JPS6341885B2 - - Google Patents
Info
- Publication number
- JPS6341885B2 JPS6341885B2 JP54017869A JP1786979A JPS6341885B2 JP S6341885 B2 JPS6341885 B2 JP S6341885B2 JP 54017869 A JP54017869 A JP 54017869A JP 1786979 A JP1786979 A JP 1786979A JP S6341885 B2 JPS6341885 B2 JP S6341885B2
- Authority
- JP
- Japan
- Prior art keywords
- geldanamycin
- formula
- cells
- solution
- group
- 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
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical class N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 231100000111 LD50 Toxicity 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- CHRHZFQUDFAQEQ-UHFFFAOYSA-L calcium;2-hydroxyacetate Chemical compound [Ca+2].OCC([O-])=O.OCC([O-])=O CHRHZFQUDFAQEQ-UHFFFAOYSA-L 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241001494479 Pecora Species 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
- 229920002472 Starch Polymers 0.000 description 1
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000002925 chemical effect Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Other In-Based Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規な抗腫瘍剤に関する。
本発明の抗腫瘍剤は、一般式
（式中Ｒはアミノ基、メチルアミノ基又はジメチ
ルアミノ基を意味する）で表わされるゲルダナマ
イシン誘導体を有効成分として含有する。
ゲルダナマイシンはストレプトミセス・ヒグロ
スコピクス・バル・ゲルダヌス・バル・ノバ株の
生産する抗原虫性抗生物質であることが知られて
おり（ジヤーナル・オブ・アンチビオテイクス第
23巻442頁1970年参照）、次式の化学構造を有する
（ジヤーナル・オブ・ザ・アメリカン・ケミカ
ル・ソサイエテイ第92巻7591頁1970年参照）。
フオルトシユリツテ・デル・ヘーミツシエン・
オルガニツシエン・ナツールシユトツフエ第33巻
231〜307頁（1976年）には、ゲルダナマイシン
（）をアンモニア、メチルアミン又はジメチル
アミンで処理すると式の化合物が得られること
が記載されている。しかし式の化合物の物性及
び生成学的作用については、これまで全く報報告
されていない。
本発明者らは先に17位のメトキシ基がモノアル
キルアミノ基で置換されたゲルダナマイシン誘導
体が、抗腫瘍剤として有用であることを見出した
（特開昭55−111469号公報参照）。この化合物のア
ルキルアミノ基に結合するアルキル基（R1又は
R2）は２個以上の炭素原子を有するものに限定
されている。本発明者らはさらに研究を進めた結
果、このアルキル基の代わりにメチル基を有する
式の化合物が優れた抗腫瘍作用を有することを
見出した。本発明はこの新知見に基づくものであ
る。
式の化合物は、前記刊行物に記載の方法によ
り製造できるが、ゲルダナマイシンに直接にアン
モニア、メチルアミン又はジメチルアミンを水溶
液の形で作用させることによつても製造できる。
後者の反応の場合には、例えば次のように操作す
ることが好ましい。有機溶媒、例えばクロロホル
ム−メタノール混合溶媒にゲルダナマイシン
（）を溶解し、これにアンモニア水、メチルア
ミン水溶液又はジメチルアミン水溶液を加え、室
温で１〜25時間撹拌する。反応終了後、目的物質
は常法により単離、精製することができる。例え
ば反応混合物を希鉱酸で洗浄し、次いで減圧下に
