JPS6126999B2 - - Google Patents
Info
- Publication number
- JPS6126999B2 JPS6126999B2 JP8643482A JP8643482A JPS6126999B2 JP S6126999 B2 JPS6126999 B2 JP S6126999B2 JP 8643482 A JP8643482 A JP 8643482A JP 8643482 A JP8643482 A JP 8643482A JP S6126999 B2 JPS6126999 B2 JP S6126999B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- compound
- ethyl acetate
- solution
- 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.)
- Expired
Links
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 21
- 229930186147 Cephalosporin Natural products 0.000 claims description 12
- 229940124587 cephalosporin Drugs 0.000 claims description 12
- 150000001780 cephalosporins Chemical class 0.000 claims description 12
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 6
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KWUCXUIDQMYNFR-UHFFFAOYSA-N 2-thiophen-2-ylsulfinylacetic acid Chemical compound OC(=O)CS(=O)C1=CC=CS1 KWUCXUIDQMYNFR-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- -1 amine salt ion Chemical group 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- PPAUMJSTRVZNNE-UHFFFAOYSA-N 2-(benzenesulfinyl)acetic acid Chemical compound OC(=O)CS(=O)C1=CC=CC=C1 PPAUMJSTRVZNNE-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DOJYVEULZCDFAR-UHFFFAOYSA-N 2-pyridin-4-ylsulfinylacetic acid Chemical compound OC(=O)CS(=O)C1=CC=NC=C1 DOJYVEULZCDFAR-UHFFFAOYSA-N 0.000 description 1
- WFWHMPLURQHHER-UHFFFAOYSA-N 2-thiophen-2-ylethanethioic s-acid Chemical compound SC(=O)CC1=CC=CS1 WFWHMPLURQHHER-UHFFFAOYSA-N 0.000 description 1
- 201000004813 Bronchopneumonia Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-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
- 241001465754 Metazoa Species 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 206010034038 Parotitis Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- SWEDAZLCYJDAGW-UHFFFAOYSA-N Thiophene-2-thiol Chemical compound SC1=CC=CS1 SWEDAZLCYJDAGW-UHFFFAOYSA-N 0.000 description 1
- 208000012931 Urologic disease Diseases 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 229940021013 electrolyte solution Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- XJLBFCVPIIFHQU-UHFFFAOYSA-N triazine;trihydrochloride Chemical compound Cl.Cl.Cl.C1=CN=NN=C1 XJLBFCVPIIFHQU-UHFFFAOYSA-N 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、広範囲に抗菌活性を有する新規なセ
フアロスポリン類およびその塩類ならびにその製
造法に関する。
セフアロスポリン誘導体が抗菌活性を有する物
質であることは知られているが、既知のセフアロ
スポリン誘導体は大量使用しなければならない。
そこで本発明者らは、より高い抗菌活性を有す
るセフアロスポリン誘導体を得るため、種々の誘
導体について研究を重ねた結果、本発明に到達し
たのである。
本発明の目的物は、次の一般式()で示され
る化合物およびその塩類のうち、スルフイニル基
がR体であるセフアロスポリン類である。
(たゞし、R1は2−チエニル、4−ピリジル、フ
エニル、Aはアセトキシ、Mは水素、アルカリ金
属、アミン塩イオンを示す。)
本発明の目的物であるR体とは、上記式()
の化合物のスルフイニル基における立体構造が、
一般式
(R1は前記と同じ)
で表わされる化合物のスルフイニル基における光
学異性体のうち、アルコール中の比旋光度〔α〕D
が正を示す立体構造と同一の立体構造をもつもの
と定義する。
式()の化合物はスルフイニル基において不
整であつて、2種類の光学異性体が存在し、した
がつて、これから誘導されるセフアロスポリン類
