカゲ
ル薄層クロマトグラフィー(展開溶媒系:クロロホルム
−メタノール=9 : 1)により精製及び単離すると
、標題ノ(6fi、 7R)−7−((Z)−2−(2
−7ミノチアゾールー4−イル)−2−(メトキシイミ
ノ)アセトアミド) −3−((S)−2−メチルイソ
オキサゾリジン−5−イルゴー3−セフェム−4−カル
ボン酸 ピバロイルオキシメチルエステル5■を得た。(6R, 7 ships)-7-((Z
)-2-(2-aminothiazol-4-yl)-2-(
methoxyimino)acetamide)-3-((S)-2-
65 μm of methylisoxazolidin-5-yl2-3-cephem-4-carboxylic acid sodium salt was dissolved in 0.4 raQ of dimethylformamide, and 40 μm of pivaloyloxymethyl iodide was added to the solution at -15°C. The mixture was stirred for 30 minutes to carry out the esterification reaction. After that,
Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, a 10% aqueous sodium thiosulfate solution, and saturated brine. The solvent was distilled off from the washed solution under reduced pressure, and the resulting residue was purified and isolated by preparative silica gel thin layer chromatography (developing solvent system: chloroform-methanol = 9:1) to obtain the title compound (6fi, 7R)-7-((Z)-2-(2
-7minothiazol-4-yl)-2-(methoxyimino)acetamide) -3-((S)-2-methylisoxazolidin-5-ylgo-3-cephem-4-carboxylic acid pivaloyloxymethyl ester 5) Obtained.
FABMS: ra/z 583(MH”)NMR(δ
、CDCl5): 1.23(ピバロイル)t 2.7
0(NMe)t5.05(H−6)、 5.26(イソ
オキサゾリジン−5)。FABMS: ra/z 583 (MH”) NMR (δ
, CDCl5): 1.23 (pivaloyl)t 2.7
0(NMe)t5.05(H-6), 5.26(Isoxazolidine-5).
5.85および5.90(OCR,O)、 6.0()
I−7)。5.85 and 5.90 (OCR, O), 6.0 ()
I-7).
失蓋五主
(6に、7尺)−7−((Z)−2−(2−アミノチア
ゾール−4−イル)−2−(メトキシイミノ)アセトア
ミド]−3−((R)−2−メチルイソオキサゾリジン
−5−イル〕−3−セフェム=4−カルボン徴 ピバロ
イルオキシメチルエステ−アミノチアゾール−4−イル
)−2−(メトキシイミノ)アセトアミド] −3−(
(R)−2−メチルイソオキサゾリジン−5−イル〕−
3−セフェムー4−カルボン酸ナトリウム塩40■から
、実施例1の方法と同様に反応及び処理することにより
、(6に、7K) −7−((Z)−2−(2−アミノ
チアゾール−4−イル)−2−(メトキシイミノ)アセ
トアミド) −3−((R)−2−メチルイソオキサゾ
リジン−5−イルゴー3−セフェム−4−カルボン酸
ピバロイルオキシメチルエステル2wgを得た。Loss of ectopia (6 to 7 shaku) -7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamide]-3-((R)-2- Methylisoxazolidin-5-yl]-3-cephem=4-carboxylic pivaloyloxymethylester-aminothiazol-4-yl)-2-(methoxyimino)acetamide]-3-(
(R)-2-methylisoxazolidin-5-yl]-
By reacting and treating 40 μl of 3-cephemu 4-carboxylic acid sodium salt in the same manner as in Example 1, (6,7K)-7-((Z)-2-(2-aminothiazole- 4-yl)-2-(methoxyimino)acetamide)-3-((R)-2-methylisoxazolidin-5-ylgo-3-cephem-4-carboxylic acid
2 wg of pivaloyloxymethyl ester was obtained.
FABMS: mHz 583(MH”)NMR(δ、
CDCl、): 1.23(ピバロイルL 2,73
(NMe)。FABMS: mHz 583 (MH”) NMR (δ,
CDCl, ): 1.23 (pivaloyl L 2,73
(NMe).
