JPH0460472B2 - - Google Patents
Info
- Publication number
- JPH0460472B2 JPH0460472B2 JP26705684A JP26705684A JPH0460472B2 JP H0460472 B2 JPH0460472 B2 JP H0460472B2 JP 26705684 A JP26705684 A JP 26705684A JP 26705684 A JP26705684 A JP 26705684A JP H0460472 B2 JPH0460472 B2 JP H0460472B2
- Authority
- JP
- Japan
- Prior art keywords
- camptothecin
- salt
- formula
- tetraalkylammonium
- present
- 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
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 29
- 229940127093 camptothecin Drugs 0.000 claims description 29
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 29
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 12
- -1 camptothecin tetraalkylammonium salt Chemical class 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 238000005185 salting out Methods 0.000 claims description 3
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 6
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 2
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 description 2
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 241000759905 Camptotheca acuminata Species 0.000 description 1
- 239000003390 Chinese drug Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は新規な化学物質であるカンプトテシ
ン・テトラアルキルアンモニウム塩およびその製
造方法に関する。更に詳細には、本発明は式
()
(式中、Rは低級アルキル基を示す)
で表わされるカンプトテシン・テトラアルキルア
ンモニウム塩ならびにその製造方法に関するもの
である。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel chemical substance, camptothecin tetraalkylammonium salt, and a method for producing the same. More specifically, the present invention relates to the formula () The present invention relates to a camptothecin tetraalkylammonium salt represented by the following formula (wherein R represents a lower alkyl group) and a method for producing the same.
カンプトテシンはCamptotheca acuminataの
樹皮、根、果実および葉などから抽出、単離され
たアルカロイドで、迅速かつ可逆的に核酸合成を
阻害し、既存の制癌剤と交叉耐性を示さないとい
うユニークな抗腫瘍性を示す物質である。さらに
動物実験においても、マウス白血病L1210、ラツ
トWAKER256肉腫などの実験癌に対して強力な
制癌効果を示すことが認められ、C.Acuminata
の原産地である中国では既に医薬品として実用に
供されている。
Camptothecin is an alkaloid extracted and isolated from the bark, roots, fruits, and leaves of Camptotheca acuminata, and has unique antitumor properties in that it rapidly and reversibly inhibits nucleic acid synthesis and does not exhibit cross-resistance with existing anticancer drugs. It is a substance that indicates Furthermore, in animal experiments, it has been shown to have a strong anticancer effect against experimental cancers such as mouse leukemia L 1210 and rat WAKER 256 sarcoma.
It is already in practical use as a medicine in China, the country of origin.
しかしながら、米国においては臨床試験Phase
の結果から毒性作用が強く有用性に乏しいと結
論され、目下有用性の高い誘導体を求めて合成研
究が進められているが、今なお満足のゆく誘導体
の成功は報告されていない。 However, in the United States, the clinical trial
It was concluded from the results that it has a strong toxic effect and is of little utility, and synthetic research is currently underway in search of highly useful derivatives, but no satisfactory derivative success has yet been reported.
ところでこのカンプトテシンは、水に難溶性の
物質であり、また経口投与したときには消化器系
に対する毒性が強くなる為に、静脈投与あるいは
皮下投与の方が望ましいとされている。その為、
カンプトテシンの水溶性の誘導体の出現が望まれ
ていた。 By the way, camptothecin is a substance that is poorly soluble in water and is highly toxic to the digestive system when administered orally, so intravenous or subcutaneous administration is considered preferable. For that reason,
The emergence of water-soluble derivatives of camptothecin has been desired.
従来、カンプトテシンの水溶性誘導体に関して
は、ナトリウム塩が知られており、前記の中国に
おける実用もカンプトテシンのナトリウム塩を水
溶液として注射としたものである。しかしなが
ら、このナトリウム塩は水溶液とした場合、その
PH値が中性付近であると結晶が析出してくるた
め、注射剤としては、使用することができず、こ
れを防ぐにはPH値を高くすることが必要となり、
前記の中国の制剤もPHを9.0以上に調整したもの
であるが、このPH値は生理学的に適合しない高い
値なので望ましいものではない。 Hitherto, sodium salts have been known as water-soluble derivatives of camptothecin, and the sodium salt of camptothecin was injected as an aqueous solution in the above-mentioned practical application in China. However, when this sodium salt is made into an aqueous solution, its
If the PH value is near neutral, crystals will precipitate, so it cannot be used as an injection, and to prevent this, it is necessary to increase the PH value.
