JPH07507811A - Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acid - Google Patents
Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acidInfo
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- JPH07507811A JPH07507811A JP6509963A JP50996393A JPH07507811A JP H07507811 A JPH07507811 A JP H07507811A JP 6509963 A JP6509963 A JP 6509963A JP 50996393 A JP50996393 A JP 50996393A JP H07507811 A JPH07507811 A JP H07507811A
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- reducing agent
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- ylmethyl
- dihydroxychroman
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 のシス−３−４６−シヒドロキシ ロマンー３−イルーメ ル 。[Detailed description of the invention] cis-3-46-cyhydroxy Romance 3-Ilume.
発明の背景 本発明は、シス−３−（４，６−シヒドロキシクロマンー３−イルメチル）安息 香酸及びこの化合物の製造方法に関する。本化合物は、シス−３−（６−アリー ルメチルオキシ−４−ヒドロキシクロマン−３−イルメチル）アニリンスルポン アミドの光学的に純粋な鏡像異性体の製造に有用な中間体である。後者の化合物 は、喘息、関節炎、乾癖、潰瘍、心筋梗塞及び関連疾患の治療に有用である。本 発明は、特には、（３Ｒ−シス）−３−（４，６−シヒドロキシクロマンー３− イルメチル）安息香酸、ラセミ体のシス−３−（４，６−シヒドロキシクロマン ー３−イルメチル）安息香酸から前記化合物を製造する方法及びそのラセミ体の 酸の新規の製造方法に関する。Background of the invention The present invention provides cis-3-(4,6-cyhydroxychroman-3-ylmethyl)benzene This invention relates to aromatic acid and a method for producing this compound. This compound is a cis-3-(6-aryl methyloxy-4-hydroxychroman-3-ylmethyl)aniline sulfone It is a useful intermediate in the preparation of optically pure enantiomers of amides. the latter compound is useful in the treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related diseases. Book The invention particularly relates to (3R-cis)-3-(4,6-cyhydroxychroman-3- ylmethyl)benzoic acid, racemic cis-3-(4,6-cyhydroxychroman) -3-ylmethyl)benzoic acid and its racemic form This invention relates to a new method for producing acids.
シス−３−（６−アリールメチルオキシ−４−ヒドロキシクロマン−３−イルメ チル）アニリンスルホンアミドの製造において、本発明の中間体を使用すること は、マーファツト（Ｍａ ｒ ｆ ａ ｔ）らの特許用＃］（本出願と同時に出 願の弁理士事件整理番号ＰＣ８２３０）に記載されている。cis-3-(6-arylmethyloxy-4-hydroxychroman-3-ylme Use of the intermediates of the invention in the production of (chill)aniline sulfonamides is for the patent of Marfat et al. (issued at the same time as this application). It is stated in the patent attorney case reference number PC8230).
発明の概要 本発明は、式 で表される化合物、その新規の製造方法、及び式（１）の化合物の製造に有用で ある式 で表される化合物の新規製造方法に関する。Summary of the invention The present invention is based on the formula A compound represented by, a new method for producing the same, and a compound useful for producing the compound of formula (1) a certain expression This invention relates to a new method for producing a compound represented by:
本発明は、式 で表される化合物と式（Ｉ）で表される化合物との光学的に純粋なジアステレオ マー塩にも関する。The present invention is based on the formula An optically pure diastereomer of the compound represented by and the compound represented by formula (I) It also concerns salt.
式（Ｉ）で表される化合物は、本発明に従って、式（ｎｌ）で表される化合物と 式（１）で表される化合物とのジアステレオマー塩を酸性化することにより製造 される。According to the present invention, the compound represented by formula (I) is a compound represented by formula (nl). Manufactured by acidifying a diastereomeric salt with a compound represented by formula (1) be done.
式（ＩＩＩ）で表される化合物と式（１）で表される化合物とのジアステレオマ ー塩は、本発明に従って、前記塩層の非溶剤の存在下で、式（ＩＩＩ）で表され る化合物によって式（ＴＩ）で表される化合物を処理することにより製造される 。Diastereomer of the compound represented by formula (III) and the compound represented by formula (1) - According to the invention, in the presence of a non-solvent of said salt layer, the salt is of the formula (III): produced by treating a compound represented by formula (TI) with a compound represented by .
