JPH0332556B2 - - Google Patents
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- Publication number
- JPH0332556B2 JPH0332556B2 JP58011835A JP1183583A JPH0332556B2 JP H0332556 B2 JPH0332556 B2 JP H0332556B2 JP 58011835 A JP58011835 A JP 58011835A JP 1183583 A JP1183583 A JP 1183583A JP H0332556 B2 JPH0332556 B2 JP H0332556B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- compound
- reaction
- water
- acid
- 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 - Lifetime
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- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 150000002960 penicillins Chemical class 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- -1 benzyloxycarbonylamino group Chemical group 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 238000000862 absorption spectrum Methods 0.000 description 7
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000002132 β-lactam antibiotic Substances 0.000 description 7
- 229940124586 β-lactam antibiotics Drugs 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 102000006635 beta-lactamase Human genes 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108090000204 Dipeptidase 1 Proteins 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 125000003460 beta-lactamyl group Chemical group 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052751 metal Chemical group 0.000 description 2
- 239000002184 metal Chemical group 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 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
- 229930186147 Cephalosporin Natural products 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [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
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal 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
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- PJBIHXWYDMFGCV-UHFFFAOYSA-N chloro(chlorosulfonyloxy)methane Chemical compound ClCOS(Cl)(=O)=O PJBIHXWYDMFGCV-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- VHILMKFSCRWWIJ-UHFFFAOYSA-N dimethyl acetylenedicarboxylate Chemical compound COC(=O)C#CC(=O)OC VHILMKFSCRWWIJ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000001240 enamine group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- LWHYKTAISUZRAD-UHFFFAOYSA-L palladium(2+);carbonate Chemical compound [Pd+2].[O-]C([O-])=O LWHYKTAISUZRAD-UHFFFAOYSA-L 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 125000004436 sodium atom Chemical group 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide 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
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 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
Description
【発明の詳細な説明】
本発明は、新規なぺニシリン誘導体及びその医
薬として許容される塩に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel penicillin derivatives and pharmaceutically acceptable salts thereof.
本発明のぺニシリン誘導体は、下記一般式
（）で表わされる。 The penicillin derivative of the present invention is represented by the following general formula ().
（式中R1及びR2はそれぞれ低級アルキル基を、
R3は水素原子又はメチル基を意味する。）
上記一般式（）で表わされる本発明のぺニシ
リン誘導体及びその医薬として許容される塩は、
いずれも新規化合物であり、これらはとりわけ、
β−ラクタマーゼを産生する菌に対して抗菌力を
有し、抗菌剤として有用である。 (In the formula, R 1 and R 2 each represent a lower alkyl group,
R 3 means a hydrogen atom or a methyl group. ) The penicillin derivative of the present invention represented by the above general formula () and its pharmaceutically acceptable salt are:
All are new compounds, and among other things,
It has antibacterial activity against bacteria that produce β-lactamase and is useful as an antibacterial agent.
市販抗生物質の中でβ−ラクタム環を有するβ
−ラクタム系抗生物質即ちぺニシリン類及びセフ
アロスポリン類は、最もよく知られ、且つ繁用さ
れている。これらβ−ラクタム系抗生物質は、有
用な化学療法剤として広く用いられるにもかかわ
らず、ある種の微生物に対しては、その耐性のた
め十分な効果が得られない。これらのある種の微
生物のβ−ラクタム系抗生物質に対する耐性は、
通常該微生物により生産されるβ−ラクタマー
ゼ、即ちβ−ラクタム系抗生物質のβ−ラクタム
環を開裂し抗菌活性を有さない生成物とする酵
素、によるものである。従つて前記β−ラクタム
系抗生物質が十分な効力を現わすためには、β−
ラクタマーゼの作用をなくするかまたはその作用
を最小に抑えることが必要である。このβ−ラク
タマーゼの作用の消失乃至抑制は、β−ラクタマ
ーゼ阻害剤により達成され、そのようなβ−ラク
タマーゼ阻害剤は、これをβ−ラクタム系抗生物
質と共に使用することにより、該抗生物質の抗菌
活性を上昇させることができる。 Among commercially available antibiotics, β-lactam ring-containing β
- Lactam antibiotics, ie penicillins and cephalosporins, are the best known and most frequently used. Although these β-lactam antibiotics are widely used as useful chemotherapeutic agents, they are not sufficiently effective against certain microorganisms due to their resistance. The resistance of some of these microorganisms to β-lactam antibiotics is
It is usually caused by β-lactamases produced by the microorganisms, that is, enzymes that cleave the β-lactam ring of β-lactam antibiotics to produce products without antibacterial activity. Therefore, in order for the β-lactam antibiotics to exhibit sufficient efficacy, β-lactam antibiotics must be
It is necessary to eliminate or minimize the action of lactamases. This elimination or inhibition of the action of β-lactamase is achieved by a β-lactamase inhibitor, and such a β-lactamase inhibitor can be used together with a β-lactam antibiotic to improve the antibacterial effects of the antibiotic. Activity can be increased.