The above-mentioned Chinese drug also has a pH adjusted to 9.0 or higher, but this PH value is not desirable because it is a high value that is not physiologically compatible.
しかもカンプトテシンの塩は金属塩以外にはそ
の製造は容易でなく、通常の塩形成反応による各
種の方法では、目的とする塩を得ることは困難な
物質である。 Moreover, salts of camptothecin are not easy to produce other than metal salts, and it is difficult to obtain the desired salt by various methods using ordinary salt-forming reactions.
本発明者らは、新規な水溶性カンプトテシン誘
導体ならびにそれを製造する方法につき種々研究
を行つた結果、本発明に係るカンプトテシン・テ
トラアルキルアンモニウム塩を合成することに成
功した。
The present inventors conducted various studies on new water-soluble camptothecin derivatives and methods for producing the same, and as a result, they succeeded in synthesizing the camptothecin tetraalkylammonium salt according to the present invention.
したがつて、本発明は、前掲の式()で表わ
される新規物質カンプトテシン・テトラアルキル
アンモニウム塩ならびにその製造方法を提供する
ものである。 Accordingly, the present invention provides a novel substance camptothecin tetraalkylammonium salt represented by the above-mentioned formula () and a method for producing the same.
本発明に係るカンプトテシン・テトラアルキル
アンモニウム塩は本発明の方法によりカンプトテ
シンをエタノールにけんだくさせ、これにテトラ
アルキルアンモニウムハイドロオキサイドを加
え、得られる溶液に塩化リチウム等のエタノール
に可溶な金属塩を加えることにより塩析させ、析
出する生成物を取得することにより製造される。 Camptothecin tetraalkylammonium salt according to the present invention is produced by suspending camptothecin in ethanol by the method of the present invention, adding tetraalkylammonium hydroxide to this, and adding an ethanol-soluble metal salt such as lithium chloride to the resulting solution. It is produced by adding salting out and obtaining the precipitated product.
以下に本発明を詳細に説明する。 The present invention will be explained in detail below.
まず本発明に係るカンプトテシン・テトラアメ
チルアンモニウム塩の製造方法について述べる
と、本発明方法はカンプトテシンを出発物質と
し、これをエタノールにけんだくさせ、次いでこ
れにテトラメチルアンモニウムハイドロキサイド
の溶液、例えば10%メタノール溶液を加える。全
体は溶液状態となつているが、これに塩化リチウ
ムを加えると目的とするカンプトテシン・テトラ
メチルアンモニウム塩が析出する。 First, the method for producing camptothecin tetramethylammonium salt according to the present invention will be described. The method of the present invention uses camptothecin as a starting material, suspends it in ethanol, and then adds a solution of tetramethylammonium hydroxide, e.g. Add 10% methanol solution. The whole is in a solution state, but when lithium chloride is added to it, the desired camptothecin tetramethylammonium salt is precipitated.
本発明方法は、出発物質カンプトテシンをけん
だくさせる有機溶媒の選択ならびにテトラアルキ
ルアンモニウム塩を析出させるために用いる金属
塩に特特異性があり、特にテトラエチルアンモニ
ウム塩を生成するためには金属塩の添加によらな
ければ結晶体として安定にとり出すことはできな
い。 The method of the present invention is specific in the selection of the organic solvent that suspends the starting material camptothecin and in the metal salt used to precipitate the tetraalkylammonium salt, in particular the addition of the metal salt to produce the tetraethylammonium salt. Otherwise, it cannot be stably extracted as a crystal.
すなわち、テトラメチルアンモニウム塩の生成
の場合は、カンプトテシンにテトラメチルアンモ
ニウムハイドロオキサイドの溶液を反応させて得
られる反応溶液を、反応後濃縮して得られる粗結
晶にアセトン或いはジエチルエーテルを加えるこ
とにより得られるが、カンプトテシンとテトラエ
チルアンモニウムハイドロオキサイドと反応させ
た時は反応液を反応後濃縮しても粗結晶は得られ
ず油状物が得られるのであり、これにアセトン或
いはジエチルエーテル等を加えても結晶化はしな
い。 That is, in the case of producing a tetramethylammonium salt, acetone or diethyl ether is added to the crude crystals obtained by concentrating the reaction solution obtained by reacting camptothecin with a solution of tetramethylammonium hydroxide. However, when camptothecin is reacted with tetraethylammonium hydroxide, even if the reaction solution is concentrated after the reaction, crude crystals are not obtained but an oily substance is obtained, and even if acetone or diethyl ether is added to this, crystals are not obtained. It will not change.
