JPS624397B2 - - Google Patents
Info
- Publication number
- JPS624397B2 JPS624397B2 JP52086612A JP8661277A JPS624397B2 JP S624397 B2 JPS624397 B2 JP S624397B2 JP 52086612 A JP52086612 A JP 52086612A JP 8661277 A JP8661277 A JP 8661277A JP S624397 B2 JPS624397 B2 JP S624397B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- general formula
- represented
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000004149 thio group Chemical group *S* 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 150000001768 cations Chemical class 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000003367 polycyclic group Chemical group 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 150000001875 compounds Chemical class 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- -1 alkali metal salt Chemical class 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 230000000844 anti-bacterial effect Effects 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 8
- 229930186147 Cephalosporin Natural products 0.000 description 7
- 229910052783 alkali metal Inorganic materials 0.000 description 7
- 229940124587 cephalosporin Drugs 0.000 description 7
- 230000002140 halogenating effect Effects 0.000 description 7
- 150000001780 cephalosporins Chemical class 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 5
- 102000006635 beta-lactamase Human genes 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 108090000204 Dipeptidase 1 Proteins 0.000 description 4
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000588747 Klebsiella pneumoniae Species 0.000 description 3
- 241000069157 Miconia aeruginosa Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 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 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-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
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- 208000031295 Animal disease Diseases 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- NXTVQNIVUKXOIL-UHFFFAOYSA-N N-chlorotoluene-p-sulfonamide Chemical compound CC1=CC=C(S(=O)(=O)NCl)C=C1 NXTVQNIVUKXOIL-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000005206 alkoxycarbonyloxymethyl group Chemical group 0.000 description 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- WAVQOKDKPHYRDY-GOSISDBHSA-N benzhydryl (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C([C@H]1SCC=2)C(=O)N1C=2C(=O)OC(C=1C=CC=CC=1)C1=CC=CC=C1 WAVQOKDKPHYRDY-GOSISDBHSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000001271 cephalosporin group Chemical group 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 238000006198 methoxylation reaction Methods 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- HSPSCWZIJWKZKD-UHFFFAOYSA-N n-chloroacetamide Chemical compound CC(=O)NCl HSPSCWZIJWKZKD-UHFFFAOYSA-N 0.000 description 1
- CHVZPRDGLWBEMJ-UHFFFAOYSA-N n-chlorobenzenesulfonamide Chemical compound ClNS(=O)(=O)C1=CC=CC=C1 CHVZPRDGLWBEMJ-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229960004319 trichloroacetic acid Drugs 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規な７α−メトキシセフアロスポリ
ン類に関する。
従来、７α−メトキシセフアロスポリン類は、
一般に、β−ラクタマーゼに対して抵抗性を有す
ることが知られていたが、その抗菌力は必ずしも
強くなかつた。特に、緑膿菌や変形菌などのグラ
ム陰性菌に対しては、有効な抗菌性を示すものが
少ない。
本発明者らは、β−ラクタマーゼに対して安定
で、且つ、広範囲な抗菌スペクトルを有する、次
の一般式
〔式中、R1、R2、R3、R4、Ａ及びＸは後述の意味
を有する。〕
で表わされる７α−メトキシセフアロスポリン類
を得ることを目的に、後述の一般式（）で表わ
されるセフアロスポリン類に後述の一般式（）
で表わされるメタノールのアルカリ金属塩を反応
させた後、次いでハロゲン化剤を作用させて、７
位を直接メトキシ化する反応を行なつたところ、
ハロゲン化剤を過剰に用いた場合に、後述の一般
式（）で表わされる７α−メトキシセフアロス
ポリン類が生成することがわかつた。この生成し
た化合物の生物活性を調べたところ、β−ラクタ
マーゼに対して安定であるばかりでなく、前述の
グラム陰性菌に対しても有効で、且つ、広範囲で
強力な抗菌スペクトルを有することを見い出し本
発明を完成した。
而して、本発明の目的とするところは、グラム
陽性菌並びにグラム陰性菌に対して広範囲で強力
な抗菌スペクトルを有すると共に、β−ラクタマ
ーゼに対して安定な性質を有し、人及び動物の疾
病に対して有効な新規７α−メトキシセフアロス
ポリン類を提供せんとするにある。
さらに具体的には、本発明の新規な７α−メト
キシセフアロスポリン類は、次の一般式（）で
表わされる。
〔式中、R1は水素原子、カルボキシル保護形成基
又は塩形成陽イオンを；R2は置換基を有してい
てもよいアシルオキシ又は含窒素五員環よりなる
複素環式チオ基を；R3及びR4は水素原子を；Ａ
はアルキル基を；示す。〕
前述の如く、本発明の化合物は、セフエム環の
７α位にメトキシ基が置換し、７β位のアミノ基
が次の基：
〔式中、R3、R4、Ａ及びＸは前記した意味を有す
る。〕
と結合していることが特徴である。
上記一般式（）で表わされる化合物の中で、
次の一般式（ａ）で表わされる化合物、その中
でも一般式（ｂ）の化合物、さらに、その中で
も一般式（ｃ）の化合物が優れている。
〔式中、A1は低級アルキル基を；A2はメチル基又
はエチル基を：R5はアセトキシ基、５−（１−メ
チル−１・２・３・４−テトラゾリル）チオ基、
２−（５−メチル−１・３・４−チアジアゾリ
ル）チオ基、５−（１・２・３−トリアゾリル）
チオ基、５−（１・２・３・４−テトラゾリル）
チオ基又は２−（１・３・４−チアジアゾリル）
チオ基を；R6はアセトキシ基、５−（１−メチル
−１・２・３・４−テトラゾリル）チオ基又は２
−（５−メチル−１・３・４−チアジアゾリル）
チオ基をR1、R4及びＸは前記した意味を有す
る。〕
以下、更に、詳細に本発明を説明する。
本明細書において、「カルボキシル保護形成
基」及び「塩形成陽イオン」とは、従来からペニ