本発明者らは種々の化合物を合成し、研究した
結果、先に下記一般式（）で示される新規化合
物がβ−ラクタマーゼ阻害作用を有することを見
い出し、該化合物に係る発明を完成し、特許出願
した（特願昭57−107171号）。 As a result of synthesizing and researching various compounds, the present inventors first discovered that a new compound represented by the following general formula () has a β-lactamase inhibitory effect, completed the invention related to the compound, and obtained a patent for the compound. An application was filed (Japanese Patent Application No. 107171/1983).
（式中R1及びR2は前記と同一の意味を示し、Ｍ
は水素原子又は金属原子を意味する。）
更に本発明者らは生体内で良好な効力を示す化
合物を開発せんとして鋭意研究を重ねた結果、上
記一般式（）で表わされる本発明化合物が、β
−ラクタマーゼ産生菌にとりわけ有効であること
を見い出し、本発明を完成するに至つた。 (In the formula, R 1 and R 2 have the same meanings as above, and M
means a hydrogen atom or a metal atom. ) Further, the present inventors have conducted extensive research in an effort to develop a compound that exhibits good efficacy in vivo, and have found that the compound of the present invention represented by the above general formula () has β
-We have discovered that this method is particularly effective against lactamase-producing bacteria, and have completed the present invention.
本発明の前記一般式（）で表わされる化合物
においてR1及びR2で定義される低級アルキル基
としては、炭素数１〜６の低級アルキル基、例え
ばメチル、エチル、プロピル、イソプロピル、ブ
チル、ぺンチル、ヘキシル等を挙げることができ
る。該一般式（）で表わされる化合物の医薬と
して許容される塩を形成させるために用いられる
酸としては、例えば、塩酸、臭化水素酸、ヨウ化
水素酸、リン酸、硫酸、硝酸等の無機酸；クエン
酸、酒石酸、酢酸、マレイン酸等の有機酸；その
他当該分野において通常使用されている酸を例示
できる。之等酸による塩形成反応は、通常の方法
に従つて行なうことができる。又、一般式（）
で表わされる化合物において、Ｍで表わされる金
属原子としては、ナトリウム原子やカリウム原子
を例示することができる。 In the compound represented by the general formula () of the present invention, the lower alkyl group defined by R 1 and R 2 is a lower alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, and penyl. Examples include ethyl, hexyl, and the like. Examples of the acid used to form a pharmaceutically acceptable salt of the compound represented by the general formula () include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid. Acids; organic acids such as citric acid, tartaric acid, acetic acid, and maleic acid; and other acids commonly used in the field. The salt-forming reaction with these acids can be carried out according to a conventional method. Also, general formula ()
In the compound represented by M, examples of the metal atom represented by M include a sodium atom and a potassium atom.
本発明のぺニシリン誘導体（）は、例えば下
記製造方法に従い製造することができる。 The penicillin derivative () of the present invention can be produced, for example, according to the following production method.
Ａ 法
下記反応式に示すように一般式（）で表わさ
れる公知化合物と、一般式（）で表わされる化
合物とを反応させる。Method A A known compound represented by the general formula () is reacted with a compound represented by the general formula () as shown in the reaction formula below.
（式中R1，R2，R3及びＭは前記と同一の意味を
示し、Ｘはハロゲン原子を意味する。）
上記においてＸで示されるハロゲン原子として
は、臭素、塩素、ヨウ素を例示することができ
る。 (In the formula, R 1 , R 2 , R 3 and M have the same meanings as above, and X means a halogen atom.) Examples of the halogen atom represented by X in the above include bromine, chlorine, and iodine. be able to.
