JPS6221795B2 - - Google Patents
Info
- Publication number
- JPS6221795B2 JPS6221795B2 JP14110078A JP14110078A JPS6221795B2 JP S6221795 B2 JPS6221795 B2 JP S6221795B2 JP 14110078 A JP14110078 A JP 14110078A JP 14110078 A JP14110078 A JP 14110078A JP S6221795 B2 JPS6221795 B2 JP S6221795B2
- Authority
- JP
- Japan
- Prior art keywords
- neothramycin
- sulfite
- adduct
- water
- sulfite adduct
- 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
- FXMOIYLVKOALHC-UHFFFAOYSA-N neothramycin B Natural products N1=CC2CCC(O)N2C(=O)C2=C1C=C(O)C(OC)=C2 FXMOIYLVKOALHC-UHFFFAOYSA-N 0.000 claims description 68
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 43
- FXMOIYLVKOALHC-MADCSZMMSA-N (6as,9s)-3,9-dihydroxy-2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=C[C@@H]2CC[C@H](O)N2C(=O)C2=C1C=C(O)C(OC)=C2 FXMOIYLVKOALHC-MADCSZMMSA-N 0.000 claims description 34
- FXMOIYLVKOALHC-JVXZTZIISA-N (6as,9r)-3,9-dihydroxy-2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=C[C@@H]2CC[C@@H](O)N2C(=O)C2=C1C=C(O)C(OC)=C2 FXMOIYLVKOALHC-JVXZTZIISA-N 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 229910052783 alkali metal Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000001340 alkali metals Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 239000000203 mixture Substances 0.000 description 18
- 239000000843 powder Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 229930188317 neothramycin Natural products 0.000 description 11
- 238000000862 absorption spectrum Methods 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 5
- DOZXCNCPKXGGBC-VKKUPAEUSA-N (6as,9s)-3,9-dihydroxy-2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one;(6as,9r)-3,9-dihydroxy-2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=C[C@@H]2CC[C@H](O)N2C(=O)C2=C1C=C(O)C(OC)=C2.N1=C[C@@H]2CC[C@@H](O)N2C(=O)C2=C1C=C(O)C(OC)=C2 DOZXCNCPKXGGBC-VKKUPAEUSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000007059 acute toxicity Effects 0.000 description 3
- 231100000403 acute toxicity Toxicity 0.000 description 3
- -1 alkali metal sulfites Chemical class 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical compound [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 208000007093 Leukemia L1210 Diseases 0.000 description 1
- 208000008342 Leukemia P388 Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- FWMBCNGLMRSLPH-UHFFFAOYSA-N O.OC=O.CC(O)=O Chemical compound O.OC=O.CC(O)=O FWMBCNGLMRSLPH-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001342 alkaline earth metals Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- ARSLNKYOPNUFFY-UHFFFAOYSA-L barium sulfite Chemical compound [Ba+2].[O-]S([O-])=O ARSLNKYOPNUFFY-UHFFFAOYSA-L 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- WMJRPJZQQSSDBU-UHFFFAOYSA-L disodium;sulfite;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])=O WMJRPJZQQSSDBU-UHFFFAOYSA-L 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical class [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 238000004108 freeze drying Methods 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
