JP2675616B2 - Separation of stereoisomers - Google Patents
Separation of stereoisomersInfo
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- JP2675616B2 JP2675616B2 JP1111315A JP11131589A JP2675616B2 JP 2675616 B2 JP2675616 B2 JP 2675616B2 JP 1111315 A JP1111315 A JP 1111315A JP 11131589 A JP11131589 A JP 11131589A JP 2675616 B2 JP2675616 B2 JP 2675616B2
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- Treatment Of Liquids With Adsorbents In General (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、ポリペプチドの各立体異性体の直接分割法
に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for directly resolving each stereoisomer of a polypeptide.
ポリペプチドはアミノ酸類から種々の方法で合成でき
るが、天然にも多数存在し、生体にとって極めて重要な
物質である。Ｐ個（Ｐは２以上の整数）のアミノ酸が結
合したポリペプチドの場合2P個の立体異性体が存在し、
このうち2P-1組が光学異性体となる。これまでこの2P個
の立体異性体を同時に完全分割できるクロマトグラフィ
ー用カラムを少なく、各々の含有量を同時に調べること
は困難であった。各異性体の分離精製においても、光学
異性体以外の立体異性体は、原理的に従来のクロマトグ
ラフィー法で分離可能であるが、各異性体間の物性差が
少ないために、充分な分離が得られないことが多かっ
た。又、2P-1組の光学異性体はジアステレオマー法や酵
素法を用いても分割可能であるが、ジアステレオマー法
の場合は、光学純度100％の他の光学活性体が少なくと
も１つ必要な上、最短でもジアステレオマー化反応と、
それに続くクロマトグラフィー法による分離の２ステッ
プが必要であった。酵素法の場合は、各立体異性体を得
るためには、通常（Ｐ−１）種の酵素と（2P-1−１）回
の反応が必要である等操作が煩雑であった。Polypeptides can be synthesized from amino acids by various methods, but they exist in large numbers in nature and are extremely important substances for living organisms. In the case of a polypeptide in which P (P is an integer of 2 or more) amino acids are bound, 2P stereoisomers exist,
Of these, 2 P-1 pairs are optical isomers. Until now, it was difficult to investigate the content of each of the 2P stereoisomers at the same time because there are few chromatography columns that can be completely resolved at the same time. In separation and purification of each isomer, stereoisomers other than optical isomers can be separated by conventional chromatographic methods in principle, but sufficient separation is not possible due to the small difference in physical properties between each isomer. I often didn't get it. The 2 P-1 pair of optical isomers can also be resolved by using the diastereomer method or the enzymatic method, but in the case of the diastereomer method, at least 1 other optically active isomer with an optical purity of 100% is used. Required, and at the shortest, a diastereomeric reaction,
Two subsequent steps of chromatographic separation were required. In the case of the enzymatic method, in order to obtain each stereoisomer, the operation is usually complicated, for example, it is necessary to react with (P-1) species of enzyme (2 P-1 -1) times.
本発明者等は種々検討の結果、光学活性な大環状ポリ
エーテルを含むクロマトグラフィー用充填剤を用いるこ
とにより、ポリペプチドの立体異性体を上記の如き欠点
なく直接分離することが可能であることを見出し、本発
明に到ったものである。As a result of various studies by the present inventors, it has been possible to directly separate stereoisomers of a polypeptide by using a packing material for chromatography containing an optically active macrocyclic polyether without the above-mentioned drawbacks. That is, the present invention has been achieved.
即ち本発明によれば、下記一般式（Ｉ） （但し、式中Ｒは水素原子又は炭素数１〜30の直鎖又は
分岐したアルキル基であり、Ｒは環状オキシエチル基上
のどの炭素に結合していても良く、その数は１〜12であ
る。ｎは４〜８の整数を示す。又Arは光学活性な２価芳
香族基であり、次の一般式（II）で表される。That is, according to the present invention, the following general formula (I) (In the formula, R is a hydrogen atom or a linear or branched alkyl group having 1 to 30 carbon atoms, R may be bonded to any carbon on the cyclic oxyethyl group, and the number is 1 to 12). N is an integer of 4 to 8. Ar is an optically active divalent aromatic group and is represented by the following general formula (II).