浴温35〜45℃で蒸発乾固し、残査をクロマトグラ
フイーにより分離精製し、再結晶すると、式の
化合物がそれぞれ結晶状で得られる。
式の化合物は、癌細胞のモデルとして広く認
められている実験腫瘍細胞Ｗ−2K−11細胞に対
し著しい生育阻止作用を有する。
１種又は２種以上の式の化合物を単独で本発
明の抗腫瘍剤として用いてもよいが、通常は普通
の賦形剤又は補助剤を配合して、経口投与ならび
に非径口投与に適する製剤の形で用いることが好
ましい。賦形剤又は補助剤としては、例えば下記
の有機もしくは無機の固体ないし液状物質が用い
られる。好適な賦形剤は、例えば水、ゼラチン、
乳糖、デンプン、繊維素グリコール酸カルシウ
ム、微結晶セルロース、ステアリルアルコール、
ステアリン酸マグネシウム、タルク、植物油、ベ
ンジルアルコール、プロピレングリコール、ゴ
ム、ポリアルキレングリコール、白色石油、ゼリ
ー、コレステロールなどである。補助剤として
は、例えば保存剤、湿潤剤、乳化剤、溶解促進
剤、浸透圧調整用塩、緩衝剤、結合剤、懸濁分散
剤などが用いられる。
製剤としては、例えば粉剤、顆粒剤、カプセル
剤、丸剤、錠剤、糖衣錠、注射剤、坐剤、軟膏な
どがあげられ、これらの製剤は常法により製造す
ることができる。
本発明の抗腫瘍剤は人間の治療のためばかりで
なく、前記の形態で獣医用医薬として用いること
もできる。
本発明の抗腫瘍剤を治療に用いる際には、有効
成分の投与量は成人につき１日当たり、非経口投
与の場合は一般に0.5〜80mg／Kg好ましくは１〜
40mg／Kg、経口的投与の場合は一般に１〜100
mg／Kg好ましくは２〜50mg／Kgである。
式の化合物の製造：
ゲルダナマイシン560mgをクロロホルム−メタ
ノール（混合比３：２）100mlに溶解し、50％ジ
メチルアミン水溶液30mlを加えたのち室温で２時
間撹拌する。次いで反応混合物を冷水100ml中に
投入し、6N−塩酸でPH３〜４となし、クロロホ
ルムで２回抽出する。抽出液を水洗したのち無水
硫酸ナトリウム上で乾燥し、減圧下に蒸発乾固す
ると油状物が得られる。これをシリカゲルクロマ
トグラフイーにより２％メタノール−クロロホル
ムで展開し、第１〜10番の分画を集め、溶媒を留
去したのちエーテルから再結晶すると、17−デメ
トキシ−17−ジメチルアミノ−ゲルダナマイシン
186mgが青色結晶として得られる。
融点：245〜247℃
元素分析値：C30H45N3O9として
Ｃ Ｈ Ｎ
計算値(%) 62.81 7.56 7.32
実測値(%) 62.75 7.44 7.16
NMRスペクトル（100MHz、CDCl3中）：
（ppm）2.93（ジメチルアミノ）、3.25（メトキ
シ）、3.31（メトキシ）
紫外部吸収スペクトル：
λCH3OH
max（ｎｍ）242、333、542
質量分析法による分子量（ｍ／ｅ）：573
ジメチルアミン水溶液の代わりにアンモニア又
はメチルアミンを用い、前記と同様にして反応さ
せると、下記の化合物が得られる。
17−デメトキシ−17−アミノ−ゲルダナマイシン
融点：278〜280℃（分解）
紫外部吸収スペクトル：
λCH3OH
max（ｎｍ）238、260、330、510
質量分析法による分子量（ｍ／ｅ）：545
17−デメトキシ−17−メチルアミノ−ゲルダナマ
イシン
融点：149〜151℃
質量分析法による分子量（ｍ／ｅ）：559
実施例
17−デメトキシ−17−ジメチルアミノ−ゲルダ
ナマイシン2500ｇ、乳糖1375ｇ、微結晶セルロー
ス775ｇ及び繊維素グリコール酸カルシウム375ｇ
を16メツシユの篩を用いて篩過し、均一に混合し
たのち練合機に入れ、これに３％ヒドロキシプロ
ピルセルロース溶液（イソプロピルアルコール：
水＝３：７の混液中）３を添加して練混する。
混合物を押出造粒機を用いて造粒し、50℃で６時
間送風乾燥する。次いで16〜60メツシユの範囲に
整粒したのち、この粒状物に対し0.3％のステア
リン酸マグネシウムを混合して打錠し、錠剤とす
る。
試験例
マウスの腎由来の線維芽細胞のC3H−2Kクロ
ーンをSV40発癌ウイルスによつて癌化させた癌
細胞Ｗ−2K−11を供試細胞とし、これを下記の
方法により培養した。
(1) 増殖培養液の調製：
イーグルMEM培地（日水製薬製）9.4ｇを蒸
留水900mlに溶解し、120℃で15分間加圧滅菌
し、冷却したのち仔牛血清100ml及び滅菌した
10％炭酸水素ナトリウム溶液３〜５mlを加えて
PH7.1〜7.2に調整する。培地使用直前にミリポ
アフイルターで過したＬ−グルタミン（2.92
ｇ／100ml）溶液10mlを加える。
(2) 移植細胞液の調製：
シープ・フリーザー（−80℃）で保存された
供試細胞を室温で溶解させ、670×ｇで５分間
