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TW203039B - - Google Patents

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Publication number
TW203039B
TW203039B TW081106307A TW81106307A TW203039B TW 203039 B TW203039 B TW 203039B TW 081106307 A TW081106307 A TW 081106307A TW 81106307 A TW81106307 A TW 81106307A TW 203039 B TW203039 B TW 203039B
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TW
Taiwan
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group
aryl
compound
general formula
aromatic
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TW081106307A
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English (en)
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Boehringer Mannheim Gmbh
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • 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
    • C07C233/68—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
    • C07C233/00—Carboxylic acid amides
    • 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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    • 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
    • C07C235/04—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
    • C—CHEMISTRY; METALLURGY
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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
    • C07C235/32—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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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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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    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • 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
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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
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    • 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
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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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Description

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Α-Χ-Γ A6 B6 五、發明説明（1 ) 本發明僳關於新穎之二-持丁基-羥苯基衍生物（ BHT衍生物），彼之製法及含彼之藥學組成物。 本發明之新穎二-特丁基-羥苯基衍生物為通式（I )之化合物，及其製藥上可接受性鹽類。 (工） 其中A為價鍵或最多含5値碩原子之直鐽或支鐽烷基，X 為一 NR — CO —(醯胺）或一 NR — CO-NR (脲） 基匾，其中之R為氫原子或Cv_C4—烷基圍且Y為最多 含有6値碩原子之直鐽或支鍵，飽和或未飽和烴鐽，彼可 被芳基，雜芳基，芳氣基或芳硫基團，（：3_(：6環烷基或 芳基團所取代，又此處之芳基或雜芳基團可在環之所有可 能位置上被氰基，羥甲基，甲二氧基，鹵素，三氟甲基， 一烷基，胺基，C;— C4 —醯基胺基，二一（ Ci-C4)烷胺基，羥基，Ci-C*—烷氣基，羧基，氣 乙酸乙酯或硝基取代一至三次，惟當A不為一CH2—或 一 CH2— CH2—時，則Y僅可代表未經取代之苯基。 A 橋最好— CHz—，_CH2— CH2—， —(CHa) a— , — CHs—CH (CHa)—或 -C H 2- C (CH3) 2—基圍。 在碩醯胺基圍（其中羥苯基圍乃經由A橋而與醯胺氮 本紙張尺度適用中國國家橒準（CNS)甲4規格（210 X 297公笼）-4 - 請 先 閲 讀 背 面 之 注 意 事 項 再 填 r-" 裝 訂 線 經濟部中央標準扃β工消费合作社印製 81.9.25.000 A6 B6 五、發明説明（2 ) 原子連接）或脲基圍方面，R最好為氫原子或甲基圍。 Y方面，以笮基，苯乙基，苯乙烯基，苯基及棻基團 較理想，彼之芳族部分可在所有位置依次被（最好為）氡 基，氟基，氯基，羥甲基，甲基，三氟甲基，甲氧基，硝 基，羥基，二甲胺基，甲二氣基，氣乙酸乙酯，羧基，2 一吡啶基，3 —吡啶基，4 一吡啶基，噠嗪基，嘧啶基，吡 嗪基或2~吲跺基取代一至三次。理想之雜芳族基圍包括 2 -呋喃基，2 -_嗯基，2 _吡咯基，2 —吡啶基及3 一吲跺基圍。 具有類同結構之化合物已發現可用以作為聚合反應中 之添加劑（參考資料，美國專利說明書第4, 152, 3 19 及 3, 780, 103 號）。 3, 5—二一特丁基一4一羥基乙醛替苯胺已知為一 種抗高血脂症之北合物（ZA 7401080)。 結構上為異構形式之醯胺類乃述於E P —A — 0 407200中，彼偽作為抗高血脂症之化合物：