本発明は、セリウム（ＩＩＩ）イオンの存在下で水素化ホウ素イオン及び水素化 ジイソブチルアルミニウムから選んだ還元剤を用いて、式で表される化合物を還 元することにより、式（ＩＩ）で表される化合物を製造する新規方法にも関する 。The present invention relates to borohydride ions and hydrogenation in the presence of cerium (III) ions. A reducing agent chosen from diisobutylaluminum is used to reduce the compound represented by the formula. It also relates to a new method for producing the compound represented by formula (II) by .
式（ｒＶ）で表される化合物から、式（ＩＩ）で表される化合物を製造するため の前記中間工程を経由して、化合物（１）を製造する全反応も、本発明の一部で ある。For producing a compound represented by formula (II) from a compound represented by formula (rV) The entire reaction to produce compound (1) via the intermediate steps described above is also part of the present invention. be.
発明の詳細な説明 式（１）で表される化合物〔本明細書中において、（３Ｒ−シス＞ −３−（４ ゜６−シヒドロキシクロマンー３−イルメチル）安息香酸とも称する〕は、遊離 酸用の溶剤の存在下で、式（ＩＩＩ）で表される化合物と式（Ｉ）で表される化 合物とのジアステレオマー塩を酸性化することにより製造される、新規の化合物 である。Detailed description of the invention The compound represented by formula (1) [herein, (3R-cis>-3-(4 ゜6-hydroxychroman-3-ylmethyl)benzoic acid] is a free In the presence of an acidic solvent, a compound of formula (III) and a compound of formula (I) are combined. Novel compounds produced by acidifying diastereomeric salts with compounds It is.
酸性化は、約３以下のｐＫａを有する酸（例えば、塩酸、硫酸、シュウ酸及びク エン酸）を用いて実施される。Acidification includes acids with a pKa of about 3 or less (e.g., hydrochloric acid, sulfuric acid, oxalic acid, and citric acid). enoic acid).
式（ＩＩＩ）で表される化合物と式（１）で表される化合物とのジアステレオマ ー塩は、前記塩川の非溶剤の存在下で、式（ＩＩ）及び（ＩＩＩ）で表される化 合物を加熱することにより製造され、室温まで冷却した後、濾過により回収され る。Diastereomer of the compound represented by formula (III) and the compound represented by formula (1) -Salt is converted into compounds represented by formulas (II) and (III) in the presence of the above-mentioned non-solvent. It is produced by heating the compound, cooled to room temperature, and recovered by filtration. Ru.
ジアステレオマー塩層の非溶剤には、エタノール及びイソプロパツールが含まれ 、好適な非溶剤はエタノールである。Nonsolvents for the diastereomeric salt layer include ethanol and isopropanol. , the preferred non-solvent is ethanol.
前記反応は、好ましくは約り℃〜約８０℃の温度で、好ましくは非溶剤の還流温 度で行なう。約８０℃で前記反応を実施することが、最も好ましい。The reaction is preferably carried out at a temperature of about 80°C to about 80°C, preferably at the reflux temperature of the non-solvent. Do it in degrees. Most preferably, the reaction is carried out at about 80°C.
式（ＩＩＩ）で表される化合物による式（ｎ）で表される化合物の処理は、約３ ０分〜約３時間、好ましくは約１時間かけて実施する。Treatment of the compound of formula (n) with the compound of formula (III) It is carried out over a period of 0 minutes to about 3 hours, preferably about 1 hour.
前記の塩は、高められた温度で非溶媒を用いてスラリー化し、続けて室温付近で 濾過することにより、精製する。スラリー化工程は、好ましくは２回で実施され る。The salt is slurried with a non-solvent at elevated temperature, followed by slurrying at around room temperature. Purify by filtration. The slurry step is preferably carried out in two steps. Ru.
