TW546138B - Compounds with 1,3-propane diol linked structure and 1,3-propane diol derivatives - Google Patents
Compounds with 1,3-propane diol linked structure and 1,3-propane diol derivatives Download PDFInfo
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經濟部中央標隼局員工消費合作社印袋 546138 A7 —_________ B7 五、發明説明(1 ) ~~—- 範圍 此説明係有關生物活性物之製品,包括藥物,必需營養 素或任何其他給予人類或動物體以治療或維護健康的化合 物。 特定地説,本説明係有關可輕易通過體内的脂障礙的親 脂性形式的生物活性物製品,或有關同一分子内有二種生 物活性物的製品(其中至少生物活性物之一爲脂肪酸或脂 肪醇),或有關能達成此二目的及/或能輕易合成無對掌性 中心的化合物目的的生物活性物製品。從藥物管理觀點言 ,單一分子中有二生物活性物較此二生物活性物爲分開二 二種爲佳。以新穎方法供應已知的生物活性物也是有益的 。此等益處包括親脂性的增加,同時供應二種生物活性物 會產生相加效果,有時此等生物活性物會產生協同效果。 本發明係關於通過特定的鍵合分子鍵合生物活性物,此 點於後面有詳細敘述,並有關新穎化合物的合成,有些化 合物從其用於治療及/或維護健康方面言也是新穎的。但 本説明也討論及使用此處未申請專利的其他鍵合分子的化 合物,也討論及直接鍵合的生物活性物,如epa_0 393 920 所揭示的脂肪酸及抗病毒素,以及Ep-95301315 8 (公佈爲 ΕΡΑ-0 675 103)所揭示的脂肪酸及非類固醇抗炎藥物。 參考資料 已公佈的專利及一般文獻中並未重視上述的觀念,但有 些文獻討論過特定的天然的二醇衍生物及二醇酯在營養及 醫藥上的用途。一般文獻中,BergelS0n等(Biochim, 本紙張尺度適用中國國家標準規格(iioxw7公釐) (請先閱讀背面之注意事項再填寫本頁) ·«衣· 訂 546138 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(2 ) Biophys. Acta 处(1966) 511-520)曾述及 1,3-丙烷二醇。但 並未述及酸基,只説明二油酸酯。Nabisco於ΕΡΑ-0 405 873及ΕΡΑ-0 405 874專利文獻中述及可食性脂肪摩擬物, 並包括亞麻酸酯(此詞爲特別註明指’’ α,'異構物)及花生四 烯酸酯,而且明顯地是指此等酸的1,4-丁烷二醇酯。 Unilever的英國專利2 161 477 (相當於ΕΡΑ-0 161 114)述及 使用亞油酸及亞麻酸(也指α異構物)的1,3·丙烷二醇酯對 植物生長及經濟性的影響。SS Pharmaceutical Co.的ΕΡΑ-0 056 189説明2,3-丁疏二醇酯的抗潰瘍藥物。Sanofi於ΕΡΑ-0 018 342顯示丙烷-1,3-二醇酯的各種藥學作用。更不同的 可能是 Terumo Κ·Κ·於 ΕΡΑ-0 222 155揭示以-CH(R)-0-(其中 R=甲基等)键合5 -氣尿喃淀於π亞麻酸、二均加瑪亞麻酸 或二十碳五烯酸上作爲抗癌劑。 酯障礙 許多藥物是藉與細胞表面受體結合作用於細胞膜表面, 或者藉特定運送系統進入細胞内。有許多藥物是藉在細胞 内改變一或多種功能(如核酸功能),改變細胞内酶的作用 ,或改變溶酶體或微管系統的行爲而發揮作用,但又不能 有效地進入細胞。此等藥物可能沒有可以键合的受體及運 送系統,或者使等運送系統只能以較低的速度運送藥物至 細胞内。同樣的藥物可能以較低的速度透過細胞内膜,如 線粒體膜及細胞核膜。 還有其他障礙對藥物移動也是重要的。特別重要的障礙 之一是血·腦障礙,其具有許多細胞膜的特點。許多藥物 -5- 本紙張尺度適用中國國家標準(CNS ) Α·4規格(210Χ 297公釐) (請先閱讀背面之注意事項再填寫本頁) 546138 A7 B7 五、發明説明(5 位私至他位,形成原始製備時所無的新分子。這很明顯 地會引起問題,特別是在藥物管理方面,藥物管理上是= 容許有此種不安定性的。 、 當投送二種不同的脂肪酸時,其優點除前述者外,還有 能同時給予在單一分子中有二種不同生物作用的物質。這 可避免管理上的問題,這一問題是在作爲二種化合物分別 給予時發生的,以及有可能有對掌性中心時發生的。在二 種藥物作爲分別的分子投送時,管理當局一般要求將每一 化合物作研究,並對二種化合物合用時作研究。如果二個 分子合成一個分子,就只需對單一分子作研究,可大量降 低發展成本。 除脂肪酸外,在有活性物時也有相似的優點。此等化合 物容許藥物或其他化合物以必較親脂性化合物的形式給予 ’此等化合物是非對掌性的(除非藥物或其他化合物是對 莩f生的)’也較易釋出活性邵分,而且在經口給予、局部 給了或非經口給予時也較有耐受性。其親脂性可使其部分 經由淋巴系統吸收,這就可繞過肝臟;減少像許多化合物 那樣對胃腸產生刺激;也易於使藥物及其他劑通過親脂障 礙運送,如皮膚、細胞膜及血-腦障礙等都是親脂障礙。 已有證明,除了易於通過脂質障礙外,使藥物更具親脂 性也還有其他特定性質。此等性質包括作用時間的延長, 副作用(特別是胃腸的副作用)的減少,繞過肝臟的代謝, 及使不同物質投送於特定的位置上。 -8 本·紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) .II - i - I- ------- (請先閱讀背面之注意事項再填寫本頁〕 經濟部中央標準局員工消費合作社印製 546138 A7 ---- B7 五、發明説明(6 ) —— ^ '一 脂肪酸衍生物;脂肪酸的效果 活性物通過脂質膜的運送可藉將活性物直接或經過中間 體键合於,特別是,加瑪亞麻酸(GLA)或二均加瑪亞麻酸 (DGLA)上而得改進,而加瑪亞麻酸及二均加瑪亞麻酸本 身即有各種所需效果。此種键合也能使生物活性物與同一 为子的脂肪fe共同投送,此等脂肪酸除了任何運送優點外 ’其本身也有所需的作用。也可用其他脂肪酸,如任何必 需脂肪酸(EFAs),特別是η·6及n-3系列的十二種天然脂肪 酸(圖1)。於此等十二種脂肪酸中,以花生四烯酸,腎上 腺敗’硬脂四綿酸,二十碳五晞酸,二十二碳六晞酸爲尤 佳,因爲其本身即有所需效果。而且也可用任何脂肪酸, 較宜的是CirC3〇或CfCso的及有二或多個順式或反式碳_碳 雙键的。可以脂肪酸的形式或對應的脂肪醇的形式使用。 共軏亞油酸及加侖賓酸(columbinic acid)爲脂肪酸的例,此 等脂肪酸本身即舉有價値的性質,也似乎特別有用。因之 此處有關脂膀酸的參考都指二種形式,唯其一或另一形式 的化學性質未明者例外。但GLA及DGLA的性質使其特別 適於作此使用。 經濟部中央標準局員工消費合作社印製 !蜷! (請先閱讀背面之注意事項再填寫本頁) 必需脂肪酸在性質上都是順式構形,系統上稱作對應的 十八燒酸、二十燒酸或二十二燒酸的衍生物,例如z,z_十 八·9,12-二烯酸或 z,z,z,z,z,z_二十二 _4,7,10,13,16,19-六晞酸 ,但其數字指示係基於碳原子的數目,不飽和中心的數目 以及由鏈不飽和開始處的鏈端算起的碳原子數目,如以 l8:2n_6或22:6n_3表示較方便。名稱的縮寫如EPA及簡稱如 -9 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 546138 A7 B7 五、發明説明( 二十碳五烯酸於某些情形下是隨意使用的 圖1 n-6 EFA's 18:2n-6 (亞油酸,LA)4 18:3η·6 (厂亞麻酸,GLA)i 20:3n-6 (二均 r 亞麻酸,DGLA)1 20:4n-6 (花生四晞酸,AA)1 22:4n-6 (腎上腺酸) 22:5n-6 d -6-去飽和酶 增長 β -5-去飽和酶 增長 -4-去飽和酶 n-3 EFA-s 18:3η-3 (α-亞麻酸,ALA)1 18:4n-3 (硬脂四烯酸,SA)4 20:4n-3 20:5n-6 (二十碳五缔酸,EPA)I 22:5n-3 22:6n-3 (二十二碳六烯酸,DHA) (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 GLA 及 DGLA GLA及DGLA本身顯示有抗炎效果,降低血壓,抑制血 小板凝急,降低膽固醇含量,抑制癌細胞生長,減少運動 障礙,解除胸痛,增進鈣的吸收並增強沉著於骨中,減少 離子化放射的副作用,治療各種精神疾病,使血管擴張, 增進腎功能,治療糖尿病併發症,鬆弛血管等。所以活性 物键合於GLA與DGLA上,不僅會變得更親脂性,增強通 過各種膜,皮膚及心腦障礙,似乎也能展現新的其他治療 效果。是以,脂肪酸可以是共生兩分的藥前體(直接鍵合 -10- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 546138 A7 B7 、發明説明(8 ) 時)或共生三分的藥前體(如果經由鍵相聯)。 在這方面有特殊價値的其他脂肪酸是花生四烯酸及二十 二碳六烯酸,此等酸是細胞膜的主要構成部分;腎上腺酸 ’硬脂四烯酸以及二十碳五晞酸也有類似GLA及DGLA的 性質。未包括於圖1中的但也有特殊價値的脂肪酸是共軛 亞油酸(cLA)及加侖賓酸(CA)。cLA在治療及預防癌症方面 ,在促進生長,特別是蛋白質合成方面,在預防及治療心 血管疾病方面,以及作爲抗氧化劑,都有特別效果。CA 也有必需脂肪酸的多種性質。 與生物活性脂肪酸有共生效果的活性物的種類 可加於此處所述化合物的活性物的種類可大致分爲:- a) 包括抗生素,抗原蟲藥,抗精神病藥,抗憂鬱藥及 NS AID s在内的藥物,以及用於治療心血管疾病,呼 吸疾病,皮膚病,精神病,神經病,腎病,肌肉疾 病’ θ >9^疾病’生殖寺疾病及癌的化合物。 b) 激素 c) 胺基酸 d) 維生素’特別是B群維生素’及其他必需營養素。 e) 細胞活素及肽 f) 神經傳遞質及神經傳遞質前體。 g) 屬於磷脂質的化合物,如肌醇,膽驗,絲胺酸及乙 醇胺,此等化合物可直接键合或經礙酸根键合。 h) 芳香族脂肪酸,如苯基醋酸,苯基丁酸,及肉桂酸 ,此等酸在治療癌症上有特殊價値。 -11 - 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ 297公釐) —---------丨 (請先閱讀背面之注意事項再填寫本頁Employees' Cooperative Printing Bag of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 —_________ B7 V. Description of the Invention (1) ~~ —- Scope This description refers to the preparation of biologically active substances, including drugs, essential nutrients or any other given to humans or animals. To treat or maintain healthy compounds. In particular, this note relates to bioactive preparations in lipophilic forms that can easily pass through dyslipidemia in the body, or to preparations with two bioactives in the same molecule (wherein at least one of the bioactives is a fatty acid or Fatty alcohols), or bioactive preparations that can accomplish both of these goals and / or can easily synthesize compounds without palm centers. From the perspective of drug management, it is better to have two biologically active substances in a single molecule than to separate the two biologically active substances. It is also beneficial to supply known bioactives in novel ways. These benefits include an increase in lipophilicity, and the simultaneous supply of two bioactives can produce additive effects, and sometimes these bioactives can produce synergistic effects. The present invention relates to the bonding of biologically active substances through specific bonding molecules, which will be described in detail later, and related to the synthesis of novel compounds. Some compounds are also novel in terms of