5.06(H−6)、 5.64(イソオキサゾリジン
−5)。5.06 (H-6), 5.64 (Isoxazolidine-5).
5.93(OCR,0)、 5.93(H−7)。5.93 (OCR, 0), 5.93 (H-7).
以下の参考例1〜4は、−数式(II)の出発化合物の
調製方法を説明するものである。Reference Examples 1 to 4 below illustrate methods for preparing starting compounds of formula (II).
蔓工舊よ
(6R,7R)−7−アミノ−3−〔値)−2−メチル
イソオキサゾリジン−5−イル〕−3−セフェムー4−
カルボン瞭4−メトキシベンジルエステルおよび(6R
,7R) −7−アミノ−3−((R)−2−メチルイ
ソオキサゾリジン−5−イルゴー3−セフェム−4−カ
ルボン酸 4−メトキシベンジルエステルの製造。Vinegar (6R,7R)-7-amino-3-[value)-2-methylisoxazolidin-5-yl]-3-cephemu4-
Carvone 4-methoxybenzyl ester and (6R
, 7R) -7-amino-3-((R)-2-methylisoxazolidin-5-ylgo-3-cephem-4-carboxylic acid 4-methoxybenzyl ester.
(a)公知の(6R,7R)−7−フェニルアセトアミ
ド−3−ビニル−3−セフェム−4−カルボン酸4−メ
トキシベンジルエステル3.72 、 、酢酸ナトリウ
ム984■および38%ホルマリン1.26鳳2をジオ
キサン75mflに懸濁し、その懸濁液にN−メチルヒ
ドロキシルアミン塩酸塩1.0 gを80%エタノール
水にとかした溶液を徐々に加え、得られた混合物を90
℃で3時間加熱する。この際、ホルムアルデヒドとN−
メチルヒドロキシルアミンとの反応によりニトロン誘導
体が生威し、さらにこのニトロン誘導体がセフェム化合
物の3位ビニル基に付加する反応が起きた。(a) Known (6R,7R)-7-phenylacetamido-3-vinyl-3-cephem-4-carboxylic acid 4-methoxybenzyl ester 3.72%, sodium acetate 984% and 38% formalin 1.26% 2 was suspended in 75 mfl of dioxane, and a solution of 1.0 g of N-methylhydroxylamine hydrochloride dissolved in 80% ethanol water was gradually added to the suspension.
Heat at ℃ for 3 hours. At this time, formaldehyde and N-
A nitrone derivative was produced by the reaction with methylhydroxylamine, and a further reaction occurred in which this nitrone derivative was added to the vinyl group at the 3-position of the cephem compound.
反応液から不溶物を濾別し、濾液を減圧下に濃縮乾固し
、モして残渣をジクロロメタンにとかし、炭酸水素ナト
リウム水溶液、水および飽和食塩水で洗浄し、無水硫酸
ナトリウムで乾燥後に減圧濃縮する。得られた固体残渣
にジエチルエーテルを加えて溶解し、溶液から不溶物を
濾別し濾液を濃縮して、 (6R,7R)−7−フェニ
ルアセトアミド−3−((S)−2−メチルイソオキサ
ゾリジン−5−イルゴー3−セフェム−4−カルボン酸
4−メトキシベンジルエステル2.0gを得た。さら
に前記の不溶物をクロロホルム−メタノール(96:
4)にとかし、シリカゲルカラムクロマトグラフィー(
展開溶媒クロロホルム−メタノール=96:4)で精製
してさらに(望)−異性体0.5gおよび(幻−異性体
0.9gを得た。Insoluble materials were filtered from the reaction solution, the filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in dichloromethane, washed with an aqueous sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Concentrate. The obtained solid residue was dissolved in diethyl ether, the insoluble matter was filtered off from the solution, and the filtrate was concentrated to give (6R,7R)-7-phenylacetamide-3-((S)-2-methyliso 2.0 g of oxazolidin-5-ylgo-3-cephem-4-carboxylic acid 4-methoxybenzyl ester was obtained.The insoluble matter was further removed from chloroform-methanol (96:
4) and silica gel column chromatography (
Purification was performed using a developing solvent chloroform-methanol=96:4) to further obtain 0.5 g of the (desired)-isomer and 0.9 g of the (phantom-isomer).