シリン及びセフアロスポリンの分野で通常知られ
ているものを意味し、具体的には、「カルボキシ
ル保護形成基」としては、例えば、次のものがあ
げられる。
(イ) 接触環元、化学的環元又は緩和な条件下で処
理すれば脱離する性質を有するエステル形成
基、例えば、Ｐ−トルエンスルホニルエチル等
の置換アリールスルホニルアルキル基；ベンジ
ル、４−ニトロベンジル、ベンズヒドリル、ト
リチル、３・５−ジ（tert.−ブチル）−４−ヒ
ドロキシベンジル等の置換又は未置換のアルア
ルキル基；ベンゾイルオキシメチル基；tert.
−ブチル、トリクロロエチル等の置換又は未置
換のアルキル基；フエナシル基；メトキシメチ
ル等のアルキルオキシアルキル基など。
(ロ) 生体内において酵素により容易に脱離する性
質を有するエステル形成基、例えば、ピバロイ
ルオキシメチル等のアシルオキシアルキル基；
エトオキシカルボニルオキシメチル基などのア
ルコキシカルボニルオキシメチル基；フタリジ
ル基；インダニル基など。
(ハ) 水又はアルコールで処理すれば容易に脱離す
る性質を有する有機ケイ素基、有機リン基又は
有機スズ基、例えば、
（CH3）3Si；
The present invention relates to novel 7α-methoxycephalosporins. Conventionally, 7α-methoxycephalosporins are
Although it was generally known to have resistance to β-lactamase, its antibacterial activity was not necessarily strong. In particular, there are few that exhibit effective antibacterial properties against Gram-negative bacteria such as Pseudomonas aeruginosa and M. aeruginosa. The present inventors have developed the following general formula, which is stable against β-lactamases and has a broad antibacterial spectrum. [In the formula, R 1 , R 2 , R 3 , R 4 , A and X have the meanings described below. ] For the purpose of obtaining 7α-methoxycephalosporins represented by the following general formula (), the cephalosporins represented by the general formula (
After reacting the alkali metal salt of methanol represented by
When a reaction was carried out to directly methoxylate the position,
It has been found that when the halogenating agent is used in excess, 7α-methoxycephalosporins represented by the general formula () below are produced. When we investigated the biological activity of this produced compound, we found that it is not only stable against β-lactamase, but also effective against the aforementioned Gram-negative bacteria, and has a strong antibacterial spectrum over a wide range. The invention has been completed. Therefore, the object of the present invention is to have a strong antibacterial spectrum over a wide range of gram-positive and gram-negative bacteria, be stable against β-lactamase, and be effective against humans and animals. It is an object of the present invention to provide novel 7α-methoxycephalosporins that are effective against diseases. More specifically, the novel 7α-methoxycephalosporin of the present invention is represented by the following general formula (). [In the formula, R 1 is a hydrogen atom, a carboxyl protection-forming group, or a salt-forming cation; R 2 is a heterocyclic thio group consisting of acyloxy or a nitrogen-containing five-membered ring which may have a substituent; R 3 and R 4 are hydrogen atoms; A
represents an alkyl group. ] As mentioned above, the compound of the present invention has a methoxy group substituted at the 7α position of the cefem ring, and an amino group at the 7β position is substituted with the following group: [In the formula, R 3 , R 4 , A and X have the above-mentioned meanings. ] It is characterized by being combined with. Among the compounds represented by the above general formula (),
Compounds represented by the following general formula (a), among which compounds represented by general formula (b), and even among them, compounds represented by general formula (c) are excellent. [In the formula, A 1 is a lower alkyl group; A 2 is a methyl group or an ethyl group; R 5 is an acetoxy group, a 5-(1-methyl-1, 2, 3, 4-tetrazolyl) thio group,
2-(5-methyl-1,3,4-thiadiazolyl)thio group, 5-(1,2,3-triazolyl)
Thio group, 5-(1,2,3,4-tetrazolyl)
Thio group or 2-(1,3,4-thiadiazolyl)
thio group; R 6 is acetoxy group, 5-(1-methyl-1,2,3,4-tetrazolyl)thio group, or 2
-(5-methyl-1,3,4-thiadiazolyl)
In the thio group, R 1 , R 4 and X have the meanings given above. ] Hereinafter, the present invention will be explained in further detail. As used herein, "carboxyl protection-forming group" and "salt-forming cation" refer to those conventionally known in the field of penicillin and cephalosporin, and specifically, "carboxyl protection-forming group" Examples include the following: (a) Catalytic ring elements, chemical ring elements, or ester-forming groups that have the property of being eliminated when treated under mild conditions, such as substituted arylsulfonylalkyl groups such as P-toluenesulfonylethyl; benzyl, 4-nitro Substituted or unsubstituted aralkyl groups such as benzyl, benzhydryl, trityl, 3,5-di(tert.-butyl)-4-hydroxybenzyl; benzoyloxymethyl group; tert.