遠心分離し、沈澱した細胞を(1)の増殖培養液50
mlに懸濁したのちルー・フラスコに移し、37℃
で培養すると細胞が増殖を始め、３〜４日で充
分に増殖する。培養液を傾瀉し、次いで0.2％
トリプシン溶液10mlを加え、室温で２〜３分間
放置したのちトリプシン溶液を傾瀉する。更に
(1)の増殖培養液50mlを加えて細胞浮遊液とす
る。
(3) 細胞培養と被験化合物の投与：
(2)で得られた細胞浮遊液を1.8mlずつシヤー
レに分注し、炭酸ガスインキユベーター（５％
CO2、95％空気）中で37℃において24時間培養
する。培養24時間後に被験化合物のエタノール
溶液0.2mlを投与して培養を継続する。
培養48時間後に、細胞増殖について顕微鏡下
で細胞の生存数を計測し、供試細胞増殖の抑制
率を次式により求めた。
抑制率（％）＝（無投与シヤーレ中の細胞数）−
（投与シヤーレ中の細胞数）／（無投与シヤーレ中の細
胞数）×100
得られた結果を次表に示す。
The present invention relates to a novel antitumor agent. The antitumor agent of the present invention has the general formula It contains a geldanamycin derivative represented by (wherein R means an amino group, a methylamino group, or a dimethylamino group) as an active ingredient. Geldanamycin is known to be an antiprotozoal antibiotic produced by Streptomyces hygroscopicus val geldanus val nova (Journal of Antibiotics Vol.
23, p. 442, 1970), and has the chemical structure of the following formula (see Journal of the American Chemical Society, vol. 92, p. 7591, 1970). Fortschüritzte der Hemitsien
Organizers Naturschutshue Volume 33
231-307 (1976) describes that treatment of geldanamycin () with ammonia, methylamine or dimethylamine gives compounds of formula. However, there have been no reports on the physical properties and chemical effects of the compound of the formula. The present inventors have previously discovered that geldanamycin derivatives in which the methoxy group at position 17 is substituted with a monoalkylamino group are useful as antitumor agents (see JP-A-55-111469). The alkyl group (R 1 or
R 2 ) is limited to those having 2 or more carbon atoms. As a result of further research, the present inventors found that a compound of the formula having a methyl group instead of this alkyl group has an excellent antitumor effect. The present invention is based on this new knowledge. Compounds of the formula can be prepared by the methods described in the above-mentioned publications, but also by reacting geldanamycin directly with ammonia, methylamine or dimethylamine in the form of an aqueous solution.