所望により、他のシス型鏡像異性体［すなわち、（３Ｓ−シス） −３−（４， ６−シヒドロキシクロマンー３−イルメチル）安息香酸」を、式（■Ｉ）で表さ れる化合物の代わりに（＋）塩基を代用することにより、製造することができる 。あるいは、この３８体の酸は、式（Ｉ）で表される化合物のジアステレオマー 塩の製造工程由来の濾液を、酸で処理し、続いて前記（＋）塩基により処理し、 続いて、（−）塩基を有するジアステレオマー塩に関して先に説明した処理をす ることにより、製造することができる。Optionally, other cis enantiomers [i.e. (3S-cis)-3-(4, 6-cyhydroxychroman-3-ylmethyl)benzoic acid” is represented by the formula (■I). can be produced by substituting (+) base for the compound . Alternatively, these 38 acids are diastereomers of the compound represented by formula (I) treating the filtrate from the salt manufacturing process with an acid followed by said (+) base; Subsequently, all the treatments described above for diastereomeric salts with (−) bases are carried out. It can be manufactured by
ラセミ体のシス−３−（４，６−シヒドロキシクロマンー３−イルメチル）安息 香酸［化合物（■）］は、本発明に従って、テトラヒドロフラン／メタノール中 の還元剤の溶液によって式（ＩＶ）で表される化合物を処理する新規の方法によ り、製造する。好ましい還元剤は、セリウム（ＩＩＩ）塩の存在下の水素化ホウ 素及び水素化ジイソブチルアルミニウムである。最も好ましい還元剤は、セリウ ム（ＩＩＩ）塩の存在下の水素化ホウ素イオンである。Racemic cis-3-(4,6-cyhydroxychroman-3-ylmethyl)rest According to the invention, aromatic acid [compound (■)] is dissolved in tetrahydrofuran/methanol. By a novel method of treating a compound of formula (IV) with a solution of a reducing agent of and manufacture. A preferred reducing agent is borohydride in the presence of a cerium(III) salt. and diisobutylaluminum hydride. The most preferred reducing agent is cerium Boron hydride ion in the presence of Mo(III) salt.
テトラヒドロフラン及びメタノールは、約３：１〜約１＝２、好ましくは約３１ の比率で存在することができる。Tetrahydrofuran and methanol in a ratio of about 3:1 to about 1=2, preferably about 31 can be present in the proportion of
還元は、約−７８℃〜約６０℃、好ましくは約０℃の温度で実施することができ 式（１）で表される新規化合物を用いる実用においては、前記化合物は、クルラ イウス転移とそれに続く水素化を経由して、式で表される光学的に純粋な鏡像異 性体化合物に変換される。式（Ｖ）で表される化合物のフェノール性水酸基は、 その後、塩基の存在下でハロゲン化アルキル又はアリールで処理して、式 て表されるアルキル又はアリールエーテルに変換され、続いて式（Ｖｌ）で表さ れる化合物のアミン基をスルホン化する。The reduction can be carried out at a temperature of about -78°C to about 60°C, preferably about 0°C. In practical use of the novel compound represented by formula (1), the compound is Via a IUS transition followed by hydrogenation, the optically pure enantiomer, represented by the formula It is converted into a sex compound. The phenolic hydroxyl group of the compound represented by formula (V) is Subsequent treatment with an alkyl or aryl halide in the presence of a base gives the formula is converted into an alkyl or aryl ether represented by formula (Vl), and then converted into an alkyl or aryl ether represented by formula (Vl) The amine group of the compound to be sulfonated.
式（Ｖｌ）で表される化合物のスルホンアミド（特にトリフルオロメタンスルポ ンアミド）は、 喘息、関節炎、乾紺、潰瘍、心筋梗塞及び関連疾患の治療に有用である。A sulfonamide (especially trifluoromethane sulfonamide) of a compound represented by formula (Vl) amide) is It is useful in the treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related diseases.
以下、実施例に基づいて説明するが、これらは本発明の範囲を限定するものては ない。The following will be explained based on examples, but these should not limit the scope of the present invention. do not have.
