JPH06510030A - 新規な３，５−ジ−ｔｅｒｔ−ブチル−４−　ヒドロキシフェニル誘導体、それらの製造方法および薬剤 - Google Patents

新規な３，５−ジ−ｔｅｒｔ−ブチル−４−　ヒドロキシフェニル誘導体、それらの製造方法および薬剤

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Publication number
JPH06510030A
JPH06510030A JP5504071A JP50407193A JPH06510030A JP H06510030 A JPH06510030 A JP H06510030A JP 5504071 A JP5504071 A JP 5504071A JP 50407193 A JP50407193 A JP 50407193A JP H06510030 A JPH06510030 A JP H06510030A
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group
formula
alkyl
aryl
tables
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ドレックマン−ベーレント，ブルーノ
ヘック，ラインハルト
ドレセル，アロイス
ミッシェル，ヘルムート
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ベーリンガー　マンハイム　ゲーエムベーハー
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/19—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/22—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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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。

Description

【発明の詳細な説明】 新規な３，５−ジーｔｅｒｔ−ブチルー４−ヒドロキシフェニル誘導体、それら の製造方法および薬剤 本発明は、一般式Ｉ Ｃ式中、Ａは原子価、１〜５個のＣ原子を有する直鎖または分枝アルキル鎖を表 し、Ｘは−ＮＲ−ＣＯ−（アミド）基または−ＮＲ−ＣＯ−ＮＲ（尿素）基（式 中、Ｒは水素原子またはＣＩ”−Ｃじアルキル基を表す）を表し、かつＹは１〜 ６個のＣ原子を有する直鎖または分枝の飽和または不飽和の炭化水素鎖（これは アリール基、全テロアリール基、アリールチオ基もしくはアリールチオ基により 置換されていてもよい）　、Ｃａ−Ｃｓ−シクロアルキル基またはアリール基を 表し、ここて当該アリール基およびヘテロアリール基は、それぞれの場合に、環 の全ての可能な位置てＣＮ、ヒドロキシメチル、メチレンジオキシ、ハロゲン、 トリフルオロメチル、Ｃ，−Ｃ，−アルキル、アミノ、Ｃ，−Ｃ，−アシルアミ ノ、ジー（ＣＩ−Ｃ，）−アルキルアミノ、ヒドロキシル、Ｃ，−Ｃ，−アルコ キン、カルボキシル、オキシ酢酸エチルエステルまたはニトロにより１〜３回置 換されていてもよく、但し、Ａが　−ＣＨ２−または−ＣＨ２〜０１１２−以外 の意味を有する場合に、Ｙは単に未置換フェニルを表すことを条件とする］の新 規なジーｔｅｒｔ−ブチルーヒドロキンフェニル誘導体（ＢＩＴ誘導体）、およ びそれらの医薬上杵される塩、それらの製造方法並びにこれらの化合物を含む薬 剤に関する。
“ブリッジ”Ａとして、−ＣＨ，−基、−ＣＨ２−ＣＨ，−基、−（ＣＬ）３− 基、−ＣＨ２−ＣＨ−基または−ＣＨ２−Ｃ（ＣＨ３）　２−基が好ましい。