In the case of the latter reaction, it is preferable to operate as follows, for example. Geldanamycin () is dissolved in an organic solvent, such as a chloroform-methanol mixed solvent, and ammonia water, methylamine aqueous solution or dimethylamine aqueous solution is added thereto, and the mixture is stirred at room temperature for 1 to 25 hours. After the reaction is completed, the target substance can be isolated and purified by conventional methods. For example, when the reaction mixture is washed with dilute mineral acid and then evaporated to dryness under reduced pressure at a bath temperature of 35-45°C, the residue is separated and purified by chromatography and recrystallized, each compound of the formula is obtained in crystalline form. can get. The compound of formula has a significant growth inhibiting effect on experimental tumor cell W-2K-11 cells, which are widely accepted as a model of cancer cells. Although one or more compounds of the formula may be used alone as the antitumor agent of the present invention, they are usually combined with common excipients or adjuvants to make them suitable for oral as well as parenteral administration. Preferably, it is used in the form of a preparation. As the excipient or auxiliary agent, for example, the following organic or inorganic solid or liquid substances can be used. Suitable excipients are, for example, water, gelatin,
Lactose, starch, cellulose calcium glycolate, microcrystalline cellulose, stearyl alcohol,
Magnesium stearate, talc, vegetable oil, benzyl alcohol, propylene glycol, gum, polyalkylene glycol, white petroleum, jelly, cholesterol, etc. Examples of auxiliary agents used include preservatives, wetting agents, emulsifiers, solubility promoters, salts for adjusting osmotic pressure, buffers, binders, suspending and dispersing agents, and the like. Examples of the preparation include powders, granules, capsules, pills, tablets, sugar-coated tablets, injections, suppositories, and ointments, and these preparations can be manufactured by conventional methods. The antitumor agent of the present invention can be used not only for human treatment, but also as a veterinary medicine in the form described above. When using the antitumor agent of the present invention for treatment, the dosage of the active ingredient is generally 0.5 to 80 mg/Kg per adult per day, preferably 1 to 80 mg/Kg in the case of parenteral administration.
40mg/Kg, generally 1-100 for oral administration
mg/Kg, preferably 2 to 50 mg/Kg. Preparation of compound of formula: 560 mg of geldanamycin is dissolved in 100 ml of chloroform-methanol (mixing ratio 3:2), 30 ml of 50% dimethylamine aqueous solution is added, and the mixture is stirred at room temperature for 2 hours. The reaction mixture was then poured into 100 ml of cold water, adjusted to pH 3-4 with 6N hydrochloric acid, and extracted twice with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain an oil. This was developed by silica gel chromatography with 2% methanol-chloroform, fractions 1 to 10 were collected, the solvent was distilled off and recrystallized from ether, and 17-demethoxy-17-dimethylamino-geldana Mycin
186 mg are obtained as blue crystals. Melting point: 245-247℃ Elemental analysis value: C 30 H 45 N 3 O 9 Calculated value (%) 62.81 7.56 7.32 Actual value (%) 62.75 7.44 7.16 NMR spectrum (100 MHz, in CDCl 3 ): (ppm ) 2.93 (dimethylamino), 3.25 (methoxy), 3.31 (methoxy) Ultraviolet absorption spectrum: λCH 3 OH max (nm) 242, 333, 542 Molecular weight by mass spectrometry (m/e): 573 Substitute for dimethylamine aqueous solution By using ammonia or methylamine and reacting in the same manner as above, the following compound is obtained. 17-demethoxy-17-amino-geldanamycin Melting point: 278-280°C (decomposition) Ultraviolet absorption spectrum: λCH 3 OH max (nm) 238, 260, 330, 510 Molecular weight by mass spectrometry (m/e): 545 17-demethoxy-17-methylamino-geldanamycin Melting point: 149-151°C Molecular weight (m/e) by mass spectrometry: 559 Example 17-demethoxy-17-dimethylamino-geldanamycin 2500 g, lactose 1375 g, 775g of microcrystalline cellulose and 375g of cellulose calcium glycolate
After sieving through a 16-mesh sieve and mixing uniformly, put it into a kneader, and add 3% hydroxypropyl cellulose solution (isopropyl alcohol:
3) in a mixture of water = 3:7 and knead.
The mixture is granulated using an extrusion granulator and dried with air at 50°C for 6 hours. Next, after sizing the granules to a size in the range of 16 to 60 meshes, the granules are mixed with 0.3% magnesium stearate and compressed into tablets. Test Example Cancer cells W-2K-11, which are C3H-2K clones of mouse kidney-derived fibroblasts transformed into cancers using the SV40 oncogenic virus, were used as test cells, and were cultured in the following manner. (1) Preparation of growth culture solution: Dissolve 9.4 g of Eagle MEM medium (manufactured by Nissui Pharmaceutical) in 900 ml of distilled water, autoclave at 120°C for 15 minutes, cool, and add 100 ml of calf serum and sterilized water.