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 description 1
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 1
- 229940043349 potassium metabisulfite Drugs 0.000 description 1
- 235000010263 potassium metabisulphite Nutrition 0.000 description 1
- BHZRJJOHZFYXTO-UHFFFAOYSA-L potassium sulfite Chemical compound [K+].[K+].[O-]S([O-])=O BHZRJJOHZFYXTO-UHFFFAOYSA-L 0.000 description 1
- 235000019252 potassium sulphite Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- KIDBBTHHMJOMAU-UHFFFAOYSA-N propan-1-ol;hydrate Chemical compound O.CCCO KIDBBTHHMJOMAU-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は抗生物質ネオスラマイシンＡまたは／
およびネオスラマイシンＢの新規で有用且つ安定
な水溶性誘導体である亜硫酸付加物とその製法に
関する。
ネオスラマイシンＡ，ネオスラマイシンＢは諸
種の細菌に弱い抗菌作用しか示さないがマウス白
血病Ｌ―1210細胞およびある種の癌細胞の発育を
強く抑制し、制癌剤として用いられる。
（特願昭49―27674号、昭和49年３月12日出願；特
願昭50―123256号、昭和50年10月15日出願；特願
昭51―259号、昭和51年１月１日出願；特願昭51
―110722号、昭和51年９月17日出願；特願昭51―
110723号、昭和51年９月17日出願；ジヤーナル・
オブ・アンチビオチツクス第29巻１月号93〜96頁
（1976）およびジヤーナル・オブ・アンチビオチ
ツクス第30巻４月号340〜343頁（1977））。
ネオスラマイシンＡ，ネオスラマイシンＢは水
溶液中のみならず粉未状態でも不安定で、酸化さ
れ易く着色する性状を示し、また水に対する溶解
が比較的低く注射剤としての使用が制限されてい
る。このような事情に鑑み、本発明者らはネオス
ラマイシンＡ，ネオスラマイシンＢの有用な且つ
安定な水溶性誘導体の製造を目的として種々検討
した結果、ネオスラマイシンＡまたはネオスラマ
イシンＢに亜硫酸塩を反応させると新規誘導体と
して亜硫酸付加物が得られることを見出した。し
かも、
１ その新規誘導体は水に極めてとけやすく（室
温での溶解度１ｇ／ml）、
２ ネオスラマイシンの抗菌力および抗腫瘍活性
を保持しており、
３ 水溶液として注射した場合、疼痛および局所
障害が少なく、
４ 粉末状態は勿論、水溶液状態でもネオスラマ
イシンＡ，ネオスラマイシンＢより安定性がす
ぐれており、着色を有効に防止しうること、お
よび
５ ネオスラマイシンＡ，ネオスラマイシンＢよ
り急性毒性が弱く安全性が高められた、などの
有利な新知見が得られた。本発明はこれらの新
知見に基づいて完成された。
すなわち、本発明の要旨とするところは、ネオ
スラマイシンＡまたはネオスラマイシンＢのアゾ
メチン基に亜硫酸基または亜硫酸塩基が付加、結
合したネオスラマイシンＡまたはネオスラマイシ
ンＢの誘導体及びその塩である。
詳しく言えば、本発明は、構造式
〔式中、Ｒは水素原子またはアルカリ金属原
子、アルカリ土類金属原子またはアンモニウム基
である〕で示されるネオスラマイシンＡまたはネ
オスラマイシンＢの亜硫酸付加物およびその薬学
的に使用し得る塩を要旨とする。
本発明の目的物はアゾメチン基を有するネオス
ラマイシンＡまたは／およびネオスラマイシンＢ
に亜硫酸塩を反応させることにより製造しうる。
本法に使用しうる亜硫酸塩としては、溶液中で
亜硫酸イオンを生成しうるものであればよく、そ
の例として酸性亜硫酸塩、例えば酸性亜硫酸ナト
リウム（NaHSO3）、酸性亜硫酸カリウム
（KHSO3）の如き酸性亜硫酸アルカリ金属塩；酸
性亜硫酸アンモニウム（NH4HSO3）；および亜硫
酸塩例えば亜硫酸ナトリウム（Na2SO3）、亜硫酸
カリウム（K2SO3）、の如き亜硫酸アルカリ金属
塩；亜硫酸カルシウム（CaSO3）、亜硫酸バリウ
ム（BaSO3）、の如き亜硫酸アルカリ土類金属
塩；並びにメタ重亜硫酸塩、例えばメタ重亜硫酸
ナトリウム（Na2S2O5）、メタ重亜硫酸カリウム
（K2S2O5）の如きメタ重亜硫酸アルカリ金属塩な
どがあげられる。
亜硫酸塩はネオスラマイシンＡまたは／および
ネオスラマイシンＢのアゾメチン基１個に対し、
１モル乃至1.5モル当量を使用しうるが最適には
１モル当量を使用する。
本法は通常水溶液中で行なわれるが、溶媒とし
て含水の有機溶媒たとえばアセトン、ジオキサ
ン、酢酸エチルなどの含水溶液を使用しうる。
反応温度は一般的には室温附近で容易に進行す
るが、望ましくは約５℃である。
上記方法で製造された本発明の目的物は、反応
終了後、反応混合物から通常の採取手段、濃縮乾
燥、凍結乾燥、不溶性溶媒添加による析出、
過、遠心分離、カラムクロマトグラフイーなどの
方法により採取しうる。
本発明に係る新規誘導体、ネオスラマイシンＡ
または／およびネオスラマイシンＢの亜硫酸ナト
リウム付加物は下式に示す反応により得られ、そ
の構造は以下に示す理化学的ならびにスペクトル
解析によつて確認された。
ネオスラマイシンＡおよびＢ平衡混合物の亜硫
酸付加物は白色粉末で明確な融点を示さず210―
220℃で発泡分解する。
比旋光度は〔α〕２２ Ｄ＝34.7゜（c1，水）の値を
得た。
元素分析の実測値はC40.47％，H4.75％，
N7.44％，O32.78％，S8.96％を示し、