（式中、Ａ及びＢは水素原子、炭素数１〜６の直鎖又は
分岐したアルキル基、炭素数６〜10のアリール基又は炭
素数７〜９のアラルキル基を表す。A,Bは異なっていて
もよい。また、Ｒ′,R″は水素原子、炭素数１〜30の直
鎖又は分岐したアルキル基、炭素数６〜18のアリール基
又は炭素数７〜30のアラルキル基である。但し、水素以
外のＲ′,R″は縮合環のA,B置換位置以外のどこについ
ても良く、各最高５ケまで置換しても良い。また、
Ｒ′,R″は異なっていても良い。））で表される光学活
性大環状ポリエーテルを含むクロマトグラフィー用充填
剤を用いて、下記一般式（III） （式中ｍは１〜10の整数で、好ましくは１〜３の整数を
示す、又R0,R1を構成する炭素原子数は１〜20であり、
構造中にエーテル結合、カルボニル結合、ヘテロ原子
や、ハロゲン、水酸基、アミノ基などの官能基を含んで
いてもよい。 (In the formula, A and B represent a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having 7 to 9 carbon atoms. A and B are different. R ′ and R ″ are a hydrogen atom, a linear or branched alkyl group having 1 to 30 carbon atoms, an aryl group having 6 to 18 carbon atoms, or an aralkyl group having 7 to 30 carbon atoms. However, R ′ and R ″ other than hydrogen may be at any positions other than the A and B substitution positions of the condensed ring, and up to 5 of each may be substituted.
R ′ and R ″ may be different from each other.)), Using a packing material for chromatography containing an optically active macrocyclic polyether represented by the following general formula (III) (In the formula, m is an integer of 1 to 10, preferably an integer of 1 to 3, and the number of carbon atoms constituting R 0 and R 1 is 1 to 20,
The structure may contain an ether bond, a carbonyl bond, a hetero atom, or a functional group such as a halogen, a hydroxyl group or an amino group.
また、R0,R1を構成する炭素原子はSP3混成（−Ｃ−Ｃ
−単結合の炭素の原子軌道）のみ、あるいはSP3,SP
2（−Ｃ＝Ｃ−二重結合の炭素の原子軌道）、SP（−Ｃ
≡Ｃ−あるいは−Ｃ≡Ｎ三重結合の炭素の原子軌道）の
うち２種あるいは３種の組み合わせからなるグループで
あり、幾何学的には鎖状でも環状でもよい。） で示されるポリペプチドの立体異性体を、１回のカラム
クロマトグラフィーで効率良く分離することが可能であ
る。Further, the carbon atoms constituting R 0 and R 1 are SP 3 hybridized (-C-C
-Single bond carbon atom orbital) or SP 3 , SP
2 (-C = C-atom orbit of carbon of double bond), SP (-C
It is a group consisting of a combination of two or three of the carbon atomic orbitals of a ≡C- or —C≡N triple bond), and may be linear or cyclic in terms of geometry. It is possible to efficiently separate the stereoisomers of the polypeptide represented by (1) by column chromatography once.
本発明に使用される前記一般式（Ｉ）で示される光学
活性な大環状ポリエーテルは、次の一般式（IV） （式中、Arは前記と同じ意味を持ち、Ｍはアルカリ金
属、例えばナトリウム、カリウム等である。） で表される光学活性な芳香族誘導体に、一般式（Ｖ） （式中、Ｘは塩素、ヨウ素又はトシルオキシ基、Ｒ及び
ｎは前記と同じ意味を持つ） で表されるポリエチレングリコールのジハロゲン化物又
はジトシル化物、又はそれらのアルキル置換体を、不活
性気体雰囲気下、例えばテトラヒドロフラン、ジオキサ
ン、N,N′−ジメチルホルムアミド等の有機溶媒中で、
ほぼ等モル量で反応させることによって製造することが
できる。The optically active macrocyclic polyether represented by the general formula (I) used in the present invention has the following general formula (IV) (In the formula, Ar has the same meaning as described above, and M is an alkali metal such as sodium or potassium.) The optically active aromatic derivative represented by the general formula (V) (Wherein, X is chlorine, iodine or tosyloxy group, R and n have the same meanings as described above), a dihalide or ditosylation product of polyethylene glycol represented by the following formula or an alkyl-substituted product thereof is prepared under an inert gas atmosphere. , In an organic solvent such as tetrahydrofuran, dioxane, N, N'-dimethylformamide,
It can be produced by reacting in approximately equimolar amounts.