- Substituted or unsubstituted alkyl groups such as butyl and trichloroethyl; phenacyl groups; alkyloxyalkyl groups such as methoxymethyl; and the like. (b) Ester-forming groups that have the property of being easily eliminated by enzymes in vivo, for example, acyloxyalkyl groups such as pivaloyloxymethyl;
Alkoxycarbonyloxymethyl groups such as ethoxycarbonyloxymethyl groups; phthalidyl groups; indanyl groups, etc. (c) An organosilicon group, an organophosphorus group, or an organotin group that has the property of being easily eliminated by treatment with water or alcohol, such as (CH 3 ) 3 Si;
【式】【formula】
で表わされるメタノールのアルカリ金属塩と反応
させ、次いで、ハロゲン化剤を作用させることに
より製造することができる。
上記一般式（）で表わされるメタノールのア
ルカリ金属塩とは、リチウムメトキシド、ナトリ
ウム、メトキシド、カリウムメトキシドなどであ
る。
以下、上記製造法の実施の態様を説明する。
まず、一般式（）で表わされるセフアロスポ
リン類を反応に不活性な溶媒、例えば、テトラヒ
ドロフラン、ジオキサン、エチレングリコールの
ジメチルエーテル、塩化メチレン、クロロホル
ム、ジメチルホルムアミド、ジメチルアセトアミ
ド、アセトニトリル、メタノールなど、又はこれ
らの２種以上の混合溶媒に溶解又は懸濁し、メタ
ノールのアルカリ金属塩（）をメタノールと共
に加えて反応させる。このとき、メタノールを過
剰量用い、メタノールのアルカリ金属塩（）の
量は、一般式（）のセフアロスポリン類に対し
て２−６当量用いるのが好ましい。また、過剰量
とは、式（）のセフアロスポリン類に対して１
当量以上であることを意味する。次いで、ハロゲ
ン化剤を加えて反応させる。
上記の全反応は、一般に、反応温度−120℃〜
−10℃、好ましくは、−100〜−50℃で行なわれ、
反応時間は５〜30分間である。次いで反応系内を
酸性化することにより７位メトキシ化反応を停止
させたのち、室温まで昇温しハロゲン化反応を完
結させる。
本方法において使用できるハロゲン化剤は、一
般に、陽性ハロゲン供給源として通常知られてい
るもので、たとえば、Cl+、Br+、又はI+等の陽性
ハロゲン原子を供給し得る任意のハロゲン化合物
を示す。具体的には、例えば、塩素、臭素等のハ
ロゲン；Ｎ−クロロスクシンイミド、Ｎ−ブロモ
スクシンイミド等のＮ−ハロイミド類；Ｎ−クロ
ロアセトアミド、Ｎ−ブロモアセトアミド等のＮ
−ハロアミド類；Ｎ−クロロベンゼンスルホンア
ミド、Ｎ−クロロ−Ｐ−トルエンスルホンアミド
等のＮ−ハロスルホンアミド類；１−ハロベンゾ
トリアゾール類；１−ハロトリアジン類；tert.