C13H15N2O4・SO3Na・H2Oとする計算値は
C40.62％，H4.45％，N7.28％，O33.30％，S8.34
％である。
ネオスラマイシンＡおよびＢ平衡混合物の亜硫
酸付加物は水によく溶け、メタノール、エタノー
ルの如き低級アルカノールに僅かに溶け、エチル
エーテル、ｎ―ヘキサンには不溶である。
ネオスラマイシンＡおよびＢ平衡混合物の亜硫
酸付加物の臭化カリ錠で測定した赤外部吸収スペ
クトル曲線を第１図に、水溶液、0.1N塩酸およ
び0.1N水酸化ナトリウム溶液（それぞれ10mc
ｇ／ml）で測定した紫外部吸収スペクトル曲線を
第２図に、重水溶液で測定した水素核および炭素
核核磁気共鳴スペクトルを第３図および第４図に
示した。
ネオスラマイシンＡおよびＢ平衡混合物の亜硫
酸付加物はライドン―スミス反応、レツドテトラ
ゾリウム反応、フアストブル―Ｂ反応、硝酸銀―
フルオレツセイン反応には陽性であり、ニンヒド
リン反応は僅かに陽性で、エールリツヒ反応は陰
性である。
本物質はシリカゲルの薄層クロマトグラフイー
（展開系ｎ―ブタノール・メタノール―水８：
１：４容）でＲf値0.38を与え、ネオスラマイシ
ンのＲf値0.80と区別された。また、本物質はセ
ルロースの薄層クロマトグラフイー（展開系ｎ―
プロパノール―水７：３容）でＲf値0.45を与
え、このときネオスラマイシンはＲf値0.88を与
えた。
蟻酸―酢酸―水（25：75：900容）を用いた高
圧紙泳動（3000V，20分）ではアラニンの原点
からの極への動きを＋1.0としたときネオスラ
マイシンＡ及びＢ平衡混合物の亜硫酸付加物のそ
れは−0.53を示した。
ネオスラマイシンＡの亜硫酸付加物は白色粉末
で明確な融点を示さず230〜240℃で分解する。比
旋光度は〔α〕２４ Ｄ＝16.4゜（c1，水）を示した。
本物質の臭化カリ錠で測定した赤外部吸収スペ
クトル曲線を第５図に、水溶液（10mcｇ／ml）
で測定した紫外部吸収スペクトル曲線Ａを第６図
に重水溶液で測定した水素核核磁気共鳴スペクト
ルを第７図に示した。
ネオスラマイシンＢの亜硫酸付加物は白色粉末
で明確な融点を示さず220〜230℃で分解する。比
旋光度は〔α〕２４ Ｄ＝＋12.6゜（c1，水）を示し
た。
本物質の臭化カリ錠で測定した赤外部吸収スペ
クトル曲線を第８図に水溶液（10mcｇ／ml）で
測定した紫外部吸収スペクトル曲線Ｂを第６図
に、重水溶液で測定した水素核核磁気共鳴スペク
トルを第９図に示した。
ネオスラマイシンＡおよびＢ平衡混合物ならび
にその亜硫酸付加物の栄養寒天平板上での最低阻
止濃度は第１表に示すとおりで、いずれも弱い抗
菌活性を示すのみである。
The present invention provides antibiotic neothramycin A or/
The present invention also relates to a sulfite adduct, which is a new, useful and stable water-soluble derivative of neothramycin B, and a method for producing the same. Neothramycin A and neothramycin B have only a weak antibacterial effect on various types of bacteria, but they strongly suppress the growth of mouse leukemia L-1210 cells and certain types of cancer cells, and are used as anticancer agents. (Japanese Patent Application No. 1972-27674, filed on March 12, 1970; Japanese Patent Application No. 123256, filed on October 15, 1975; Japanese Patent Application No. 1972-259, filed on January 1, 1978) Application: Patent application 1977
-No. 110722, filed on September 17, 1975; patent application 1977-
No. 110723, filed on September 17, 1975; Journal
Journal of Antibiotics, Vol. 29, January issue, pp. 93-96 (1976) and Journal of Antibiotics, Vol. 30, April issue, pp. 340-343 (1977)). Neothramycin A and neothramycin B are unstable not only in aqueous solution but also in powdered form, exhibiting the property of being easily oxidized and colored, and their relatively low solubility in water, limiting their use as injections. . In view of these circumstances, the present inventors conducted various studies aimed at producing useful and stable water-soluble derivatives of neothramycin A and neothramycin B. We have discovered that sulfite adducts can be obtained as new derivatives by reacting sulfites. Moreover, 1 the new derivative is highly soluble in water (solubility 1 g/ml at room temperature), 2 retains the antibacterial and antitumor activity of neothramycin, and 3 reduces pain and local damage when injected as an aqueous solution. 