their use in the treatment and / or maintenance of health. However, this description also discusses and uses other compounds that are not patented here for bonding molecules, and also discusses and directly binds biologically active substances such as the fatty acids and antivirins disclosed in epa_0 393 920, and Ep-95301315 8 ( Published as EpA-0 675 103) fatty acids and non-steroidal anti-inflammatory drugs. References The published concepts and general literature do not pay attention to the above concepts, but some literatures discuss the specific natural diol derivatives and diol esters for nutritional and medical uses. In general literature, BergelSon, etc. (Biochim, this paper size applies Chinese national standard specifications (iioxw7 mm) (Please read the precautions on the back before filling out this page) · «Clothes · Order 546138 Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of A7 B7 V. Description of the invention (2) Biophys. Acta (1966) 511-520) has mentioned 1,3-propanediol. It does not mention acid groups, only dioleate. Nabisco in the EPA-0 405 873 and EPA-0 405 874 patent documents describe edible fat mimetics and include linolenates (the term is specifically noted to mean `` α, 'isomers) and arachidene Acid esters, and obviously the 1,4-butanediol esters of these acids. Unilever's UK Patent 2 161 477 (equivalent to EPA-0-0 161 114) describes the effects of the use of 1,3 · propanediol esters of linoleic acid and linolenic acid (also referred to as alpha isomers) on plant growth and economics . EPA-0 056 189 from SS Pharmaceutical Co. describes an anti-ulcer drug for 2,3-butanediol. Sanofi at EPA-0 018 342 showed various pharmaceutical effects of propane-1,3-diol esters. A more different possibility is that Terumo K · K · in EPA-0 222 155 revealed that -CH (R) -0- (where R = methyl, etc.) was bonded to 5-urethane deposited on π-linolenic acid, dijunca Maleic acid or eicosapentaenoic acid acts as an anticancer agent. Ester disorders Many drugs act on the surface of cell membranes by binding to cell surface receptors, or enter cells by specific transport systems. Many drugs work by changing one or more functions within the cell (such as nucleic acid functions), changing the role of enzymes in the cell, or changing the behavior of the lysosome or microtubule system, but they do not enter the cell effectively. These drugs may not have binding receptors and delivery systems, or such delivery systems can only deliver drugs into cells at a slower rate. The same drugs may penetrate the inner membranes of cells, such as the mitochondrial membrane and the nuclear membrane, at a lower rate. There are other obstacles that are also important for drug movement. One of the most important obstacles is the blood-brain disorder, which has many cell membrane characteristics. Many drugs-5- This paper is in accordance with the Chinese National Standard (CNS) A · 4 size (210 × 297 mm) (Please read the precautions on the back before filling out this page) 546138 A7 B7 5. Description of the invention (5 private Other sites, forming new molecules that were not present in the original preparation. This will obviously cause problems, especially in terms of drug management, which is tolerant of this instability. When two different fatty acids are delivered In addition to the foregoing, its advantages are that it can simultaneously administer substances with two different biological effects in a single molecule. This can avoid management problems, which occur when the two compounds are administered separately, And it may happen when the center of the palm is matched. When two drugs are delivered as separate molecules, the regulatory authority generally requires each compound to be studied and the two compounds to be used in combination. If two molecules are synthesized For one molecule, only a single molecule needs to be studied, which can greatly reduce the development cost. In addition to fatty acids, there are similar advantages in the presence of actives. These compounds allow Drugs or other compounds are given in the form of more lipophilic compounds 'these compounds are non-palladium (unless the drug or other compound is anti-peptide)' are also more likely to release active ingredients and are given orally It is also more tolerated when given topically or parenterally. Its lipophilicity allows it to be partially absorbed through the lymphatic system, which bypasses the liver; reduces the gastrointestinal irritation like many compounds; it is also easy to make drugs And other agents are transported through lipophilic disorders, such as skin, cell membranes, and blood-brain disorders. They are all lipophilic disorders. It has been proven that in addition to being easy to pass through lipid disorders, there are other specific properties that make drugs more lipophilic. This Other properties include prolonged action time, reduced side effects (especially gastrointestinal side effects), bypassing the liver's metabolism, and allowing different substances to be delivered to specific locations. -8 This paper size applies Chinese National Standards (CNS) A4 specification (210X297mm) .II-i-I- ------- (Please read the notes on the back before filling out this page] Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Print 546138 A7 ---- B7 V. Description of the invention (6) —— 'A fatty acid derivative; the effect of fatty acid The active substance can be transported through the lipid membrane directly or through an intermediate, especially Yes, it is improved on Gamma linolenic acid (GLA) or Dijungamaric linolenic acid (DGLA), while Gamma linolenic acid and dijungalma linolenic acid itself have various desired effects. This bonding can also By co-delivering the biologically active substance with the same fat fe, these fatty acids have the required effect in addition to any transport advantages. Other fatty acids, such as any essential fatty acids (EFAs), especially η · 6, can also be used. And twelve natural fatty acids of the n-3 series (Figure 1). Among these twelve fatty acids, arachidonic acid, adrenal 'stearic acid, icosatepentarate, and twenty-two Hexanoic acid is particularly preferred because it has the desired effect. Also, any fatty acid may be used, preferably CirC30 or CfCso and having two or more cis or trans carbon-carbon double bonds. It can be used in the form of a fatty acid or the corresponding fatty alcohol. Co-linoleic acid and columbinic acid are examples of fatty acids, and these fatty acids, by themselves, have valuable properties and seem to be particularly useful. As such, references to lipoic acid refer to both forms, with the exception that the chemical nature of one or the other form is unknown. However, the properties of GLA and DGLA make them particularly suitable for this purpose. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs! (Please read the notes on the back before filling out this page) Essential fatty acids are all cis configuration in nature, which are called corresponding derivatives of octadecanoic acid, behenic acid or behenic acid in the system. For example, z, z_stearyl 9,12-dienoic acid or z, z, z, z, z, z_twenty-two_4,7,10,13,16,19-hexadecanoic acid, but its The numerical indication is based on the number of carbon atoms, the number of unsaturated centers, and the number of carbon atoms counted from the end of the chain at the beginning of chain unsaturation. For example, it is more convenient to use 18: 2n_6 or 22: 6n_3. Abbreviations of names such as EPA and abbreviations such as -9-This paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm) 546138 A7 B7 V. Description of the invention (Eicosapentaenoic acid is arbitrary in some cases Figure 1 used n-6 EFA's 18: 2n-6 (linoleic acid, LA) 4 18: 3η · 6 (plant linolenic acid, GLA) i 20: 3n-6 (di-m-r-linolenic acid, DGLA) 1 20 : 4n-6 (arachidonic acid, AA) 1 22: 4n-6 (adrenal acid) 22: 5n-6 d -6-desaturase growth β-5-desaturase growth-4-desaturase n -3 EFA-s 18: 3η-3 (α-linolenic acid, ALA) 1 18: 4n-3 (stearyltetraenoic acid, SA) 4 20: 4n-3 20: 5n-6 (20 carbon five associations Acid, EPA) I 22: 5n-3 22: 6n-3 (Docosahexaenoic acid, DHA) (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs GLA and DGLA GLA and DGLA itself have anti-inflammatory effects, lower blood pressure, inhibit platelet coagulation, reduce cholesterol content, inhibit cancer cell growth, reduce movement disorders, relieve chest pain, improve calcium absorption and enhance fixation in bones, reduce ions Side effects of radiation to treat various mental illnesses It can dilate blood vessels, improve renal function, treat diabetic complications, relax blood vessels, etc. Therefore, the bonding of active substances to GLA and DGLA will not only become more lipophilic, but also enhance the passage through various membranes, skin and cardio-brain disorders. It can show new and other therapeutic effects. Therefore, fatty acids can be symbiotic prodrugs (direct bonding-10- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 546138 A7 B7, invention Note (at time 8)) or a symbiotic three-pronged prodrug (if linked via a bond). Other fatty acids with special valences in this regard are arachidonic acid and docosahexaenoic acid. These acids are cell membranes. The main constituents of adrenaline; stearic tetraenoic acid and eicosapentaic acid also have properties similar to GLA and DGLA. The fatty acids that are not included in Figure 1 but also have a special valence fluorene are cLA And galenic acid (CA). CLA has special properties in the treatment and prevention of cancer, in the promotion of growth, especially in protein synthesis, in the prevention and treatment of cardiovascular disease, and as an antioxidant. Effects. CA also has various properties of essential fatty acids. The types of actives that have a symbiotic effect with bioactive fatty acids can be broadly divided into the types of actives added to the compounds described here:-a) including antibiotics, antiprotozoal drugs, Antipsychotics, antidepressants, and NS AIDs, as well as drugs used to treat cardiovascular disease, respiratory disease, skin disease, mental illness, neuropathy, kidney disease, and muscle disease. Cancer compounds. b) hormones c) amino acids d) vitamins, especially B vitamins, and other essential nutrients. e) cytokines and peptides f) neurotransmitters and neurotransmitter precursors. g) Phospholipid compounds, such as inositol, bile test, serine and ethanolamine. These compounds can be directly bonded or hindered by acid radical bonding. h) Aromatic fatty acids, such as phenylacetic acid, phenylbutyric acid, and cinnamic acid. These acids are of particular value in the treatment of cancer. -11-This paper size applies to Chinese National Standard (CNS) Α4 specification (210 × 297 mm) —--------- 丨 (Please read the precautions on the back before filling this page
、1T 經濟部中央標準局員工消費合作社印製 546138 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(9 ) 功效 藥物的治療功效與脂肪酸的治療功效的結合可從下述例 子考慮: a) 影響精神狀況的藥物可鍵合於類如GLA,DGLA,花 生四烯酸,二十碳五烯酸或二十二碳六烯酸之脂肪 酸上,此等酸對腦功能有重要作用,可產生雙重治 療效果。 b) 用以治療心血管疾病的藥物可鍵合於也具此種治療 價値的脂肪酸上,類如降低三酸甘油酯含量及抑制 血小板凝集的二十碳五烯酸,能降低膽固醇含量及 具血管擴張作用的GLA或DGLA,或如有效膽固醇降 低劑的花生四烯酸,或具抗心律不整性質的DHA。 c) 用以治療任何形式的發炎的藥物可鍵合於類如加瑪 亞麻酸,二均加瑪亞麻酸或二十碳五烯酸或二十二 碳六烯酸上,此等脂肪酸具抗炎作用。 d) 用於治療骨質疏鬆症的藥物可键合於能增強鈣沉著 於骨内的GLA或DGLA上,或键合於減少鈣從尿中排 出的EPA或DHA上。 e) 用於皮膚病的藥物可键合於於皮膚具抗炎效果的 GLA或 DGLA上。 f) 用於癌症的藥物可鍵合於其本身有抗癌效果及減少 對抗癌藥物抗性的GLA,DGLA,花生四烯酸,EPA ,或DHA上。 (請先閱讀背面之注意事項再填寫本頁) -12- 本紙張尺度適用中國國家標準(CNS ) A4規格(2lOX 297公釐) 546138 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(1〇 ) 使用於以必需脂肪酸作爲活性物的觀念 前述必需脂肪酸(EFAs)是熟知的,由一系列十二種化合 物構成。雖則亞油酸(n-6系列的母體化合物)及[亞麻酸 (n-3系列的母體化合物)爲主要的食物必需脂肪酸,但此等 物質本身在體内的作用不大。要在體内充分利用,此等母 體化合物必須代謝成較長鏈的及更不飽和的化合物。從量 方面説,由細胞膜及其他脂質反應含量判斷,二均加瑪亞 麻酸(DGLA)花生四烯酸(AA)爲n-6系列主要EFA代謝物, 而二十碳五烯酸(EPA)及二十二碳六晞酸(DHA)爲n-3系列 的主要代謝物。DGLA,AA,EPA及DHA是體内多數脂質 的重要成分。除了其本身重要外,也能生成多種氧化衍生 物,二十燒類,包括前列腺素,白三晞及其他化合物。