本発明で用いる光学活性な大環状ポリエーテルは、Ｒ
体、Ｓ体のいずれの光学異性体でも良い。The optically active macrocyclic polyether used in the present invention is R
Either optical isomer or optical isomer may be used.
本発明で用いられる充填剤は、前記光学活性大環状ポ
リエーテルを、担体に化学結合又は物理吸着したもの、
もしくは、大環状ポリエーテルが固体の場合は、大環状
ポリエーテル自体を粉砕して微粒子とすることによって
調整されたものであるが、好ましくは表面疎水性の担体
（逆相吸着剤）に、大環状ポリエーテルを吸着担持して
調整される。この際用いられる表面疎水性の担体は、従
来公知の方法に従って、担体の表面を、疎水性化合物を
用いて修飾することによって得られる。この場合、担体
としては、従来公知の各種のもの、例えばシリカ、アル
ミナ、マグネシア、シリカ・アルミナ等が挙げられる。
一方、疎水性化合物としては、炭化水素類、例えば、メ
チル基、プロピル基、ブチル基等の低級アルキル基や、
オクチル、ドデシル、オクタデシル等の高級アルキル
基、フェニル、アルキルフェニル等のアリール基等を有
する化合物や、フッ素や塩素等を有するハロアルキル基
を有する化合物等が挙げられる。また、疎水性化合物を
用いる担体の表面修飾法としては、従来公知の方法、例
えば、物理吸着法や、化学的結合法等が挙げられ、特に
制約を受けない。本発明においては、従来市販されてい
る無機及び有機系の表面疎水性担体をそのまま用いるこ
とができる。The filler used in the present invention, the optically active macrocyclic polyether, chemically bonded or physically adsorbed on a carrier,
Alternatively, when the macrocyclic polyether is a solid, it is prepared by pulverizing the macrocyclic polyether itself to form fine particles, but it is preferable that the macrocyclic polyether is used as a surface hydrophobic carrier (reverse phase adsorbent). It is adjusted by adsorption of cyclic polyether. The surface-hydrophobic carrier used at this time can be obtained by modifying the surface of the carrier with a hydrophobic compound according to a conventionally known method. In this case, the carrier includes various conventionally known carriers such as silica, alumina, magnesia, and silica / alumina.
On the other hand, as the hydrophobic compound, hydrocarbons, for example, a lower alkyl group such as a methyl group, a propyl group and a butyl group,
Examples thereof include compounds having a higher alkyl group such as octyl, dodecyl and octadecyl, aryl groups such as phenyl and alkylphenyl, and compounds having a haloalkyl group such as fluorine and chlorine. The surface modification method of the carrier using the hydrophobic compound may be a conventionally known method such as a physical adsorption method or a chemical bonding method, and is not particularly limited. In the present invention, commercially available inorganic and organic surface hydrophobic carriers can be used as they are.
担体を使用する場合、担体中に含まれる大環状ポリエ
ーテルの量に特に制約はないが、良好な分離結果を得る
には、担体1cc当たり10-6モル以上0.1モル以下、好まし
くは10-5モル以上10-3モル以下に調製するのが良い。When using a carrier, the amount of macrocyclic polyether contained in the carrier is not particularly limited, but in order to obtain good separation results, 10 -6 mol or more and 0.1 mol or less, preferably 10 -5 mol, per 1 cc of the carrier. It is preferable to adjust the amount to be not less than 10 -3 mol.