上記反応は通常溶媒中で行なわれる。使用され
る溶媒としては、反応に関与しないものである限
り特に限定されないが、例えば、ジメチルホルム
アミド、ジメチルアセタアミド、ジメチルスルホ
キシド等の極性溶媒、あるいはこれらの溶媒に少
量の水を混合させた溶媒等を例示することができ
る。また上記反応においてはアルカリを反応補助
剤として使用することができる。該アルカリとし
ては、例えば炭酸水素カリウム、炭酸水素ナトリ
ウム等の弱アルカリ性無機物が好ましく使用され
る。化合物（）、化合物（）および反応補助
剤の使用割合は、特に限定されないが、それぞれ
等モル量づつ用いると反応は円滑に進行する。又
反応温度は０℃〜室温付近とするのがよく、通常
２〜５時間で反応は完結する。尚、上記において
出発原料のひとつとして用いる一般式（）の化
合物は、新規化合物であり、これは例えば本発明
者らが先に開発した一般式（）の化合物を経て
容易に製造することができる。該製造方法につい
ては、後記参考例において詳述する。 The above reaction is usually carried out in a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction, but for example, polar solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, or a mixture of these solvents with a small amount of water can be used. etc. can be exemplified. Further, in the above reaction, an alkali can be used as a reaction aid. As the alkali, weakly alkaline inorganic substances such as potassium hydrogen carbonate and sodium hydrogen carbonate are preferably used. The proportions of Compound (), Compound () and reaction aid are not particularly limited, but if equimolar amounts of each are used, the reaction will proceed smoothly. The reaction temperature is preferably 0° C. to around room temperature, and the reaction is usually completed in 2 to 5 hours. The compound of general formula () used as one of the starting materials in the above is a new compound, which can be easily produced, for example, by using the compound of general formula () previously developed by the present inventors. . The manufacturing method will be described in detail in Reference Examples below.
Ｂ 法
下記反応式に示すように、本発明者らが先に開
発した一般式（）で表わされる化合物と一般式
（）で表わされる化合物とを反応させて、化合
物（）を得、次いで、該化合物のR4基をアミ
ノ基に変換させる。Method B As shown in the reaction formula below, the compound represented by the general formula () previously developed by the present inventors is reacted with the compound represented by the general formula () to obtain the compound (), and then, The R 4 group of the compound is converted to an amino group.
（式中R1，R2，R3，Ｍ及びＸは前記と同一の意
味を示し、R4は保護アミノ基又はアミノ基に変
換し得る基を示す。）
上記においてR4で表わされる保護アミノ基又
はアミノ基に変換し得る基としては、一般式
（式中R5はアルキル基、アラルキル基又はアリ
ール基を、R6は水素原子又はアルキル基を、R7
はアルキル基又はアルコキシ基をそれぞれ意味す
る。）
で表わされるエナミン基、アジド基及び一般式
（式中R8は水素原子又はニトロ基を意味する。）
で表わされるベンシルオキシカルボニルアミノ基
等が挙げられる。 (In the formula, R 1 , R 2 , R 3 , M and X have the same meanings as above , and R 4 represents a protected amino group or a group that can be converted into an amino group.) As an amino group or a group that can be converted into an amino group, the general formula (In the formula, R 5 is an alkyl group, aralkyl group, or aryl group, R 6 is a hydrogen atom or an alkyl group, R 7
means an alkyl group or an alkoxy group, respectively. ) Enamine group, azide group and general formula represented by (In the formula, R 8 means a hydrogen atom or a nitro group.) Examples include a benzyloxycarbonylamino group represented by the following.
上記Ｂ法において、一般式（）の化合物と一
般式（）の化合物との反応は、前記したＡ法に
おける一般式（）の化合物と一般式（）の化
合物との反応に準じて実施でき、その反応条件、
反応操作等も亦略々同様である。また用いられる
一般式（）の化合物は、公知化合物であるか又
は当該技術分野における公知の方法に従い製造す
ることができる。 In the above method B, the reaction between the compound of the general formula () and the compound of the general formula () can be carried out in the same manner as the reaction between the compound of the general formula () and the compound of the general formula () in the above method A, The reaction conditions,
Reaction operations and the like are also approximately the same. Further, the compound of general formula () used is a known compound or can be produced according to a method known in the art.