4. It has better stability than neothramycin A and neothramycin B, both in powder form and in aqueous solution state, and can effectively prevent coloring, and 5. Advantageous new findings were obtained, including lower acute toxicity and increased safety. The present invention was completed based on these new findings. That is, the gist of the present invention is a derivative of neothramycin A or neothramycin B, in which a sulfite group or a sulfite group is added and bonded to the azomethine group of neothramycin A or neothramycin B, and a salt thereof. . Specifically, the present invention provides structural formula [wherein R is a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or an ammonium group] A sulfite adduct of neothramycin A or neothramycin B and a pharmaceutically usable salt thereof This is the summary. The object of the present invention is neothramycin A or/and neothramycin B having an azomethine group.
It can be produced by reacting sulfite with sulfite. Any sulfite that can be used in this method may be one that can generate sulfite ions in solution; examples include acidic sulfites, such as sodium acid sulfite (NaHSO 3 ) and potassium acid sulfite (KHSO 3 ). Acidic alkali metal sulfites such as acidic ammonium sulfite (NH 4 HSO 3 ); and sulfites such as sodium sulfite (Na 2 SO 3 ), potassium sulfite (K 2 SO 3 ); 3 ), alkaline earth metal salts of sulfite, such as barium sulfite (BaSO 3 ); and metabisulfites, such as sodium metabisulfite (Na 2 S 2 O 5 ), potassium metabisulfite (K 2 S 2 O 5 ) and alkali metal salts of metabisulfite. Sulfite per one azomethine group of neothramycin A or/and neothramycin B,
1 to 1.5 molar equivalents may be used, but most preferably 1 molar equivalent is used. This method is usually carried out in an aqueous solution, but a water-containing solution of a water-containing organic solvent such as acetone, dioxane, ethyl acetate, etc. can be used as the solvent. The reaction temperature generally proceeds easily at around room temperature, but is preferably about 5°C. After completion of the reaction, the object of the present invention produced by the above method can be obtained by conventional collection means from the reaction mixture, concentration drying, freeze drying, precipitation by adding an insoluble solvent,
It can be collected by methods such as filtration, centrifugation, and column chromatography. New derivative according to the present invention, neothramycin A
Or/and a sodium sulfite adduct of neothramycin B was obtained by the reaction shown in the following formula, and its structure was confirmed by the physicochemical and spectral analysis shown below. The sulfite adduct of neothramycin A and B equilibrium mixture is a white powder with no clear melting point.