■ 　Ｈ３ ヒドロキシフェニル基が“ブリッジ”Ａを介してアミド窒素と連結されているカ ーボンアミド基または尿素基Ｘにおいて、Ｒは水素原子またはメチル基を表すこ とが好ましい。
Ｙに関して、ベンジル基、フェネチル基、スチリル基、フェニル基およびナフチ ル基が好ましく、これらの芳香族基は、あらゆる位置てＣＮ、フルオロ、クロロ 、ヒドロキシメチル、メチル、トリフルオロメチル、メトキシ、ニトロ、ヒドロ キシル、ジメチルアミノ、メチレンジオキシ、オキシ酢酸エチルエステル、カル ボキシル、２−ピリジル、３−ピリジル、４−ピリジル、ピリダジル、ピリミジ ニル、ピラジルまたは２−インドリルにより１〜３回置換されていてもよい。好 ましいヘテロアリール基として、２−フリル基、２〜チエニル基、２−ピリル基 、２−ピリジル基、および３−インドリル基が挙げられる。
構造が似ている化合物は重合反応の場合の添加剤としての用途がある（米国特許 第４．１５２．３１９号、同第３．７８０．１０３号明細書を参照のこと）。
３．５−ジーｔｅｒｔ−ブチルー４−ヒドロキシアセトアニリドは抗高脂血症薬 （ＺＡ　７４０１０８０）として知られている。
また、構造異性体のアミドが欧州特許出願第４０７２００号明細書に抗高脂血症 薬として記載されている。
抗アテローム硬化活性の酸化防止剤である。それは、ＬＤＬ中に蓄更に、酸化防 止作用の化合物が欧州特許出願第４０７２００号明細書積する立体障害アルキル フェノールである。動物実験において、プロブコールは動脈壁中のＬＤＬの酸化 的修飾を阻止し、そして酸化防止活性に基いてじゆく腫形成を直接防止すること が示された（Ｄ、Ｓｔｅｉｎｂｅｒｇら、Ａｍｅｒ、Ｊ、Ｃａｒｄｉｏｌ、、５ ７．　１６Ｍ　（１９８６））。
プロブコール（商標）の欠点はその物質の低吸収性にあるだけでなく、生体組織 中の極めて長い滞留期間にある。プロブコールの排出は主として糞便により行わ れる（Ｍ、　Ｎ、　Ｃａｙｅｎ、　Ｐｈａｒｍａｃｏｌ。
Ｔｈｅｒ、、２９．１５７　（１９８５）を参考のこと）。
更に、式■の化合物は、それらが腸のコレステロール吸収を阻止し、その結果、 遊離コレステロールの肝臓内プールを減少し、それに応じて肝臓から血漿への栄 養依存性リポタンパク質の分泌を減少する点で血漿脂質を低下する。コレステロ ール吸収の抑制はアシル補酵素Ａのコレステロールトランスフェラーゼ（ＡＣＡ Ｔ）反応の抑制に依存する。腸細胞中で、ＡＣＡＴは、コレステロールをカイロ ミクロンに充填し、そしてそれを腸リンパ管および胸管を介して循環血液に導入 するために必要であるコレステロールのエステル化を触媒作用する。
これらの物質は良好な吸収性を有し、そして腸細胞中だけでなく、しゆく腫それ 自体の細胞中の遊離コレステロールのＡＣＡＴ依存性エステル化を抑制する。そ れにより、それらはコレステロールエステルによる過負荷の結果としてのそれら の泡沫細胞の変性を防止する。
式Ｉのノーｔｅｒｔ−ブチルフェノール誘導体は、それ自体知られている合成方 法により、例えば、式ＩＩのアミンと一般式１１１のカルボン酸またはカルボン 酸誘導体の反応により得ることができる。
（式中、Ａ、ＲおよびＹは式■に示された意味を有し、かつＺはヒドロキシル、 ハロゲン、Ｃ，−Ｃ，−アルコキシまたはアジドを表す）原則として、その反応 は炭化水素、ジメチルホルムアミド、ジクロロメタンの如き不活性溶媒またはエ ーテル中で行われる。
等モル量の塩基、例えば、三級有機アミン、好ましくはトリエチルアミン、アル カリ金属の重炭酸塩、水酸化物または炭酸塩の存在下で等モル量のアミンとカル ボン酸を使用することが好ましい。
カルボン酸の誘導体（式ＩＩＩ）として、酸ハライド、アジド、酸無水物または エステルが利用できる。