上記反応により得られる一般式（）の化合物
のR4基のアミノ基への変換反応は、当該技術分
野における公知慣用の手段、例えばジヤーナル
オブ アンテイバイオテイツクス（J.of
Antibiotics，33，10，1183〜1192，1980年）、特
開昭56−104886号公報、特開昭57−169493号公報
等に記載の酸あるいは還元手段に従い、容易に実
施することができる。 The reaction of converting the R 4 group of the compound of general formula () obtained by the above reaction into an amino group can be carried out by means known and common in the art, such as journal
of Antibiotics (J.of
Antibiotics, 33 , 10, 1183-1192, 1980), JP-A-56-104886, JP-A-57-169493, etc., and can be easily carried out according to the acid or reduction means described.
上記各方法に従い得られる本発明化合物は、常
法に従い例えば再結晶、抽出等の手段により単離
精製することができる。 The compounds of the present invention obtained according to each of the above methods can be isolated and purified by conventional methods such as recrystallization and extraction.
次に参考例および実施例を挙げて、本発明を更
に詳細に説明する。 Next, the present invention will be explained in more detail with reference to Reference Examples and Examples.
参考例 １
2β−アジドメチル−2α−メチルぺナム−3α−
カルボン酸 ｐ−ニトロベンジルエステルの製
造
2β−アジドメチル−2α−メチルぺナム−3α−
カルボン酸 ｐ−ニトロベンジルエステル3.7ｇ
のジメチルホルムアミド溶液100ml中に、アジ化
ナトリウム3.9ｇの水40ml溶液を加え、室温で４
時間撹拌した。反応混合物を冷水に注ぎ、酢酸エ
チルで抽出した。酢酸エチル層を水洗後、硫酸マ
グネシウムで乾燥し、濃縮して、油状物質3.2ｇ
を得た。Reference example 1 2β-azidomethyl-2α-methylpenam-3α-
Production of carboxylic acid p-nitrobenzyl ester 2β-azidomethyl-2α-methylpenam-3α-
Carboxylic acid p-nitrobenzyl ester 3.7g
A solution of 3.9 g of sodium azide in 40 ml of water was added to 100 ml of dimethylformamide solution of
Stir for hours. The reaction mixture was poured into cold water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated to give 3.2 g of an oily substance.
I got it.
赤外吸収スペクトル（KBr）；
υmax（cm-1）＝2120、1798、1760
核磁気共鳴スペクトル（CDCl3）；
δ（ppm）＝1.40（3H，ｓ）、3.12（1H，dd）、
3.50（2H，ｓ）、3.62（1H，dd）、
4.83（1H，ｓ）、5.29（2H，ｓ）、
5.36（1H，dd）、7.56（2H，ｄ）、
8.26（2H，ｄ）
参考例 ２
2β−アジドメチル−2α−メチルぺナム−3α−
カルボン酸−１，１−ジオキシド ｐ−ニトロ
ベンジルエステルの製造
2β−アジドメチル−2α−メチルぺナム−3α−
カルボン酸 ｐ−ニトロベンジルエステル2.9ｇ
に酢酸120ml及び水20ml中、撹拌下に過マンガン
酸カリウム2.7ｇをゆつくり加えた。3.5時間室温
で撹拌し、次いで過酸化水素水を反応液の色が消
失するまで加えた。反応溶液に氷水を加えてクロ
ロホルムにて３回抽出した。クロロホルム溶液を
水及び炭酸水素ナトリウム水溶液で順次洗浄後、
硫酸マグネシウムにて乾燥し、濃縮して、目的物
2.1ｇを得た。 Infrared absorption spectrum (KBr); υmax (cm -1 ) = 2120, 1798, 1760 Nuclear magnetic resonance spectrum (CDCl 3 ); δ (ppm) = 1.40 (3H, s), 3.12 (1H, dd), 3.50 ( 2H, s), 3.62 (1H, dd), 4.83 (1H, s), 5.29 (2H, s), 5.36 (1H, dd), 7.56 (2H, d), 8.26 (2H, d) Reference example 2 2β -azidomethyl-2α-methylpenam-3α-
Production of carboxylic acid-1,1-dioxide p-nitrobenzyl ester 2β-azidomethyl-2α-methylpenam-3α-
Carboxylic acid p-nitrobenzyl ester 2.9g
In 120 ml of acetic acid and 20 ml of water, 2.7 g of potassium permanganate was slowly added with stirring. The mixture was stirred at room temperature for 3.5 hours, and then hydrogen peroxide solution was added until the color of the reaction solution disappeared. Ice water was added to the reaction solution, and the mixture was extracted three times with chloroform. After sequentially washing the chloroform solution with water and aqueous sodium bicarbonate solution,
Dry with magnesium sulfate and concentrate to obtain the desired product.