この吸着担持を好ましく実施するには、前記表面処理
済みの担体をカラムに充填し、この充填カラム中を、前
記光学活性な脂溶性大環状ポリエーテルを一定組成の有
機溶媒と水との混合溶媒に溶解した溶液を、ポンプを用
いて循環させる。この場合、大環状ポリエーテルの担体
への吸着により、循環溶液中の大環状ポリエーテルの濃
度は、時間とともに減少するので、一定時間後更に水を
加えて、循環溶液に対する大環状ポリエーテルの溶解度
を低めて再びカラム中に循環させる。この様な操作を順
次繰り返すことによって大環状ポリエーテルを所定濃度
で吸着した充填剤を、直接カラム中で製造することがで
きる。なお、前記有機溶媒としては、水と相溶性があっ
て大環状ポリエーテルを溶解するもの、例えば、メタノ
ール、エタノール、プロパノール等のアルコールの他、
アセトニトリル、テトラヒドロフラン等が用いられる。In order to preferably carry out this adsorption and loading, the surface-treated carrier is packed in a column, and the optically active, lipophilic macrocyclic polyether is mixed with an organic solvent of a constant composition and water in the packed column. The solution dissolved in is circulated using a pump. In this case, the concentration of the macrocyclic polyether in the circulating solution decreases with time due to the adsorption of the macrocyclic polyether on the carrier.Therefore, after a certain period of time, water is further added to increase the solubility of the macrocyclic polyether in the circulating solution. And recirculate through the column again. By repeating such operations in sequence, the packing material in which the macrocyclic polyether is adsorbed at a predetermined concentration can be directly produced in the column. As the organic solvent, those which are compatible with water and dissolve the macrocyclic polyether, for example, alcohols such as methanol, ethanol and propanol,
Acetonitrile, tetrahydrofuran, etc. are used.
また、この吸着担持は、前記の方法以外にも、該大環
状ポリエーテルを可溶性の溶剤に溶解させ、担体とよく
混合し、減圧下、又は加圧下気流により溶剤を留去させ
る方法や、該大環状ポリエテールを可溶性の溶剤に溶解
させ、担体とよく混合した後、該溶媒と相溶性のない液
体中に、撹拌、分散せしめ、該溶剤を拡散させる方法を
用いることによっても行うことができる。Further, in addition to the above-mentioned method, this adsorption-supporting method comprises dissolving the macrocyclic polyether in a soluble solvent, mixing it well with the carrier, and distilling the solvent off under reduced pressure or under pressure, It is also possible to use a method in which the macrocyclic polyether is dissolved in a soluble solvent, thoroughly mixed with the carrier, then stirred and dispersed in a liquid that is incompatible with the solvent, and the solvent is diffused.
本発明で使用される溶離液としては、純水、希薄な塩
あるいは酸の水溶液、又は水と相溶性のある有機溶媒、
例えばメタノール、アセトニトリムと、前記溶離液との
混合物が用いられる。又、分離を行う際の温度は、溶離
液が凝結又は沸騰しない温度であれば何度でもよいが、
好ましくは−10℃〜50℃の範囲で行われる。As the eluent used in the present invention, pure water, an aqueous solution of a dilute salt or acid, or an organic solvent compatible with water,
For example, a mixture of methanol and acetonitrim and the eluent is used. Further, the temperature at which the separation is performed may be any number as long as the eluent does not condense or boil.
It is preferably carried out in the range of -10 ° C to 50 ° C.
次に本発明を実施例により更に詳細に説明するが、本
発明が以下の実施例のみに限定されるものでないことは
言うまでもない。Next, the present invention will be described in more detail with reference to Examples, but it goes without saying that the present invention is not limited to only the following Examples.
本実施例に使用した機器は以下の通りである。 The equipment used in this example is as follows.
送液ポンプ：日本分光製 TRI ROTAR V 島津製作所製 LC−6A UV検出器：日本分光製 UVIDEC−100−IV 島津製作所製 SPD−6A データー処理機：日本クロマト製 CDS 86 インジェクター：レオダイン製 7125 表−１中ｋ′,Nは各々次の如く定義される。Liquid delivery pump: JASCO TRI ROTAR V Shimadzu LC-6A UV detector: JASCO UVIDEC-100-IV Shimadzu SPD-6A Data processor: Nihon Chromato CDS 86 Injector: Rheodyne 7125 Table- K ′, N in 1 is defined as follows.