−ブチルヒポクロリド、tert.−ブチルヨ−ジド
等の有機ヒポハロゲニド類；Ｎ・N′−ジブロモ
ヒダントイン等のハロヒダントインなどがあげら
れる。特に好ましいハロゲン化剤としては、有機
ヒポハロゲニド類があげられる。
ハロゲン化剤は、一般式（）で表わされるセ
フアロスポリン類に対し、２当量の陽性ハロゲン
を供給するのに充分な量で使用される。生成した
７α−メトキシセフアロスポリン類（）は、反
応混合物中より、常法により単離精製することが
できる。
なお、過剰のハロゲン化剤は、反応後亜リン酸
のトリアルキルエステル、チオ硫酸ナトリウムな
どの還元剤で処理することによつて除去すること
ができる。
また、反応系内を酸性にするための適当な酸と
しては、冷反応混合物中に加えたとき、反応混合
物の固化又は重い粘稠混合物への凍結を惹起しな
いようなものが好ましい。
例えば、98％−蟻酸、氷酢酸、トリクロル酢
酸、メタンスルホン酸などが使用できる。
また、一般式（）で表わされる本発明化合物
の他の製法としては、次のようなものがあげられ
る。
即ち、一般式（）
〔式中、R7は水素原子、有機ケイ素基又は有機リ
ン酸を；そして、R1、R2及びＸは前記した意味
を有する。〕
で表わされる化合物に一般式（）
〔式中、R3、R4、及びＡは前記した意味を有す
る。〕
で表わされる化合物のカルボキシル基における反
応性誘導体を反応させて、一般式（）で表わさ
れる７α−メトキシセフアロスポリン類を製造す
る方法、あるいは、一般式（）
〔式中、R1、R2及びR7は前記した意味を有す
る。〕
で表わされる化合物に一般式（）
〔式中、R3、R4、Ａ及びＸは前記した意味を有す
る。〕
で表わされる化合物又はそのカルボキシル基にお
ける反応性誘導体を反応させて、一般式（）で
表わされる７α−メトキシセフアロスポリン類を
製造する方法、あるいは、一般式（）
〔式中、R8はアシル基を；R9はカルボキシル保護
形成基を；R2は前記した意味を有する。〕
で表わされる化合物にイミノハロゲン化剤を反応
せしめ、次いでイミノエーテル化剤を反応させ、
しかる後一般式（）で表わされる化合物のカル
ボキシル基における反応性誘導体を反応させ、更
に、加水分解反応に付して、一般式（）で表わ
される７α−メトキシセフアロスポリン類を製造
する方法、
あるいは、一般式（）
〔式中、R10は求核試薬により容易に置き換えられ
る置換基を；R1、R3、R4、Ａ及びＸは前記した
意味を有する。〕
で表わされる化合物に一般式（）
R2M′ （）
〔式中、R2は前記したと同様の意味；M′は水素原
子、アルカリ金属又はアルカリ土類金属を示
す。〕
で表わされる化合物を反応させて、一般式（）
で表わされる７α−メトキシセフアロスポリン類
を製造する方法である。
これらの方法によつて製造される一般式（）
の本発明化合物において、R1が水素原子である
場合はR1が塩形成陽イオン若しくはカルボキシ
ル保護形成基に、R1が塩形成陽イオンである場
合はR1が水素原子若しくはカルボキシル保護形
成基に、又はR1がカルボキシル保護形成基であ
る場合はR1が水素原子若しくは塩形成陽イオン
に、それぞれ、常法によつて変換することができ
る。
また、本発明において、R2が反応に活性な基
である場合は、本反応に際し、通常カルボキシル
基、アミノ基又はヒドロキシル基などを保護する
為に用いられている任意の保護基で保護しておく
こともでき、反応後、常法によりその保護基を脱
離させ、Ａ及びR2に変換させてもよい。
かくして得られる新規な本発明化合物（）は
グラム陽性菌並びにグラム陰性菌に対して広範囲
な抗菌スペクトルを有するばかりでなく、緑膿菌
に対して極めて優れた抗菌活性を有し、β−ラク
タマーゼに対して安定であり、人及び動物の疾病
に対する治療薬として極めて価置あるものであ
る。
本発明の７α−メトキシセフアロスポリン類の
具体例としては、表１の組み合せによる化合物が
あげられる。
It can be produced by reacting methanol with an alkali metal salt represented by the following formula, and then reacting with a halogenating agent. The alkali metal salt of methanol represented by the above general formula () includes lithium methoxide, sodium, methoxide, potassium methoxide, and the like. Hereinafter, embodiments of the above manufacturing method will be described. First, a cephalosporin represented by the general formula () is treated with a solvent inert to the reaction, such as tetrahydrofuran, dioxane, dimethyl ether of ethylene glycol, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, acetonitrile, methanol, etc., or two of these. It is dissolved or suspended in a mixed solvent of more than one species, and an alkali metal salt of methanol () is added together with methanol to react. At this time, it is preferable to use an excess amount of methanol and to use the alkali metal salt of methanol () in an amount of 2 to 6 equivalents relative to the cephalosporin of the general formula (). In addition, the excess amount is 1 for the cephalosporins of formula ().
It means more than the equivalent amount. Next, a halogenating agent is added and reacted. All the above reactions are generally carried out at a reaction temperature of −120°C to
carried out at -10°C, preferably -100 to -50°C,
Reaction time is 5-30 minutes. Next, the reaction system is acidified to stop the 7-position methoxylation reaction, and then the temperature is raised to room temperature to complete the halogenation reaction. The halogenating agents that can be used in the present method are generally those commonly known as positive halogen sources, such as any halogen compound capable of supplying positive halogen atoms, such as Cl + , Br + , or I + . show. Specifically, for example, halogens such as chlorine and bromine; N-haloimides such as N-chlorosuccinimide and N-bromosuccinimide; N-halogens such as N-chloroacetamide and N-bromoacetamide;
- Haloamides; N-halosulfonamides such as N-chlorobenzenesulfonamide and N-chloro-P-toluenesulfonamide; 1-halobenzotriazoles; 1-halotriazines; tert.