2.1g was obtained.
赤外吸収スぺクトル（KBr）；
νmax（cm-1）＝2120、1770
磁気共鳴スぺクトル（CDCl3）；
δ（ppm）＝1.42（3H，ｓ）、3.45〜3.60（2H，
ｍ）、
3.75（1H，ｄ）、3.96（1H，ｄ）、
4.56〜4.75（1H，ｍ）、4.64（1H，
ｓ）、
5.33（2H，ｓ）、7.56（2H，ｄ）、
8.26（2H，ｄ）
参考例 ３
2β−（４，５−ジメトキシカルボニル−１，
２，３−トリアゾール−１−イル）メチル−
2α−メチルぺナム−3α−カルボン酸−１，１
−ジオキシド
ｐ−ニトロベンジルエステルの製造
2β−アジドメチル−2α−メチルぺナム−3α−
カルボン酸−１，１−ジオキシド ｐ−ニトロベ
ンジルエステル3.5ｇとジメチルアセチレンジカ
ルボキシレート4.8ｇとを無水ベンゼン80ml中で
窒素雰囲気下に18時間還流した。溶媒を減圧下留
去して、目的物4.7ｇを得た。 Infrared absorption spectrum (KBr); νmax (cm -1 ) = 2120, 1770 Magnetic resonance spectrum (CDCl 3 ); δ (ppm) = 1.42 (3H, s), 3.45-3.60 (2H,
m), 3.75 (1H, d), 3.96 (1H, d), 4.56-4.75 (1H, m), 4.64 (1H,
s), 5.33 (2H, s), 7.56 (2H, d), 8.26 (2H, d) Reference example 3 2β-(4,5-dimethoxycarbonyl-1,
2,3-triazol-1-yl)methyl-
2α-methylpenam-3α-carboxylic acid-1,1
-Production of dioxide p-nitrobenzyl ester 2β-azidomethyl-2α-methylpenam-3α-
3.5 g of carboxylic acid p-nitrobenzyl ester and 4.8 g of dimethyl acetylene dicarboxylate were refluxed in 80 ml of anhydrous benzene under a nitrogen atmosphere for 18 hours. The solvent was distilled off under reduced pressure to obtain 4.7 g of the target product.
赤外吸収スぺクトル（KBr）；
νmax（cm-1）＝1805、1735
核磁気共鳴スぺクトル（CDCl3）；
δ（ppm）＝1.43（3H，ｓ）、3.2〜3.4（2H，ｍ）、
3.96（3H，ｓ）、3.99（3H，ｓ）、
4.64〜4.76（1H，ｍ）、4.98（1H，
ｓ）、
5.04〜5.44（4H，ｍ）、7.56（2H，
ｄ）、
8.23（2H，ｄ）
参考例 ４
2β−（４，５−ジメトキシカルボニル−１，
２，３−トリアゾール−１−イル）メチル−
2α−メチルぺナム−3α−カルボン酸の製造
2β−（４，５−ジメトキシカルボニル−１，
２，３−トリアゾール−１−イル）メチル−
2α−メチルぺナム−3α−カルボン酸−１，１
−ジオキシド
ｐ−ニトロベンジルエステル4.7ｇ、炭酸水素
ナトリウム1.5ｇ及び10％パラジウム炭酸触媒１
ｇを酢酸エチル125ml及び水125ml中に加え、初圧
３気圧で１時間水添した。次に反応混合物より水
層を分取し、エーテルにて洗浄後、希塩酸にてPH
1.7とした。この水溶液を酢酸エチル抽出して、
硫酸マグネシウムにて乾燥した。溶媒を減圧下留
去後、融点135〜145℃（分解）の無定形晶2.7ｇ
を得た。 Infrared absorption spectrum (KBr); νmax (cm -1 ) = 1805, 1735 Nuclear magnetic resonance spectrum (CDCl 3 ); δ (ppm) = 1.43 (3H, s), 3.2-3.4 (2H, m ), 3.96 (3H, s), 3.99 (3H, s), 4.64-4.76 (1H, m), 4.98 (1H,
s), 5.04-5.44 (4H, m), 7.56 (2H,
d), 8.23 (2H, d) Reference example 4 2β-(4,5-dimethoxycarbonyl-1,
2,3-triazol-1-yl)methyl-
Production of 2α-methylpenam-3α-carboxylic acid 2β-(4,5-dimethoxycarbonyl-1,
2,3-triazol-1-yl)methyl-
2α-methylpenam-3α-carboxylic acid-1,1
- Dioxide p-nitrobenzyl ester 4.7g, sodium bicarbonate 1.5g and 10% palladium carbonate catalyst 1
g was added to 125 ml of ethyl acetate and 125 ml of water, and hydrogenated at an initial pressure of 3 atm for 1 hour. Next, separate the aqueous layer from the reaction mixture, wash with ether, and PH with dilute hydrochloric acid.