実施例−１ A:光学異性体分離カラムの作製 前記一般式（Ｉ）において、Ar:3,3′−ジフェニル−
1,1′−ビナフチル−2,2′−ジイル、R;H、n;5である下
記構造式（VI）で表されるＳ体の光学活性な大環状ポリ
エーテル150mgを約85％のメタノール水溶液に溶解し
た。 Example-1 A: Preparation of optical isomer separation column In the above general formula (I), Ar: 3,3'-diphenyl-
1,1′-binaphthyl-2,2′-diyl, R; H, n; 5, which is an S-type optically active macrocyclic polyether represented by the following structural formula (VI) (150 mg) and about 85% methanol It dissolved in an aqueous solution.
この溶液を、オクタデシル基をシリカゲル表面に化学
結合した担体であるODS（粒径５μ）が充填された４φ
×150L（mm）ステンレスカラム製パックドカラム中に３
時間循環させる。次にこの操作において、循環液に順次
水を加え、循環液中のメタノール含量を順次減少させ
（最後の循環液のメタノール含量は約30％である）、こ
れによりほぼ完全に大環状ポリエーテルをカラム中の表
面処理済み担体に吸着させた。 This solution was filled with ODS (particle size 5μ), which is a carrier in which octadecyl groups were chemically bonded to the surface of silica gel, and was filled with 4φ.
× 150L (mm) 3 in stainless steel packed column
Circulate for hours. Next, in this operation, water was sequentially added to the circulating fluid to sequentially reduce the methanol content in the circulating fluid (the final circulating fluid had a methanol content of about 30%), which almost completely removed the macrocyclic polyether. It was adsorbed on the surface-treated carrier in the column.
B:光学異性体の分離 高速液体クロマトグラフ装置に上記の立体異性体分離
カラムを接続して、各種ポリペプチドの立体異性体を分
離させた例を表−１に示す。B: Separation of optical isomers Table 1 shows an example in which the above-mentioned stereoisomer separation column was connected to a high performance liquid chromatograph to separate stereoisomers of various polypeptides.
表中、例えばＳ−Ｒ（OH）とは、ジペプチドのカルボ
キシル基側の絶対配置がＲ、アミノ基側の絶対配置がＳ
であることを示す。In the table, for example, SR (OH) means that the absolute configuration on the carboxyl group side of the dipeptide is R and the absolute configuration on the amino group side is S.
It is shown that.
〔発明の効果〕 実施例からも明らかなように、本発明の分離法は、ポ
リペプチドの立体異性体の分離に極めて有効である。な
お本分離法は大型の分取カラムにも容易に適用できるの
で、ポリペプチドの立体異性体の分離分析手段としてば
かりでなく、分離精製手段としても極めて有効である。 [Effects of the Invention] As is clear from the examples, the separation method of the present invention is extremely effective in separating stereoisomers of a polypeptide. Since this separation method can be easily applied to a large-scale preparative column, it is extremely effective not only as a means for separating and analyzing stereoisomers of a polypeptide, but also as a means for separating and purifying.