遊離カルボン酸の反応に関して、原則として、ＰＯＣＩａ　、５ＯＣＩ２または ＰＣｌ３の存在が必要であり、そしてカルボン酸エステルとアミンの反応に関し ては、塩基触媒、好ましくはアルカリ金属アルコラードが必要である。多くの場 合、カルボン酸とアミンの反応はまた、溶媒、例えば、キシレン中で、水分離器 で還流下で加熱することにより行われる。
一般式Ｉの尿素誘導体（Ｘ　＝−ＮＲ−Ｃ−ＮＲ−）は、不活性溶媒、例えば、 トルエン中で行われる一般式Ｈのアミンへのイソシアネート＋ｖの付加により得 られることが好ましい（）ｌｏｕｂｅｎ−Ｗｅｙｌ、Ｖｌｌ１巻。
１５７頁を参考のこと）。
リポタンパク質に対するそれらの安定化作用のために、式Ｉの化合物は、薬剤、 特に抗アテローム硬化症薬としての用途がある。
更に、それらは抗炎症的、細胞保護的に作用するだけでなく、抗喘息的に作用す る。しかしながら、それらはまた再潅流依存性脂質過酸化のインヒビターおよび “肺表面活性因子”の安定剤として使用し得る。
個々の反応生成物が充分な純度で得られない場合、粗生成物の精製は結晶化また はカラムクロマトグラフィーにより行い得る。
生理学上適合性の有機または無機の塩基、例えば、水酸化ナトリウム、水酸化カ リウム、水酸化カルシウム、水酸化アンモニウム、メチルグルカミン、モルホリ ン、トリエチルアミンまたはエタノールアミンとの塩の製造に関して、式■の化 合物は適当な塩基と反応し得る。また、酸性化合物と適当なアルカリ金属の炭酸 塩または炭酸水素塩の混合物が考えられる。
薬剤の調製に関して、一般式Ｉの化合物は、それ自体知られている方法で、適当 な医薬担体物質、香料、矯味矯臭剤および着色剤と混合され、そして例えば、錠 剤または糖衣剤として成形され、または適当なアジュバントが添加されて、水ま たは油、例えば、オリーブ油中に懸濁または溶解される。
一般式Ｉの物質は、液体または固体形態で経口投与でき、また非経口投与し得る 。注射媒体として、安定剤、可溶化剤および／または注射液の場合に通常使用さ れる緩衝液、エタノール、ジメチルスルホキシド、錯生成剤（例えば、エチレン ジアミンテトラ酢酸）、粘度調節用の高分子量のポリマー（例えば、液体ポリエ チレンオキサイド）またはソルビトール無水物のポリエチレン誘導体を含む水を 使用することが好ましい。
固体担体物質は、例えば、澱粉、ラクトース、マンニトール、メチルセルロース 、タルク、高分散ケイ酸、高分子量の脂肪酸（例えば、ステアリン酸）、ゼラチ ン、寒天、リン酸カルシウム、ステアリン酸マグネシウム、動物および植物の脂 肪または固体の高分子量のポリマー（例えば、ポリエチレングリコール）である 。
経口投与に適した組成物は、所望により、矯味矯臭剤および甘味料を含むことが できる。
投与される投薬量は、レシピエンドの年齢、健康の状態および体重、疾患の程度 、おそらく同時に行われる更に別の治療の性質、治療の頻度並びに所望の作用の 性質に依存する。通常、活性化合物の１日の投薬量は体重１ｋｇ当たり０．１〜 ｌｏｍｇの量である。
下記の実施例は、本発明の化合物の合成に使用し得る変法の幾つかを示すが、そ れらは本発明の概念の意味の限定を表すものでＮ−（３，５−ジーｔｅｒｔ、− ブチルー４−ヒドロキシベンジル）−３−（４−クロロ−フェニル）−アクリル アミド 無水トルエン１００　ｍｌ中の３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキ シベンジルアミンＨＣＩ　（例えば、Ｈｏｕｂｅｎ−Ｗｅｙｌ、　１１／１巻、 ５０２頁と同様にして製造）ＩＯ，Ｏｇ（４２ミリモル）およびトリエチルアミ ン５．４ｍｌの溶液に、室温で１時間以内にトルエン３０ｍ１に溶解した４−ク ロロケイ皮酸クロリド（Ｈｏｕｂｅｎ−Ｗｅｙｌ、　８巻、４６４頁と同様にし てクロロケイ皮酸７．３ｇ（４０ミリモル）から製造）　４０ミリモルを滴下し て添加する。１４時間後、そのバッチをＩＮの冷塩酸に注ぎ、相を分離し、それ ぞれの場合に水１００　ｍｌで有機相を２回振とうする。トルエン相を　Ｍｇ５ Ｏ＋で乾燥した後、溶媒を減圧で除去し、残渣を少量のりグロインですり砕き、 吸引濾過する。