Examples include organic hypohalogenides such as -butylhypochloride and tert.-butyliodide; and halohydantoins such as N.N'-dibromohydantoin. Particularly preferred halogenating agents include organic hypohalogenides. The halogenating agent is used in an amount sufficient to supply 2 equivalents of positive halogen to the cephalosporins represented by the general formula (). The produced 7α-methoxycephalosporin () can be isolated and purified from the reaction mixture by a conventional method. Incidentally, the excess halogenating agent can be removed by treatment with a reducing agent such as trialkyl ester of phosphorous acid or sodium thiosulfate after the reaction. The suitable acid for acidifying the reaction system is preferably one that does not cause the reaction mixture to solidify or freeze into a heavy viscous mixture when added to the cold reaction mixture. For example, 98% formic acid, glacial acetic acid, trichloroacetic acid, methanesulfonic acid, etc. can be used. Further, other methods for producing the compound of the present invention represented by the general formula () include the following. That is, the general formula () [In the formula, R 7 represents a hydrogen atom, an organosilicon group, or an organophosphoric acid; and R 1 , R 2 and X have the meanings described above. ] For the compound represented by the general formula () [In the formula, R 3 , R 4 and A have the meanings described above. ] A method for producing 7α-methoxycephalosporins represented by the general formula () by reacting a reactive derivative at the carboxyl group of the compound represented by the formula (), or a method for producing 7α-methoxycephalosporins represented by the general formula () [In the formula, R 1 , R 2 and R 7 have the meanings described above. ] For the compound represented by the general formula () [In the formula, R 3 , R 4 , A and X have the above-mentioned meanings. ] A method for producing 7α-methoxycephalosporins represented by the general formula () by reacting a compound represented by the formula () or a reactive derivative thereof at the carboxyl group, or a method for producing a 7α-methoxycephalosporin represented by the general formula (). [In the formula, R 8 represents an acyl group; R 9 represents a carboxyl protection forming group; R 2 has the meaning described above. ] The compound represented by is reacted with an iminohalogenating agent, and then reacted with an iminoetherifying agent,
A method for producing 7α-methoxycephalosporins represented by the general formula () by subsequently reacting a reactive derivative at the carboxyl group of the compound represented by the general formula () and further subjecting it to a hydrolysis reaction, Alternatively, the general expression () [In the formula, R 10 represents a substituent that can be easily replaced by a nucleophile; R 1 , R 3 , R 4 , A and X have the meanings described above. ] The compound represented by the general formula () R 2 M′ () [wherein R 2 has the same meaning as above; M′ represents a hydrogen atom, an alkali metal or an alkaline earth metal. ] By reacting the compound represented by the general formula ()
This is a method for producing 7α-methoxycephalosporin represented by General formula () produced by these methods