(b)五塩化リン1.43 gをジクロロメタン20−
に懸濁させ、更にその懸濁液に5℃でピリジン544■
を加えて1時間撹拌した。得られた反応液に前項(b)
で得られた(6R,?R)−7−フェニルアセトアミド
−3−((S)−2−メチルイソオキサゾリジン−5−
イルツー3−セフェム−4−カルボン醜 4−メトキシ
ベンジルエステル1.2gを加え、8〜10℃で1.5
時間反応させた6反応液をさらに一35℃に冷却した後
メタノール9.2m12を加え、その混合物を一15℃
で1.5時間撹拌した。これを氷冷した飽和食塩水50
mmとジクロロメタン50薦Qに加えた。これらの工程
により、セフェム化合物からフェニルアセチル基の脱離
反応が完了した6反応液から、水層を分離し水冷下に炭
酸水素ナトリウム水溶液で中和し、その後、得られた水
溶液をジクロロメタンで抽出した。ジクロロメタン抽出
液を無水硫酸ナトリウムで乾燥後に減圧濃縮して、 (
6R,7R)−7−アミノ−3−[(S) −2−メチ
ルイソオキサゾリジン−5−イルツー3−セフェム−4
−カルボン酸 4−メトキシベンジルエステル811■
を得た。(b) 1.43 g of phosphorus pentachloride and 20-20 g of dichloromethane
and then add pyridine 544■ to the suspension at 5°C.
was added and stirred for 1 hour. Add step (b) to the obtained reaction solution.
(6R,?R)-7-phenylacetamido-3-((S)-2-methylisoxazolidine-5-
Add 1.2 g of il2-3-cephem-4-carboxylic 4-methoxybenzyl ester, and heat to 1.5 g at 8-10°C.
After cooling the reaction mixture for 6 hours to -35°C, 9.2ml of methanol was added, and the mixture was cooled to -15°C.
The mixture was stirred for 1.5 hours. Ice-cooled 50% saturated salt solution
mm and dichloromethane were added to 50 recommended Q. Through these steps, the aqueous layer was separated from the 6 reaction solution in which the elimination reaction of the phenylacetyl group from the cephem compound was completed, and the aqueous layer was neutralized with an aqueous sodium hydrogen carbonate solution while cooling with water.Then, the obtained aqueous solution was extracted with dichloromethane. did. The dichloromethane extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain (
6R,7R)-7-amino-3-[(S)-2-methylisoxazolidin-5-yl2-3-cephem-4
-Carboxylic acid 4-methoxybenzyl ester 811■
I got it.
FABMS: mHz 406 (MH”)NMR(δ
= CDC1a): 2,67(NMe)、4−71(
l(−7)。FABMS: mHz 406 (MH”) NMR (δ
= CDC1a): 2,67 (NMe), 4-71 (
l(-7).
4.89(H−6)、 5.25(イソオキサゾリジン
−5)。4.89 (H-6), 5.25 (isoxazolidine-5).
(c)前項(b)と同様の脱7−N−アシル化法により
フェニルアセチル基を脱離させると、前項(a)で得ら
れた(R)−異性体、即ち(6に、 7R)−7−フェ
ニルアセトアミド−3−[(R)−2−メチルイソオキ
サゾリジン−5−イルツー3−セフェム−4−カルボン
酸 4−メトキシベンジルエステル398■より、(6
R,7R)−7−アミノ−3−((R)−2−メチルイ
ソオキサゾリジン−5−イル〕−3−セフェムー4−カ
ルボン酸 4−メトキシベンジルエステル240■を得
た。(c) When the phenylacetyl group is removed by the same de7-N-acylation method as in the previous section (b), the (R)-isomer obtained in the previous section (a), that is, (6, 7R) -7-phenylacetamido-3-[(R)-2-methylisoxazolidin-5-yl2-cephem-4-carboxylic acid 4-methoxybenzyl ester 398■, (6
240 ml of 4-methoxybenzyl R,7R)-7-amino-3-((R)-2-methylisoxazolidin-5-yl]-3-cephemu 4-carboxylic acid ester were obtained.