殆ど無色の結晶８．７ｇ、融点１７５℃。
無水トルエン２００　ｍｌ中の３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキ シフェネチルアミン３０．０ｇ（０，１２モル）およびベンズアルデヒド１３． ４ｍｌ　（０，１３モル）の混合物を、反応の水が最早分離しなくなるまで水分 離器で還流下で沸騰させる。続いて、減圧で蒸発させ、無水トルエン１００　ｍ ｌに再度溶解し、この溶液をジメチル硫酸１２．６ｍ１（０，１３モル）と混合 する。３時間加熱した後、それを冷却し、水１５０　ｍｌをそれに添加し、１２ ０℃で１時間にわたって再度加熱し、再度冷却する。水相を分離し、有機相を少 量の濃ＨＣＩ　と混合し、続いて減圧で蒸発させる。未だ存在している水をトル エンで共沸して除去する。残っている残渣を少量のエーテル／リグロインですり 砕き、吸引濾過する。
褐色の結晶２５．８ｇ、融点２００〜２０３℃。
ｂ）Ｎ−２−（３，５−ジーｊｅｒｔ、−ブチルー４−ヒドロキシ］−フェニル ）−エチル−Ｎ−メチル−３−（４−クロロフェニル）−アクリルアミドａ）で 得られたアミン４．０ｇ（１５，６ミリモル）、ピリジン２．６　ｍｌ（３６ミ リモル）およびジクロロメタン１００　ｍｌの混合物を室温で３０分以内にジク ロロメタン２０ｍ１中の４−クロロケイ皮酸クロリド（Ｈｏｕｂｅｎ−Ｗｅｙｌ 、　８巻、４６４頁と同様にして４−クロロケイ皮酸２．９ｇ（１６ミリモル） から製造）１６ミリモルの溶液と混合する。
６時間攪拌した後、ＩＮの冷塩酸に注ぎ、相を分離し、有機相を水で２回振とう する。Ｎａ　２　ＳＯ４でジクロロメタン相を乾燥した後、溶媒を減圧で除去す る。リグロイン／トルエンですり砕いた後、結晶性生成物を得る。無色の結晶１ ．６ｇ、融点１５６℃。
実施例３ Ｎ−（３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジル）−３（３， ４−メチレンジオキシフェニル）−アクリルアミドテトラヒドロフラン５０＋ｎ ｌ中の３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジルアミン塩酸塩 （Ｈｏｕｂｅｎ−Ｗｅｙｌ、　１１／１巻、５０２頁と同様にして３，５−ジー ｔｅｒｔ、〜ブチルー４−ヒドロキシベンズアルドキシムから製造）　２．７ｇ （１０ミリモル）の溶液に、トリエチルアミン４．２ｍｌを添加し、そして２時 間攪拌した後、生成したトリエチルアミン塩酸塩を吸引濾過する。その塩基の溶 解のために、テトラヒドロフラン５０ｍ１中の３，４−メチレン−ジオキシフェ ニルアクリル酸アジド２．２ｇ（１０ミリモル）を氷で冷却しながらそれに添加 し、室温で一夜攪拌する。テトラヒドロフラン溶液の蒸発後に、それを水および 酢酸エチルに取り、有機相を分離し、更に酢酸エチルで２回振とうする。Ｎａ２ ｓＯｔで酢酸エチル相を乾燥した後、それを留去し、残渣をエーテル／イソヘキ サンですり砕き、吸引濾過する。無色の結晶１，４ｇが残る。融点１９４〜１９ ７℃。
実施例４ ■Ｌ遥≦包塑二び二［堕弧址二ミ且三び−Ｎ’−フェニル尿素 トノはン３０ｍ１中の３．５−ジーｔｅｒｔ、−ブチル＋ヒドロキシフェネチル アミン（例えば、Ｊ、Ａ＋ｎ、Ｃｈｅ＋ｎ、Ｓｏｃ、８４．１６２９　（１９６ ２）　ｉ：従ッテ製造）２．０ｇ（８ミリモル）の溶液をフェニルイソシアネー ト０．８７＋ｎ１（８ミリモル）と滴下、混合する。２時間攪拌した後、溶媒を 実質的に除去し、残渣を吸引濾過し、エタノール／トルエンＣ１：３）で再結晶 する。無色の結晶２゜８ｇ、融点１８１〜１８３℃。