Foaming decomposes at 220℃. The specific optical rotation was [α] 22 D =34.7° (c1, water). The actual values of elemental analysis are C40.47%, H4.75%,
Showing N7.44%, O32.78%, S8.96%,
The calculated value for C 13 H 15 N 2 O 4・SO 3 Na・H 2 O is
C40.62%, H4.45%, N7.28%, O33.30%, S8.34
%. The sulfite adduct of neothramycin A and B equilibrium mixture is highly soluble in water, slightly soluble in lower alkanols such as methanol and ethanol, and insoluble in ethyl ether and n-hexane. Figure 1 shows the infrared absorption spectrum curves measured with potassium bromide tablets of sulfite adducts of neothramycin A and B equilibrium mixtures.
Fig. 2 shows the ultraviolet absorption spectrum curve measured at 100 g/ml), and Figs. 3 and 4 show the hydrogen nuclear and carbon nuclear magnetic resonance spectra measured in a heavy aqueous solution. The sulfite adducts of neothramycin A and B equilibrium mixtures are Lydon-Smith reaction, red tetrazolium reaction, FastBlue-B reaction, silver nitrate-
The fluorescein reaction is positive, the ninhydrin reaction is slightly positive, and the Ehrlich reaction is negative. This substance was analyzed by silica gel thin layer chromatography (developing system n-butanol/methanol-water 8:
1:4 volume) gave an R f value of 0.38, which was distinguishable from the R f value of neothramycin of 0.80. In addition, this substance can be used in cellulose thin layer chromatography (development system n-
propanol-water (7:3 vol) gave an R f value of 0.45, while neothramycin gave an R f value of 0.88. In high-pressure paper migration (3000V, 20 minutes) using formic acid-acetic acid-water (25:75:900 volume), when the movement of alanine from the origin to the pole is +1.0, the equilibrium mixture of neothramycin A and B that of the sulfite adduct showed −0.53. The sulfite adduct of neothramycin A is a white powder with no definite melting point and decomposes at 230-240°C. The specific optical rotation was [α] 24 D = 16.4° (c1, water). Figure 5 shows the infrared absorption spectrum curve of this substance measured with potassium bromide tablets, and the aqueous solution (10mcg/ml)
The ultraviolet absorption spectrum curve A measured in FIG. 6 is shown in FIG. 6, and the hydrogen nuclear magnetic resonance spectrum measured in a heavy water solution is shown in FIG. The sulfite adduct of neothramycin B is a white powder with no clear melting point and decomposes at 220-230°C. The specific optical rotation was [α] 24 D =+12.6° (c1, water). Figure 8 shows the infrared absorption spectrum curve measured with potassium bromide tablets of this substance. Figure 6 shows the ultraviolet absorption spectrum curve B measured in an aqueous solution (10 mcg/ml), and hydrogen nuclear magnetic field measured in a heavy aqueous solution. The resonance spectrum is shown in FIG. The minimum inhibitory concentrations of neothramycin A and B equilibrium mixtures and their sulfite adducts on nutrient agar plates are shown in Table 1, and both exhibit only weak antibacterial activity.
【表】
ネオスラマイシンＡおよびＢ平衡混合物ならび
にその亜硫酸付加物のマウス白血病ロイケミアＰ
―388に対する治療効果はマウス腹腔に106個／マ
ウスの率でロイケミア細胞を移殖後、ネオスラマ
イシン（Ａ及びＢの平衡混合物）又はそれの亜硫
酸付加物を腹腔内に連続３日間投与すると第２表
に示すような延命効果が認められた。[Table] Neothramycin A and B equilibrium mixture and its sulfite adduct for murine leukemia Leukemia P
-388, when neothramycin (an equilibrium mixture of A and B) or its sulfite adduct was intraperitoneally administered for 3 consecutive days after leukemia cells were transplanted into the peritoneal cavity of a mouse at a rate of 10 6 cells/mouse. The life-prolonging effect shown in Table 2 was observed.