此外，抗氧化作用之化合物乃述於EP-A—Ο 4 0 7 2 0 0 中。 N — （3, 5 —二一特丁基一 4 —羥基）一苯乙基一 苯甲酸醯胺亦為已知（參見J. A. C. S.这土，1629/1962 本紙張尺度適用中a國家標準（CNS)甲4規格（210 X 297公楚）一 5 - (請先閲讀背面之注意事項再填 丨裝_ 訂- 經濟部中央標準局ία工消費合作社印製 81.9.25,000 0303b A6 B6 五、發明説明（3 ) )，但此化合物僅有物化性質述於上述專利公告中。 亦具有抗氣化作用之含兩値BHT基函之化合物則述 於 EP — A — Ο 4 0 4 039 號中。 俄國專利公告中，N— （3， 5—二一特丁基一4_ 羥基）一甲基一 N / —苯基脲乃被述及為燃料添加物（參 見 Nef thekh i m i ya，2_7_ (5)，703)。 本發明之通式I化合物具有強抗氣化之效力。此抗氣 化基圃之親脂性顯示此化合物富含於産粥瘤之低密度脂蛋 白（LDL)中且可有效地保護LDL之敏感部分以避免 到氧之反應。然而，LDL匯入巨噬泡沫細胞中之作用受 到顯著地障礙；産粥瘤性LDL致病性地增加吸收至粥瘤 細胞中之作用預料將導致氣化改性作用。 經濟部中央標準局貝工消費合作社印製 抗氧化劑為一種可阻礙氧化過程度使産物受到保護之 物質。Probucol®為有效抗動脈硬化之抗氣化劑，彼具有 降低各種動物及人類之血脂之作用。其乃累積於LDL中 之位阻之烷基苯酚。在動物實驗中顯示，Probucol可阻斷 動脈壁中LDL之氣化改性作用，且可依其抗氣化之效力 而直接預防粥瘤之形成。（參見D . Ste i nberg et a 1 .， Amer. J. Cardiol.， 57, 16M(1986)) 〇
Probucoi ®之缺點為此化合物之低吸收力及其於身體 組織内極長之逗留時間；Probucol之排泄主要僳經由糞 便排出（參考資料，Μ. N. Cayen，Pharmacol. Ther.,ai ,157(1985))。 此外，通式I化合物可降低血漿脂肪，彼可阻斷腸部 81.9.25,000 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐）-6 - ^03039 A6 B6 五、發明説明（4 ) 對膽固醇之吸收，因此可降低肝内游離賸固醇之收集且因 降低將營養依賴性脂蛋白由肝分泌至血漿中之能力。此膽 固醇吸收之抑制作用乃依酵基一輔酶A:—膽固醇轉換酶 (A CAT)反應而定。腸細胞中，ACAT可催化膽固 醇之酯化作用，此酯化作用乃膽固醇包入乳糜微粒中及經 由腸淋巴及胸管以將膽固醇置入循環血液中所必需。 此化合物具有良好之吸收力且不僅於腸細胞中，亦可 於粥瘤細胞本身中抑制游離膽固醇之ACAT—依賴性酯 化作用。因此彼等可預防泡沫細胞降解所致之膽固醇酯之 超載。 通式I之二-特丁基苯酚衍生物可藉由已知之合成法 製得，例如藉令通式（I I)之胺 (請先《讀背面之注意事哎再填iz: 丨裝· 訂
7線· 緩濟部中央櫺準局员工消费合作社印焚 與通式（I I I)之羧酸或羧酸衍生物起反應而得： Ο
II Y - c - Z (III) 其中A, R及Y乃如同通式I所述之定義，Z為羥基，囪 素，Ci_C4 一院氣基或昼氮化物。 本紙張夂度通用中國國家標準（CNS)甲4規格（210 X 297公釐）-7- 81·9·25,〇〇〇 2030 沾 A6 B6 五、發明説明$ ) 一般而言，反應僳於惰性溶劑例如烴，二甲替甲醛胺 ，二氣甲烷或二乙醇中進行。 最好係使用等莫耳量之胺及羧酸而於等莫耳量之鹼， 例如三级有機胺，最好為三乙胺，或於驗金屬碩酸氫鹽， 氫氧化物或碩酸鹽之存在下進行。 在通式III之羧酸衍生物方面，可採用酸式鹵化物 ，疊氮化物，酐或酯。 一般而言，供游離羧酸之反應方面，磷醛氯，亞硫醛 氯或三氣化磷之存在為供羧酸酯與胺之反應，並使用齡性 催化劑，最好為鹼金屬醇化物時所必需。許多事例中，羧 酸與胺之反應亦可於溶劑例如二甲苯中藉使用水分離器於 迴流下加熱來進行。 通式I之脲衍生物（X = — NR — C — NR —）最好 藉將通式（IV)之異氣酸酯：
Ο = C = N — Y (IV) 請 it 閲 讀 背 面 之 注 意 事 項· 再 填 寫* 頁 裝 訂 經濟部中央標準居RX消费合作社印製
加至於惰性溶劑内，例如甲苯内之通式II之胺中而製得 (參考資料。Houben-Weyl, Vol. VIII，p.157),由此 即得下列通式之本發明化合物： X 〇 H0-(/ V-A-NH-C-NH-T ^紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐i 8 81.9.25,000 A6 B6 ^〇30S9 五、發明説明（6 ) 因為於脂蛋白上所呈現之安定作用，故通式I化合物 已發現可以作為藥物，尤其作為抗動脈硬化劑。 此外，彼等具有消炎，保護细胞及抗氣喘之作用；故 彼等亦可作為再灌注依賴性脂肪過氣化作用之抑制劑及作 為a肺表面活化劑因子〃之安定劑。 如果所得之各種反應産物之純度不足，則粗製産物可 藉結晶作用或柱色層分離作用予以純化。 欲製備含生理上可接受性有機或無機鹼，例如氩氣化 鈉，氫氣化鉀，氫氣化鈣，氫氣化銨，甲基葡糖胺，嗎啉 ，三乙胺或乙醇胺等之鹽類，乃令通式I化合物與適當之 鹼起反應，而酸性化合物與適當鹼金靥碩酸鹽或碩酸氫鹽 之混合物亦可予以考慮。 欲製備藥學組成物，乃使用已知玻璃將通式I化合物 與適當之製藥載體物質，香嗅，增香及著色物質混合，再 予定形成（例如）藥片或糖衣錠之形式，或（同時加入適 當輔劑）令之懸浮於或溶於水或油，例如橄攬油中。 經濟部中央標準局貝工消费合作社印製 通式I化合物可以液體或固體形式經由口部或非經腸 部施入，在注射用之介質方面，最好使用含有安定劑，溶 解劑及/或注射溶液中所常用缓衝劑之水。此添加劑之實 例包括乙醇，二甲亞硯，錯合物形成劑（諸如乙撑二胺一 四乙酸），供調整黏度之高分子量聚合物（諸如液體聚氣 化乙烯）或山梨糖醇酐之聚乙烯衍生物。 固態載體包括（例如）澱粉，乳糖，甘露糖醇，甲基 纖維素，滑石，高度分散之矽酸，高分子置之脂肪酸（諸 81.9.25,00 本紙張又度適用中國國家樣準（CNS)甲4规格（210 X 297公楚4 9 .0303^ A6 B6 五、發明説明（7 ) 如硬脂酸），凝膠，瓊脂，磷酸0,硬脂酸鎂，動物及植 物脂及固態高分子量聚合物（諸如聚乙二醇）。如期望的 話，適於供口服之組成物可含有增香劑及甜化劑。 所施用之劑量乃依年齡，接受者之健康狀況及體重， 疾病程度，同時所可能進行之其它治療之特性，治療頻率 及所期望作用之特性而定。 奮例1 N— (3. 5 —二一特丁甚 一 4 一藓芏甚）一 3 — （4 一 氣荣某）一丙烯轆胺 經濟部中央揉準局R工消費合作社印製 於室溫下，於1小時期間將40毫莫耳4一氯基肉桂 酸氣化物（依類同於Houben-Weyl，Voi. 8，p.464)之 法而由7. 