実施例５ Ｎ−（３，５−ジーｔｅｒｔ、−ブチ ーー　／１ｚ−４ニリ汐］４シヴＬ月Ｈ５±上ロキシーフェニル）−アクリルア ミド トランス＋ヒドロキシケイ皮酸４．９ｇ（３０ミリモル）を無水アセトン５０ｍ １中に懸濁させ、トリエチルアミン１２．６ｍｌ　（９０ミリモル）と混合する 。水浴中で約５℃に冷却し、アセトン１２０１中のインブチルクロロホルメ−１ −Ｉｌ、　７ｇ（９０ミリモル）の溶液をそれに滴下して添加する。氷で冷却し ながら２時間攪拌した後、水２４ｍ１中のアジ化ナトリウム６．３ｇ（９６ミリ モル）の溶液をそれに滴下して添加し、冷却しないで更に２時間攪拌する。水約 ３００　ｍｌで希釈し、生成したアジドを酢酸エチルで数回抽出する。蒸発後、 融点７４〜７６℃の結晶性生成物を得る。
そのアジドを３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジルアミン （実施例３に記載したようにして製造した）　２０ミリモルのテトラヒドロフラ ン溶液１００　ｍｌに固体のまま導入し、室温で２分間攪拌する。水３００　ｍ ｌを添加し、酢酸エチルで抽出することにより、イソブトキシカルボニル化合物 ｌｏｇを得る。そのエステルをテトラヒドロフラン７５ｍ！で溶解し、濃アンモ ニア２５ｍ１を添加することによりケン化する。その溶液を留去し、水および酢 酸エチルに溶解し、有機相をＮａ２ｓＯ＋で乾燥し、減圧で除去する。すり砕き 、吸引濾過した後、殆ど無色の結晶２．６ｇを得る。融点２０５〜２０８℃。
−アミノ−（３−オキソ−１−プロペニルフェノキシ）−酢酸エチルエス二双 Ｎ−（３，訃ジーｔｅｒｔ、−ブトキシー４−ヒドロキシ−ベンジル）−３−（ ４−ヒドロキシフェニル）−アクリルアミド５．６ｇ（１５ミリモル）をアセト ン１５０　ｍｌに溶解し、炭酸カリウム４．２ｇをそれに添加し、ブロモ酢酸エ チルエステル３．４　ｍｌ（３０ミリモル）と混合する。室温で２４時間攪拌し た後、それを減圧で蒸発させ、水および酢酸エチルに溶解し、酢酸エチル相を分 離し、Ｎａ　２　ＳＯｔで乾燥し、留去する。
固体残渣をエーテルですり砕き、吸引濾過する。無色の結晶４．５ｇか残る。融 点１４４〜１４７℃。
実施例７ ４−ジメチルアミノケイ皮酸３．８ｇ（２０ミリモル）をテトラヒドロフラン７ ５ｍ１に溶解し、トリエチルアミン０．４　ｍｌ（６０ミリモル）をそれに添加 し、そして約５℃に冷却しながら、クロロギ酸イソブチルエステル２．９　ｍｌ （２２ミリモル）をそれに滴下して添加する。
その後、水浴中で更に１時間攪拌し、室温で１時間攪拌する。続いて、３，５− ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジルアミン塩酸塩２．８ｇ（１０ ミリモル）を固体形態で室温で添加し、更に２４時間攪拌する。水３００　ｍｌ の添加後に、それを酢酸エチルで３回抽出する。
有機相をＮａ２５Ｏ＋で乾燥し、留去する。残っている残渣を、イソヘキサン／ 酢酸エチル１：１を用いてシリカゲル６０カラム（６０ｘ　ｅｏ。
ｍｍ）で精製する。純粋な化合物を含む画分を留去し、残渣をエーテルですり砕 き、吸引濾過する。無色の結晶２．６ｇが残る。融点１９５〜１９７℃。
実施例８ 実施例１に記載した方法と同様の方法で下記の化合物を製造する。
＋不飽和アクリル誘導体は常に（Ｅ）配置を有する。
実施例１０ 実施例１に記載した方法と同様の方法で下記の化合物を製造する。
実施例１２ Ｎ−（３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジル）−３−（４ −フェノキシ−酢酸）−アクリルアミド Ｎ−（３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジル）−３−（４ −フェノキシ酢酸エチルエステル）−アクリルアミド（実施例６）５．８ｇ（０ ，０１２４モル）をＫＯ）１１．０６ｇ（０，０１９モル）と共にエタノール５ ０ｍ１および水５０ｍ１中で室温で２４時間攪拌する。そのアルコールを蒸留し て除き、希塩酸で酸性にし、酢酸エチルで抽出する。酢酸エチルの蒸発後、生成 物をジエチルエーテル／イソヘキサン（１：１）で結晶化する。融点１２５〜１ ２６℃の物質１．１ｇを得る。