火應！匡 ラセミ体のシス−３−（４６−シヒドロキシクロマンー３−イルメチル）″′″ 息筐 テトラヒドロフラン２４ｍ１中の３−（６−ヒドロキシ−４−オキソ−クロマン −３−イルメチル）安息香酸（２，００ｇｍ、６．７０ｍｍｏ Ｉ）の溶液に、 メタノール１２ｍ１及び続いて塩化セリウム（ＣｅＣｌ３）１．５０ｇｍ （４ ，０２ｍｍｏｌ）を加えた。得られた濁った溶液を０℃に冷やし、全ｊｌｏ、５ ２ｇｍの水素化ホウ素ナトリウム（ＮａＢＨ４）で少しずつ、５５分間かけて処 理した。ＩＮ塩酸を反応混合液に加え、その後、回転式エバポレータで濃縮し、 分離用漏斗に移して、水と酢酸エチルとの間で分配した。有機相を、ＩＮ塩酸で ２回、水で１回、及びプラインで１回洗浄し、続けて硫酸ナトリウムにて乾燥し 、濾過した。濾液を濃縮し、明褐色の油状物を得、脱気して淡褐色の気泡体を得 た。収率：１．９３ｇｍ（９６％）； ’ＨＮＭＲ（ジメチルスルホキシド−δ６）６７、 ８８ （ｍ、２Ｈ）、７． ４４（ｍ、２Ｈ）、６．６４（ｍ、３Ｈ）、４．４０（ｓ、ＩＨ）、３．９１ （ｍ、２Ｈ）、３．３０（ｍ、ＩＨ）、２．９１（ｍ、ＩＨ）、２．６１（ｍ、 ｌｈ）；１３ＣＮＭＲ（ジメチルスルホキシド−ｄ、）δ１６７．４９２，１５ ０，４７３゜１４６．３８６，１４０．４５２，１３３，６２１，１３０．８７ ６．１２９．９０７．１２８，５６８，１２７．０５８，１２５，８６６．１１ ６．３６１，１１６．０２１，１１５，９４１，６４，２４６，６３．５３２， ３１．８５８゜実施ガ１ （−）−シス−３−（４６−シヒドロキシクロマンー３−イルメチル）゛息−酸 の（＝）−シス−Ｎ−ベンジル−２−ヒ′ロキシメチル シ ロヘキシルアミン 皇 無水エチルアルコール１０ｍＩ中のラセミ体のシス−３−（４，６−シヒドロキ シクロマンー３−イルメチル）安息香酸（実施例１で調製）１．７６６ｇｍ （ ５８８ｍｍｏｌ）の溶液に、エチルアルコール９ｍｌ中の（−）−シス−Ｎ−ペ ンジルー２−（ヒドロキシメチル）シクロヘキシルアミン１．２９０ｇｍ（５， ８８ｍｍｏ＋）の溶液を加えた。得られた懸濁液を、１時間還流下で加熱し、室 温まで冷却し、１時間攪拌し、濾過した。得られたわずかに灰色を帯びた白色の 固体（１゜９９６ ｇｍ）を、無水エチルアルコ−／Ｌ４２０ ｍ ｌに懸濁し 、還流下で３時間加熱し、続けて室温まで冷却し、更に１時間攪拌した。濾取し た明灰色の固体１．２９５ｇｍを、再度還流するエタノール（１５ｍｌ）中に２ 時間懸濁した。懸濁液を冷却した後、濾過し、わずかに灰色を帯びた白色の固体 １．０６５ｇｍ（取得可能な鏡像異性体の６３．２％）を得た。融点： ２１６ −２１８℃： ［α］Ｄ＝＋４２．７゜（ｃ＝０．３０９．メタノール）。Fire!匡 Racemic cis-3-(46-cyhydroxychroman-3-ylmethyl)'''' breather 3-(6-hydroxy-4-oxo-chroman in 24 ml of tetrahydrofuran) -3-ylmethyl)benzoic acid (2,00 gm, 6.70 mmol I), 12 ml of methanol followed by 1.50 gm of cerium chloride (CeCl3) (4 , 02 mmol) was added. The resulting cloudy solution was cooled to 0 °C and the total jlo, 5 Treat with 2 gm of sodium borohydride (NaBH4) in portions over 55 minutes. I understood. IN hydrochloric acid was added to the reaction mixture, then concentrated on a rotary evaporator, Transferred to a separatory funnel and partitioned between water and ethyl acetate. The organic phase was treated with IN hydrochloric acid. Washed twice, once with water, and once with prine, followed by drying with sodium sulfate. , filtered. The filtrate was concentrated to give a light brown oil and degassed to give a light brown foam. Ta. Yield: 1.93gm (96%); 'HNMR (dimethyl sulfoxide-δ6) 67, 88 (m, 2H), 7. 