更にテトラメチルアンモニウム塩の生成の際に
も金属塩を使用しない場合は反応溶媒であるエタ
ノールを完全に溜去しなければならず、この時に
熱が加わるのは避けがたい。特に水が少しでも存
在する状態で熱が加わることは生成したカンプト
テシンのテトラメチルアンモニウム塩が着色分解
する原因となる。 Furthermore, when a metal salt is not used during the production of the tetramethylammonium salt, the reaction solvent ethanol must be completely distilled off, and it is unavoidable that heat is added at this time. In particular, the application of heat in the presence of even a small amount of water causes the tetramethylammonium salt of camptothecin produced to color and decompose.
以上の様な事実から、目的とするテトラアルキ
ルアンモニウム塩を得るためには塩化リチウム等
の金属塩の添加が必要である。 From the above facts, it is necessary to add a metal salt such as lithium chloride in order to obtain the desired tetraalkylammonium salt.
一般的に水溶性物質をその水溶液から析出させ
るために塩化ナトリウム等を用いて塩析させるこ
とはよく行われる手段であるが、本発明のように
有機溶媒中に溶解している物質を塩析して得た例
は少なく、特に本発明の場合の様に原料であるテ
トラアルキルアンモニウムハイドロオキサイドを
分別するためには欠くべからざる手段と言える。 Generally, in order to precipitate a water-soluble substance from an aqueous solution, salting out using sodium chloride etc. is a common method, but as in the present invention, a substance dissolved in an organic solvent is salted out. There are few examples where this method has been obtained, and it can be said that this method is indispensable for fractionating the raw material, tetraalkylammonium hydroxide, as in the case of the present invention.
なお式()の内、Rが大きな分子になるとカ
ンプトテシンとの塩形成が生成されない。 In formula (), if R becomes a large molecule, salt formation with camptothecin will not occur.
次に実施例を挙げて説明する。 Next, an example will be given and explained.
実施例 1
カンプトテシン500mgをエタノール100mlにけん
だくさせ、これにテトラメチルアンモニウムハイ
ドロオキサイドのメタノール溶液(10%)を2ml
加える。この混合液をよく撹拌し、溶解させる。
この反応液をろ過し、ろ液に塩化リチウム1.5g
を加えかくはんするとカンプトテシン・テトラメ
チキルアンモニウム塩が析出する。析出した結晶
をろ取し、脱水したジエチルエーテルで洗浄した
後、減圧下室温で乾燥すると、カンプトテシン・
テトラメチルアンモニウム塩413mg(収率65.5%)
を得る。Example 1 500 mg of camptothecin was suspended in 100 ml of ethanol, and 2 ml of a methanol solution (10%) of tetramethylammonium hydroxide was added to this.
Add. Stir this mixture well to dissolve.
Filter this reaction solution and add 1.5 g of lithium chloride to the filtrate.
When added and stirred, camptothecin tetramethykylammonium salt precipitates. The precipitated crystals were collected by filtration, washed with dehydrated diethyl ether, and dried at room temperature under reduced pressure to form camptothecin.
Tetramethylammonium salt 413mg (yield 65.5%)
get.
IRνKBr naxcm-1:
3200〜3400(OH)
1560〜1690(−COO-)
NMR:D2Oを溶媒として2,2,3,3−
(トリメチルシリル)−3−プロピオン酸ナト
リウム塩を内部標準として測定する。 IRν KBr nax cm -1 : 3200-3400 (OH) 1560-1690 (-COO - ) NMR: 2,2,3,3- using D 2 O as a solvent
(Trimethylsilyl)-3-propionate sodium salt is used as an internal standard for measurement.