特 另具治療價値的脂肪酸是DGLA,AA,EPA及DHA,以及 GLA (DGLA前體)硬脂四烯酸(SA),EPA及 DPA (22:5n-3)前 體,DHA前體,及腎上腺酸。 還有些脂肪酸,如油酸,十八碳四烯酸及加侖賓酸,並 不是必需脂肪酸,但在體内有重要作用。其中最使人感興 趣的是共軏亞油酸,如前所述,有多種所需效果。 人們曾想到,在營養及疾病治療上,補充亞油酸及^ -亞 麻酸即足夠,身體的代謝會完成其餘工作。現在已知這並 不眞實。不同的疾病會有不同的不正常的必需脂肪酸形式 ,而且因爲代謝上的問題,只供應亞油酸或心亞麻酸不 能簡單地獲得校正。所以在多數情形下,須特別多供應一 種EFA或同時給予二或多種EFA。由於EFA能以各種形式 -13 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 4461路 A7 B7 五、發明説明(12 的物質包括(a) (ii)類的二酯;n=3。另一申請專利的物質 是(b) (iv)類的磷酸酯;n=3。η較此爲大或小的物質,或键 合不是酯键合的,基於類似理由,可能也有價値,於此處 只作揭示,但大部分尚未申請專利。 (a) 有自由態叛基的生物活性物一又可再分爲: ⑴ 與不飽和脂肪醇(UFA)偶合的酯 (ii)與不飽和脂肪酸的ω_經基燒基酯偶合的酯 :II -蜷! (請先閱讀背面之注意事項再填寫本頁)1T Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 546138 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (9) The combination of the efficacy of therapeutic drugs with fatty acids can be considered from the following examples : A) Drugs that affect mental conditions can be bonded to fatty acids such as GLA, DGLA, arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. These acids have important effects on brain function. , Can produce dual treatment effects. b) Drugs used to treat cardiovascular diseases can be bonded to fatty acids that also have such therapeutic value, such as eicosapentaenoic acid that reduces triglyceride content and inhibits platelet aggregation, which can reduce cholesterol content and have Vasodilatory GLA or DGLA, or arachidonic acid such as an effective cholesterol lowering agent, or DHA with antiarrhythmic properties. c) Drugs used to treat any form of inflammation can be bound to classes such as Gamma Linolenic Acid, Dijungamaric Acid or Eicosapentaenoic Acid or Docosahexaenoic Acid. These fatty acids are resistant to Inflammatory effect. d) Drugs used to treat osteoporosis can be bonded to GLA or DGLA, which enhances calcium deposition in bone, or to EPA or DHA, which reduces calcium excretion from urine. e) Drugs for skin diseases can be bonded to GLA or DGLA with anti-inflammatory effects on the skin. f) Drugs for cancer can be bonded to GLA, DGLA, arachidonic acid, EPA, or DHA, which have anticancer effects and reduce resistance to anticancer drugs. (Please read the precautions on the back before filling this page) -12- This paper size applies to Chinese National Standard (CNS) A4 (2lOX 297 mm) 546138 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Explanation (10) The concept of using essential fatty acids as an active substance The aforementioned essential fatty acids (EFAs) are well known and are composed of a series of twelve compounds. Although linoleic acid (the parent compound of the n-6 series) and [linolenic acid (the parent compound of the n-3 series) are the main food essential fatty acids, these substances themselves have little effect in the body. To be fully utilized in the body, these parent compounds must be metabolized into longer chain and more unsaturated compounds. In terms of quantity, judging from the content of the cell membrane and other lipids, dijungamalin (DGLA) arachidonic acid (AA) is the main EFA metabolite of the n-6 series, and eicosapentaenoic acid (EPA) And docosahexahexanoic acid (DHA) is the main metabolite of the n-3 series. DGLA, AA, EPA and DHA are important components of most lipids in the body. In addition to being important in its own right, it can also generate a variety of oxidative derivatives, twenty kinds of burners, including prostaglandins, white scutellaria and other compounds. Specially treated fatty acids are DGLA, AA, EPA and DHA, and GLA (DGLA precursor) stearate (SA), EPA and DPA (22: 5n-3) precursors, DHA precursors, and Adrenaline. Some fatty acids, such as oleic acid, octadecatenoic acid, and galanthine, are not essential fatty acids, but they play an important role in the body. The most interesting of these is linoleic acid, which, as mentioned earlier, has several desired effects. It has been thought that in nutrition and disease treatment, supplementing with linoleic acid and ^ -linolenic acid is sufficient, and the body's metabolism will complete the rest of the work. It is now known that this is not true. Different diseases have different forms of abnormal essential fatty acids, and due to metabolic problems, only the supply of linoleic acid or cardiolenic acid cannot be easily corrected. Therefore, in most cases, one extra EFA or two or more EFAs must be given at the same time. As EFA can be in various forms-13-This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X 297 mm) (Please read the precautions on the back before filling this page) Road 4461 A7 B7 V. Description of Invention (12 Substances include (a) (ii) diesters; n = 3. Another patent pending substance is (b) (iv) phosphate esters; n = 3. Η is larger or smaller than this, Or the bond is not ester-bonded. For similar reasons, it may also be valuable. It is only disclosed here, but most of them have not yet been applied for patents. (A) Biological actives with free-state defect groups can be divided into: ⑴ Esters coupled with unsaturated fatty alcohols (UFA) (ii) Esters coupled with unsaturated fatty acid ω-alkylene esters: II-蜷! (Please read the precautions on the back before filling this page)
經濟部中央標準局員工消費合作杜印製 (iii)與不飽和脂脖醇的藉基垸基叛基酯偶合的酯Production cooperation between employees of the Central Bureau of Standards of the Ministry of Economic Affairs, Du Printing (iii) Esters coupled with unsaturated ethyl esters of unsaturated fatty alcohols
(b) 有自由態羥基的生物活性物—又可分爲: (i) 與不飽和脂肪酸偶合的酯(b) Biologically active compounds with free hydroxyl groups-can also be divided into: (i) Esters coupled with unsaturated fatty acids
— -15- 本紙張尺度適用中國國家標準(CNs ) A4規格(210X 297公釐) 546138 A7 _________ B7 五、發明説明(13 ) (ii)與不飽和脂肪醇的羧基烷基羧基酯偶合的酯— -15- This paper size applies to Chinese National Standards (CNs) A4 specification (210X 297 mm) 546138 A7 _________ B7 V. Description of the invention (13) (ii) Esters coupled with carboxyalkylcarboxylates of unsaturated fatty alcohols
(iii)與不飽和脂肪酸的羧基燒基酯偶合的酯 0(iii) Esters coupled with carboxyalkyl esters of unsaturated fatty acids 0