In the compound of the present invention, when R 1 is a hydrogen atom, R 1 is a salt-forming cation or a carboxyl protection-forming group, and when R 1 is a salt-forming cation, R 1 is a hydrogen atom or a carboxyl protection-forming group. or, when R 1 is a carboxyl protection-forming group, R 1 can be converted to a hydrogen atom or a salt-forming cation, respectively, by a conventional method. In addition, in the present invention, if R 2 is a group active in the reaction, it may be protected with any protective group normally used to protect carboxyl groups, amino groups, hydroxyl groups, etc. After the reaction, the protecting group may be removed by a conventional method and converted into A and R 2 . The novel compound of the present invention thus obtained not only has a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, but also has extremely excellent antibacterial activity against Pseudomonas aeruginosa and is highly effective against β-lactamase. It is stable and highly valuable as a therapeutic drug for human and animal diseases. Specific examples of the 7α-methoxycephalosporins of the present invention include compounds according to the combinations shown in Table 1.
【表】【table】
【表】【table】
【表】
更に、上記表１の組み合せに係る化合物のナト
リウム塩などの非毒性塩及びベンズヒドリルエス
テル、β・β・β−トリクロルエチルエステルな
どの各種保護形成基でカルボキシル基が保護され
た化合物があげられる。
本発明の（）式の化合物は、遊離酸の形、ま
た非毒性塩若しくは生理的に許容されるエステル
の形として人及び動物に投与する。当該化合物
は、通常のペニシリン又はセフアロスポリン系薬
剤の場合に適用されている剤形、例えば、錠剤、
カプセル剤、シロツプ剤、注射剤の形に調整し、
経口的若しくは非経口的に投与できる。
次に、本発明の代表的化合物について、その製
造例及び抗菌力を掲げる。なお、抗菌力は全て最
小発育防止濃度（MIC）mg／mlで示す（接種菌
量：106cells／ml）。
製造例 １
(1) ７β−〔Ｄ（−）−α−（４−エチル−２・３
−ジオキソ−１−ピペラジンカルボキサミド）
−α−（４−ヒドロキシフエニル）アセトアミ
ド〕−３−（１−メチル−１・２・３・４−テト
ラゾリル）チオメチル−Δ３−セフエム−４−
カルボン酸のベンズヒドリルエステル0.81ｇを
無水クロロホルム20ml及び無水テトラヒドロフ
ラン５mlの混合溶媒に溶解させた後−75℃に冷
却する。次に、この中へ、リチウムメトキシド
のメタノール溶液3.5ml（5mMのリチウムメト
キシドを含む）を加えて２分間反応させ、次い
でtert.−ブチルヒポクロリド0.36mlを加えて同
温度で20分間反応させる。
次に、反応液に酢酸0.3mlを加え、室温まで
昇温させる。溶媒を減圧下に留去し、残留物に
水20ml及び酢酸エチル20mlを加えて溶解した
後、酢酸エチル層を分取する。
酢酸エチル溶液を、希炭酸水素ナトリウム水
溶液、水、飽和食塩水で順次洗浄した後、無水
硫酸マグネシウムで乾燥する。溶媒を減圧下に
留去し、残留物をシリカゲルカラムクロマトグ
ラフイー（酢酸エチル−ベンゼン混合溶媒で溶
出）にて精製すれば７β−〔Ｄ（−）−α−（４
−エチル−２・３−ジオキソ−１−ピペラジン
カルボキサミド）−α−（３−クロル−４−ヒド
ロキシフエニル）アセトアミド〕−７α−メト
キシ−３−〔５−（１−メチル−１・２・３・４
−テトラゾリル）チオメチル〕−Δ３−セフエ
ム−４−カルボン酸のベンズヒドリルエステル
0.57ｇ（65％）を得る。
NMR（CDCl3）ppm値：
1.15（3H、ｔ−CH2CH3）、3.2〜4.0
（8H、[Table] Furthermore, non-toxic salts such as sodium salts of the compounds according to the combinations in Table 1 above, and compounds whose carboxyl groups are protected with various protection-forming groups such as benzhydryl ester, β, β, β-trichloroethyl ester, etc. can give. The compounds of formula () of the present invention are administered to humans and animals in the form of the free acid as well as in the form of non-toxic salts or physiologically acceptable esters. The compound can be prepared in the dosage forms that are commonly used for penicillin or cephalosporin drugs, such as tablets,
Adjusted into capsules, syrups, and injections,
It can be administered orally or parenterally. Next, examples of production and antibacterial activity of typical compounds of the present invention are listed. All antibacterial activity is expressed in minimum inhibitory concentration (MIC) mg/ml (inoculum amount: 10 6 cells/ml). Production example 1 (1) 7β-[D(-)-α-(4-ethyl-2.3
-dioxo-1-piperazinecarboxamide)
-α-(4-hydroxyphenyl)acetamide]-3-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl- Δ3 -cephem-4-
0.81 g of benzhydryl ester of carboxylic acid is dissolved in a mixed solvent of 20 ml of anhydrous chloroform and 5 ml of anhydrous tetrahydrofuran, and then cooled to -75°C. Next, 3.5ml of a methanol solution of lithium methoxide (containing 5mM lithium methoxide) was added to this and reacted for 2 minutes, then 0.36ml of tert.-butylhypochloride was added and reacted for 20 minutes at the same temperature. let Next, 0.3 ml of acetic acid is added to the reaction solution, and the temperature is raised to room temperature. The solvent is distilled off under reduced pressure, 20 ml of water and 20 ml of ethyl acetate are added to the residue to dissolve it, and the ethyl acetate layer is separated. The ethyl acetate solution is washed successively with a dilute aqueous sodium bicarbonate solution, water, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with a mixed solvent of ethyl acetate and benzene) to obtain 7β-[D(-)-α-(4