FABMS: m、/z 406 (MH”)NMR(
δ−coct、): 2.67(NMe)、4.67(
l(−7)。FABMS: m, /z 406 (MH”) NMR (
δ-coct, ): 2.67 (NMe), 4.67 (
l(-7).
4.90(H−6)、 5.53(イソオキサゾリジン
−5)。4.90 (H-6), 5.53 (isoxazolidine-5).
豊1114
(吐、7幻−7−〔惺)−2−(2−アミノチアゾール
−4−イル〕−2〜(メトキシイミノ)アセトアミド)
−3−((S)−2−メチルイソオキサゾリジン−5−
イルゴー3−セフェム−4−カルボン酸ナトリウム塩の
製造
(a)参考例1(b)で得られた(6R,IR)−7−
アミノ−3−((S)−2−メチルイソオキサゾリジン
−5−イル)−3−セフェム−4−カルボン酸 4−メ
トキシベンジルエステル810■、公知の(Z)−2−
メトキシイミノ−2−(2−トリチルアミノチアゾール
−4−イル)酢酸888.およびヒドロキシベンゾトリ
アゾール298■をジメチルホルムアミド10−に溶か
し、得られた溶液を5℃に冷却した。この溶液に縮合剤
としてジシクロへキシルカルボジイミド454■を加え
25℃で2時間反応させセフェム化合物の7−N−アシ
ル化を行った。その反応液を減圧濃縮して溶媒を除去し
。Yutaka 1114 (vomit, 7-7-[惺)-2-(2-aminothiazol-4-yl]-2~(methoxyimino)acetamide)
-3-((S)-2-methylisoxazolidine-5-
Preparation of Irgo 3-cephem-4-carboxylic acid sodium salt (a) (6R,IR)-7- obtained in Reference Example 1(b)
Amino-3-((S)-2-methylisoxazolidin-5-yl)-3-cephem-4-carboxylic acid 4-methoxybenzyl ester 810■, known (Z)-2-
Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid 888. and 298 ml of hydroxybenzotriazole were dissolved in 10-dimethylformamide, and the resulting solution was cooled to 5°C. To this solution, 454 ml of dicyclohexylcarbodiimide was added as a condensing agent and reacted at 25 DEG C. for 2 hours to effect 7-N-acylation of the cephem compound. The reaction solution was concentrated under reduced pressure to remove the solvent.
残渣に酢酸エチルを加えて溶解し、溶液から不溶物を濾
別した。濾液を水および飽和食塩水で洗浄し、無水硫酸
ナトリウムで乾燥後に減圧濃縮して固体を得た。この固
体をクロロホルムにとかし、シリカゲルカラムクロマト
グラフィー(展開溶媒、クロロホルム)により精製して
(6R,7且)−7−((Z)−2−(メトキシイミノ
)−2−(2−トリチルアミノチアゾール−4−イル)
アセトアミド)−3−((旦)−2−メチルイソオキサ
ゾリジン−5−イル〕−3−セフェムー4−カルボン酸
4−メトキシベンジルエステル1.43gを得た。Ethyl acetate was added to the residue to dissolve it, and insoluble materials were filtered from the solution. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a solid. This solid was dissolved in chloroform and purified by silica gel column chromatography (developing solvent: chloroform) to give (6R,7 and)-7-((Z)-2-(methoxyimino)-2-(2-tritylaminothiazole). -4-yl)
1.43 g of acetamido)-3-((dan)-2-methylisoxazolidin-5-yl]-3-cephemu 4-carboxylic acid 4-methoxybenzyl ester was obtained.