にも、スルフイニル基において2種類の異性体が
存在する。本発明者らは、この2種類の異性体の
中で式()で示される化合物のうち、エタノー
ル中の〔α〕Dが正である光学活性体から誘導され
るセフアロスポリン類、またはエタノール中で正
の〔α〕Dを示す式()の化合物を含む混合体か
ら誘導されるセフアロスポリン類が、それぞれ対
応するエタノール中で負の〔α〕Dを示す式()
の化合物から誘導されるセフアロスポリン類より
も強い抗菌活性を有することを発見した。
R1の基のうちで好ましい基は、2−チエニ
ル、4−ピリジル、フエニルであり、特に2−チ
エニルが好ましい。Aとして特に好ましい基は、
アセトキシ、1−メチル−1H−テトラゾール−
5−イルチオ、5−メチル−1・3・4−チアジ
アゾール−2−イルチオであり、最も抗菌活性が
大である。
本発明による化合物は以下のようにして製造す
ることができる。
(a) 式()
(式中、A、Mは前記と同じ)
の化合物またはその反応性誘導体を式()の
R体カルボン酸またはその反応性誘導体と反応
させる。
式()のR体カルボン酸の具体例は、本発
明目的化合物R体の部分
に−COOHが結合したものと同じで、即ちそ
のエタノール中の〔α〕Dが正を示すものであ
る。
式()の化合物の反応性誘導体は、たとえ
ば、シリルエステルまたはアミン塩である。
式()のカルボン酸の反応性誘導体は、た
とえば、酸塩化物、酸無水物、アミド、アジ化
物、活性エステルまたは塩(たとえば、アルカ
リ金属またはアルカリ土類金属、アンモニアま
たは有機塩基によつて形成される塩)である。
式()の化合物と式()の化合物との間
の反応は、適当な溶媒、たとえば、アセトン、
ジオキサン、テトラヒドロフラン、アセトニト
リル、クロロホルム、塩化メチレン中で、また
所望の場合には塩基たとえば、重炭酸ナトリウ
ムまたは重炭酸カリウムまたはトリアルキルア
ミンの存在下で、室温または冷却下で行なう。
式()の化合物を遊離酸として、あるいは
塩として反応させる場合には、縮合剤として、
ジシクロヘキシルカルボジイミド、ジフエニル
リン酸アジド、ジエチルリン酸シアニド、ヘキ
サクロルシクロトリフオスフアトリアジン、ト
リアジントリクロリドなどの存在下、反応を行
なうのが望ましい。
本発明の化合物()は、動物および人間にお
いてグラム陽性菌およびグラム陰性菌に対して高
度の抗菌作用を有し、したがつて、該細菌により
引起される感染疾患、たとえば、気管支炎、気管
支肺炎、肋膜炎などの気道疾患、胆のう炎、腹膜
炎などの肝胆汁および腹部疾患、敗血症のような
血液および心臓血管の疾患、腎孟腎炎、膀胱炎な
どの尿路疾患、中耳炎、耳下腺炎などの耳鼻咽喉
疾患の治療に有用である。
本発明の化合物は経口投与によるか、または非
経口投与により有効に吸収される。後者の場合に
は、これらの化合物は適当な溶剤、たとえば、殺
菌水、生理的食塩溶液、ぶどう糖溶液または常用
の静脈内注射用液体または電解質溶液に溶かし
て、たとえば、成人用に用量当り約100mg〜約200
mgの量で投与することができる。
以下の実施例は本発明を詳述するものである
が、本発明は、これらの実施例に限定されるもの
ではない。
参考例 1
2−メルカプトチオフエン11.6gとモノクロル
酢酸10.4gをカセイソーダ8.8g、水100mlと3時
間還流したのち、塩酸でPH2.0とすると油状物が
析出する。これを酢酸エチルで抽出し、無水硫酸
ソーダで乾燥後、濃縮すると、淡黄色結晶12.1g
を得た。NMR(CDCl3)δ3.5(2H、s)、δ6.9
〜7.4(multi 3H)、δ11.6(s、1H)。
参考例 2
2−チエニルチオ酢酸8.7gを酢酸30mlに溶解
し、氷冷下で撹拌しつゝ、30%過酸化水素水6.8
mlを加え、さらに室温で5時間撹拌する。反応液
から減圧下に酢酸を除き、残渣を酢酸エチルから
再結晶して2−チエニルスルフイニル酢酸5.3g
を得た。融点114〜116℃、NMR(DMSO−d6)δ
4.1(s、2H)、7.15(multi、1H)、7.55(t、
1H)、7.9(d、1H)、元素分析C6H6S2O3とし
て、計算値C:37.88、H:3.18、S:33.71、実
測値C:37.76、H:3.31、S:33.48。
参考例 3
2−チエニルスルフイニル酢酸1.00gとブルシ
ン2.57gを25mlのエタノールに溶解したのち、濃
縮乾固する。残渣の粉末を35mlの熱ベンゼンで洗
滌したのち、不溶物2.35gをエタノール20mlから
再結晶する。得られた結晶1.50gを塩酸で処理
し、酢酸エチルで抽出し、有機層を濃縮して、さ
らに酢酸エチルから結晶化させることにより、
0.35gの光学活性な2−チエニルスルフイニル酢
酸を得た。エタノール中〔α〕22゜D+11.0゜C=
1.0であつた。
実施例 1
参考例3により得た2−チエニルスルフイニル
酢酸(〔α〕22゜D+11.0゜C=1.00エタノール)
0.38gを乾燥アセトン8mlに溶解し、さらにトリ
エチルアミン0.28mlおよびN・N−ジメチルベン
ジルアミン3滴を添加して撹拌する。溶液を−10
℃に冷却し、撹拌しながらピバリン酸クロリド
0.24gを添加する。滴下後、さらに−10℃で30分
撹拌したのち、該温度で激しく撹拌しながら7−
アミノセフアロスポラン酸0.54g、トリエチルア
ミン0.28gおよびアセトン3ml、水3mlの混合溶
液を一挙に添加する。その後、−10℃で30分、0
℃で1時間、室温で1時間撹拌する。反応液を40
℃以下で濃縮し、酢酸エチルで洗滌後、2規定塩
酸でPH3とし、酢酸エチルで抽出する。有機層を
減圧濃縮したのち、減圧下に乾燥することによ
り、スルホキシドにおいて光学活性なR体の7−
(2−チエニルスルフイニルアセトアミド)セフ
アロスポラン酸を含む粗結晶0.43gを得た。これ
を純品として確認するために、粗結晶をメタノー
ルを溶媒するセフアデツクスLH−20
(Pharmaira Fine Chemicals AB社製)カラムク
ロマトグラフイーにより分別取得した。NMRス
ペクトル(DMSO−d6)δppm:2.0(s、3H)、
3.6(q、2H)、4.1(q、2H)、4.8(q、2H)、
5.1(d、1H)、5.7(q、1H)、7.2(t、1H)、
7.6(d、1H)、8.0(d、1H)、9.2(d、1H)、
元素分析C16H16N2O7S3・1/2H2Oとして、計算値
C:42.38、H:3.78、N:6.18、S:21.21、実