It was set to 1.7. This aqueous solution was extracted with ethyl acetate,
It was dried with magnesium sulfate. After distilling off the solvent under reduced pressure, 2.7 g of amorphous crystals with a melting point of 135-145°C (decomposition) were obtained.
I got it.
赤外吸収スぺクトル（KBr）；
νmax（cm-1）＝1805，1735
核磁気共鳴スぺクトル（CDCl3＋DMSO−
d6）；
δ（ppm）＝1.55（3H，ｓ）、3.24〜3.64（2H，
ｍ）、
3.96（3H，ｓ）、4.02（3H，ｓ）、
4.68（1H，ｓ）、4.6〜4.8（1H，ｍ）、
5.35（2H，ｓ）
参考例 ５
2β−（４，５−ジメトキシカルボニル−１，
２，３−トリアゾール−１−イル）メチル−
2α−メチルぺナム−3α−カルボン酸−１，１
−ジオキシド
クロルメチルエステル〔一般式（）の化合
物〕の製造
2β−（４，５−ジメトキシカルボニル−１，
２，３−トリアゾール−１−イル）メチル−2α
−メチルぺナム−3α−カルボン酸−１，１−ジ
オキシド1.61ｇに、ジクロルメタン８ml及び水８
ml中、撹拌下、10℃以下で炭酸水素ナトリウム
1.25ｇ及び硫酸水素テトラブチルアンモニウム
0.133ｇを加え、次に同温度でクロルスルホン酸
クロルメチルエステル0.74ｇを滴下した。その
後、室温で30分間撹拌させて、有機層を分取し、
一度水洗後、硫酸マグネシウムにて乾燥させた。
溶媒を減圧下留去して、残渣として無定形晶1.5
ｇを得た（収率83％）。 Infrared absorption spectrum (KBr); νmax (cm -1 ) = 1805, 1735 Nuclear magnetic resonance spectrum (CDCl 3 +DMSO−
d 6 ); δ (ppm) = 1.55 (3H, s), 3.24 to 3.64 (2H,
m), 3.96 (3H, s), 4.02 (3H, s), 4.68 (1H, s), 4.6-4.8 (1H, m), 5.35 (2H, s) Reference example 5 2β-(4,5-dimethoxy carbonyl-1,
2,3-triazol-1-yl)methyl-
2α-methylpenam-3α-carboxylic acid-1,1
-Production of dioxide chloromethyl ester [compound of general formula ()] 2β-(4,5-dimethoxycarbonyl-1,
2,3-triazol-1-yl)methyl-2α
-Methylpenam-3α-carboxylic acid-1,1-dioxide (1.61 g), dichloromethane (8 ml) and water (8 ml)
ml of sodium bicarbonate under stirring at below 10°C.
1.25g and tetrabutylammonium hydrogen sulfate
0.133 g was added thereto, and then 0.74 g of chloromethyl chlorosulfonic acid was added dropwise at the same temperature. Then, stir at room temperature for 30 minutes, separate the organic layer,
After washing once with water, it was dried with magnesium sulfate.
The solvent was distilled off under reduced pressure, leaving 1.5% amorphous crystals as a residue.
g (yield 83%).