(b)前項(a)で得られた(6R,7fi)−7−[
(Z)−2−(メトキシイミノ)−2−(2−トリチル
アミノチアゾール−4−イル)アセトアミド)−3−(
(S)−2−メチルイソオキサゾリジン−5−イルツー
3−セフェム−4−カルボン酸4−メトキシベンジルエ
ステル150■にアニソール0.15mQとトリフルオ
ロ酢酸1.5−を5℃で加え工時間反応させた。セフェ
ム化合物のカルボキシル基から4−メトキシベンジル基
の脱離反応が起り、またアミノ保護基のトリチル基が部
分的に脱離された。この反応液にイソプロピルエーテル
を加え減圧下に濃縮した。得られたあめ状の残渣にイソ
プロピルエーテルをさらに加えて固体を得た。これを5
0%蟻酸に溶解してその溶液を50℃にて1時間加熱し
て反応させると、アミノ保護基のトリチル基の脱離が完
了した。その反応液から不溶物を濾別し濾液を減圧濃縮
し、得られたあめ状残渣をクロロホルムで粉末化した。(b) (6R,7fi)-7-[ obtained in the previous section (a)
(Z)-2-(methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-3-(
Add 0.15 mQ of anisole and 1.5 mQ of trifluoroacetic acid to 150 μm of (S)-2-methylisoxazolidin-5-yl2-3-cephem-4-carboxylic acid 4-methoxybenzyl ester at 5°C and react for a working time. Ta. Elimination reaction of the 4-methoxybenzyl group from the carboxyl group of the cephem compound occurred, and the trityl group of the amino protecting group was partially eliminated. Isopropyl ether was added to this reaction solution and concentrated under reduced pressure. Isopropyl ether was further added to the resulting candy-like residue to obtain a solid. This is 5
When it was dissolved in 0% formic acid and the solution was heated at 50° C. for 1 hour to react, the removal of the trityl group of the amino protecting group was completed. Insoluble materials were filtered off from the reaction solution, the filtrate was concentrated under reduced pressure, and the resulting candy-like residue was powdered with chloroform.
この粉末を水に懸濁させ、炭酸水素ナトリウム水溶液に
より、pH7に調整した後、アンバーライトXAD−2
レジンのカラムクロマトグラフィーにより精製すると、
siiの(吐、 7R)−7−((Z)−2−(2−ア
ミノチアゾール−4−イル)−2−(メトキシイミノ)
アセトアミド)−3−[(S)−2−メチルイソオキサ
ゾリジン−5−イルゴー3−セフェム−4−カルボン酸
のナトリウム塩42■を得た。After suspending this powder in water and adjusting the pH to 7 with an aqueous sodium hydrogen carbonate solution, Amberlite XAD-2
When purified by resin column chromatography,
sii (7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)
42 ml of sodium salt of acetamido)-3-[(S)-2-methylisoxazolidin-5-ylgo-3-cephem-4-carboxylic acid was obtained.
FABMS: ta/z 491 (MH”)NMR(
δ、 D、0): 2.74および2.84(NMe)
、 5.03および5.30(イソオキサゾリジン−5
)。FABMS: ta/z 491 (MH”) NMR (
δ, D, 0): 2.74 and 2.84 (NMe)
, 5.03 and 5.30 (isoxazolidine-5
).
5.26(H−6) 、5.82および5.83(H−
7)。5.26 (H-6), 5.82 and 5.83 (H-
7).
参JJL走
(6R,7R)−7−[(Z)−2−(2−アミノチア
ゾール−4−イル)−2−(メトキシイミノ)アセトア
ミド)−3−((R)−2−メチルイソオキサゾリジン
−5−イル〕−3−セフェム=4−カルボン酸ナトリウ
ム塩の製造
参考例1(c)で得られた(6R,7R) −7−アミ
ノ−3−[(R)−2−メチルイソオキサゾリジン−5
−イルゴー3−セフェム−4−カルボン酸 4−メトキ
シベンジルエステル223■と公知の(Z)−2−メト
キシイミノ−(2−トリチルアミノチアゾール−4−イ
ル)酢酸244■から、参考例2(a)の方法と同様に
セフェム化合物の7−N−アシル化反応の工程により、
(6に、 7R)−7−((1)=2−(メトキシイミ
ノ)−2−(2−トリチルアミノチアゾール−4−イル
)アセトアミド) −3−((R)−2−メチルイソオ
キサゾリジン−5−イル〕−3−セフェムー4−カルボ
ン酸 4−メトキシベンジルエステル382■を得た。(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamide)-3-((R)-2-methylisoxazolidine -5-yl]-3-cephem=4-carboxylic acid sodium salt production (6R,7R)-7-amino-3-[(R)-2-methylisoxazolidine obtained in Reference Example 1(c) -5
Reference Example 2 (a ), by the step of 7-N-acylation reaction of cephem compounds,
(6, 7R)-7-((1)=2-(methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-3-((R)-2-methylisoxazolidine- 382 ml of 4-methoxybenzyl 5-yl]-3-cephemu-4-carboxylic acid ester was obtained.