44 (m, 2H), 6.64 (m, 3H), 4.40 (s, IH), 3.91 (m, 2H), 3.30 (m, IH), 2.91 (m, IH), 2.61 (m, lh); 13CNMR (dimethyl sulfoxide-d,) δ167.492,15 0,473°146.386,140.452,133,621,130.87 6.129.907.128,568,127.058,125,866.11 6.361, 116.021, 115, 941, 64, 246, 63.532, 31.858゜Execution Ga 1 (-)-cis-3-(46-cyhydroxychroman-3-ylmethyl)-acid (=)-cis-N-benzyl-2-hydroxymethylcylohexylamine Emperor Racemic cis-3-(4,6-cyhydroxy) in 10 ml of absolute ethyl alcohol. cycloman-3-ylmethyl)benzoic acid (prepared in Example 1) 1.766 gm ( 588 mmol) in 9 ml of ethyl alcohol. 2-(hydroxymethyl)cyclohexylamine 1.290 gm (5, A solution of 88 mmo+) was added. The resulting suspension was heated under reflux for 1 h and then brought to room temperature. Cool to warm, stir for 1 hour, and filter. The resulting slightly off-white color The solid (1°996 gm) was suspended in 420 ml of anhydrous ethyl alcohol/L. , heated under reflux for 3 hours, followed by cooling to room temperature and stirring for a further 1 hour. Filtering 1.295 gm of a light gray solid were dissolved in refluxing ethanol (15 ml) for 2 hours. Suspended for hours. After the suspension has cooled, it is filtered and a slightly off-white solid is obtained. 1.065 gm (63.2% of obtainable enantiomer) was obtained. Melting point: 216 -218°C: [α]D=+42.7° (c=0.309.methanol).
叉施且止 ３Ｒ−シス −３−４６−ジヒ３０キシ ロマジー３−イルメチル） 急激 実施例２で調製した鏡像異性体塩１．０６１ｇｍ（２，０４２ｍｍｏｌ）を水に 懸濁し、１０％塩酸でＰｈｉに調整し、酢酸エチルを装填した分離用漏斗に移し た。Forking and stopping 3R-cis-3-46-dihy30xromazi-3-ylmethyl) acute 1.061 gm (2,042 mmol) of the enantiomeric salt prepared in Example 2 was added to water. Suspend, adjust to Phi with 10% hydrochloric acid, and transfer to a separatory funnel loaded with ethyl acetate. Ta.
有機層をＩＮ塩酸で２回、水で１回及びブラインで１回洗浄し、その後、硫酸ナ トリウムにて乾燥した。回転式エバポレータで濃縮し、高真空下で脱気し、白色 の気泡体として標記化合物０．６０４ｇｍを得た。融点８５−９５℃； ［α］ Ｄ＝＋１００° （ｃ＝０．４７５．テトラヒドロフラン）。The organic layer was washed twice with IN hydrochloric acid, once with water and once with brine, then washed with sodium sulfate. It was dried with thorium. Concentrate on a rotary evaporator and degas under high vacuum, white 0.604 gm of the title compound was obtained as a foam. Melting point 85-95℃; [α] D=+100° (c=0.475.tetrahydrofuran).