【表】
未処理マウスの生存日数
ネオスラマイシン亜硫酸付加物の急性毒性はマ
ウスの静脈内に投与してLD5046mg／Kg（雄）、
46.5mg／Kg（雌）である。これに対しネオスラマ
イシンの急性毒性は同一条件でLD5023.1mg／Kg
（雄）、27.0mg／Kg（雌）であり、ネオスラマイシ
ン亜硫酸付加塩の毒性はネオスラマイシンに比べ
軽減されている。ネオスラマイシン亜硫酸付加物
は上記のごとき有用性を示すので原料の抗生物質
ネオスラマイシンと同様制癌剤としての目的に使
用しうる。
実施例 １
ネオスラマイシンＡ，Ｂ平衡混合物１ｇおよび
び亜硫酸水素ナトリウム397mgを水10mlに溶解、
室温で反応後セフアデツクスＧ―10（200ml）を
充填した塔（内径21mm）にかけ５℃で水で展開す
る。20ml宛分画し、活性を有する画分（No.７―
11）を集め、凍結乾燥して白色粉末1214mgを得
た。
この粉末を上記セフアデツクス塔でくりかえし
２回、同様の操作を行ないネオスラマイシンＡ，
Ｂ平衡混合物の亜硫酸付加物の白色粉末（934
mg、収率66.8％）を得た。
実施例 ２
ネオスラマイシンＡ，Ｂ平衡混合物１ｇおよび
亜硫酸ナトリウム７水塩0.97ｇを水10mlに溶解、
反応後セフアデツクスＧ―10（200ml）を充填し
た塔（内径21mm）にかけ実施例１と同様の操作を
行ないネオスラマイシンＡ，Ｂ平衡混合物の亜硫
酸付加物の淡黄色粉末（1.30ｇ、収率87.5％）を
得た。
実施例 ３
ネオスラマイシンＡ，Ｂ平衡混合物１ｇおよび
メタ重亜硫酸ナトリウム0.37ｇを水10mlに溶解、
反応後、セフアデツクスＧ―10（200ml）を充填
した塔（内径21mm）にかけ実施例１および２と同
様の操作を行ないネオスラマイシンＡ，Ｂ平衡混
合物の亜硫酸付加物の白色粉末（1.19ｇ、収率85
％）を得た。
実施例 ４
１ml中ネオスラマイシンＡ，Ｂ平衡混合物10mg
および亜硫酸水素ナトリウム４mg（ネオスラマイ
シン１モルに対して１モル比）を含む水溶液を無
菌過後、５mlアンプルに１ml宛充填し、凍結乾
燥するとネオスラマイシンＡ，Ｂ平衡混合物の亜
硫酸ナトリウム付加物の白色粉末が得られる。ア
ンプル空間の空気は窒素ガスで置換した後アンプ
ルを密閉する。
実施例 ５
ネオスラマイシンＡ（ネオスラマイシンA95.6
％含有）200mgおよび亜硫酸水素ナトリウム79.4
mg（ネオスラマイシンＡ、１モルに対して１モル
比）を４mgの水に溶解後、凍結乾燥してネオスラ
マイシンＡ亜硫酸付加物の白色粉末250mgを得
た。
実施例 ６
ネオスラマイシンＢ（ネオスラマイシンB91.2
％含有）200mgおよび亜硫酸水素ナトリウム79.4
mg（ネオスラマイシンB1モルに対して１モル
比）を４mlの水に溶解後、凍結乾燥してネオスラ
マイシンＢ亜硫酸付加物の白色粉来214mgを得
た。[Table] Survival days of untreated mice Acute toxicity of neothramycin sulfite adduct was administered intravenously to mice, LD 50 46 mg/Kg (male);
46.5 mg/Kg (female). In contrast, the acute toxicity of neothramycin was LD 50 23.1 mg/Kg under the same conditions.
(male) and 27.0 mg/Kg (female), and the toxicity of neothuramycin sulfite addition salt is reduced compared to neothuramycin. Since the neothramycin sulfite adduct exhibits the above-mentioned usefulness, it can be used for the purpose of an anticancer agent like the raw material antibiotic neothramycin. Example 1 1 g of neothramycin A, B equilibrium mixture and 397 mg of sodium bisulfite were dissolved in 10 ml of water.