測値C:42.52、H:4.15、N:5.78、S:
20.85。
このものゝ各種グラム陽性、陰性菌に対する最
小抑制濃度(MIC)を表1に示す。比較のため
に、後述の比較例に示す〔α〕20゜Dが−9.2゜の2
−チエニルスルフイニル酢酸から得たセフアロス
ポリンのMICを示す。
The present invention relates to novel cephalosporins and salts thereof having a wide range of antibacterial activity and a method for producing the same. Although cephalosporin derivatives are known to be substances with antibacterial activity, the known cephalosporin derivatives must be used in large quantities. Therefore, in order to obtain a cephalosporin derivative having higher antibacterial activity, the present inventors conducted repeated research on various derivatives, and as a result, arrived at the present invention. The objects of the present invention are cephalosporins in which the sulfinyl group is in the R form among the compounds represented by the following general formula () and salts thereof. (However, R 1 is 2-thienyl, 4-pyridyl, phenyl, A is acetoxy, and M is hydrogen, alkali metal, or amine salt ion.) ()
The three-dimensional structure of the sulfinyl group of the compound is
general formula (R 1 is the same as above) Among the optical isomers at the sulfinyl group of the compound represented by, the specific optical rotation in alcohol [α] D
It is defined as having the same three-dimensional structure as the three-dimensional structure in which is positive. The compound of formula () is asymmetric in the sulfinyl group and has two types of optical isomers, and therefore, the cephalosporins derived therefrom also have two types of isomers in the sulfinyl group. Among these two types of isomers, the cephalosporins derived from the optically active form of the compound represented by the formula () in which [α] D is positive in ethanol, or Cephalosporins derived from mixtures containing compounds of formula () exhibiting a positive [α] D exhibiting a negative [α] D in the corresponding ethanol ()
discovered that it has stronger antibacterial activity than cephalosporins derived from compounds of Among the R 1 groups, preferred are 2-thienyl, 4-pyridyl, and phenyl, with 2-thienyl being particularly preferred. Particularly preferred groups as A are:
Acetoxy, 1-methyl-1H-tetrazole-
5-ylthio and 5-methyl-1,3,4-thiadiazol-2-ylthio, which have the highest antibacterial activity. The compounds according to the invention can be produced as follows. (a) Formula () (In the formula, A and M are the same as above) The compound or its reactive derivative is reacted with the R-carboxylic acid of the formula () or its reactive derivative. Specific examples of the R-form carboxylic acid of the formula () are the parts of the R-form of the object compound of the present invention. It is the same as when −COOH is bonded to , that is, [α] D in the ethanol is positive. Reactive derivatives of compounds of formula () are, for example, silyl esters or amine salts. Reactive derivatives of carboxylic acids of formula () are, for example, acid chlorides, acid anhydrides, amides, azides, active esters or salts (formed, for example, with alkali metals or alkaline earth metals, ammonia or organic bases). salt). The reaction between a compound of formula () and a compound of formula () can be carried out in a suitable solvent such as acetone,