この生成物を参考例2(b)と同様な要領で脱保護反応
にかけ、更に炭酸水素ナトリウム処理を含めて参考例2
(b)の後段の工程と同様に処理すると。This product was subjected to a deprotection reaction in the same manner as in Reference Example 2(b), and further including sodium hydrogen carbonate treatment.
When processed in the same manner as the latter step of (b).
標題の(6尺、7K)−7−((孟)−2−(2−アミ
ノチアゾール−4−イル)−2−(メトキシイミノ)ア
セトアミド〕−3−((R)−2−メチルイソオキサゾ
リジン−5−イル〕−3−セフェムー4−カルボン酸の
ナトリウム塩148■を得た。Titled (6 shaku, 7K)-7-((Meng)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-((R)-2-methylisoxazolidine 148 ml of the sodium salt of -5-yl]-3-cephemu-4-carboxylic acid was obtained.
FABMS: mHz 491 (MH”)NMR(δ
、 D、O): 2.73および2.80(NNe)、
5.0および5.31(イソオキサゾリジン−5)。FABMS: mHz 491 (MH”) NMR (δ
, D, O): 2.73 and 2.80 (NNe),
5.0 and 5.31 (isoxazolidine-5).
5.24および5.25(H−6)。5.24 and 5.25 (H-6).
5.81 (H−7)。5.81 (H-7).
参JJL髪
(吐、7幻−7−((Z)−2−(2−アミノチアゾー
ル−4−イル)−2−(ヒドロキシイミノ)アセトアミ
ド)−3−((S)−2−メチルイソオキサゾリジン−
5−イル〕−3−セフェムー4−カルボン酸ナトリウム
塩の製造。3-(S)-2-methylisoxazolidine −
Preparation of 5-yl]-3-cephemu 4-carboxylic acid sodium salt.
参考例1(b)で得られた(6R,7R)−7−アミノ
−3−((S)−2−メチルイソオキサゾリジン−5−
イル〕−3−セフェムー4−カルボン酸 4−メトキシ
ベンジルエステル487mgと公知の(Z)−2−(ト
リチルアミノチアゾール−4−イル)−2−(トリチル
オキシイミノ)酢酸805■から、参考例2(a)の方
法と同様にセフェム化合物の7−N−アシル化反応の工
程により、(6R,7R)−3−[(S)−2−メチル
イソオキサゾリジン−5−イル]−7−((Z)−2−
(2−トリチルアミノチアゾール−4−イル)−2−(
トリチルオキシイミノ)アセトアミド〕−3−セフェム
−4−カルボン酸 4−メトキシベンジルエステル92
6■を得た。この生成物の150■を参考例2(b)と
同様に脱保護反応にかけ、更に炭酸水素ナトリウム処理
を含めて同様に後処理すると、標題の(6に、釧)−7
−[(Z)−2−(2−アミノチアゾール−4−イル)
=2−(ヒドロキシイミノ)アセトアミド)−3−((
S)−2−メチルイソオキサゾリジン−5−イルゴー3
−セフェム−4−カルボン酸のナトリウム塩45■を得
た。(6R,7R)-7-amino-3-((S)-2-methylisoxazolidine-5- obtained in Reference Example 1(b)
Reference Example 2 was prepared from 487 mg of 4-methoxybenzyl]-3-cephemu-4-carboxylic acid 4-methoxybenzyl ester and 805 μg of the known (Z)-2-(tritylaminothiazol-4-yl)-2-(trityloxyimino)acetic acid. (6R,7R)-3-[(S)-2-methylisoxazolidin-5-yl]-7-(( Z)-2-
(2-tritylaminothiazol-4-yl)-2-(
Trityloxyimino)acetamide]-3-cephem-4-carboxylic acid 4-methoxybenzyl ester 92
I got 6■. 150 μ of this product was subjected to the deprotection reaction in the same manner as in Reference Example 2(b), and further treated in the same manner including sodium bicarbonate treatment, resulting in the title (6, Sen)-7.