(請先閱讀背面之注意事項再填寫本頁) -II^衣. (iv)與不飽和脂防酸的ω-經基燒基酯偶合的磷酸酯(Please read the notes on the back before filling this page) -II ^ 衣. (Iv) ω-based alkyl esters coupled with unsaturated fatty acids
R=H,CH3,或陽離子相對離子 (c) 有自由態胺基的生物活性物-·又可分爲: (i) 與必需脂肪酸偶合的醯胺R = H, CH3, or cation counter ion (c) Biological actives with free amine groups-· They can also be divided into: (i) Amidoamine coupled with essential fatty acids
經濟部中央標準局員工消費合作社印製 (ii)與必需脂肪醇的ω-羧基烷基羧基酯偶合的醯胺 -16- 本紙張尺度適用中國國家標準(CNS ) Α4規格(21〇 X 297公釐) Α7 Β7 五、發明説明(14Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (ii) Amidine-16 coupled with the ω-carboxyalkylcarboxylate of an essential fatty alcohol-16- (%) Α7 Β7 V. Description of the invention (14
於上述所有範圍中,至3,不飽和脂肪酸或醇的碳鏈 以下式代表: ^λ) 於上述所有範圍中,,,不飽和脂肪酸”(及衍生出來的,,不飽 和脂肪醇"代表包括有二或多個順式或反式雙鍵的油酸(及 油酸基醇)與任何脂肪酸(或對應的脂肪醇)之一。但在此中 最具價値的脂肪酸是如圖1所示之必需脂肪酸,特別是 GLA,DGLA,ΑΑ,SA,ΕΡΑ及DHA。於特定目的下,以 共軛亞油酸及加侖賓酸爲最佳。 合成通論 個別的脂肪酸可由純化天然的動物、植物或礦物源製得 ,也可用精於此技藝者已知的或以後發展成的方法合成。 個別的脂肪醇可由上述脂肪酸以精於此技藝者已知的或 以後發展成的方法行化學還原製備。 -17- !蜷丨丨 (請先閱讀背面之注意事項再填寫本頁) 、1Τ 經濟部中央標準局員工消費合作杜印製 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X^97公釐) · 經濟部中央標準局員工消費合作社印製 546138 A7 B7 — -----—- ----— --__ ._____ 五、發明説明(15 ) (a),(b)及(c)[(ii)和(iii)次類]類生物活性物之生成需一或 多個酯键。此種化學特性可以任何合理的酯合成方法完成 ,特別是: (a) 以醇與醯基氯,酸酐或合適的活化酯反應,反應時 可有或無有機三級驗如吡淀之存在,反應係在合適的惰性 溶劑如二氯甲烷内於0。至120°C間的溫度進行。 (b) 以醇與酸,或酸、短或中等鏈烷基酯,在有合適的 酸催化劑,如4-甲苯磺酸,之存在下反應,反應可用或不 用合適的惰性溶劑如甲苯,在50。至180°C溫度間進行, 這樣可使反應中生成的水於眞空下除去。 (c) 以醇與酸在有縮合劑如丨,夂二環己基碳化亞醯胺之 存在下反應,反應可有或無合適的有機三級鹼,如4_ (N,N-一甲基胺基吡啶)之存在,於惰性溶劑如二氯甲燒内 於〇°至50°C溫度間進行。 (d) 以醇與酸,或酸、短或中等鏈烷基酯,或酸、活化 醋如乙烯基醋在有水解酶如豬肝酯酶之存在下反應,反應 可用或不用合適溶劑如己烷,在20。至8〇χ:溫度間進行, 反應條件須能使反應中生成的水或醇或醛副產物能,例如 在眞空下,除去。 (e) 以酸與合適的醇衍生物,如破化物,在有或無合適 的驗如碳酸神之存在下反應,反應係在合適的惰性溶劑如 一甲基甲醯胺内於〇。至180°C溫度間進行。 ()、醇”版’短或中等鍵悦基酯在有催化量的Μ;+〇γ_ 土的k氧化物之存在下反應,於式Μ+〇γ_中,μ是驗或驗 (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央標隼局員工消費合作社印製 A7 B7 五、發明説明(16 ) ' ^金屬,如鈉,γ是含丨_4個碳原子的烷基,此烷基可以是 刀支的,不分支的,飽和的或不飽和的,反應可有或無合 適的溶劑如甲苯之存在,於5〇。至18(rc溫度間進行,這 樣可使低醇,H0Y,由反應混合物於眞空移除。 (c)類生物活性物之生成需形成醯胺鍵。此種化學特性可 以任何合理的醯胺合成方法完成,特別是: (g) 以胺與酸基氯,酸酐或合適的活化的酯在有或無有 機二級鹼如吡啶之存在下,於合適的惰性溶劑如二氯甲烷 内於〇。至120X:溫度間反應。 (h) 以胺與酸在有縮合劑如13-二環己基碳化亞醯胺之 存在下反應’反應可有或無合適的有機三級鹼,如4_ (N,N-二甲基胺基吡啶)之存在,於惰性溶劑如二氯甲烷内 於〇°至50X:溫度間進行。 (1)以胺與酸,或酸、短或中等鏈烷基酯,或酸、活化 酯如乙烯基酯在有水解酶如豬肝酯酶之存在下反應,反應 可用或不用合適溶劑如己烷,在2〇。至8〇°C溫度間進行, 反應條件須能使反應中生成的水或醇或醛副產物能,例如 在眞空下,除去。 (b) (IV)類生物活性物之生成需形成磷酸酯鍵。此種化學 特性可以任何合理的磷酸酯合成方法完成,特別是: ⑴以醇(如UFA,3·羥基丙基酯)與合適的活化的磷酸 衍生物(如POCI3)與三級鹼(如石研)於合適的溶劑(如THF)内 於低於10 C溫度反應製成粗製二氣磷酸酯。然後再以醇( 如“生同®7 )與粗製一氣轉酸醋用三級驗(如Et3N)於合適 __ -19-In all the above ranges, the carbon chain of 3 to 3, unsaturated fatty acids or alcohols is represented by the following formula: ^ λ) In all the above ranges, "unsaturated fatty acids" (and derived, unsaturated fatty alcohols "represent Including two or more cis or trans double bonds of oleic acid (and oleic alcohol) and any fatty acid (or corresponding fatty alcohol). But the most expensive fatty acid in this is shown in Figure 1 The essential fatty acids shown, especially GLA, DGLA, AA, SA, EPA and DHA. For specific purposes, conjugated linoleic acid and gallbentamic acid are the best. Synthesis of individual fatty acids can be purified from natural animals and plants Or from mineral sources, can also be synthesized by methods known to those skilled in the art or later developed. Individual fatty alcohols can be prepared by the chemical reduction of the above fatty acids by methods known to those skilled in the art or later developed. -17-! 蜷 丨 丨 (Please read the notes on the back before filling out this page), 1T Consumer Cooperation with Central Standards Bureau of the Ministry of Economic Affairs Du printed paper sizes are applicable to China National Standard (CNS) Α4 specifications (210X ^ 97 (B)) • Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 B7 — -----—- ----— --_. ._____ V. Description of the Invention c) [(ii) and (iii) sub-class] biological actives need one or more ester bonds. Such chemical properties can be accomplished by any reasonable method of ester synthesis, in particular: (a) Alcohol and hydrazone The reaction is based on chloride, acid anhydride or suitable activated ester, with or without organic tertiary test such as pyridine. The reaction is performed in a suitable inert solvent such as dichloromethane at a temperature between 0 ° and 120 ° C. (B) Alcohol and acid, or acid, short or medium chain alkyl ester, in the presence of a suitable acid catalyst, such as 4-toluenesulfonic acid, the reaction may or may not use a suitable inert solvent such as toluene, It is carried out at a temperature between 50 ° and 180 ° C, so that the water generated in the reaction can be removed under the air. (C) The reaction is carried out with an alcohol and an acid in the presence of a condensing agent such as 如, dicyclohexylcarbomide The reaction can be performed with or without a suitable organic tertiary base, such as 4- (N, N-monomethylaminopyridine), in an inert solvent such as dichloro The roasting is carried out at a temperature of 0 ° to 50 ° C. (D) Alcohol and acid, or acid, short or medium chain alkyl ester, or acid, activated vinegar such as vinyl vinegar in the presence of hydrolase such as porcine liver esterase In the presence of the reaction, the reaction can be carried out with or without a suitable solvent, such as hexane, at a temperature between 20 ° and 80 ° C: the reaction conditions must be such that the water or alcohol or aldehyde by-products produced during the reaction can (E) Reaction with an acid with a suitable alcohol derivative, such as a decomposed compound, with or without a suitable test such as the presence of carbonic acid, the reaction is in a suitable inert solvent such as monomethylformamide. To 180 ° C. (), Alcohol "version" short or medium bond ester ester in the presence of a catalytic amount of M; + 〇γ_ soil in the presence of k oxide, in the formula M + 〇γ_ , Μ is the inspection or inspection (please read the notes on the back before filling out this page). Order printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. A7 B7 V. Description of the invention (16) '^ Metals such as sodium, γ丨 _4 carbon atom alkyl group, this alkyl group can be knife branched, unbranched, saturated or unsaturated, the reaction can be With or without a suitable solvent such as toluene is present at 5〇. It can be carried out at a temperature between 18 and rc, so that the low alcohol and H0Y can be removed from the reaction mixture in the air. (C) The formation of bioactive compounds requires the formation of amido bonds. This chemical property can be synthesized by any reasonable amidine. The method is completed, in particular: (g) amine with acid chloride, acid anhydride or a suitable activated ester in the presence or absence of an organic secondary base such as pyridine in a suitable inert solvent such as methylene chloride. To 120X: temperature reaction. (H) Reaction with amine and acid in the presence of a condensing agent such as 13-dicyclohexylcarbodiimide. The reaction may be with or without a suitable organic tertiary base, such as 4- (N, N-dimethylaminopyridine), in an inert solvent such as dichloromethane at 0 ° to 50X: temperature. (1) amine and acid, or acid, short or medium chain alkyl ester, or Acids, activated esters such as vinyl esters are reacted in the presence of hydrolytic enzymes such as porcine liver esterase. The reaction can be carried out at a temperature between 20 ° and 80 ° C with or without a suitable solvent such as hexane. The reaction conditions must be such that The water or alcohol or aldehyde by-products produced during the reaction can be removed, for example, in the air. (B) (IV) The formation of actives requires the formation of phosphate ester linkages. This chemical property can be accomplished by any reasonable phosphate synthesis method, in particular: ⑴ Alcohols (such as UFA, 3 · hydroxypropyl esters) and suitable activated phosphate derivatives ( Such as POCI3) and a tertiary base (such as Shiyan) in a suitable solvent (such as THF) at a temperature below 10 C to produce crude digas phosphate ester. Then use alcohol (such as "Shengtong® 7") and crude A three-level test (such as Et3N) is used to convert vinegar to __ -19-
本紙張尺度適财目财縣(CNS ) 10X I丨丨·丨蜷丨丨 (請先閲讀背面之注意事項再填寫本頁) 訂 546138 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(17 ) 的溶劑(如THF)内於低於近週邊溫度反應,製成粗製氯磷 酸酯。再將此氯磷酸醋水解(例如藉加水及Et3N行水解)製 成磷二酯。或者加甲醇製成磷三酯,再用合適的親核劑( 如溴化鋰)於合適的溶劑(如甲基乙基酮)内行脱甲基化,製 成鱗二酉旨。 (k) 以磷單酯(如UFA,3_羥基丙基酯的磷酸酯)與醇(如 膽鹼)在有縮合劑(如1,3-二環己基碳化亞醯胺)之存在下於 合適的溶劑内於適宜的溫度反應。 (l) 以2-脱氧-2-溶血磷酯醯膽鹼用初級或二級醇行磷酯 醯轉移,反應用磷酯酶D催化。 一般而言,化學特性自然決定於要鍵合的化合物的性質 及键合是直接的或間接的。例如,脂肪酸偶可以脂肪酸-脂肪醇酯直接键合或以酐直接键合,如果使用二醇键合劑 可將醚键合於脂肪醇上以代替一般使用的將酯键合於脂肪 酸上;所有情形下,键合都是用已知的化學方法進行。 可直接键合或經鍵合劑,特別是1,3-丙烷二醇键,鍵合的 活性物偶的例 活性物偶的例,下列製成的化合物,根據發明人所知, 大部分是新穎的。因之本發明部分是新穎化學實體,在治 療或預防疾病上也是新穎的,不論此處是否提出專利申請 〇 脂肪酸 GLA-OA (0A=油酸),GLA-GLA,EPA-EPA,GLA-EPA, GLA-DHA,AA-DHA,AA-EPA,GLA-AA,GLA-SA,SA· -20- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 衣·The paper size is suitable for financial and financial counties (CNS) 10X I 丨 丨 · 丨 蜷 丨 丨 (Please read the notes on the back before filling out this page) Order 546138 Printed by the Consumers Cooperative of the Central Standard Bureau of the Ministry of Economic Affairs A7 B7 V. Invention It is shown that the solvent (such as THF) in (17) reacts at a temperature lower than the surrounding temperature to make a crude chlorophosphate. This chlorophosphoric acid vinegar is hydrolyzed (for example, by adding water and Et3N) to form a phosphoric diester. Or add methanol to make phosphorus triester, and then use a suitable nucleophile (such as lithium bromide) in a suitable solvent (such as methyl ethyl ketone) to demethylate, to make scaly diazepam. (k) Phosphorus monoesters (such as phosphate esters of UFA, 3-hydroxypropyl esters) and alcohols (such as choline) in the presence of a condensing agent (such as 1,3-dicyclohexylcarbodiimide) A suitable solvent reacts at a suitable temperature. (1) 2-deoxy-2-lysophospholipid phosphocholine is transferred with a primary or secondary alcohol to phospholipid phosphonium, and the reaction is catalyzed by phospholipase D. In general, chemical properties naturally depend on the nature of the compound to be bonded and whether the bonding is direct or indirect. For example, a fatty acid couple can be directly bonded with a fatty acid-fatty alcohol ester or directly with an anhydride. If a diol bonding agent is used, an ether can be bonded to a fatty alcohol instead of the ester generally bonded to a fatty acid; all cases In the following, bonding is performed by known chemical methods. Can be directly bonded or via a bonding agent, especially 1,3-propanediol bond, examples of active couples that are bonded, examples of active couples, and the following compounds are, according to the inventors' knowledge, mostly novel of. Therefore, part of the present invention is a novel chemical entity and is also novel in the treatment or prevention of diseases, regardless of whether a patent application is filed here. 0 fatty acids GLA-OA (0A = oleic acid), GLA-GLA, EPA-EPA, GLA-EPA , GLA-DHA, AA-DHA, AA-EPA, GLA-AA, GLA-SA, SA · -20- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the back (Please fill in this page again)