Claims (1)
分岐したアルキル基であり、Ｒは環状オキシエチル基上
のどの炭素に結合していても良く、その数は１〜12であ
る。ｎは４〜８の整数を示す。又Arは光学活性な２価芳
香族基であり、次の一般式（II） で表される。 （式中、Ａ及びＢは水素原子、炭素数１〜６の直鎖又は
分岐したアルキル基、炭素数６〜10のアリール基又は炭
素数７〜９のアラルキル基を表す。A,Bは異なっていて
もよい。また、Ｒ′,R″は水素原子、炭素数１〜30の直
鎖又は分岐したアルキル基、炭素数６〜18のアリール基
又は炭素数７〜30のアラルキル基である。但し、水素以
外のＲ′,R″は縮合環のA,B置換位置以外のどこについ
ても良く、各最高５ケまで置換しても良い。また、
Ｒ′,R″は異なっていても良い。））で表される光学活
性大環状ポリエーテルを含むクロマトグラフィー用充填
剤を用いることにより、下記一般式（III） （式中ｍは１〜10の整数を示し、又R0,R1を構成する炭
素原子数は１〜20であり、構造中にエーテル結合、カル
ボニル結合、ヘテロ原子や、ハロゲン、水酸基、アミノ
基などの官能基を含んでいてもよい。 また、R0,R1を構成する炭素原子はSP3混成（−Ｃ−Ｃ−
単結合の炭素の原子軌道）のみ、あるいはSP3,SP2（−
Ｃ＝Ｃ−二重結合の炭素の原子軌道）、SP（−Ｃ≡Ｃ−
あるいは−Ｃ≡Ｎ三重結合の炭素の原子軌道）のうち２
種あるいは３種の組み合わせからなるグループであり、
幾何学的には鎖状でも環状でもよい。） で示されるポリペプチドの立体異性体を直接分割するこ
とを特徴とする立体異性体の分離法。1. A compound represented by the following general formula (I) (In the formula, R is a hydrogen atom or a linear or branched alkyl group having 1 to 30 carbon atoms, R may be bonded to any carbon on the cyclic oxyethyl group, and the number is 1 to 12). N is an integer of 4 to 8. Ar is an optically active divalent aromatic group and has the following general formula (II): It is represented by (In the formula, A and B represent a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having 7 to 9 carbon atoms. A and B are different. R ′ and R ″ are a hydrogen atom, a linear or branched alkyl group having 1 to 30 carbon atoms, an aryl group having 6 to 18 carbon atoms, or an aralkyl group having 7 to 30 carbon atoms. However, R ′ and R ″ other than hydrogen may be at any positions other than the A and B substitution positions of the condensed ring, and up to 5 of each may be substituted.
R ′ and R ″ may be different from each other.) By using a packing material for chromatography containing an optically active macrocyclic polyether represented by the following general formula (III) (In the formula, m represents an integer of 1 to 10, the number of carbon atoms constituting R 0 and R 1 is 1 to 20, and an ether bond, a carbonyl bond, a hetero atom, a halogen, a hydroxyl group, an amino group are included in the structure. It may contain a functional group such as a group, etc. Further, the carbon atoms constituting R 0 and R 1 are SP 3 hybridized (—C—C—
Single bond carbon atom orbital) or SP 3 , SP 2 (-
C = C-atom orbit of carbon of double bond), SP (-C≡C-
Or -C≡N triple bond carbon atom orbital) 2
It is a group consisting of species or a combination of three species,
Geometrically, it may be a chain or a ring. ) A method for separating stereoisomers, which comprises directly resolving the stereoisomers of the polypeptide represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1111315A JP2675616B2 (en) | 1989-04-28 | 1989-04-28 | Separation of stereoisomers |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1111315A JP2675616B2 (en) | 1989-04-28 | 1989-04-28 | Separation of stereoisomers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02290898A JPH02290898A (en) | 1990-11-30 |
| JP2675616B2 true JP2675616B2 (en) | 1997-11-12 |
Family
ID=14558104
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1111315A Expired - Fee Related JP2675616B2 (en) | 1989-04-28 | 1989-04-28 | Separation of stereoisomers |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2675616B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5940979B2 (en) * | 2010-10-13 | 2016-06-29 | 株式会社ダイセル | Chromatographic separation agent |
| JP5898425B2 (en) * | 2011-07-22 | 2016-04-06 | 嶋田 豊司 | NOVEL COMPOUND HAVING CROWN ETHER-LIKE CYCLIC STRUCTURE AND BIAFTYL GROUP AND PROCESS FOR PRODUCING THE SAME |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62210053A (en) * | 1986-03-07 | 1987-09-16 | Agency Of Ind Science & Technol | Packing material for separating optical isomer |
-
1989
- 1989-04-28 JP JP1111315A patent/JP2675616B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02290898A (en) | 1990-11-30 |
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