It is carried out in dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride and, if desired, in the presence of a base such as sodium or potassium bicarbonate or a trialkylamine, at room temperature or under cooling. When reacting the compound of formula () as a free acid or as a salt, as a condensing agent,
The reaction is preferably carried out in the presence of dicyclohexylcarbodiimide, diphenylphosphoric azide, diethylphosphoric cyanide, hexachlorocyclotriphosphatriazine, triazine trichloride, or the like. The compound () of the present invention has a high degree of antibacterial activity against Gram-positive bacteria and Gram-negative bacteria in animals and humans, and is therefore effective against infectious diseases caused by these bacteria, such as bronchitis and bronchopneumonia. , respiratory tract diseases such as pleurisy, hepatobiliary and abdominal diseases such as cholecystitis, peritonitis, blood and cardiovascular diseases such as sepsis, urinary tract diseases such as pyelonephritis, cystitis, otitis media, parotitis, etc. Useful in the treatment of ear, nose and throat diseases. The compounds of the present invention are effectively absorbed by oral or parenteral administration. In the latter case, these compounds may be dissolved in a suitable solvent, such as sterile water, physiological saline solution, dextrose solution, or conventional intravenous fluids or electrolyte solutions, at a dosage of, for example, about 100 mg per dose for adults. ~about 200
It can be administered in an amount of mg. The following examples illustrate the invention in detail, but the invention is not limited to these examples. Reference Example 1 11.6 g of 2-mercaptothiophene and 10.4 g of monochloroacetic acid are refluxed with 8.8 g of caustic soda and 100 ml of water for 3 hours, and then the pH is adjusted to 2.0 with hydrochloric acid to precipitate an oily substance. This was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to yield 12.1 g of pale yellow crystals.
I got it. NMR (CDCl 3 ) δ3.5 (2H, s), δ6.9
~7.4 (multi 3H), δ11.6 (s, 1H). Reference Example 2 Dissolve 8.7 g of 2-thienylthioacetic acid in 30 ml of acetic acid, stir under ice cooling, and add 6.8 g of 30% hydrogen peroxide solution.
ml and further stirred at room temperature for 5 hours. Acetic acid was removed from the reaction solution under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 5.3 g of 2-thienylsulfinyl acetic acid.