国際調査報告 国際調査報告 ＵＳ ９３０６０６１international search report international search report US9306061
Claims (15)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US96433692A | 1992-10-21 | 1992-10-21 | |
| US964,336 | 1992-10-21 | ||
| PCT/US1993/006061 WO1994008986A1 (en) | 1992-10-21 | 1993-06-30 | Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH07507811A true JPH07507811A (en) | 1995-08-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP6509963A Pending JPH07507811A (en) | 1992-10-21 | 1993-06-30 | Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acid |
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| Country | Link |
|---|---|
| EP (1) | EP0665839A1 (en) |
| JP (1) | JPH07507811A (en) |
| KR (1) | KR950704291A (en) |
| CN (1) | CN1090577A (en) |
| AU (1) | AU4650493A (en) |
| CA (1) | CA2146005A1 (en) |
| CZ (1) | CZ100895A3 (en) |
| FI (1) | FI934624A (en) |
| HU (1) | HUT65128A (en) |
| IL (1) | IL107293A0 (en) |
| MX (1) | MX9306526A (en) |
| MY (1) | MY131378A (en) |
| NO (1) | NO951507L (en) |
| PL (1) | PL308473A1 (en) |
| WO (1) | WO1994008986A1 (en) |
| ZA (1) | ZA937737B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SK31399A3 (en) * | 1996-09-16 | 2000-05-16 | Pfizer | Processes and intermediates for preparing substituted chromanol derivatives |
| IL149256A0 (en) * | 1999-10-27 | 2002-11-10 | Nobex Corp | Resolution of intermediates in the synthesis of substantially pure bicalutamide |
| TWI270545B (en) | 2000-05-24 | 2007-01-11 | Sugen Inc | Mannich base prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives |
| US6479692B1 (en) | 2001-05-02 | 2002-11-12 | Nobex Corporation | Methods of synthesizing acylanilides including bicalutamide and derivatives thereof |
| EP1794141B1 (en) | 2004-09-21 | 2011-11-09 | Marshall Edwards, Inc. | Substituted chroman derivatives, medicaments and use in therapy |
| US8080675B2 (en) | 2004-09-21 | 2011-12-20 | Marshall Edwards, Inc. | Chroman derivatives, medicaments and use in therapy |
| CA2816319C (en) | 2010-11-01 | 2020-06-30 | Marshall Edwards, Inc. | Isoflavonoid compounds and methods for the treatment of cancer |
| US10980774B2 (en) | 2015-02-02 | 2021-04-20 | Mei Pharma, Inc. | Combination therapies |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5059609A (en) * | 1987-10-19 | 1991-10-22 | Pfizer Inc. | Substituted tetralins, chromans and related compounds in the treatment of asthma, arthritis and related diseases |
-
1993
- 1993-06-30 AU AU46504/93A patent/AU4650493A/en not_active Abandoned
- 1993-06-30 CA CA002146005A patent/CA2146005A1/en not_active Abandoned
- 1993-06-30 KR KR1019950701524A patent/KR950704291A/en not_active Application Discontinuation
- 1993-06-30 JP JP6509963A patent/JPH07507811A/en active Pending
- 1993-06-30 CZ CZ951008A patent/CZ100895A3/en unknown
- 1993-06-30 WO PCT/US1993/006061 patent/WO1994008986A1/en not_active Application Discontinuation
- 1993-06-30 EP EP93916752A patent/EP0665839A1/en not_active Withdrawn
- 1993-06-30 PL PL93308473A patent/PL308473A1/en unknown
- 1993-10-14 IL IL107293A patent/IL107293A0/en unknown
- 1993-10-19 ZA ZA937737A patent/ZA937737B/en unknown
- 1993-10-20 MY MYPI93002174A patent/MY131378A/en unknown
- 1993-10-20 FI FI934624A patent/FI934624A/en not_active Application Discontinuation
- 1993-10-20 CN CN93119050A patent/CN1090577A/en active Pending
- 1993-10-20 MX MX9306526A patent/MX9306526A/en unknown
- 1993-10-20 HU HU9302973A patent/HUT65128A/en unknown
-
1995
- 1995-04-20 NO NO951507A patent/NO951507L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO951507D0 (en) | 1995-04-20 |
| WO1994008986A1 (en) | 1994-04-28 |
| HU9302973D0 (en) | 1993-12-28 |
| ZA937737B (en) | 1995-04-19 |
| PL308473A1 (en) | 1995-08-07 |
| MY131378A (en) | 2007-08-30 |
| CZ100895A3 (en) | 1995-10-18 |
| CA2146005A1 (en) | 1994-04-28 |
| NO951507L (en) | 1995-04-20 |
| HUT65128A (en) | 1994-04-28 |
| CN1090577A (en) | 1994-08-10 |
| AU4650493A (en) | 1994-05-09 |
| FI934624A (en) | 1994-04-22 |
| FI934624A0 (en) | 1993-10-20 |
| IL107293A0 (en) | 1994-01-25 |
| KR950704291A (en) | 1995-11-17 |
| MX9306526A (en) | 1994-04-29 |
| EP0665839A1 (en) | 1995-08-09 |
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