、1T 546138 Μ Β7 五、發明説明(18 ) DHA,AA-SA,DGLA-DGLA,DGLA-GLA,DGLA-SA, DGLA-AA,DGLA-EPA,DGLA-DHA,AA-AA,EPA-SA, EPA-DHA,DHA-DHA,cLA-cLA,cLA_GLA,cLA_DGLA, cLA-AA,cLA_SA,cLA-EPA,cLA-DHA,CA-CA,CA-GLA ,CA-DGLA,CA-AA,CA_SA,CA-EPA,CA_DHA 〇 維生素 GLA·菸酸,GLA-視黃酸,GLA-視黃醇,GLA-吡哆醛, 二-GLA_p比吟醇,二-EPA-卩比吟酸,以及,例如GLA, DGLA,AA,SA,EPA或DHA與任何維生素包括抗壞血酸 ,維生素D及其衍生物與同類物,維生素E及其衍生物與 同類物,維生素K及其衍生物與同樣物,維生素31 (硫胺) ,維生素B2 (核素),葉酸及相關的蝶呤,維生素B12,生 物素及泛酸。 胺基酸 GLA-色胺酸,GLA-哺胺酸,GLA-精胺酸,GLA-或DHA-苯丙胺酸,GLA-GABA,GLA_胺基乙醯丙酸,以及,例如 任何GLA,DGLA,AA,SA,EPA或DHA與任何天然的胺 基酸或相關化合物如牛續酸及肉毒驗。 芳香酸 經濟部中央榡準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) GLA-苯基丁酸,GLA-苯基醋酸,GLA·反式肉桂酸及一 般任何GLA,DGLA,AA,SA,EPA或DHA與任何芳基烷 酸或芳基烯酸。 類固醇 GLA-氫化可體松,GLA_雌二醇,GLA-及DHA-脱氫表雄 -21 - 一 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 546138 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(19 ) 甾酮及一般任何GLA,DGLA,AA,SA,EPA或DHA與任 何天然的或合成的類固醇,如任何雌激素,任何孕激素, 任何腎上腺類固醇與任何抗炎類固醇,特別是Θ -米松, 強的松(prednisone),強的松龍(prednisolone),氫經潑尼松 龍(triamcinolone),布得松耐得(budesonide),克羅貝他蘇 (clobetasol),倍克羅米松(beclomethasone),及其他相關類 固醇。 抗氧化劑 GLA-硫辛酸,DHA-硫辛酸,GLA-生育酚,二-GLA-3,3’-硫代二丙酸,及一般任何GLA,DGLA,AA,SA,EPA或 DHA與任何天然的或成的可行化學鍵合的抗氧化劑。此等 抗氧化劑包括紛類抗氧化劑(如丁子香酴,卡#酸(carnosic acid),咖啡酸,BHT,五倍子酸,生育酚,生育三烯醇 (tocotrienols)及類黃酮抗氧化劑(如楊梅黃酮,非瑟酮)), 多晞類(如視黃酸),不飽和固醇(如Λ5-燕麥固醇),有機硫 化合物(如蒜素),帖晞類(如香葉醇,樅酸)及胺基酸抗氧 化劑(如半胱胺酸,肌肽)。 藥物 GLA與消炎痛(indomethacin),異丁苯丙酸,氟苯氧丙胺 ,胺苄青黴素,青黴素V,蘇靈大,水楊酸,甲硝嗒唑, 氟奮乃靜(fluphenazine),胺苯楓(dapsone),反苯環丙胺, 乙酿基肉毒驗,氟派丁苯,阿的平(mepacrine),氯酉昆 (chloroquine),青黴素,四環素,普瓦斯丁(pravastin),雙 膦酸類如埃非得隆酸(efidronic acid),帕米得隆酸 -22- 本紙張尺度適用中國國家標i(—CNS—)一1^格丁^^97公釐) ~~ — (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 546138 A7 ~~ -——~B7 ___ 五、發明説明(2〇 ) (pamidromc acid)及克羅得隆酸(cl〇rdr〇nic aci句及其鈉鹽, 腺答基丁二酸鹽及腺苷酸丁二酸鹽及相關的用作χ_光顯影 介質的化合物與劑,及一般任何gla,DGLA,ΑΑ,SA, ΕΡΑ或DHA與任何藥物,特別是用於治療感染的、炎性疾 病的(包括各形式的關節炎)、癌、心血管疾病、呼吸疾病 、皮膚科疾病、精神疾病、神經疾病、肌肉疾病、腎疾病 、胃腸疾病、生殖系統疾病的藥物。 使用於NSAIDs的觀念;示其效果 爲以特定實例討論此觀念,發明人等製備了各種非類固 醇抗炎藥物(NSAIDs)特別是消炎痛的GLA-S旨。作爲非類固 醇抗炎藥物,一般相信消炎痛的主要細胞内作用機制係抑 制環氧酶,此環氧酶將花生四烯酸轉化成前炎(pr〇-inflammatory)前列腺素代謝產物。 已知消炎痛不易透過細胞,所以必須給予大劑量,而大 劑量又產生許多副作用,是以用消炎痛-GLA與單純的消 炎痛比較其透過細胞的能力,此比較係使用正常的纖維細 胞系,乳癌系,及惡性黑色素瘤系。1T 546138 Μ B7 V. Description of the invention (18) DHA, AA-SA, DGLA-DGLA, DGLA-GLA, DGLA-SA, DGLA-AA, DGLA-EPA, DGLA-DHA, AA-AA, EPA-SA, EPA-DHA, DHA-DHA, cLA-cLA, cLA_GLA, cLA_DGLA, cLA-AA, cLA_SA, cLA-EPA, cLA-DHA, CA-CA, CA-GLA, CA-DGLA, CA-AA, CA_SA, CA- EPA, CA_DHA 〇Vitamins GLA · niacin, GLA-retinoic acid, GLA-retinol, GLA-pyridoxal, di-GLA_p bilinol, di-EPA-bibinolic acid, and, for example, GLA, DGLA , AA, SA, EPA or DHA with any vitamin including ascorbic acid, vitamin D and its derivatives and analogues, vitamin E and its derivatives and analogues, vitamin K and its derivatives and analogues, and vitamin 31 (thiamine) , Vitamin B2 (nuclides), folic acid and related pterinates, vitamin B12, biotin and pantothenic acid. Amino acids GLA-tryptophan, GLA-peptamine, GLA-arginine, GLA- or DHA-phenylalanine, GLA-GABA, GLA-aminoacetamidine, and, for example, any GLA, DGLA, AA, SA, EPA or DHA with any natural amino acids or related compounds such as taurine and botulinum toxicity. Printed by the Consumers' Cooperative of the Central Bureau of Quasi-Agency of the Ministry of Aromatic Acids (please read the notes on the back before filling this page) GLA-phenylbutyric acid, GLA-phenylacetic acid, GLA · trans-cinnamic acid and any GLA, DGLA, AA, SA, EPA or DHA with any arylalkanoic acid or arylenoic acid. Steroids GLA-hydrocortisone, GLA_estradiol, GLA- and DHA-dehydroepiandroster-21-a paper size applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 546138 Central Bureau of Standards, Ministry of Economic Affairs Printed by employees' consumer cooperatives A7 B7 V. Description of invention (19) Sterolone and generally any GLA, DGLA, AA, SA, EPA or DHA with any natural or synthetic steroid, such as any estrogen, any progestin, any adrenal gland Steroids and any anti-inflammatory steroids, especially Θ-misone, prednisone, prednisolone, triamcinolone, budesonide, crobe Clobetasol, beclomethasone, and other related steroids. Antioxidants GLA-lipoic acid, DHA-lipoic acid, GLA-tocopherol, di-GLA-3,3'-thiodipropionic acid, and generally any GLA, DGLA, AA, SA, EPA or DHA with any natural Or made into a feasible chemically bonded antioxidant. These antioxidants include various antioxidants (such as citronella, carnosic acid, caffeic acid, BHT, gallic acid, tocopherols, tocotrienols, and flavonoid antioxidants (such as bayberry flavonoids) , Featherone)), Polyammoniums (such as retinoic acid), Unsaturated sterols (such as Λ5-oatosterol), Organic sulfur compounds (such as allicin), Theophylline (such as geraniol, abietic acid) ) And amino acid antioxidants (such as cysteine, carnosine). Drugs GLA and indomethacin, indomethacin, fluphenoxamine, ampicillin, penicillin V, sulindac, salicylic acid, metronidazole, fluphenazine, flubenazine Maple (dapsone), tranylcypromine, ethyl alcohol-based botulinum test, fluphene, mepacrine, chloroquine, penicillin, tetracycline, pravastin, bisphosphonates Such as efidronic acid, pamidronic acid-22- This paper size is applicable to Chinese national standard i (—CNS —) — 1 ^ Geding ^^ 97mm) ~~ — (Please read the back first Please pay attention to this page, please fill out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 ~~ -—— ~ B7 ___ V. Description of the invention (20) (pamidromc acid) and clodronic acid (clOrdr 〇nic aci sentence and its sodium salt, adenyl succinate and adenylate succinate and related compounds and agents used as x-ray developing medium, and generally any gla, DGLA, ΑΑ, SA, EPA or DHA with any drug, especially for the treatment of infectious, inflammatory diseases (including all forms of arthritis , Cancer, cardiovascular disease, respiratory disease, dermatological disease, mental disease, neurological disease, muscle disease, kidney disease, gastrointestinal disease, reproductive system disease. Concepts used in NSAIDs; show their effects to discuss this with specific examples Concept, the inventors have prepared various non-steroidal anti-inflammatory drugs (NSAIDs), especially GLA-S for indomethacin. As non-steroidal anti-inflammatory drugs, it is generally believed that the main intracellular mechanism of indomethacin is to inhibit cyclooxygenase. The cyclooxygenase converts arachidonic acid into a pro-inflammatory prostaglandin metabolite. It is known that indomethacin does not easily penetrate cells, so large doses must be given, and large doses produce many side effects, so indomethacin is used. -GLA compares its ability to permeate cells with indomethacin alone. This comparison uses normal fibroblast lines, breast cancer lines, and malignant melanoma lines.