I got it. Melting point 114-116℃, NMR (DMSO-d 6 ) δ
4.1 (s, 2H), 7.15 (multi, 1H), 7.55 (t,
1H), 7.9 (d, 1H ) , elemental analysis C6H6S2O3 , calculated values C: 37.88 , H: 3.18, S: 33.71, actual values C: 37.76, H: 3.31, S: 33.48. Reference Example 3 1.00 g of 2-thienylsulfinyl acetic acid and 2.57 g of brucine are dissolved in 25 ml of ethanol, and then concentrated to dryness. After washing the residual powder with 35 ml of hot benzene, 2.35 g of insoluble matter is recrystallized from 20 ml of ethanol. By treating 1.50 g of the obtained crystals with hydrochloric acid, extracting with ethyl acetate, concentrating the organic layer, and further crystallizing from ethyl acetate,
0.35 g of optically active 2-thienylsulfinyl acetic acid was obtained. In ethanol [α] 22 ° D +11.0°C=
It was 1.0. Example 1 2-thienylsulfinylacetic acid obtained according to Reference Example 3 ([α] 22 ° D + 11.0°C = 1.00 ethanol)
Dissolve 0.38 g in 8 ml of dry acetone, add 0.28 ml of triethylamine and 3 drops of N.N-dimethylbenzylamine and stir. -10 solution
Pivalic acid chloride while stirring and cooling to °C.
Add 0.24g. After the dropwise addition, the mixture was further stirred at -10℃ for 30 minutes, and then stirred at that temperature with vigorous stirring.
A mixed solution of 0.54 g of aminocephalosporanic acid, 0.28 g of triethylamine, 3 ml of acetone, and 3 ml of water is added all at once. Then, at -10℃ for 30 minutes, 0
Stir for 1 hour at ℃ and 1 hour at room temperature. 40% reaction solution
Concentrate at below ℃, wash with ethyl acetate, adjust the pH to 3 with 2N hydrochloric acid, and extract with ethyl acetate. The organic layer is concentrated under reduced pressure and then dried under reduced pressure to obtain the optically active R-7-
0.43 g of crude crystals containing (2-thienylsulfinyl acetamide) cephalosporanic acid were obtained. In order to confirm this as a pure product, the crude crystals were washed with methanol as a solvent using Sephadex LH-20.
(manufactured by Pharmaira Fine Chemicals AB) Column chromatography was used to obtain the fraction. NMR spectrum (DMSO-d 6 ) δppm: 2.0 (s, 3H),
3.6 (q, 2H), 4.1 (q, 2H), 4.8 (q, 2H),
5.1 (d, 1H), 5.7 (q, 1H), 7.2 (t, 1H),
7.6 (d, 1H), 8.0 (d, 1H), 9.2 (d, 1H),
Elemental analysis: Calculated value C: 42.38 , H: 3.78 , N: 6.18 , S: 21.21 , actual value C: 42.52, H: 4.15, N: 5.78, S:
20.85. Table 1 shows the minimum inhibitory concentration (MIC) of this product against various Gram-positive and -negative bacteria. For comparison, [α] 20 ° D is -9.2° shown in the comparative example below.
- Shows the MIC of cephalosporin obtained from thienylsulfinylacetic acid.