3g (40毫莫耳）氯基肉桂酸中製得）之 3〇mi2甲苯溶液逐滴加至1〇. 〇g (42毫莫耳）3 ,5 —二一特丁基一 4 一羥基苄胺氫氯化物（例如類同於 Houben-Weyl，Vol 11/1, ρ·502 之法）及 5. 4mi 三乙 胺之lOOmP無水甲苯溶液中。14小時後，將反應混 合物倒至冷1N氫氣酸中，再將諸相分離，繼而將有機相 與（每次）lOOmj?水搖動。乾燥後，於無水硫酸鎂上 將甲苯相乾燥，再將溶劑於真空中移去，餘留物則以少許 石油英碾磨，並予空吸濾出。即得8. 7g幾乎無色之結 晶；熔點1 7 5 1C。 81.9.25,000 本紙張尺度適用中S國家揉準（CNS)甲4规格（210 X 297公落）1〇_ 203039 A6 B6 經濟部中央標準屬MC工消费合作社印製 五、發明説明（8 ) 窨例2 a ) N —甲基_ (3. 5 —二一特丁基一 5 —翔苯基）5 胺氣氣化物 將 30. 〇g (◦. 12 莫耳）3，5-二-待丁基 一4一羥基苯乙胺及13. (0.13莫耳）苯甲 醛之2 0 0m 5無水甲苯混合液於迴流下於水分離器上沸 煮直至反應之水不再分離出為止。繼而將反應混合物於真 空中蒸發，令餘留物再度溶於l〇〇mi無水甲苯中，再 將此溶液與12. 6m5 (◦.13莫耳）硫酸二甲酯混 合。加熱3小時後，將反應混合物冷卻，再將150mi 水加入，繼而再度加熱1小時至1201C,並予再度冷卻 。而後將水相分離出，再將有機相與少許濃鹽酸混合，繼 而於真空中蒸發。再與甲苯共沸以移去任何仍存在之水。 而後將所得餘留物與少許二乙醚/石油英碾磨，並予空吸 濾出，即得25. 8g棕色結晶；熔點200 — 2031C 0 b ) N— (2 — (3, 5 —二一特 T 甚一 4·—锊荣某）一 乙基一N —甲基一 3 — （4 一氛笨某）一两嫌酿胺 將4.〇g (15. 6毫莫耳）a)所得之胺， 2. 6m$(36毫莫耳）吡啶及loome二氯甲烷之 混合液於室溫下於3◦分鐘期間與16毫莫耳4一氣基肉 桂酸氯化物（依類问於Houben-Weyl，Vol. 8, p.464之法
(請先閲讀背面之注意事*![·再填IP 頁) •丨裝- 訂· ••.4· 本紙張尺度適用中國國家標準（CNS)甲4规格（21〇 X 297公 11 - 81.9.25,000 ^03039 A6 B6 五、發明説明（9 ) 請 先 閲 讀 背 面 之 注 意 事 項- 再 場 寫· 分一s 頁 而由2. 9g (16毫莫耳）4_氣基肉桂酸中製得）之 2 Omi二氣甲烷溶液混合。6小時後，將反應混合物倒 至冷1N氫氯酸中，再將諸相分離，繼而將有有機相與水 搖動兩次。於無水硫酸納上將二氯甲烷相乾燥後，將溶劑 於真空中移去。將餘留物與石油英/甲苯碾磨後，即得 1. 6g晶狀産物；焰點：156*^。 窨例3 N— (3. 5 —二一恃丁基一4 一锊笔某）一 3— (3· 4 _甲二氩某荣甚）一丙烯酴胺 將4. 2mi三乙胺加至2. 7g (10毫莫耳）3 ,5 -二一特丁基一 4 一羥基苄胺氫氣化物（依類同於卜 ouben-Weyl, Vol 11/1, p.502 之法而由 3, 5 -二一特 丁基一 4 一羥基苯醛肟中製得）之50mi?四氫呋喃溶液 中，2小時後，再將所形成之三乙胺氫氛化物空吸濾出。 欲使鹼溶解，乃邊以冰冷卻邊將2. (10毫莫耳） 經濟部中央標準局員工消費合作社印« 3, 4 —甲二氣基苯基丙烯酸叠氮化物之50mi?四氫呋 喃液加入，再於室溫下攪拌過夜。將四氫呋喃溶液蒸發後 ，再將餘留物置於水及乙酸乙酯中，繼而將有機相分離出 ，再將水相與乙酸乙酯搖動兩次。於無水硫酸鈉上將乙酸 乙酯相乾燥後，再將乙酸乙酯蒸餾出，繼而將餘留物以二 乙醚/異己烷碾磨，並予空吸過濾，即得1.4g無色結 晶；熔點·· 194-197 °C。 81.9.25,000 未紙張尺度適用中國國家櫺準（CNS)甲4规格（210 X 297公楚J 12 _ 2030 於 A6 _ B6 五、發明説明（1()) 奮例4 Μ二（2 - 3，5 -二一待丁華—4 一镩芏苓、一 乙某 Ν 一茱基脲 將2. Og (8毫其耳）3, 5 一特丁基_ 4 — 羥基苯乙胺（例如，根據J. A. C. S.，1629/1962) 之30mi2甲苯溶液逐滴與〇. 87πιβ (8毫莫耳）異 氟酸苯酯混合。攪拌2小時後，移去溶劑，再將餘留物空 吸濾出，並由乙醇/甲苯（1 : 3 v/v)中予以再結 晶，即將2. 8g無色結晶；溶點181一183¾。 奮例5 請 先 閲 讀 背 面 之 注 意 事 項· 再 填 寫.· r" 1 装 訂 經濟部中央標準居R工消费合作社印製 N — （3· 5— 二一特丁基一4一卸苄基）_·3 — (4 — 锊荣甚）_丙烯醅胺 令4. 9g (30毫莫耳）反式一4一羥基肉桂酸懸 浮於50m$無水丙酮中，再與12. 6mj? (90毫莫 耳）三乙胺混合。繼而將反應混合物於冰浴中冷卻至約5 〇，再將11· 7g (90毫莫耳）氛甲酸異丁酯之12 m 5丙酮溶液逐滴加入。邊以冰冷卻邊搜拌2小時後，將 6. 3g (96毫莫耳）壘氮化鈉之24mi?水溶液逐滴 加入，再將反應混合物更進一步攪拌2小時，此時不用冷 卻。繼而將之以約3 0 0m又水稀釋，再將所形成之叠氮 線 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公«)13 - 81.9.25,000 030S3 A6 ____B6_ 五、發明説明（11 > 化物以乙酸乙酯萃取數次。蒸發後，即得晶狀産物；熔點 7 4 - 7 6 1C 〇 將此固狀形式之β氮化物置入20毫莫耳3, 5—二 一特丁基一 4 一羥基苄胺（依實例3所述之法製得）之 1 ◦ 0m ί四氫呋喃溶液中，再將反應混合物於室溫下攪 拌2分鐘。加入300mi?水，並以乙酸乙酯萃取後，可 得l〇g具丁氧羰基化合物。藉令此酯溶於75mi?四氫 呋喃中，再加入2 5m $濃氨溶液以將此酯皂化。繼而將 溶液蒸餾，令餘留物溶於水及乙酸乙酯中。再將育機相於 無水硫酸鈉上乾燥，並於真空中移去溶劑。經碾磨及吸濾 後，即得2. 6g幾乎無色之結晶；熔點205 — 208 〇C 〇 81.9.25,000 本紙張尺度適用中國國家橒準（CNS)甲4规格（210 X 297公釐14 - 五、發明説明（12) A6 B6 18?