δppm:
7.46(1H,s)キノリン環
7.09(4H,m)キノリン環
6.90(1H,s)
3.74(1H,m)テトラメチルアンモニウムの
OH
3.20(12H,s)テトラメチルアンモニウム
のメチル
2.25(2H,m)ラクトン環エチル
1.05(3H,t)ラクトン環エチル
元素分析値
C H N
計算値(%):65.58 6.65 9.56
実測値(%):65.19 6.37 9.17
MASS:M+=348(カンプトテシン)
実施例 2
カンプトテシン500mgをエタノール100mlにけん
だくさせ、これにテトラエチルアンモニウムハイ
ドロオキサイドの水溶液(10%)を2ml加える。
この混合液をよくかくはんし、溶解させる。溶解
後、反応液をろ過し、ろ液に塩化リチウム1.5g
を加えるとカンプトテシンテトラエチルアンモニ
ウム塩が析出する。これをろ取し、乾燥したジエ
チルエーテルで洗浄した後、減圧で乾燥するとカ
ンプトテシン・テトラエチルアンモニウム塩315
mg(収率42.1%)が得られる。 δppm: 7.46 (1H, s) Quinoline ring 7.09 (4H, m) Quinoline ring 6.90 (1H, s) 3.74 (1H, m) Tetramethylammonium
OH 3.20 (12H, s) Methyl of tetramethylammonium 2.25 (2H, m) Lactone ring ethyl 1.05 (3H, t) Lactone ring ethyl Elemental analysis value C H N Calculated value (%): 65.58 6.65 9.56 Actual value (%) :65.19 6.37 9.17 MASS: M + =348 (camptothecin) Example 2 500 mg of camptothecin is suspended in 100 ml of ethanol, and 2 ml of an aqueous solution (10%) of tetraethylammonium hydroxide is added thereto.
Stir this mixture well to dissolve. After dissolving, filter the reaction solution and add 1.5g of lithium chloride to the filtrate.
When added, camptothecin tetraethylammonium salt precipitates out. This was collected by filtration, washed with dry diethyl ether, and dried under reduced pressure to produce camptothecin tetraethylammonium salt 315.
mg (yield 42.1%) is obtained.
IRνKBr naxcm-1:
3200〜3400(−OH)
1560〜〜1690(−COO-)
NMR:D2Oを溶媒として2,2,3,3−
(トリメチルシリル)−3−プロピオン酸ナト
リウム塩を内部標準として測定する。IRν KBr nax cm -1 : 3200 ~ 3400 (-OH) 1560 ~ ~ 1690 (-COO - ) NMR: 2,2,3,3- using D 2 O as a solvent
(Trimethylsilyl)-3-propionate sodium salt is used as an internal standard for measurement.
δppm:
7.54(1H,s)
7.19(4H,m)
7.03(1H,s),3.80(1H,m)
3.46,3.39,3.31,3.24(8H,q)
2.33(2H,m)
1.43,1.42,1.36,1.34,1.29,1.27(24H,
dt)
1.16(1H,m)
Mass:M+=348(カンプトテシン) δppm: 7.54 (1H, s) 7.19 (4H, m) 7.03 (1H, s), 3.80 (1H, m) 3.46, 3.39, 3.31, 3.24 (8H, q) 2.33 (2H, m) 1.43, 1.42, 1.36 , 1.34, 1.29, 1.27 (24H,
dt) 1.16 (1H, m) Mass: M + = 348 (camptothecin)
Claims (1)
ンモニウム塩。 2 カンプトテシンをエタノールにけんだくさ
せ、これにテトラアルキルアンモニウムハイドロ
オキサイドを加え、得られる溶液に塩化リチウム
等の金属塩を加えることにより塩析させ、析出す
る生成物を取得することを特徴とする式 (式中、Rは低級アルキル基を示す) で表わされるカンプトテシン・テトラアルキルア
ンモニウム塩の製造方法。[Claims] 1 formula (In the formula, R represents a lower alkyl group) A camptothecin tetraalkylammonium salt represented by: 2. A formula characterized by suspending camptothecin in ethanol, adding tetraalkylammonium hydroxide thereto, salting out by adding a metal salt such as lithium chloride to the resulting solution, and obtaining a precipitated product. (In the formula, R represents a lower alkyl group.) A method for producing a camptothecin tetraalkylammonium salt represented by the formula:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP26705684A JPS61145184A (en) | 1984-12-18 | 1984-12-18 | Camptothecin-tetraalkylammonium salt and preparation thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP26705684A JPS61145184A (en) | 1984-12-18 | 1984-12-18 | Camptothecin-tetraalkylammonium salt and preparation thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS61145184A JPS61145184A (en) | 1986-07-02 |
JPH0460472B2 true JPH0460472B2 (en) | 1992-09-28 |
Family
ID=17439419
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP26705684A Granted JPS61145184A (en) | 1984-12-18 | 1984-12-18 | Camptothecin-tetraalkylammonium salt and preparation thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS61145184A (en) |
-
1984
- 1984-12-18 JP JP26705684A patent/JPS61145184A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS61145184A (en) | 1986-07-02 |
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Legal Events
Date | Code | Title | Description |
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LAPS | Cancellation because of no payment of annual fees |