【表】【table】
【表】
また粗結晶をそのまゝ用いても同様に秀れた効
果を示した。
比較例
2−チエニルスルフイニル酢酸(〔α〕22゜D:−
9.2°C=1.00エタノール)0.38gを乾燥アセトン
8mlに溶解し、さらにトリエチルアミン0.28mlお
よびN・N−ジメチルベンジルアミン3滴を添加
して撹拌する。溶液を−10℃に冷却し、撹拌しな
がらピバリン酸クロライド0.24gを添加する。滴
下後、さらに−10℃で30分撹拌したのち、該温度
で激しく撹拌しながら7−アミノセフアロスポラ
ン酸0.54g、トリエチルアミン0.28gおよびアセ
トン3ml、水3mlの混合溶液を一挙に添加する。
その後、−10℃で30分、0℃で1時間、室温で1
時間撹拌する。反応液を40℃以下で濃縮し、残渣
を3%炭酸水素ナトリウム水溶液に溶解し、酢酸
エチルで洗滌後、2規定塩酸でPH3とし、酢酸エ
チルで抽出する。有機層を濃縮したのち、減圧下
に乾燥することにより、スルホキシドにおいて光
学活性な7−(2−チエニルスルフイニルアセト
アミド)セフアロスポラン酸の粗結晶0.38gを得
た。NMRスペクトルは、実施例1の化合物と
ほゞ一致した。
実施例 2
スルホキシドにおいて実質的に光学的不活性な
7−(2−チエニルスルフイニルアセトアミド)
セフアロスポラン酸のジアステレオマー混合物
150mgを非極性のコーテイング樹脂を担体とし、
溶媒として、水−メタノール混合溶液を用いる逆
相クロマトグラフイーにより分離した。分離され
た2つのフラクシヨン主成分は、各々スルホキシ
ドにおいて光学活性な2−チエニルスルフイニル
酢酸から導かれる2種の7−(2−チエニルスル
フイニルアセトアミド)セフアロスポラン酸に一
致した。このうち実施例1の化合物を多く含む部
分の施光度は〔α〕25゜D:+115.9゜(C=0.80、
クロロホルム)であつた。
実施例 3
R体の4−ピリジルスルフイニル酢酸0.52gを
乾燥アセトン20mlに溶解し、さらにトリエチルア
ミン0.5およびN・N−ジメチルベンジルアミン
2滴を添加して撹拌する。溶液を−20℃に冷却
し、撹拌しながらピバリン酸クロリド0.36mlを滴
下する。滴下後さらに−20℃で30分撹拌した後、
該温度で激しく撹拌しながら、7−アミノセフア
ロスポラン酸0.81g、トリエチルアミン0.5mlお
よびメタノール10mlの混合溶液を一挙に添加す
る。その後、−20℃で30分、0℃で1時間、室温
で2時間撹拌する。反応液を濃縮し、残渣を水で
溶解する。溶液を酢酸エチルで洗滌し、さらにク
ロロホルムで洗滌後、2規定塩酸でPHを2.0と
し、沈澱物を過する。液をクロロホルムで抽
出し、さらに酢酸エチルで抽出し、酢酸エチル層
を活性炭で処理し、乾燥し、減圧下に濃縮するこ
とにより、R体の7−(4−ピリジルスルフイニ
ルアセトアミド)セフアロスポラン酸0.27gを得
た。NMR(DMSO−d6)δppm:3.02(s、
3H)、3.54(dd、2H)、4.12(dd、2H)、4.82
(dd、2H)、5.18(d、1H)、5.75(q、1H)、7.7
(m、2H)、8.7(m、2H)。
このものゝMICは表2に示すとおりである。[Table] Furthermore, even when the crude crystals were used as they were, similar excellent effects were obtained. Comparative example 2-thienylsulfinyl acetic acid ([α] 22 ° D :-
9.2°C = 1.00 ethanol) is dissolved in 8 ml of dry acetone, and 0.28 ml of triethylamine and 3 drops of N·N-dimethylbenzylamine are added and stirred. The solution is cooled to -10°C and 0.24 g of pivalic chloride is added with stirring. After the dropwise addition, the mixture was further stirred at -10°C for 30 minutes, and then a mixed solution of 0.54 g of 7-aminocephalosporanic acid, 0.28 g of triethylamine, 3 ml of acetone, and 3 ml of water was added all at once while stirring vigorously at the same temperature.
Then, it was heated to -10℃ for 30 minutes, 0℃ for 1 hour, and room temperature for 1 hour.