濟部中央標準局員工消费合作社印製 A R Y [熔點C] 5.1 ch2 H och3 -CH=CH-^~^ -OCH3 OCH-i 158-161 5.2 ch2 H /〇CH3 -CH=CH-《》-〇H 193-195 5.3 ch2 H 弋 H=CH、_ — xo COOC2H5 214-216 5.4 ch2 H -CH=CH-^ 148-150 5.5 ch2 H -ch=ch_Gk=3 185-188 5.6 ch2 H ch3 -CH=CH-^ —CH3 CHa 232-234 5.7 * ch2 H 〇c〇ch3 -CH=CH-^^\-〇c〇CH3 198-200 5.8 ch2 H ~CH=CH-/ Λ 128-130 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐- 81.9.25,000 2030 防 五、發明説明（13 ) A6 B6 經濟部中央標準局貝工消費合作社印製 A R Y [熔點t:] 5.9 ch2 H -CH=CH_<--CH3 CH-, 195_196 5.10 ch2 H -CH=CH-^ ^ -0-CH2 117-118 5.11 ch2 H -ch=ch-〇-〇 173-174 5.12 ch2 H -CH=CH-^~~^-CN 213-215 5.13 ch2 H _N H 218-221 5.14 ch2 H -CH=CH^_u 〇 . H 231-233 5.15 ch2 H /C2H5 -ch2-〇-^"C2H5 134-135 5.16 ch2 H -0 136-138 5.17 ch2 H -G 189-190 請 先 閲 讀 背 面 之 注 意 事 項 再 填 A 貝 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐）16 81.9.25,000 9 ctj 0: 3 ο i.'tu
6 6 A B 五、發明説明（14 ) A R Y [熔點^ ] 5.18 ch2 H 213-215 5.19 ch2 H 220-222 5.20 ch2 H -D N~N 158-160 5.21 ch2 H 153-155 請 先 閲 讀 背 面 之 注 意 事 項 再 填 寫 i 頁 經濟部中央標準局工消费合作社印製 本纸張尺度適用中國國家標準（CNS)甲4規格（210X297公犛 81.9.25,000 附件：〇30沾 第 81106307號專利申請案中文説明書修正頁 民國82年1月呈 B6
五、發明説) 啻例6 (請先面之注意事项再填寫本頁) Γ4- Γ (3. 5 —二一恃丁基一4 —锊笨基）一甲甚Ί 一胺基一（3 —氣代一1 一丙燃基笨氣基）乙酸乙酷 令 5. 6g ( 1 5 毫莫耳）N - (3, 5-二一待丁 氣基一 4 一經爷基）一3 — （4 一羥苯基）一乙燃酿胺溶 於150mP丙酮中，再將4. 2g碩酸鉀加入，繼而將 混合物與3. (3 ◦毫莫耳）溴乙酸乙酯混合。於 室溫下攪拌2 4小時後，將反應混合物於真空中蒸發，令 餘留物溶於水及乙酸乙酯中，再將乙酸乙酯相分離出，以 無水硫酸鈉乾燥，並予濾出。繼而將固狀餘留物以二乙醚 碾磨，並予空吸濾出。即得4 . 5 g無色結晶；熔點 144-147 °C〇 曹例7 _N- (3. 5 — 二一恃丁基—4一 镩苌某）-S- (4 — 甲胺某荣甚）一丙烯醯胺 經濟部中央標準局具工消費合作社印製 令3. 8g (20毫莫耳）4一二甲胺基肉桂酸溶於 75mp四氫呋喃中，再將◦. 4m5 (6毫莫耳）三乙 胺加入，繼而邊冷卻至約5 °C，邊將2 . 9 m β ( 2 2毫 莫耳）氯甲酸異丁酯逐滴加入。再將反應混合物於冰浴中 另攪拌1小時及於室溫下1小時。其後，將2 . 8 g ( 10毫某耳）固體形式之3, 5 —二一特丁基一 4 一羥基 本紙張尺度適用中B國家標準（CNS)甲4规格（210 X 297公釐〉 -18 - 3 3 ο 3 ο 經濟部中央標準局tK工消费合作社印製
6 6 A B 五、發明説明（16 ) 笮胺置入，再將反應混合物另攪拌24小時。加入300 mi水後，以乙酸乙酯萃取三次。繼而將有機相以無水硫 酸納乾燥，再將溶劑蒸皤出。所得之餘留物則置於硅膠 60柱（60x600mm)上純化並以異己烷/乙酸乙 酯（1 : 1 v/v)洗提。將含有純化合物之部分蒸餾 出後，將餘留物以二乙醚碾磨並予空吸濾出。即得2. 6 g無色之結晶；熔點1 95 - 1 97 °C。 奮例8 下列化合物僳依類同於實例1之方法製得：
HO- A R Y [熔點〇 8.1 ch2 Η XI 209-11 8.2 ch2 H L丨丨 194-96 -------------------------装------，订-----—線 (請先閲讀背面之注意事哏再填寫(i頁) ( 本纸張尺度適用中國國家標準（CNS)甲4规格（210 X 297公笼）19 一 81.9.25,000 •'.v ί 3 ο 3 ο
6 6 A B 五、發明説明（17 ) 經濟部中央標準局βκ工消費合作社印製 A R Y [熔點c ] 8.3 ch2 H Xj) 158-59 8.4 ch2 H XI CH 二 CH A il 〆 1 COOC2H5 153-55 8.5 ch2 H ri CH=CH八N〆 H 168-70 8·6 ch2 H CH=CH U〇 H 128-30 (請先閲讀背面之注意事項再填寫/頁) 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐泛〇 _ 81.9.25,000 經濟部中央標準局R工消费合作社印製 A6 B6 五、發明説明（18 ) 奮例9 下列化合物僳依類同於實例4之方法製得 A R Y [熔點t：] 9.1 CH2 H i-C3H7 161-62 9.2 ch2 H -.苯塞 200-02 81.9.25,000 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公落_)21- A6 B6 經 濟 部 中 央 標 準 局 工 消 费 合 作 社 印 製 五、發明説明（19 ) A R Y [熔點t ] 9·3 ch2 H 〇% 216-17 9.4 ch2 H -〇-f 190-92 9.5 ch2 H •〇-ci 217-18 9·6 ch2 H 165-66 9.7 ch2-ch2 H c2h5 160-61 9.8 ch2ch2 H i-C3H7 188-90 9.9 ch2ch2 H 189-90 9.10 ch2ch2 H -〇-f 171-72 9.11 ch2ch2 H -o- 200-01 9.12 ch2ch2 H 0,3 164-65 請 先 閲 讀 背 面 之 注 意 事 項― 再 填 ★ η 裝 訂 線 本纸張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐）22 _ 81.9.25,000 A6 B6 五、發明説明（20 ) 經濟部中央標準局MK工消费合作社印製 A R Y [熔點t：] 9.13 ch2 H 175-77 9.14 ch2 H 174-76 9.15 ch2 H CH=>Cff-^~~y -CH3 202-05 9·16 ch2 H CH-CH-^ ^-OCH3 188 9· 17 ch2 H CH=CH-^^)-N02 176-78 9.18 ch2 H 191-93 9.19 ch2 H _/CI CH=CH-/ \ 169-71 9,20 ch2 H 严3 CH=CH-/ \ 173 9.21 ch2 H /CF3 174 (請先閱讀背面之注意事來再填寫广頁) .裝. 訂. .線. 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公笼）. 