赤外吸収スぺクトル（KBr）；
νmax（cm-1）＝1805，1735
核磁気共鳴スぺクトル（CDCl3）；
δ（ppm）＝1.55（3H，ｓ）、3.2〜3.8（2H，ｍ）、
3.99（3H，ｓ）、4.03（3H，ｓ）、
4.6〜4.8（1H，ｍ）、5.01（1H，ｓ）、
5.32（2H，ｄ）、5.62（1H，ｄ）、
5.81（1H，ｄ）
参考例 ６
2β−（４，５−ジメトキシカルボニル−１，
２，３−トリアゾール−１−イル）メチル−
2α−メチルぺナム−3α−カルボン酸−１，１
−ジオキシド
ヨードメチルエステル〔一般式（）の化合
物〕の製造
2β−（４，５−ジメトキシカルボニル−１，
２，３−トリアゾール−１−イル）メチル−2α
−メチルペナム−3α−カルボン酸−１，１−ジ
オキシド
クロルメチルエステル1.05ｇとヨウ化ナトリウ
ム0.52ｇとをアセトン1.8ml中、18時間室温で撹
拌した。次に反応混合物に水15mlを加え、炭酸水
素ナトリウム水溶液にてPH７〜８とした。水1.5
mlを再度加えた後、0.5Mチオ硫酸ナトリウム水
溶液にて脱色させて、ジクロルメタンより抽出
し、水洗後、硫酸マグネシウムにて乾燥させた。
溶媒を減圧下留去後、無定形晶1.1ｇを得た（収
率78％）。 Infrared absorption spectrum (KBr); νmax (cm -1 ) = 1805, 1735 Nuclear magnetic resonance spectrum (CDCl 3 ); δ (ppm) = 1.55 (3H, s), 3.2-3.8 (2H, m ), 3.99 (3H, s), 4.03 (3H, s), 4.6-4.8 (1H, m), 5.01 (1H, s), 5.32 (2H, d), 5.62 (1H, d), 5.81 (1H, d) Reference example 6 2β-(4,5-dimethoxycarbonyl-1,
2,3-triazol-1-yl)methyl-
2α-methylpenam-3α-carboxylic acid-1,1
-Production of iodomethyl ester [compound of general formula ()] 2β-(4,5-dimethoxycarbonyl-1,
2,3-triazol-1-yl)methyl-2α
-Methylpenam-3α-carboxylic acid-1,1-dioxide 1.05 g of chloromethyl ester and 0.52 g of sodium iodide were stirred in 1.8 ml of acetone at room temperature for 18 hours. Next, 15 ml of water was added to the reaction mixture, and the pH was adjusted to 7 to 8 with an aqueous sodium hydrogen carbonate solution. water 1.5
ml was added again, decolorized with 0.5M aqueous sodium thiosulfate solution, extracted with dichloromethane, washed with water, and dried over magnesium sulfate.
After distilling off the solvent under reduced pressure, 1.1 g of amorphous crystals were obtained (yield 78%).
赤外吸収スぺクトル（KBr）；
νmax（cm-1）＝1800、1730
核磁気共鳴スぺクトル（CDCl3）；
δ（ppm）＝1.56（3H，ｓ）、3.2〜3.8（2H，ｍ）、
3.99（3H，ｓ）、4.03（3H，ｓ）、
4.6〜4.8（1H，ｍ）、4.97（1H，ｓ）、
5.30（2H，ｄ）、5.85（1H，ｄ）、
5.96（1H，ｄ）
実施例
６−（２−アミノ−２−フエニルアセタミド）
ぺニシラノイルオキシメチル2β−（４，５−ジ
メトキシカルボニル−１，２，３−トリアゾー
ル−１−イル）メチル−2α−メチルぺナム−
3α−カルボキシレート−１，１−ジオキシ
ド・塩酸塩の製造
炭酸水素カリウム0.23ｇに、水0.2ml及びジメ
チルホルムアミド７ml中、５℃以下で撹拌下、ア
ンピシリン0.8ｇを加えた。反応液が均一化した
ところで、2β−（４，５−ジメトキシカルボニル
−１，２，３−トリアゾール−１−イル）メチル
−2α−メチルぺナム−3α−カルボン酸−１，１
−ジオキシド ヨードメチルエステル1.27ｇを加
え、２時間同温度にて撹拌した。次いで酢酸エチ
ル13mlを加えて、氷水６mlで２回洗浄した。洗浄
液を酢酸エチルにて再抽出し、先の酢酸エチル液
と合わして、これに氷水10mlを加え、６規定塩酸
水溶液にてPH3.0にした。水層を分取し、有機層
を水2.5mlにて再抽出した。先の水層と合わして、
塩化ナトリウムを飽和させて、ジクロルメタンに
て抽出した。ジクロルメタン溶液を硫酸マグネシ
ウムにて乾燥後、溶媒を減圧下留去した。残渣に
水を加えて溶かし、凍結乾燥して、融点155〜170
℃（分解）の無定形晶0.9ｇを得た（収率48％）。 Infrared absorption spectrum (KBr); νmax (cm -1 ) = 1800, 1730 Nuclear magnetic resonance spectrum (CDCl 3 ); δ (ppm) = 1.56 (3H, s), 3.2-3.8 (2H, m ), 3.99 (3H, s), 4.03 (3H, s), 4.6-4.8 (1H, m), 4.97 (1H, s), 5.30 (2H, d), 5.85 (1H, d), 5.96 (1H, d) Example 6-(2-amino-2-phenylacetamide)
Penicillanoyloxymethyl 2β-(4,5-dimethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2α-methylpenam-