Stir for an hour. The reaction solution is concentrated at below 40°C, the residue is dissolved in a 3% aqueous sodium bicarbonate solution, washed with ethyl acetate, adjusted to pH 3 with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated and then dried under reduced pressure to obtain 0.38 g of crude crystals of 7-(2-thienylsulfinylacetamido)cephalosporanic acid, which is optically active in sulfoxide. The NMR spectrum was almost identical to that of the compound of Example 1. Example 2 Substantially optically inactive 7-(2-thienylsulfinyl acetamide) in sulfoxide
Diastereomeric mixture of cephalosporanic acid
150mg using non-polar coating resin as carrier,
Separation was performed by reverse phase chromatography using a water-methanol mixed solution as a solvent. The two main components of the separated fractions corresponded to two types of 7-(2-thienylsulfinylacetamido)cephalosporanic acid derived from 2-thienylsulfinyl acetic acid, each of which is optically active in its sulfoxide. Among these, the light intensity of the part containing a large amount of the compound of Example 1 was [α] 25 ° D : +115.9° (C = 0.80,
chloroform). Example 3 0.52 g of R-form 4-pyridylsulfinyl acetic acid is dissolved in 20 ml of dry acetone, and 0.5 g of triethylamine and 2 drops of N.N-dimethylbenzylamine are added and stirred. The solution is cooled to -20°C and 0.36 ml of pivalic acid chloride is added dropwise with stirring. After the dropwise addition, the solution was further stirred at -20℃ for 30 minutes.
While stirring vigorously at this temperature, a mixed solution of 0.81 g of 7-aminocephalosporanic acid, 0.5 ml of triethylamine, and 10 ml of methanol is added all at once. Thereafter, the mixture was stirred at -20°C for 30 minutes, at 0°C for 1 hour, and at room temperature for 2 hours. Concentrate the reaction solution and dissolve the residue in water. After washing the solution with ethyl acetate and further with chloroform, the pH was adjusted to 2.0 with 2N hydrochloric acid, and the precipitate was filtered. The liquid was extracted with chloroform and further extracted with ethyl acetate, and the ethyl acetate layer was treated with activated carbon, dried, and concentrated under reduced pressure to obtain R-form 7-(4-pyridylsulfinylacetamido)cephalosporanic acid. 0.27g was obtained. NMR (DMSO-d 6 ) δppm: 3.02 (s,
3H), 3.54 (dd, 2H), 4.12 (dd, 2H), 4.82
(dd, 2H), 5.18 (d, 1H), 5.75 (q, 1H), 7.7
(m, 2H), 8.7 (m, 2H). The MIC of this product is as shown in Table 2.
【表】【table】
【表】
実施例 4
R体のフエニルスルフイニル酢酸(〔α〕20 D:+
183゜、C=1.00、エタノール中)0.37gを乾燥
アセトン8mlに溶解し、さらにトリエチルアミン
0.28mlおよびN・N−ジメチルベンジルアミン1
滴を添加して撹拌する。溶液を−20℃に冷却し、
撹拌しながらピバリン酸クロリド0.24gを加え
る。さらに−20℃で30分撹拌した後、該温度で激
しく撹拌しながら、7−アミノセフアロスポラン
酸0.54g、トリエチルアミン0.28mlおよびメタノ
ール4mlの混合溶液を一挙に添加する。その後−
20℃で30分、0℃で1時間、室温で2時間撹拌す
る。反応後、減圧下に溶媒を濃縮し、残渣を水で
溶解する。溶液を酢酸エチルで洗滌し、水層を2
規定塩酸でPHを2.5とし、少量のクロロホルムで
抽出後、酢酸エチルで抽出し、酢酸エチル層を乾
燥後、減圧濃縮することにより、R体の7−(フ
エニルフイニルアセトアミド)セフアロスポラン
酸0.18gを得た。NMR(DMSO−d6)δppm:
2.02(s、3H)、3.56(dd、2H)、3.86(dd、
2H)、4.85(dd、2H)、5.10(d、1H)、5.68
(q、1H)、7.44−7.8(m、5H)、9.10(d、
1H)
このものゝ各種グラム陽性、陰性菌に対する最
小抑制濃度(MIC)を表3に示す。なお、施光度
〔α〕Dはエタノール中濃度1.00%で測定した。比
較例として〔α〕20 Dが−182゜のフエニルスルフイ
ニル酢酸から得たセフアロスポリンのMICを示
す。[Table] Example 4 R-form phenylsulfinyl acetic acid ([α] 20 D :+
183°, C=1.00, in ethanol) was dissolved in 8 ml of dry acetone, and then triethylamine was added.