81.9.25,000 9 A6 B6 五、發明説明（21 ) 經濟部中央標準扃R工消费合作社印製 .A R Y [熔點t] 9.22 ch2 H ch3 ch-ch-Z y x CHj 180-82 9.23 ch2 H d 191-94 9.24 ch2 H Π CH^CH^ 〇 ^ 174-76 9.25 ch2 H CH^CH^ s ^ 166—69 9.26 ch2 H J| i) l cooc2h5 149-50 9.27 ch2 H CH=CH u 116 (Z) 9.28 -CH2- H -CH=CH-^ 168-170 9.29 ch3 H i—C3—H7 170 請 it « 讀 背 面 之 注 意 事 項 再 填 寫 才 頁 衣紙張尺度適用中國國家標準（CNS)甲4规格（210 J24 81.9.25.000 A6 B6 五、發明説明（22 ) 經濟部中央標準局R工消费合作社印製 A R Y [熔點tn 9.30 —CH2"*^H— ch3 H 苯基+ 102 9.31 ch3 H 137-138 9·32 ch3 H 〇-f 129-131 9.33 ch3 H •〇-ci 159-160 9.34 ch3 H -Q cf3 182-183 9·35 〒h3 ch3 H ΐ-〇3Η7 192-194 9.36 p -CH2**〒- ch3 H 苯基\ 157-158 9.37 〒h3 -CH2_〒- ch3 H •Ο, 167-168 請 先 閲 讀 背 面 之 注 意 事 項. 再 填 寫一 i 頁 裝 訂 本紙張尺度適用中國國家標準（CMS)甲4規格（210 X 297公洚- 81.9.25,000 ^030^9 五、發明説明（23 ) A6 B6 (請先閱讀背.面之注意事項再填寫疒貝) A R Y [熔點tn 9.38 严3 -CH2-〒- ch3 H -〇-f 189-190 9.39 产3 -ch2-〒_ ch3 H 〇-ci 173-174 9.40 产3 ch3 H -Q cf3 131-132 ;4.· 經濟部中央標準局員工消费合作社印製 +未飽和之丙烯性衍生物通常具有（E)構型 窨例1 0 下列化合物傜依類同於實例1之方法製得： 81.9.25,000 五、發明説明（24 ) Α6 Β6
K ·H0-< ^-A-N-CO-Y 經濟部中央標準局ΜΚ工消费合作社印製 A R Y [熔點〇 ] 10.1 價鍵 . -H Phenyl 194-195 10.2 II " -CH2-hQ 160-161 10.3 II II -ch2-ch2*^^ 132 10·4 II II -(CH2) 3-~ 116 10.5 ch2 H 苯基 188-189 10.6 fl ” -CH2—(^) 133-134 10·7 II " -CH2-0— 135-137 10.8 II II -ch2-s-<^> 117-118 10-9 11 II -CH=CH—<^~^) 161-161 10· 10 II 11 153 10.11 II If -CH=CH— 173-174 請 先 閲 讀 背 面 之 注 意 事 項 再 填 寫 頁 衣紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公笔）27 81.9.25,000 A6 B6 五、發明説明（25 經濟部中央標準局员工消費合作社印製 A R Y [熔點t:] 10,12 II II -CH«CH—OCH3 156-157 10.13 11 " _CH]CH— 153-155 10.14 tf " ^ch3 -ch»ch— 178-180 10.15 II 11 -CH-CH— /7^CH3 135-137 10·16 II It -CH-CH—\^} ch3 197-199 10.17 10.18 II 1« It If -CH=CH-^^>~N02： -CH=CH-〇 O 184-187 192-194 10.19 II It -CH»C(CH3) 154-156 10.20 ch2-ch2 H -C1 153 10.21 " If C(CH3)3 153-155 10.22 II II -CH2—0> 138-139 10.23 II tl -ch2-ch2— 106-107 請先閱讀背面 之注专3事項再填.k .斗頁) 裝· 訂· 本紙張尺度適用中國國家標準（CMS)甲4規格（210 X 297公釐）28 _ 81.9.25,000 ^030^ 五、發明説明（26 ) Α6 Β6 經濟部中央標準局®:工消費合作社印製 A R Y [熔點t] 10.24 Μ If -(CH2) 3-' 75 10.25 II II -CH=CH— 176 10.26 1« II -CH-CH——F 176 10·27 11 II CL1 157 10.28 1曹 II -CH=CH^^-C1 178 10.29 11 " -CH=CH~-Cl 167 10.30 II II _CH:CH—◎一 ％ 175-176 10·31 " II -CH=CH—--COOEt 180-181 10.32 II II -CH^CH—-COOH 246-248 10·33 Η If —CH^CH·1 " ^ ^ ~ "-OH 153 10.34 II II -CH=CH--OCH3 168-169 10.35 II 1曹 -ch2-ch2— 80-81 10.36 11 If -CH2 -CH2 88-89 S 請 先 閲 讀 背 面 之 注 意 事 項 再 填 寫 頁 適 度 尺 張 紙 s) N (c 準 標 格 規 9S- 公 97 81·9·25,000 030^9 A6 B6 五、發明説明（27 ) A R Y [熔點t：] 10.37 II u -CH2-CH2 —COOEt 120-121 10.38 II II CH2*CH-CH2-CH2- 91-93 10.39 " 11 -CSC—{〇) 135 10.40 II II -csc-^〇)~ci 138 10.41 ch2 H ch3 111-113 10.42 It II _CH2 —O—〈》- och3 141-143 ch3 10.43 II It -ch2-o-/ \ 105-107 ch3 ch3 10.44 11 11 -ch2-o-<^"^— ——ch3 129-131 ch3 10.45 II II 92-94 請 先 閲 讀 背 面 之 注 意 事 項， 再 塡 窝 頁 裝 訂 準 標 家 固 國 中 用 適 度 尺 張 紙 衣 經濟部中央標準局8工消費合作社印製 甲 s) 4規格（210 X 297公楚） 30 - 81.9.25,000 五、發明説明（28 ) A6 B6 經濟部中央標準局R工消費合作杜印製