Production of 3α-carboxylate-1,1-dioxide hydrochloride 0.8 g of ampicillin was added to 0.23 g of potassium hydrogen carbonate in 0.2 ml of water and 7 ml of dimethylformamide while stirring at 5° C. or lower. Once the reaction solution was homogenized, 2β-(4,5-dimethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2α-methylpenam-3α-carboxylic acid-1,1
-Dioxide iodomethyl ester (1.27 g) was added, and the mixture was stirred at the same temperature for 2 hours. Next, 13 ml of ethyl acetate was added and the mixture was washed twice with 6 ml of ice water. The washing solution was re-extracted with ethyl acetate and combined with the previous ethyl acetate solution, 10 ml of ice water was added thereto, and the pH was adjusted to 3.0 with 6N aqueous hydrochloric acid. The aqueous layer was separated, and the organic layer was re-extracted with 2.5 ml of water. Combined with the previous water layer,
The mixture was saturated with sodium chloride and extracted with dichloromethane. After drying the dichloromethane solution over magnesium sulfate, the solvent was distilled off under reduced pressure. Dissolve the residue by adding water and freeze-dry it to a melting point of 155-170.
0.9 g of amorphous crystals (yield: 48%) were obtained.
赤外吸収スぺクトル（KBr）；
νmax（cm-1）＝1790、1660
核磁気共鳴スぺクトル（D2O）；
δ（ppm）＝1.34（3H，ｓ）、1.42（3H，ｓ）、
1.47（3H，ｓ）、3.0〜4.0（2H，ｍ）、
3.89（3H，ｓ）、3.93（3H，ｓ）、
4.44（1H，ｓ）、5.07（1H，ｓ）、
5.1〜5.7（6H，ｍ）、5.89（2H，ｓ）、
7.2〜7.6（5H，ｍ）、8.4〜9.0（2H，
ｂ）、9.41（1H，bd）。 Infrared absorption spectrum (KBr); νmax (cm -1 ) = 1790, 1660 Nuclear magnetic resonance spectrum (D 2 O); δ (ppm) = 1.34 (3H, s), 1.42 (3H, s) , 1.47 (3H, s), 3.0 ~ 4.0 (2H, m), 3.89 (3H, s), 3.93 (3H, s), 4.44 (1H, s), 5.07 (1H, s), 5.1 ~ 5.7 (6H , m), 5.89 (2H, s), 7.2-7.6 (5H, m), 8.4-9.0 (2H,
b), 9.41 (1H, bd).
Claims (1)
R3は水素原子又はメチル基を意味する。） で表されるぺニシリン誘導体及びその医薬として
許容される塩。[Claims] 1. General formula (In the formula, R 1 and R 2 each represent a lower alkyl group,
R 3 means a hydrogen atom or a methyl group. ) Penicillin derivatives and pharmaceutically acceptable salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58011835A JPS59137488A (en) | 1983-01-26 | 1983-01-26 | Penicillin derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58011835A JPS59137488A (en) | 1983-01-26 | 1983-01-26 | Penicillin derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59137488A JPS59137488A (en) | 1984-08-07 |
| JPH0332556B2 true JPH0332556B2 (en) | 1991-05-13 |
Family
ID=11788795
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58011835A Granted JPS59137488A (en) | 1983-01-26 | 1983-01-26 | Penicillin derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59137488A (en) |
-
1983
- 1983-01-26 JP JP58011835A patent/JPS59137488A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59137488A (en) | 1984-08-07 |
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