0.28ml and N-N-dimethylbenzylamine 1
Add drops and stir. Cool the solution to −20°C,
Add 0.24 g of pivalic acid chloride while stirring. After further stirring at -20°C for 30 minutes, a mixed solution of 0.54 g of 7-aminocephalosporanic acid, 0.28 ml of triethylamine, and 4 ml of methanol is added all at once while stirring vigorously at that temperature. After that-
Stir at 20°C for 30 minutes, at 0°C for 1 hour, and at room temperature for 2 hours. After the reaction, the solvent is concentrated under reduced pressure and the residue is dissolved in water. The solution was washed with ethyl acetate and the aqueous layer was
Adjust the pH to 2.5 with normal hydrochloric acid, extract with a small amount of chloroform, extract with ethyl acetate, dry the ethyl acetate layer, and concentrate under reduced pressure to obtain 0.18 g of R-form 7-(phenylphinylacetamido)cephalosporanic acid. I got it. NMR (DMSO−d 6 ) δppm:
2.02 (s, 3H), 3.56 (dd, 2H), 3.86 (dd,
2H), 4.85 (dd, 2H), 5.10 (d, 1H), 5.68
(q, 1H), 7.44−7.8 (m, 5H), 9.10 (d,
1H) Table 3 shows the minimum inhibitory concentration (MIC) of this product against various Gram-positive and -negative bacteria. The light intensity [α] D was measured at a concentration of 1.00% in ethanol. As a comparative example, the MIC of cephalosporin obtained from phenylsulfinylacetic acid with [α] 20 D of −182° is shown.
Claims (1)
エニル、Aはアセトキシ、Mは水素、アルカリ金
属、アミン塩イオンを示す。) で表わされるセフアロスポリン類において、スル
フイニル基がR体である化合物。 〔ここでR体とは (R1は前記と同じ) で表わされる化合物のスルフイルニル基における
光学異性体のうち、アルコール中の比旋光度
〔α〕Dが正を示す立体構造と同一の立体構造をも
つものと定義する。〕[Claims] 1. General formula (However, R 1 is 2-thienyl, 4-pyridyl, phenyl, A is acetoxy, and M is hydrogen, alkali metal, or amine salt ion.) In the cephalosporins represented by, the sulfinyl group is in the R form. Compound. [What is R body here? (R 1 is the same as above) Among the optical isomers of the sulfuryl group of the compound represented by, it is defined as having the same steric structure as the steric structure in which the specific rotation [α] D in alcohol is positive. ]
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8643482A JPS5832886A (en) | 1982-05-24 | 1982-05-24 | Cephalosporin |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8643482A JPS5832886A (en) | 1982-05-24 | 1982-05-24 | Cephalosporin |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP51007902A Division JPS5814440B2 (en) | 1976-01-29 | 1976-01-29 | Cephalosporins |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5832886A JPS5832886A (en) | 1983-02-25 |
JPS6126999B2 true JPS6126999B2 (en) | 1986-06-23 |
Family
ID=13886798
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP8643482A Granted JPS5832886A (en) | 1982-05-24 | 1982-05-24 | Cephalosporin |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5832886A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6432733A (en) * | 1987-07-29 | 1989-02-02 | Oki Electric Ind Co Ltd | System for detecting optical link trouble |
JPH06216845A (en) * | 1990-05-22 | 1994-08-05 | Hughes Aircraft Co | Long-distance two-way optical fiber communication link |
JPH06343061A (en) * | 1990-05-21 | 1994-12-13 | Hughes Aircraft Co | Bidirectional single-wavelength optical fiber communication links |
-
1982
- 1982-05-24 JP JP8643482A patent/JPS5832886A/en active Granted
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6432733A (en) * | 1987-07-29 | 1989-02-02 | Oki Electric Ind Co Ltd | System for detecting optical link trouble |
JPH06343061A (en) * | 1990-05-21 | 1994-12-13 | Hughes Aircraft Co | Bidirectional single-wavelength optical fiber communication links |
JPH06216845A (en) * | 1990-05-22 | 1994-08-05 | Hughes Aircraft Co | Long-distance two-way optical fiber communication link |
Also Published As
Publication number | Publication date |
---|---|
JPS5832886A (en) | 1983-02-25 |
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