請 先 閲 讀 背 面 之 注 意 事 項 再 填 頁 裝 訂 線 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公笔） 31 81.9.25,000 五、發明説明（29 ) A6 B6 經濟部中央標準局员工消费合作社印製 A R Y [熔點tn 10.53 II II /CF3 99-100 10.54 II " -ch2-〇-^ ^)-CN 160-162 10·55 Μ II -CH=CH-^ -COOC2H5 149-150 10·56 II II 177-178 10.57 " 1« -CH=CH-/ V〇CH3 160-161 10.58 It If JU 220-222 10.59 ch2-ch2 H 141-142 10.60 tl 11 /〇 129-130 10-61 ft II r\ -H2c 127-128 (請先閲讀背面之注意事哫再填 貝) 裝· 訂· .線 適 度 尺 張 紙 本 2 )3 公 97 2 X ο 21 /V 格 規 4 甲 s) N (c 準 標 家 國 國 中 81.9.25,000 ^〇3〇^9 Α6 Β6 五、發明説明（30 ) 經濟部中央標準局MC工消费合作社印製 A R Υ [熔點°c ] 10·62 II II -ο 128 10.63 II II -ο 153 10.64 II II ο 131 10.65 II II —ο 151 10.66 " II -ch2-ch2-^3 133 10.67 II Μ -Ο 165 10.68 " tl -ο 134 奮例1 1 下列化合物像依類同於實例2之方法製得： 公 97 2 X ο 21 /(\ 格 規 4 甲Ο Ν (c 準 標 家 國 國 中 用 適 度 尺 張 紙 33 81,9·25,000 請 先 閱 讀 背 面 之 注 意 事 項 再 填 寫 頁 裝 訂 線 ^030^3 A6 B6 五、發明説明（31 ) H0-
R I-A-N-CO-Y 經 濟 部 中 央 標 準 局 Ά 工 消 費 合 if 社 印 製 A R Y [熔點〇 ] 11.1 ch2-ch2 ch3 -C(CH3)3 151-153 11·2 II If -ch2-ch2-^^sF 133 11.3 π 11 -ch2-ch2 —-ch3 124-125 11·4 It II -CH2-CH2 —~~~-COOEt 118-119 11·5 11 tl -CH=CH-F -CH=CH-/^S 133 11· 6 II II /~<cl 150 11.7 II II -CH=CH—Cl 123-124 11·8 II II -CH=CH~^ ^-—CH3 115-116 11.9 It II -CH=CH一--COOEt 118—119 11.10 «1 11 -CH=CH-—--COOH 199-201 11.11 If II -CH=CH--OCH3 146-147 11.12 ft It 'C-=C 'Ο 119 11.13 11 II -c~^—》-'-1 146 請 先 閲 讀 背 面 之 注 意 事 項 再 填 寫 頁 本纸張尺度適用中國國家標準（CNS).甲4規格（210 X 297公釐）α -34 81.9.25,000 A6 B6 五、發明説明（32 ) 窨例1 2
N (·?· 5 -二一恃 丁基一 4 -琛芏某）一·？一 （4· 荣氩甚酸）一丙烯醅胺 將 5. 8g (0. 0124 莫耳）N —（3, 5 -二 一特丁基一 4_經窄基）一 3 — （4 一苯氣基乙酸乙醋） 一丙烯醯胺（參見實例6)於室溫下，於50m5乙醇及 5〇mJ2水中，與1. 06g (0. 019莫耳）氫氣化 鉀共同攪拌24小時。而後將醇濾出，再將餘留物以稀氫 氯酸酸化及以乙酸乙酯萃取。將乙酸乙酯蒸發後，將産物 由二乙醚/異己烷（1 : 1 v/v)中予以再結晶，産 量為 1. lg;熔點 125— 1261C。 下列化合物偽依類同之方法製得： 12.1 N— (3, 5 —二—特丁基一 4 一 羥苄基）一 3 — （3, 4 —二羥基苯基）.一丙烯醯胺，幾 乎無色之結晶形式，熔點2 3 3 - 2 3 5 Ό , 由N- (3，4 一二一特丁基一4 —羥笮基一 3— （3, 4—二乙醯氣基苯基）一丙烯醯胺 請 闖 讀 背 面 之 注 意 事 再 填 裝 訂 線 短濟部中央標準局貝工消費合作杜印製 2 . 2 中製得（參見實例5. 7) N — （3, 5—二一特丁基一 4_羥苄基）一 3— （4—羥羰基苯基）一丙烯醯胺，由N-3, 5 —二一特丁基—4—羥笮基）一 3 — （ 4 一乙氣羰基苯基） 實例1 0 · 5 5 ) 丙烯醯胺中製得（參見 ：紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐Β5- 81.9.25,000- a 9 A6 B6 五、發明説明（33 )
富例1 .S N — （3. 5 — 二一特丁甚-4—挥苌基）一3- (4· — 特戍醅某荣某）一丙烯醅除 令 3. 8g (10 毫莫耳）N — (3，5 —二一特丁 基一 4一羥苄基）一 3 —（4 一羥苯基）一丙烯醯胺（參 見實例5)溶於100mi四氫呋喃中，再將2. 8mi (20毫莫耳）三乙胺加入。邊冷卻至5至10¾間，邊 將1. (12毫莫耳）特戊酸氛化物之四氫 呋喃液逐滴加入，於室溫下攪拌24小時後，將反應混合 物以水稀釋，並以乙酸乙酯萃取，將乙酸乙酯蒸餾出後所 得之餘留物置於硅膠柱（KG6 0)上予以純化，並以異 己烷/乙酸乙酯洗提。將蒸發之餘留物以二乙醚碾磨後， 即得無色之結晶；熔點172—1731。 奮例1 4 N (3. 5~~ 二一特丁基—4~~ 掷书基）~~3 ~~ (4 — 胺基笨某）一丙烯醅胺 令4.1g (10毫莫耳）N_ (3, 5—二一特丁 基一 4 —羥笮基）一3 — （4 一硝苯基）一丙烯醯胺（參 見實例10. 17)溶於250mi2乙醇中，再與6. 5 s ( 1 7 0毫莫耳）鋅粉混合。繼而邊強烈攪拌邊於1小 時期間將100m52莫耳氫氮酸逐滴加入。攪拌3小時 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐）36- (請先閱讀背面之注意事項再填寫疒¾) _裝· 訂. 經濟部中央搮準局S工消費合作社印製 81.9.25,000 ^〇3〇ύ Α6 Β6 五、發明説明（34 ) 後，令反應終止。繼而將反應混合物空吸濾出，再將濾液 蒸餾出，而後令餘留物置於乙酸乙酯及水中。乙酸乙酯蒸 發作用餘留物則置於硅膠柱（KG60)上予以純化。以 異己烷碾磨後，卽得1. 5g産物；熔點801C (熔結） Ο 奮例1 5 N— (3， 5 —二一恃丁基一 4 一經书基）一 4 —辉甚 氩基乙醯胺 令 1. 5g (3. 2 毫莫耳）Ν — （3, 5 — 二一持 丁基一 4一羥笮基）一4_苄氧基苯氣基乙醯胺（參見實 例10. 50)溶於5〇mi?甲醇中，與◦. 5gl0% 把-炭混合，再於室溫下及常壓下氫化3小時。以空吸法 將催化劑濾出再將溶劑蒸發後，即得1 . 2 s無色之結晶 ;熔點 1 14—1 16t：。 下列化合物係依類同於實例1 5之方法製得： 經濟部中央標準局R工消费合作社印製 · ν A R Y 熔點.c 11.1 ch2 H -CH2-°-0'NH2 » 109-111 11.2 ch2 H /=M -CH2-CH2 人》 140-141 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公落）37 - 81.9.25,000 A6 B6 五、發明説明（35 )