同様にして、下記の化合物を得る。
１２、１　Ｎ−（３，４−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジル） −３（３，４−ジアセトキシフェニル）−アクリルアミド（実施例５．７）から Ｎ−（３゜５−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジル）−３−（３ ，４−ジヒドロキシフェニル）−アクリルアミド、殆ど無色の結晶、融点２３３ 〜２３５℃ １２．２　Ｎ−（３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジル） −３−（４−エトキシカルボニル−フェニル）−アクリルアミド（実施例１０． ５５）からＮ（３，５−ジーｊｅｒｔ、−ブチルー４−ヒドロキシベンジル）− ３−（４−ヒドロキシカルボニルフェニル）−アクリルアミド実施例１３ Ｎ−（３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジル）−３−（４ −ピノくロイル）−フェニル）−アクリルアミドＮ−（３，５−ジーｔｅｒｔ、 −ブチルー４−ヒドロキシベンジル）−３−（４−ヒドロキシフェニル）−アク リルアミド（実施例５　）　３．８ｇ（１０ミリモル）をテトラヒドロフラン１ ００　ｍｌに溶解し、トリエチルアミン２．８１１１＋（２０ミリモル）をそれ に添加する。５〜１０℃に冷却しながら、テトラヒドロフラン５ｍｌに溶解した ピバリン酸クロリド１．５ｍ１（１２ミリモル）をそれに滴下して添加する。室 温で２４時間攪拌した後、それを水で希釈し、酢酸エチルで抽出する。酢酸エチ ル残渣を、イソヘキサン／酢酸エチルを用いてシリカゲルカラム（ＫＧ６０）で 精製する。エーテルですり砕いた後、融点１７２〜１７３℃の無色の結晶が残る 。
実施例１４ Ｎ−（３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジル）−３−（４ −アミノ−フェニル）−アクリルアミド Ｎ−（３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジル）−３−（４ −ニトロフェニル）−アクリルアミド（実施例１０．１７）４．１ｇ（１０ミリ モル）をエタノール２５０　ｍｌに溶解し、亜鉛微粉末６．５ｇ（１００ミリモ ル）と混合する。２モルの塩酸１００１Ｉ１１を激しく攪拌しながら１時間以内 に滴下して添加する。３時間攪拌した後、反応を停止する。それを吸引濾過し、 濾液を留去し、酢酸エチルおよび水に取り上げる。
酢酸エチル残渣をシリカゲルカラム（ＫＧ　６０）で精製する。イソヘキサンで すり砕いた後、融点８０℃（焼結）の生成物１．５ｇを得る。
Ｎ−（３，４〜ジーｔｅｒｔ、−ブチル−４−ヒドロキシベンジル）−４−ベン ジルオキシフェノキシ酢酸アミド（実施例１０．５０）１．５ｇ（３，２ミリモ ル）をメタノール５０ｍ１に溶解し、１０％のＰｄ／木炭０．５ｇと混合し、室 温て常圧で３時間水素化する。触媒を吸引濾過し、溶媒を蒸発させた後、融点１ １４〜１１６℃の無色の結晶１．２ｇを得る。
実施例１５と同様にして、下記の化合物を得る。
Ｎ−（３，５−ジーｔｅｒｔ、−ブチルー４−ヒドロキシベンジル）−３−（４ −ヒドロキシ−メチルフェニル）−アクリルアミドＮ−（３，５−ジーｔｅｒｔ 、−ブチルー４−ヒドロキシベンジル）−３−（４−エトキシカルボニルフェニ ル）−アクリルアミド（実施例１０．５５）２．７ｇ（６ミリモル）をエチレン グリコールジメチルエーテル１００　ｍｌ中でＬｉＢＨｔ（ＮａＢｔ（＋　１． ４ｇ（３７ミリモル）およびＬｉＣ１１，６ｇ（３７ミリモル）から製造した） と共に室温で２４時間攪拌し、続いて５０℃で４時間攪拌する。還元錯体を水お よび硫酸２モルで分解し、生成物を酢酸エチルで抽出する。酢酸エチル相を蒸発 させ、エーテル／イソヘキサンですり砕いた後、融点１７７〜１７９°Ｃの無色 の結晶１．１ｇを得る。