-[(Z)-2-(2-aminothiazol-4-yl)
=2-(hydroxyimino)acetamide)-3-((
S)-2-methylisoxazolidine-5-ylgo 3
45 µm of the sodium salt of -cephem-4-carboxylic acid was obtained.
FABMS: mHz 477 (MH”)NMR(δ
、 D、0): 2.79および2.89(NMa)、
5.08および5.33(インオキサゾリジン−5)
。FABMS: mHz 477 (MH”) NMR (δ
, D, 0): 2.79 and 2.89 (NMa),
5.08 and 5.33 (inoxazolidine-5)
.
5.27(H−6)、 5.85および5.86(H−
7)。5.27 (H-6), 5.85 and 5.86 (H-
7).
Claims (1)
し、*印の炭素原子の立体化学は、¥R¥、¥S¥、ま
たは¥RS¥を示し、R^2は−CHR^3OCOR^
4基(式中、R^3は水素原子または低級アルキル基を
表わし、R^4は低級アルキル基、低級アルコキシ基ま
たはシクロアルキルオキシ基を表わす)を示す〕で示さ
れるセフェム化合物およびそれらの薬理学上許容される
酸付加塩。 2、一般式( I ) ▲数式、化学式、表等があります▼( I ) 〔式中、R^1は水素原子または低級アルキル基を表わ
し、*印の炭素原子の立体化学は、¥R¥、¥S¥、ま
たは¥RS¥を示し、R^2は−CHR^3OCOR^
4基(式中、R^3は水素原子または低級アルキル基を
表わし、R^4は低級アルキル基、低級アルコキシ基ま
たはシクロアルキルオキシ基を表わす)を示す〕で示さ
れるセフェム化合物およびそれらの薬理学上許容される
酸付加塩を有効成分として含有することを特徴とする経
口投与用抗菌剤。[Claims] 1. General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R^1 represents a hydrogen atom or a lower alkyl group, and the three-dimensional shape of the carbon atom marked with * Chemistry indicates ¥R¥, ¥S¥, or ¥RS¥, where R^2 is -CHR^3OCOR^
4 groups (wherein R^3 represents a hydrogen atom or a lower alkyl group, and R^4 represents a lower alkyl group, a lower alkoxy group, or a cycloalkyloxy group)] and drugs thereof Physically acceptable acid addition salts. 2. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R^1 represents a hydrogen atom or a lower alkyl group, and the stereochemistry of the carbon atom marked with an * is ¥R¥ , ¥S¥, or ¥RS¥, and R^2 is -CHR^3OCOR^
4 groups (wherein R^3 represents a hydrogen atom or a lower alkyl group, and R^4 represents a lower alkyl group, a lower alkoxy group, or a cycloalkyloxy group)] and drugs thereof An antibacterial agent for oral administration characterized by containing a physically acceptable acid addition salt as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3139090A JPH03236392A (en) | 1990-02-14 | 1990-02-14 | 3-isooxazolidinylcepharosporin derivative for oral administration |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3139090A JPH03236392A (en) | 1990-02-14 | 1990-02-14 | 3-isooxazolidinylcepharosporin derivative for oral administration |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH03236392A true JPH03236392A (en) | 1991-10-22 |
Family
ID=12329937
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP3139090A Pending JPH03236392A (en) | 1990-02-14 | 1990-02-14 | 3-isooxazolidinylcepharosporin derivative for oral administration |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH03236392A (en) |
-
1990
- 1990-02-14 JP JP3139090A patent/JPH03236392A/en active Pending
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