官例1 R N- (3. 5 - 二一特T某一 4-铧芏某）一3 — 涇甲基苯基）一7.醅胺 將2· 7g (6毫莫耳）N— （3, 5—二一特丁基 —4 一羥笮基）一 3- （4 一乙氣羰基苯基）一丙烯醯胺 (參見實例10. 55)於室溫下與氫硼化鋰（由1. 4 g氫硼化納（37毫莫耳）及1. 6g氯化鋰（37毫莫 耳）中製得）於ΙΟΟπιβ乙二醇二甲醚中共同攪拌，繼 而於5 0Ϊ：下攪拌4小時。而後用水及2莫耳硫酸將還原 錯合物分解，再將産物以乙酸乙酯萃取，將乙酸乙酯相蒸 發，並將餘留物以二乙醚/異己烷碾磨後，即得1 . 1 g 無色之寧晶；熔點1 77- 1 79t：。 經濟部中央標準局R工消费合作社印製 適 度 尺 張 紙 8 3 \—/ 公 97 2 X ο 21 /V 格 规 4 甲 Ο Ν (c 準 標 81.9.25,000

Claims (1)

  1. 六、申請專利範团 附件三 : _ • 第81106307號申請專利案 中文申請專利範圍修正本 民國82年1月修正 1 .通式I化合物及其製藥上可接受性鹽類：
    -Α.-Χ-Γ (請先閲讀背面之注意事項再蜞寫本頁) (I) 經濟部中央標準局β:工消費合作杜印製 其中A為價鍵或最多含5個碩原子之直鏈或支鏈烷基，X 為一 NR-CO - （醯胺）或一 NR-CO — NR —（脲 )基團，其中之R為氫原子或C2_C4 —烷基團，且Y為 最多含有6個硕原子之直鍵或支鍵，飽和或未飽和烴鍵， 彼可被芳基，雜芳基，芳氧基或芳硫基取代，其中芳基為 苯基或某基，雜芳基為睡吩基，呋喃基，吡咯基或蚓跺基 ，或Y為C3_Ce-環烷基或芳基，該芳基為苯基或某基 ,又此處之芳基或雜芳基圍可在環之所有可能位置上被氣 基，羥甲基，甲二氧基，鹵素，三氟甲基， 基，胺基，Ci— C4 一酸基胺基，二一 （Ci—C4) 一院 胺基，羥基，Ci 一 c4_烷氣基，羧基，氧乙酸乙酯或硝 基取代一至三次，惟當A不為一 CH2—或一 CH2 — CH 2—時，則Y僅可代表未經取代之苯基。 2. —種製造通式（I)化合物及其製藥上可接受性 本紙張尺度適用中國國家樣準（CNS)甲4規格（210 X 297公笼） 81,9,10,000 ^〇3〇^9 A7 B7 C7 D7 六、申請專利範圍 鹽類之方法： Ο Ν> -Α-Ϊ-Τ (I) 經濟部中央揉準局S工消費合作社印製 其中A為價鍵或最多含5個碩原子之直鏈或支鏈烷基，X 為一 NR-CO - （醯胺）或—NR-CO — NR—(脲 )基圍，其中之R為氫原子或Cz— C4 一烷基團且Y為最 多含有6個磺原子之直鏈或支鏈，飽和或未飽和烴鏈，彼 可被芳基，雜芳基，芳氧基或芳硫基團取代，或丫為〇3 一 Ce環烷基或芳基圍，其中芳基為苯基或某基，而雜芳 基為吡啶基，睡盼基，呋喃基，吡咯基或嗍晬基，又此處 之芳基或雜芳基圍可在環之所有可能位置上被氰基，羥甲 基，甲二氧基，鹵素，三氟甲基，C; 一 C4 一烷基，胺基 ,C 2 — C 4 —醯基胺基，二一 （C ; — C 4) 一烷胺基，羥 基，C, 一 C4—烷氧基，羧基，氧乙酸乙酯或硝基取代一 至二次，惟當A不為一 CHz—或一 CH2— CHs—時， 則Y僅可代表未經取代之苯基，此方法包括： a)當X為一 CO — NR —基圃時，乃令通式（I I)化 合物： ------------{----ί ------裝------trH (請先閲讀背面之注意事項再填窝本頁) 衣纸張尺度適用中国國家標準（CNS)甲4规格（210 X 297 *：釐）_ 2 81.9.10,000
    -A1-NHH (III) 六、申請專利範圍 (II) 與通式（I I I)化合物起反應 0 Y - C - Z 其中Y乃如上所述且Z為羥基，鹵素，C, — c4 —烷氣基 或昼氮化物；或者 b)當X為一NR — C〇 — NR —基圍時，乃令通式（ I I )化合物 ------------<----< ------裝------.Tri (請先閲讀背面之注意事項再填寫本頁)
    HQ-// n-A-NHR (II) 經濟部中央標準局R工消費合作社印製 其中A及R乃如上所述，與通式（IV)之異氰酸酯起反 應 0 = C = N - Y (IV) 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） 81.9.10,000 A7 B7 C7 D7 其串、，如期望的話，再依己知之方法將所得 之通式I化合物轉換成另一種通式I化合物，且如期望的 話，再將所得化合物轉換成藥學上可接受性鹽。 3 .根據申請專利範圍第1項之化合物，彼像由如申 請專利範圍第2項之方法製得。 4.一種用於治療代謝疾病之藥學組成物，含有如申 請專利範圍第1或3項中之至少一種化合物，及含有慣用 之載髏及輔劑。 (請先閲讀背面之注意事項再填寫本頁) .丄----^ ------裝------訂一{----f 經濟部中央標準房R工消費合作社印« 本紙張尺度適用中國國家標準（CNS)甲4规格（210X297公楚） 81.9.10,000 ίο is 附件一： ，正 ik:. i. < ί f.~~~ 第81] 06307號專利申請案中文補充資料 民國82年1月呈 式I化合物之活體外功效（結果列於表中） 垩，十曰—π筑纟円日知由Bg固酉皋四旨^开^成的f 制Μ乍用（~砍照H u h P r等 人 Π ΏΏΟ ) Free Rad, R^s . Comms . 8,1 R7-T 7^) ； MAK1: 以預先選擇之密度，藉連續超離心法，由健康之男性非 吸煙者之血锻中分離出人類血駿L D L ,再於3 7 中在 F — 1_ Ο介質+ 1 " M C u (II)中再培育5小時，以耗 盡其親脂性抗氣化劑。當細胞（2 X 1 〇6/m)於f — 1 〇介質 + 1 U M C \Λ ( II) + δ Ο g / m 1 L· D L· -h B 96 F C S中培育1 8小時後，在經調整之人類血繼L 〇 L之 影響下，膽固醇酯在P 3 8 8 D . 1巨_細胞内之生 成情形，係在中性脂肪之萃取後藉薄層色層分析法測最。 參考物質：卩「〇1^(:〇1,10“卩對膽固醇酯形成之抑制程 度：58-75 (無藥物時為1〇〇)。 對士 W Η旨fl方讓合_ί Ί.6 - Η旨氬合1¾)-在LD L基耆庶>J!gjg：ILx Ψ4 (2X0X297^·*) —---- 20 ίο 16 依照 C：社h ⑺ rt 等人（195311 __丄丄 Res · 32，63-70)： 在 20mM Tris-Cl PH8.3, 150mM NaC 1 中，有及無試驗物 質（溶於乙醇中，乙醇之最終濃度為Ο. 5%)之情況下 ，S>： 3 T TJW500011/2m l 大豆貝旨肪氣合酶（S i gma， Munich)中，1笞養LDL (100". g蛋白質/m])。觀察_氧化作用 ，偽在A234連缠測量二燃類。