After reacting at room temperature, the mixture was placed in a column (inner diameter 21 mm) packed with Cephadex G-10 (200 ml) and developed with water at 5°C. Fractionate into 20ml and collect the active fraction (No. 7-
11) was collected and lyophilized to obtain 1214 mg of white powder. This powder was placed in the Cephadex tower and the same operation was repeated twice to obtain Neothramycin A,
White powder of sulfite adduct of B equilibrium mixture (934
mg, yield 66.8%). Example 2 1 g of neothramycin A, B equilibrium mixture and 0.97 g of sodium sulfite heptahydrate were dissolved in 10 ml of water.
After the reaction, a column (inner diameter 21 mm) packed with Cephadex G-10 (200 ml) was applied and the same operation as in Example 1 was carried out to obtain a pale yellow powder (1.30 g, yield 87.5) of the sulfite adduct of neothramycin A and B equilibrium mixture. %) was obtained. Example 3 1 g of neothramycin A, B equilibrium mixture and 0.37 g of sodium metabisulfite were dissolved in 10 ml of water,
After the reaction, a column (inner diameter 21 mm) packed with Cephadex G-10 (200 ml) was operated in the same manner as in Examples 1 and 2 to obtain a white powder (1.19 g, yield) of the sulfite adduct of neothramycin A and B equilibrium mixture. rate 85
%) was obtained. Example 4 Neothramycin A, B equilibrium mixture 10 mg in 1 ml
After aseptic filtration, an aqueous solution containing 4 mg of sodium bisulfite (1 molar ratio to 1 mol of neothramycin) was filled into 5 ml ampoules and lyophilized to form a sodium sulfite adduct of the neothramycin A, B equilibrium mixture. A white powder is obtained. After replacing the air in the ampoule space with nitrogen gas, the ampoule is sealed. Example 5 Neothramycin A (Neothramycin A95.6
%) 200 mg and sodium bisulfite 79.4
mg (1 molar ratio to 1 molar of neothramycin A) was dissolved in 4 mg of water and then lyophilized to obtain 250 mg of a white powder of neothramycin A sulfite adduct. Example 6 Neothramycin B (Neothramycin B91.2
%) 200 mg and sodium bisulfite 79.4
mg (1 molar ratio to 1 mol of neothramycin B) was dissolved in 4 ml of water and lyophilized to obtain 214 mg of neothramycin B sulfite adduct as a white powder.
第１図は本発明のネオスラマイシンＡ，Ｂ平衡
混合物の亜硫酸付加物（実施例１の生成物）の赤
外部吸収スペクトル曲線、第２図は同じ亜硫酸付
加物の紫外部吸収スペクトル曲線（水溶液、
0.1N塩酸および0.1N水酸化ナトリウム水溶液
中）、第３図は同じ亜硫酸付加物の水素核核磁気
共鳴スペクトル曲線、第４図は同じ亜硫酸付加物
の炭素核核磁気共鳴スペクトル曲線、第５図はネ
オスラマイシンＡ亜硫酸付加物（実施例５の生成
物）の赤外吸収スペクトル曲線、第６図はネオス
ラマイシンＡ亜硫酸付加物とネオスラマイシンＢ
亜硫酸付加物（実施例６の生成物）との紫外部吸
収スペクトル曲線、第７図はネオスラマイシンＡ
亜硫酸付加物の水素核核磁気共鳴スペクトル曲
線、第８図はネオスラマイシンＢ亜硫酸付加物の
赤外部吸収スペクトル曲線、また第９図はネオス
ラマイシンＢ亜硫酸付加物の水素核核磁気共鳴ス
ペクトル曲線を示す。
Figure 1 shows the infrared absorption spectral curve of the sulfite adduct of the neothramycin A, B equilibrium mixture of the present invention (product of Example 1), and Figure 2 shows the ultraviolet absorption spectral curve of the same sulfite adduct (aqueous solution). ,
(in 0.1N hydrochloric acid and 0.1N sodium hydroxide aqueous solution), Figure 3 is the hydrogen nuclear magnetic resonance spectrum curve of the same sulfite adduct, Figure 4 is the carbon nuclear magnetic resonance spectrum curve of the same sulfite adduct, Figure 5 6 is an infrared absorption spectrum curve of neothramycin A sulfite adduct (product of Example 5), and FIG. 6 shows neothramycin A sulfite adduct and neothramycin B.