国際調査報告 フロントページの続き （５１）　Ｉｎｔ、　Ｃ１，５識別記号　庁内整理番号Ａ６１Ｋ　３１／１６５ 　ＡＤＮ　９４５４−４Ｃ３１／１７　９４５４−４Ｃ ３１／３４　９４５４−４Ｃ ３１／３６　９４５４−４Ｃ ３１／３８　９４５４−４Ｃ ３１／４０　９４５４−４Ｃ ３１／４１５　９４５４−４Ｃ ３１／４４　９４５４−４Ｃ ３１／４５５　９４５４−４Ｃ ＣＯ７Ｃ２３３／２７ Ｉ フロントページの続き Ｃ０７Ｄ　２０７／３３７　８２１７−４Ｃ２０９／４２　９２８４−４Ｃ ２１３１５６９１６４−４Ｃ ２１３／７５　９１６４−４Ｃ ２１３／８１　９１６４−４Ｃ ２１３／８２　９１６４−４Ｃ ２３３／６４　１０６　９３６０−４Ｃ２３７／２２　８６１５−４Ｃ ２３７／２４　８６１５−４Ｃ ２４１／２０　８６１５−４Ｃ ２４１／２４　８６１５−４Ｃ ３０７１５４８２１７−４Ｃ ３０７／６８　８２１７−４Ｃ ３１７／６４　９４５４−４Ｃ ３３３／２４　９４５５−４Ｃ ３３３／７０　９４５５−４Ｃ （７２）発明者　ドレセル、アロイス ドイツ連邦共和国　ディー−６９０５シュリーシャイム　モーツァルトシュトラ ーセ（７２）発明者　ミツシェル、ヘルムートドイツ連邦共和国　ディー−６８ ００マンハイム　３１　ツィーゲルガッセ　２エイ

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  1. 【特許請求の範囲】 １．式Ｉにより表される化合物、およびそれらの薬理学上許される塩。 ▲数式、化学式、表等があります▼（Ｉ）［式中、Ａは原子価、１〜５個のＣ原 子を有する直鎖または分枝アルキル鎖を表し、Ｘは−ＮＲ−ＣＯ−（アミド）基 または−ＮＲ−ＣＯ−ＮＲ（尿素）基（式中、Ｒは水素原子またはＣ１−Ｃ４− アルキル基を表す）を表し、かつＹは１〜６個のＣ原子を有する直鎖または分枝 の飽和または不飽和の炭化水素鎖（これはアリール基、ヘテロアリール基、アリ ールオキシ基もしくはアリールチオ基により置換されていてもよい）、Ｃ３−Ｃ ６−シクロアルキル基またはアリール基を表し、ここで当該アリール基およびヘ テロアリール基は、それぞれの場合に、環の全ての可能な位置でＣＮ、ヒドロキ シメチル、メチレンジオキシ、ハロゲン、トリフルオロメチル、Ｃ１−Ｃ４−ア ルキル、アミノ、Ｃ１−Ｃ４−アシルアミノ、ジ−（Ｃ１−Ｃ４）−アルキルア ミノ、ヒドロキシル、Ｃ１−Ｃ４−アルコキシ、カルボキシル、オキシ酢酸エチ ルエステルまたはニトロにより１〜３回置換されていてもよく、但し、Ａが−Ｃ Ｈ２−または−ＣＨ２−ＣＨ２−以外の意味を有する場合に、Ｙは単に未置換フ ェニルを表すことを条件とする］２．式Ｉ ▲数式、化学式、表等があります▼（Ｉ）［式中、Ａは原子価、１〜５個のＣ原 子を有する直鎖または分枝アルキル鎖を表し、Ｘは−ＮＲ−ＣＯ−（アミド）基 または−ＮＲ−ＣＯ−ＮＲ（尿素）基（式中、Ｒは水素原子またはＣ１−Ｃ４− アルキル基を表す）を表し、かつＹは１〜６個のＣ原子を有する直鎖または分枝 の飽和または不飽和の炭化水素鎖（これはアリール基、ヘテロアリール基、アリ ールオキシ基もしくはアリールチオ基により置換されていてもよい）、Ｃ３−Ｃ ６−シクロアルキル基またはアリール基を表し、ここで当該アリール基およびヘ テロアリール基は、それぞれの場合に、環の全ての可能な位置でＣＮ、ヒドロキ シメチル、メチレンジオキシ、ハロゲン、トリフルオロメチル、Ｃ１−Ｃ４−ア ルキル、アミノ、Ｃ１−Ｃ４−アシルアミノ、ジ−（Ｃ１−Ｃ４）−アルキルア ミノ、ヒドロキシル、Ｃ１−Ｃ４−アルコキシ、カルボキシル、オキシ酢酸エチ ルエステルまたはニトロにより１〜３回置換されていてもよく、但し、Ａが−Ｃ Ｈ２−または−ＣＨ２−ＣＨ２−以外の意味を有する場合に、Ｙは単に未置換フ ェニルを表すことを条件とする］により表される化合物、およびそれらの薬理学 上許される塩の製造方法であって、 それ自体知られている方法で、 ａ）Ｘが−ＣＯ−ＮＲ−基を表す場合に、式ＩＩ ▲数式、化学式、表等があります▼（ＩＩ）（式中、ＡおよびＲは示された意味 を有する）の化合物を式ＩＩＩ ▲数式、化学式、表等があります▼（ＩＩＩ）（式中、Ｙは示された意味を有し 、かつＺはヒドロキシル、ハロゲン、Ｃ１−Ｃ４−アルコキシまたはアジドを表 す）の化合物と反応させ、また ｂ）Ｘが−ＮＲ−ＣＯ−ＮＲ−基を表す場合には、式ＩＩ ▲数式、化学式、表等があります▼（ＩＩ）（式中、ＡおよびＲは示された意味 を有する）の化合物を式ＩＶ ▲数式、化学式、表等があります▼（ＩＶ）（式中、Ｙは示された意味を有する ） のイソシアネートと反応させ、続いて、所望により、式Ｉの得られた化合物を適 当な手段により式Ｉのその他の化合物に変換し、またはその化合物を薬理学上許 される塩に変換することを特徴とする前記化合物の製造方法。 ３．通常の担体およびアジュバント物質の他に、請求項１に記載の化合物を含む 薬剤。 ４．代謝性疾患の治療のための請求項１に記載の化合物の使用。
JP5504071A 1991-08-13 1992-08-10 新規な３，５−ジ−ｔｅｒｔ−ブチル−４−　ヒドロキシフェニル誘導体、それらの製造方法および薬剤 Pending JPH06510030A (ja)

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DE4126662,5 1991-08-13
DE4126662A DE4126662A1 (de) 1991-08-13 1991-08-13 Neue 3,5-di-tert.butyl-4-hydroxyphenyl-derivate, verfahren zu ihrer herstellung und arzneimittel
PCT/EP1992/001821 WO1993004035A1 (de) 1991-08-13 1992-08-10 Neue 3,5-di-tert.butyl-4-hydroxyphenyl-derivate, verfahren zu ihrer herstellung und arzneimittel

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JP2009522220A (ja) * 2005-12-28 2009-06-11 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 置換されたビス（ヘテロ）芳香族ｎ−エチルプロピオールアミド及び医薬の製造へのその使用

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MX9204622A (es) 1993-04-01
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EP0527458A1 (de) 1993-02-17
IL102772A0 (en) 1993-01-31
EP0600949B1 (de) 1996-01-10
DE4126662A1 (de) 1993-02-18
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AU2418692A (en) 1993-03-16
ZA926049B (en) 1994-02-14

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