受試物質之濃度定義為ICso 值，其導致二傭形成之一半，且與試驗期間之時間成線性關 參考物質 ：Probucol , ICso-M = 20 ^ Μ (21βΧ297公*) 20 103咖 在巨嗤細胞 (P388 D.1) 中對膽固醇酷生 生成作用之限制10 μΐά % 15-7 對經15-脂肪 氯合酶調節 之LDL氧化作 用的限制 lc50 (⑽）0.1 實例號碼 29306415 u8183036 2 13 2 6 2 7 1 6849304002 5595845288 1111113221 14-5 22.4 38.5 19.8 23.7 20.1 58*7 40.7 50.7 22.0 22-7 25.3 42.3 59.5 53*8 5 53 Ϊ 5 ; 3 21 5 7 5 5 9 5 7 9 8 7 7 3 8 :， 5 6 3 7 2 2 5 9 5 5 6 2 X 5 4 5 5 010011800000822000400022501120501011110112 0000000000001013030110000000000000000000001 0.160*2 2 3 4 5 67 〇3〇^ 37.4 56.4 34*9 35·7 51.5 ,83*9 62.0 57 · 2；；， 34.4 31*0 39.0 47.0 57.2 58.1 46.0 53.1 72.2 61.5 61*8 96*2 64.3 34.9 50.5 50*0 63.2 21.8 30*5 3 3 3 : 8 4 39 9 5 79 55 5 5 594562 4 5 6 3.2 7 7 6 5 13 8 8 8 8 1020122210 2222530212161706313000013001112 οοοοοοοοοο OOQOOOOOOOOOOOOOOOOOOOOOOOOOOOO 0.12 0·15 574130125 737356506 112222546 0*093 0*13 10/59 10/60 10/61 10/62 10/63 10/64 10/65 10/66 10/67 10/68 9/ΪΟ 9/11 9/12 9/13 9/14 9/15 9/16 9/17 9/18 9/19 9/20 9/21 9/22 9/23 9/24 9/25 9/26 9/27 9/28 9/29 9/30 9/31 9/32 9/33 9/34 9/35 9/36 9/37ι 9/38 9/39 9/40 11/1 11/1 11/2 11/2 11/3 11/4 11/5 11/6 11/7 11/8 11/9 12/1 12/2 * · _ο3ο 9 0 5 4 3 11 9 2 2 3 7 3 6 4 4 5 6 3 X 1 4415657 113 3 4 2 1 4836341211108153 0037053297 1161122223 9 θ o 16 6 8 6 5 4 73411961043355951032576005009493134397455 孤 »k · r I p — I, k ki kF 0 kvF 0 0·15 0.22 0 .035 0 .047 0 -03 0 -12 0 .1 0 .2 1 .0 0 .1 0 .3 0 .2 0 .55 0 -7 0 .105 0 .5 0 .2 ο ο ο 8 ♦ o 40030190000000 3 5 3 9 467055150 3 8 5 8 2 50303411 10/110/2 10/3 10/4 10/5 10/6 10/710/8 10/9 10/10 10/11 10/12 10/13 10/14 10/15 10/16 10/17 10/18 10/19 10/20 10/21 10/25 10/26 10/27 10/28 10/29 10/30 10/31 10/32 10/33 10/34 10/35 10/36 10/37 10/38 10/39 10/40 10/41 10/42 10/43 10/44 10/45 10/46 10/47 lp/48 10/49 10/50 10/51 10/52 10/53 10/54 10/55 10/56 10/57 10/58
    N M R -值 1 H-NMR(CDC13 4.48(d, 2H, 5.8(t(br.), =CH)； 7.12 (s, 2tt, H) ； 7.61(d, TLCiRF=0.62 )S = 1.44(3, 18H, 2 X t-BU-CH3)/ CH2-NH)； 5.33(s, 1H, OH)； 1H, -NH) ； 6.36(d, 3 j = 16Hz, 1H, ，芳族，H); 7.3 - 7_45(m, 4H,芳族-· 3 j = 16Hz, 1H = CH). 實 例 TLC：Rf=0.61 y 例 10.26: 1 H-NMR(CDC15 ) <5 = 1.43 (s, 18H, 2 X t-Bu-CH3 )； 2-7(t, 2H# Ar-CH2)； 3.62(m, 2H, CH2-NH), 5.13(s, 1H, OH)/ 5.7(t(br.), 1H, NH)； 6.28(d, • ： 3 j = 16Hz) , 1H, = Cfn ; 7.0(s, 2H,芳族.H〉； ' 7.05 - 7.1(m; 2H,芳族 Η) ; 7·4 - 7.5(πι, 2H, TLC:Rf==〇-54 arom. H) ; 7.6 (d, 3 j = 16Hz, 1H, = CH) · 1 H-NMR(d6-DMSO)S = 1.38(s, 18H, 2 X t-BU-CH3); 2.63(t, 2H, CH2-Ar)； 3.3(m, 2H, -CH2-NH)； 6.05 (t(br. ) , 1H, ..NH) ; 6.72 (s, 1H , OH); 6.8 - 7.4(m, 5H,芳& H); 6*95(s, 2H,芳族 H); 8.45(s, 1H, NH). 寫--.例 8-3: 1 H-NMR(d6-DMSO)ί « 1.39(s, 18H, 2 X t-Bu-CH3 ); 4.3(d, 2H, CHZ-NH)； 6.8(d, 3j = 15Hz, 1H, =C2)7 6.9(s, 1H* OH); 7:95(s, 2H,芳族-H>; 7.35 - 7.4(m, 1H,批 _.陡基_二-11); 7,52(d, 3j = TLC:Rf=0.05 15Hz, 1H, =* CH) ; 8.0(d(br.),lH,NH);8.5- 8.8(m, 3H,.吡啶基，H). 一寅—Μ： 9·20: 1 H-NMR(d6-DtiSO) 5 * 1.38(s, 18H, 2 X t-BU-CH3 ); ., 2.26(5, 3H, Ar - CH3 ) / 4.17 (d, 2H, 0¾-NH)； ί ? 5.7(d„ 3j = 15Hz, 1H, = CH)； 6.6(t(br.), 1H, NH) ; 6‘85(S, 1H, OH) ; 6.85 - 7.15(ro, 4H,芳族 TLC:Rf=〇.65 H) ； 7.35(dd, 3 j = 15H2 U. 12Hz, 1H, = CH-NH)； 8.55(d, = 12Hz, 1H, = CH-NH)； 在砂膠（MERCK HPTLC)上測得之TLC數據•元素— 甲苯/乙酸乙酯（3 : 1)
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