-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(3-chloro-4-hydroxyphenyl)acetamide]-7α-methoxy-3-[5-(1-methyl-1,2,3・4
-tetrazolyl)thiomethyl]-Δ 3 -cephem-4-carboxylic acid benzhydryl ester
Obtain 0.57g (65%). NMR ( CDCl3 ) ppm value: 1.15 (3H, t- CH2CH3 ), 3.2-4.0
(8H,
【式】 ）、3.45（3H、ｓ、[Formula] ), 3.45 (3H, s,
【式】）、3.75（3H、ｓ、−OCH3）、4.3 （2H、ｑ、[Formula]), 3.75 (3H, s, -OCH 3 ), 4.3 (2H, q,
【式】）、5.0（1H、ｓ、C6−Ｈ）、5.5
（1H、ｄ、Ｃα−Ｈ）、6.82（1H、ｓ、−CH
（C6H5）2）、7.27（13H、aromatic proton）、8.0
（1H、ｓ、[Formula]), 5.0 (1H, s, C 6 -H), 5.5 (1H, d, Cα-H), 6.82 (1H, s, -CH
( C6H5 ) 2 ), 7.27 (13H, aromatic proton), 8.0
(1H, s,
【式】 ）、9.65（1H、ｄ、[Formula] ), 9.65 (1H, d,
【式】(2) (1)で得られた７β−〔Ｄ（−）−α−
（４−エチル−２・３−ジオキソ−１−ピペラジ
ンカルボキサミド）−α−（３−クロル−４−ヒド
ロキシフエニル）アセトアミド〕−７α−メトキ
シ−３−〔５−（１−メチル−１・２・３・４−テ
トラゾリル）チオメチル〕−Δ３−セフエム−４
−カルボン酸のベンズヒドリルエステル0.4ｇを
アニソール３mlに懸濁し、氷冷下トリフルオロ酢
酸２mlを加えて１時間反応させる。反応後、減圧
下に濃縮乾固し、残留物に水15ml及び酢酸エチル
15mlを加えて溶解させた後、炭酸水素ナトリウム
を加えてPH7.0に調整する。水層を分取し、酢酸
エチル20mlを加えた後、2N−塩酸でPH2.0に調整
する。酢酸エチル層を分取し、水洗した後、無水
硫酸マグネシウムで乾燥する。その後、溶媒を減
圧下に留去すれば７β−〔Ｄ（−）−α−（４−エ
チル−２・３−ジオキソ−１−ピペラジンカルボ
キサミド）−α−（３−クロル−４−ヒドロキシフ
エニル）アセトアミド〕−７α−メトキシ−３−
〔５−（１−メチル−１・２・３・４−テトラゾリ
ル）チオメチル〕−Δ３−セフエム−４−カルボ
ン酸0.25ｇ（78.1％）を得る。
IR（KBr）cm-1：γNH3270γC＝o1770、1670〜
1720
NMR（d6−DMSO）ppm値：
1.6（3H、ｔ、−CH2CH3）、3.26〜4.0
（8H、[Formula] (2) 7β-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(3-chloro-4-hydroxy) obtained in (1) phenyl)acetamide]-7α-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl] -Δ3 -cephem-4
- Suspend 0.4 g of benzhydryl ester of carboxylic acid in 3 ml of anisole, add 2 ml of trifluoroacetic acid under ice cooling, and react for 1 hour. After the reaction, concentrate to dryness under reduced pressure, and add 15 ml of water and ethyl acetate to the residue.
Add 15ml and dissolve, then add sodium bicarbonate and adjust the pH to 7.0. Separate the aqueous layer, add 20 ml of ethyl acetate, and adjust the pH to 2.0 with 2N hydrochloric acid. The ethyl acetate layer is separated, washed with water, and then dried over anhydrous magnesium sulfate. Thereafter, by distilling off the solvent under reduced pressure, 7β-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(3-chloro-4-hydroxyphenyl ) Acetamide]-7α-methoxy-3-
0.25 g (78.1%) of [5-(1-methyl-1.2.3.4-tetrazolyl)thiomethyl]-Δ 3 -cephem-4-carboxylic acid is obtained. IR (KBr) cm -1 :γ NH 3270γ C = o1770, 1670~
1720 NMR ( d6 -DMSO) ppm value : 1.6 (3H, t, -CH2CH3 ), 3.26-4.0
(8H,
【式】）、3.36（3H、ｓ、[Formula]), 3.36 (3H, s,
【式】）、3.86（3H、ｓ、−OCH3）、4.25 （2H、ｑ、[Formula]), 3.86 (3H, s, -OCH 3 ), 4.25 (2H, q,
【式】）、5.03（1H、ｓ、C6−Ｈ）、5.45
（1H、ｄ、Ｃα−Ｈ）、6.8〜7.35（3H、aromatic
proton）、9.70（2H、[Formula]), 5.03 (1H, s, C 6 -H), 5.45 (1H, d, Cα-H), 6.8-7.35 (3H, aromatic
proton), 9.70 (2H,
【式】本品のMICは次の通りである。
黄色ブドウ状球菌FDA209P 3.13
大腸菌NIHJ ＜0.1
肺炎桿菌Ｙ−50 0.78
変形菌GN3027 1.56
緑膿菌IFO3445 6.25
同様にして７β−〔Ｄ（−）−α−（４−エチル
−２・３−ジオキソ−１−ピペラジンカルボキサ
ミド）−α−（３−クロル−４−ヒドロキシフエニ
ル）アセトアミド〕−７α−メトキシ−３−アセ
トキシメチル−Δ３−セフエム−４−カルボン酸
を得た。本品のMICは次の通りである。
黄色ブドウ状球菌FDA209P 3.13
大腸菌NIHJ 0.2
肺炎桿菌Ｙ−50 1.56
変形菌GN3027 1.56
緑膿菌IFO3445 6.25
さらに、同様にして次の化合物を得た。
７β−〔Ｄ（−）−α−（４−エチル−２・３−
ジオキソ−１−ピペラジンカルボキサミド）−α
−（３−クロル−４−ヒドロキシフエニル）アセ
トアミド〕−７α−メトキシ−３−〔２−（５−メ
チル−１・３・４−チアジゾリル）チオメチル〕
−Δ３−セフエム−４−カルボン酸
本品のMICは次の通りである。
黄色ブドウ状球菌FDA209P 6.25
大腸菌NIHJ ＜0.1
肺炎桿菌Ｙ−50 1.56
変形菌GN3027 1.56
緑膿菌IFO3445 25[Formula] The MIC of this product is as follows. Staphylococcus aureus FDA209P 3.13 Escherichia coli NIHJ <0.1 Klebsiella pneumoniae Y-50 0.78 M. aeruginosa GN3027 1.56 Pseudomonas aeruginosa IFO3445 6.25 Similarly, 7β-[D(-)-α-(4-ethyl-2,3-dioxo-1) -piperazinecarboxamide)-α-(3-chloro-4-hydroxyphenyl)acetamide]-7α-methoxy-3-acetoxymethyl-Δ 3 -cephem-4-carboxylic acid was obtained. The MIC of this product is as follows. Staphylococcus aureus FDA209P 3.13 Escherichia coli NIHJ 0.2 Klebsiella pneumoniae Y-50 1.56 Pneumoniae GN3027 1.56 Pseudomonas aeruginosa IFO3445 6.25 Furthermore, the following compounds were obtained in the same manner. 7β-[D(-)-α-(4-ethyl-2,3-
dioxo-1-piperazinecarboxamide)-α
-(3-chloro-4-hydroxyphenyl)acetamide]-7α-methoxy-3-[2-(5-methyl-1,3,4-thiadizolyl)thiomethyl]
-Δ3-Cefem-4-carboxylic acid The MIC of this product is as follows. Staphylococcus aureus FDA209P 6.25 Escherichia coli NIHJ <0.1 Klebsiella pneumoniae Y-50 1.56 M. aeruginosa GN3027 1.56 Pseudomonas aeruginosa IFO3445 25
Claims (1)
又は塩形成陽イオン；R2は置換基を有していて
もよいアシルオキシ又は含窒素五員環よりなる複
数環式チオ基を；R3及びR4は水素原子を；Ａは
アルキル基を；Ｘはハロゲン原子を示す。］ で表わされる７α−メトキシセフアロスポリン
類。 ２ 一般式 ［式中、A1は低級アルキル基を；R5はアセトキシ
基、５−（１−メチル−１・２・３・４−テトラ
ゾリル）チオ基、２−（５−メチル−１・３・４
−チアジアゾリル）チオ基、５−（１・２・３−
トリアゾリル）チオ基、５−（１・２・３・４−
テトラゾリル）チオ基又は２−（１・３・４−チ
アジアゾリル）チオ基を；R1、R4及びＸは特許
請求の範囲第１項に記載された意味を有する。］ で表わされる特許請求の範囲第１項記載の７α−
メトキシセフアロスポリン類。 ３ 一般式 ［式中、A2はメチル基又はエチル基を；R6はアセ
トキシ基、５−（１−メチル−１・２・３・４−
テトラゾリル）チオ基又は２−（５−メチル−
１・３・４−チアジアゾリル）チオ基を；R1及
びＸは特許請求の範囲第２項に記載された意味を
有する。］ で表わされる特許請求の範囲第２項記載の７α−
メトキシセフアロスポリン類。 ４ 一般式 ［式中、R1、R6及びＸは特許請求の範囲第３項に
記載された意味を有する。］ で表わされる特許請求の範囲第３項記載の７α−
メトキシセフアロスポリン類。[Claims] 1. General formula [In the formula, R 1 is a hydrogen atom, a carboxyl protection-forming group, or a salt-forming cation; R 2 is a polycyclic thio group consisting of acyloxy or a nitrogen-containing five-membered ring which may have a substituent; R 3 and R 4 represents a hydrogen atom; A represents an alkyl group; and X represents a halogen atom. ] 7α-methoxycephalosporins represented by: 2 General formula [In the formula, A 1 is a lower alkyl group; R 5 is an acetoxy group, 5-(1-methyl-1, 2, 3, 4-tetrazolyl) thio group, 2-(5-methyl-1, 3, 4)
-thiadiazolyl)thio group, 5-(1,2,3-
triazolyl)thio group, 5-(1.2.3.4-
tetrazolyl)thio group or 2-(1.3.4-thiadiazolyl)thio group; R 1 , R 4 and X have the meanings given in claim 1. ] 7α- according to claim 1, which is represented by
Methoxycephalosporins. 3 General formula [In the formula, A 2 is a methyl group or an ethyl group; R 6 is an acetoxy group, 5-(1-methyl-1, 2, 3, 4-
Tetrazolyl)thio group or 2-(5-methyl-
1,3,4-thiadiazolyl)thio group; R 1 and X have the meanings given in claim 2. ] 7α- according to claim 2, which is represented by
Methoxycephalosporins. 4 General formula [In the formula, R 1 , R 6 and X have the meanings set forth in claim 3. ] 7α- according to claim 3, which is represented by
Methoxycephalosporins.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8661277A JPS5422388A (en) | 1977-07-21 | 1977-07-21 | Novel 7alpha-methoxycephalosporins |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8661277A JPS5422388A (en) | 1977-07-21 | 1977-07-21 | Novel 7alpha-methoxycephalosporins |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5422388A JPS5422388A (en) | 1979-02-20 |
| JPS624397B2 true JPS624397B2 (en) | 1987-01-30 |
Family
ID=13891829
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8661277A Granted JPS5422388A (en) | 1977-07-21 | 1977-07-21 | Novel 7alpha-methoxycephalosporins |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5422388A (en) |
-
1977
- 1977-07-21 JP JP8661277A patent/JPS5422388A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5422388A (en) | 1979-02-20 |
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