Ultraviolet absorption spectrum curve with sulfite adduct (product of Example 6), Figure 7 is Neothramycin A
The hydrogen nuclear magnetic resonance spectrum curve of the sulfite adduct, Figure 8 is the infrared absorption spectrum curve of the neothuramycin B sulfite adduct, and Figure 9 is the hydrogen nuclear magnetic resonance spectrum curve of the neothuramycin B sulfite adduct. shows.
Claims (1)
子、アルカリ土類金属原子またはアンモニウム基
である〕で示されるネオスラマイシンＡまたは
ネオスラマイシンＢの亜硫酸付加物およびその薬
学的に使用し得る塩。 ２ 構造式 〔式中、Ｒは水素原子またはアルカリ金属原子
である〕で示されるネオスラマイシンＡの亜硫酸
付加物およびその薬学的に使用し得る塩である特
許請求の範囲第１項記載の化合物。 ３ 構造式 〔式中、Ｒは水素原子またはアルカリ金属原子
である〕で示されるネオスラマイシンＢの亜硫酸
付加物およびその薬学的に使用し得る塩である特
許請求の範囲第１項記載の化合物。 ４ 構造式 を有するネオスラマイシンＡまたは／およびネオ
スラマイシンＢを水溶液中または含水有機溶媒中
で亜硫酸塩と反応させることを特徴とする次の構
造式 〔式中、Ｒは水素原子またはアルカリ金属原子
である〕で示されるネオスラマイシンＡまたは／
およびネオスラマイシンＢの亜硫酸付加物の製
法。[Claims] 1. Structural formula Neothramycin A or
A sulfite adduct of neothramycin B and a pharmaceutically usable salt thereof. 2 Structural formula The compound according to claim 1, which is a sulfite adduct of neothramycin A represented by the formula [wherein R is a hydrogen atom or an alkali metal atom] and a pharmaceutically usable salt thereof. 3 Structural formula The compound according to claim 1, which is a sulfite adduct of neothramycin B represented by the formula [wherein R is a hydrogen atom or an alkali metal atom] and a pharmaceutically usable salt thereof. 4 Structural formula Neothramycin A or/and Neothramycin B having the following structural formula is reacted with a sulfite in an aqueous solution or in a water-containing organic solvent. Neothramycin A or/in which R is a hydrogen atom or an alkali metal atom
and a method for producing a sulfite adduct of neothramycin B.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14110078A JPS5569587A (en) | 1978-11-17 | 1978-11-17 | Novel antibiotic neothramycin derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14110078A JPS5569587A (en) | 1978-11-17 | 1978-11-17 | Novel antibiotic neothramycin derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5569587A JPS5569587A (en) | 1980-05-26 |
| JPS6221795B2 true JPS6221795B2 (en) | 1987-05-14 |
Family
ID=15284181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14110078A Granted JPS5569587A (en) | 1978-11-17 | 1978-11-17 | Novel antibiotic neothramycin derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5569587A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE602006011300D1 (en) * | 2005-04-21 | 2010-02-04 | Spirogen Ltd | PYRROLOBENZODIAZEPINE |
| ATE427949T1 (en) | 2005-10-05 | 2009-04-15 | Spirogen Ltd | 4-A4-(5-OXO-2,3,5,11A-TETRAHYDRO-5H-PYRROLO A2, 1-CUA1,4UBENZODIAZEPINE-8-YLOXY)-BUTYRYLAMINOU-1 - PYRROLE-2-CARBONATE ALKYL ESTER DERIVATIVES AND RELATED COMPOUND FOR THE TREATMENT OF A PROLIFERATIVE DISEASE |
| GB0813432D0 (en) | 2008-07-22 | 2008-08-27 | Spirogen Ltd | Pyrrolobenzodiazepines |
| BR112014027143B1 (en) | 2012-04-30 | 2020-06-09 | Medimmune Ltd | pyrrolobenzodiazepines |
| MX2014013144A (en) | 2012-04-30 | 2015-05-11 | Ucl Business Plc | Pyrrolobenzodiazepines. |
-
1978
- 1978-11-17 JP JP14110078A patent/JPS5569587A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5569587A (en) | 1980-05-26 |
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