Add 3-5 ml of 10% sodium bicarbonate solution
Adjust to PH7.1~7.2. L-glutamine (2.92
g/100ml) solution. (2) Preparation of transplant cell solution: The test cells stored in a sheep freezer (-80℃) were lysed at room temperature, centrifuged at 670 x g for 5 minutes, and the precipitated cells were cultured for proliferation in (1). liquid 50
ml, then transferred to a Roux flask and heated at 37°C.
When cultured in , the cells begin to proliferate and fully proliferate in 3 to 4 days. Decant the culture and then add 0.2%
Add 10 ml of trypsin solution, let stand at room temperature for 2-3 minutes, and then decant the trypsin solution. Furthermore
Add 50 ml of the growth culture solution from (1) to make a cell suspension. (3) Cell culture and administration of test compound: Dispense 1.8 ml of the cell suspension obtained in (2) into a shear dish, and place it in a carbon dioxide incubator (5%
Incubate for 24 hours at 37°C in CO2 , 95% air). After 24 hours of culture, 0.2 ml of an ethanol solution of the test compound is administered to continue the culture. After 48 hours of culture, the number of surviving cells was counted under a microscope for cell proliferation, and the inhibition rate of the test cell proliferation was determined using the following formula. Inhibition rate (%) = (number of cells in non-administered shear) -
(Number of cells in treated shear dish)/(Number of cells in non-administered shear dish) x 100 The obtained results are shown in the following table.
【表】
急性毒性：
マウスに対する50％致死量（LD50）は、腹腔
内投与で17−デメトキシ−17−ジメチルアミノ−
ゲルダナマイシンは約120mg／Kgであつた。ゲル
ダナマイシンのLD50は15mg／Kgであり、これと
比較して毒性が著しく低下している。[Table] Acute toxicity: The 50% lethal dose (LD 50 ) for mice is 17-demethoxy-17-dimethylamino-
Geldanamycin was approximately 120 mg/Kg. The LD 50 of geldanamycin is 15 mg/Kg, which shows significantly reduced toxicity.
Claims (1)
ルアミノ基を意味する）で表わされる化合物を有
効成分とする抗腫瘍剤。[Claims] 1. General formula (In the formula, R means an amino group, a methylamino group, or a dimethylamino group) as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1786979A JPS55111419A (en) | 1979-02-20 | 1979-02-20 | Antitumorigenic agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1786979A JPS55111419A (en) | 1979-02-20 | 1979-02-20 | Antitumorigenic agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55111419A JPS55111419A (en) | 1980-08-28 |
| JPS6341885B2 true JPS6341885B2 (en) | 1988-08-19 |
Family
ID=11955670
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1786979A Granted JPS55111419A (en) | 1979-02-20 | 1979-02-20 | Antitumorigenic agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS55111419A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE334119T1 (en) | 2001-03-30 | 2006-08-15 | Us Health | MONEY ANAMYCIN DERIVATIVES FOR CANCER TREATMENT |
| EP1420747A4 (en) * | 2001-08-06 | 2010-06-02 | Kosan Biosciences Inc | Benzoquinone ansamycins |
| US6872715B2 (en) | 2001-08-06 | 2005-03-29 | Kosan Biosciences, Inc. | Benzoquinone ansamycins |
| US7259156B2 (en) | 2004-05-20 | 2007-08-21 | Kosan Biosciences Incorporated | Geldanamycin compounds and method of use |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55111469A (en) * | 1979-02-19 | 1980-08-28 | Kaken Pharmaceut Co Ltd | Novel geldanamycin derivative, its preparation, and antitumor drug comprising it as active ingredient |
-
1979
- 1979-02-20 JP JP1786979A patent/JPS55111419A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55111469A (en) * | 1979-02-19 | 1980-08-28 | Kaken Pharmaceut Co Ltd | Novel geldanamycin derivative, its preparation, and antitumor drug comprising it as active ingredient |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55111419A (en) | 1980-08-28 |
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