此結果於ΕΡΑ-0 675 103有説明,此結果顯示在所有細胞 系中,以消炎痛培育後,細胞内的消炎痛含量都很低,只 能測出微量。相反的,在此等細胞系中,以消炎痛-GLA 培育後,細胞内測出大量的消炎痛-GLA及自由態的消炎 痛。此結果明白地顯示消炎痛的GLA酯可有效地透過細胞 並在細胞内行脱酯化,產生自由態的消炎痛,而且有見於 細胞膜障礙與血·腦及皮膚障礙有多處相似,消炎痛-GLA •23- 本紙張尺度適用中國國家標準(CNS ) A4規格(X 297公釐) ---------衣-- (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 546138 A7 B7 五、發明説明(21 ) 定也能有效地透過此等障礙。此種滲透及分解成自由態的 活性物也可見於此處所述的所有化合物。 申清專利的本發明 本發明各方面於此處申請專利範園内説明,主要專利係 關於化合物,用於治療時其中1,3-丙烷二醇殘基在111與1^2 殘基間形成键合,其中R1是衍生自C12-3〇,較佳是Ci6_3〇脂肪 酸的醯基或脂肪醇基,須具二或多個順式或反式雙鍵,R2 是氫或與R1相同或相異的醯基或脂肪醇基,或關於其他營 養劑,藥物或其他生物活性物殘基。 此等化合物一般爲帶有酸官能的活性物,直接於二醇殘 基上發生酯化,但例如具脂肪醇或其他帶有羥基_官能的 活性物時,在Ri及/或r2基及丙烷二醇殘基會插入磷酸 、丁二酸或其他二官能酸基,特別是在R2是營養劑,藥物 或其他具護基或胺基官能的生物活性劑時爲然。 下面以多種在體内可釋出的活性物就本發明作廣泛討論 〇 雖則前面已就生物活性物及脂肪酸((a)[i],(b)[i]及⑷⑴ 類鍵合作了討論,本發明主要係關於鍵合於脂肪酸上 成爲1,3-丙烷二醇的二酯的⑷出]類n=3的生物活性物,而 此生物活性物本身可爲脂肪酸,及通過磷酸鍵鍵合Si 3_ 丙,二醇的脂肪酸單酯的卬)(1幻類,n=3的生物活性物’, 此等生物活性物本身可爲脂肪醇或脂防酸3 -經基丙基醋。 此二醇也可看作是2_脱氧甘油及對應的2·脱氧_U_二酸甘 油醋二酉旨。(b)(iv),n=3類化合物也以13-丙燒二醇爲基礎 ____________ - 24 _ 本紙張尺舰财關家轉~ - (請先閱讀背面之注意事項再填寫本頁) 衣. 訂 五 、發明説明(22 A7 B7 經濟部中央標準局員工消費合作社印製 丄作是2·脫氧_2_溶血,脂質。此處所列出的化合 物疾病。 次至)過去未曾用於治療人類或動 作爲化合物,用作鍵合的二醇曾在文獻中與其他許多二 鮮共同被討論過,但發明人等未見過其以必需脂防酸二❿ :形式用於治療,也未見過其作爲一個位置上是必需脂脸 酸而另—位置上是生物活性物(非必需脂肪酸)的化合物這 二的揭示。本發明的確提供一有利的方法,如果需完整界 足的化合物時,使單一脂肪酸生成單酯或二酯,因爲不像 甘油1(3)-單酯及二酸甘油酯(從,卢及丨,3_二酸甘油酯,其中 1位的脂肪酸與3位的脂肪酸不同)那樣有對掌中心,也沒 有位置JL體異構物。而且,⑨了給予個別的酸外,此等單 及二酯也有作爲醫藥調配物的乳化劑的價値。I%丙烷二 醇的構造與天然三酸甘油酯的甘油的構造近似,並且是有 效的安全的投送系統。此外,也易於合成要求的化合物, 不會有二酸甘油酯那樣會發生醯基移動問題,也不會有光 學異構物的問題。例如,發明人等已顯示,以13_丙烷二 醇GLA/EPA二酷乳液作靜脈内輸液或經口給予,導致gLa 及EPA在活體内快速釋出進一步使gLa代謝成AA,使EPA 代謝成DHA。同樣,GLA-GLA及EPA_EPA二酯,及菸酸· GLA與消炎痛-GLA二酯也在經口給予後被吸收並釋出其 性部分。此外’據發明人等所知,於17,18及19頁所述的衍生 1,3-丙燒二醇的化合物是新穎的,過去從未被敘述過。 活 白 所 I—I — 衊! (請先閱讀背面之注意事項再填寫本頁) -訂_ -25-This result is described in EPA-0 675 103. This result shows that the indomethacin content in the cells is very low after incubation with indomethacin in all cell lines, and only a small amount can be measured. In contrast, in these cell lines, after incubation with indomethacin-GLA, a large amount of indomethacin-GLA and free form indomethacin were detected in the cells. This result clearly shows that the GLA ester of indomethacin can effectively pass through the cells and deesterify in the cells, resulting in free-form indomethacin. It is also found that cell membrane disorders are similar to blood, brain, and skin disorders in many places, indomethacin- GLA • 23- This paper size applies Chinese National Standard (CNS) A4 specification (X 297 mm) --------- Clothing-(Please read the precautions on the back before filling this page) Order the Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 546138 A7 B7 V. Invention Description (21) must also effectively pass through these obstacles. Actives that penetrate and decompose into free states are also found in all compounds described herein. The aspects of the invention claimed in the patent are explained here in the patent application park. The main patent is about compounds, in which 1,3-propanediol residues form a bond between 111 and 1 ^ 2 residues. R1 is a fluorenyl or fatty alcohol group derived from a C12-30, preferably a Ci6_30 fatty acid, and must have two or more cis or trans double bonds, R2 is hydrogen or the same or different from R1 Fluorenyl or fatty alcohol, or residues about other nutrients, drugs or other biologically active substances. These compounds are generally actives with acid functions and are esterified directly on the diol residues. However, for example, with fatty alcohols or other actives with hydroxyl functions, the Ri and / or r2 groups and propane Diol residues can be inserted with phosphoric acid, succinic acid, or other difunctional acid groups, especially when R2 is a nutrient, drug, or other bioactive agent with a protecting or amine functional group. In the following, the present invention is discussed extensively with a variety of active substances that can be released in vivo. Although the biological actives and fatty acids ((a) [i], (b) [i], and ⑷⑴-type bonds have been discussed previously, The present invention mainly relates to the dehydration of a fatty acid that becomes a diester of 1,3-propanediol by bonding to a fatty acid] class n = 3 biologically active substance, and the biologically active substance itself may be a fatty acid, and is bonded through a phosphate bond Si 3-propane, a fatty acid monoester of a diol) (a bioactive species of n = 3 ', these bioactive species may themselves be fatty alcohols or fatty acid-resistant 3-hydroxypropyl vinegars. Diols can also be regarded as 2_deoxyglycerin and the corresponding 2 · deoxy_U_diacidyl acetate. (B) (iv), n = 3 compounds are also based on 13-propanediol ____________-24 _ This paper ruler is transferred to the house ~-(Please read the precautions on the back before filling out this page) Clothing. Order 5. Invention Description (22 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 丄The action is 2 · deoxy_2_ hemolysis, lipids. The diseases of the compounds listed here. Time to) have not been used in the past to treat humans or act as compounds. The diol used as a bond has been discussed in the literature together with many other dioxins, but the inventors have not seen it used in the form of essential lipid antacid dihydrazone: for treatment, nor has it been seen as a Disclosure of essential fatty acid and other-biologically active (non-essential fatty acid) compounds in position. The present invention does provide an advantageous method to generate a single fatty acid if a complete compound is needed Monoesters or diesters, because unlike glycerol 1 (3) -monoesters and diglycerides (from, Lu and 丨, 3-diglycerides, where the fatty acid at the 1st position is different from the fatty acid at the 3rd position) On the palm center, there are no positional JL isomers. Moreover, in addition to the individual acids, these mono- and diesters also have the value of emulsifiers for pharmaceutical formulations. The structure of 1% propanediol and the natural three The structure of glycerol is similar to that of glycerol, and it is an effective and safe delivery system. In addition, it is easy to synthesize the required compounds. Problems. The inventors have shown that the use of 13-propanediol GLA / EPA diluent as an intravenous infusion or oral administration results in the rapid release of gLa and EPA in the living body, further metabolizing gLa to AA, and metabolizing EPA to DHA. Similarly, GLA-GLA and EPA_EPA diesters, as well as niacin · GLA and indomethacin-GLA diesters were also absorbed and released their sexual parts after oral administration. In addition, 'as known by the inventors, on 17, The compounds derived from 1,3-propanediol described on pages 18 and 19 are novel and have never been described before. White House I—I—Small! (Please read the notes on the back before filling out this page ) -Order_ -25-
本紙張尺度適用中國國家標準(CNS ) A4^ ( 21〇xl97^F 546138 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(23 ) 列二個脂肪酸的特定的二醇及採自GLA,DGLA,AA,SA ,EPA,DHA,cLA,及CA的脂肪酸位於一個位置而另一 位置上是維生素,胺基酸,芳香酸,類固醇,抗氧化劑或 其他藥物的二醇,是新穎物質。 脂肪酸二酯有各種用途。可用作醫藥物以治療或預防已 證明脂肪酸不正常的疾病。也可加於食物中,或加於或用 於營養補充物給須特定脂肪酸以治療或預防疾病的人用。 也可用食物或醫藥供獸醫用。也可用於皮膚保養。 由申請專利中包括的優點及各特定方面言,本發明提供 (i) 用於治療或營養目的,給予一或二種不飽和脂肪酸 基,或一種不飽和脂肪酸及一不爲脂肪酸的生物活 性物的方便而安全的方法。 (ii) 一種生物活性物經1,3-丙烷二醇鍵合於天然n-6或η-3系列的脂肪酸並特別是GLA或DGLA,AA,SA, EPA或DHA或有關的脂肪酸cLA或CA上的衍生物, 其中之生物活性物質需在體内通過脂質膜進入細胞 内或通過皮膚,血-腦障礙或其他障礙以發揮其作 用0 (iii) 一種藥物的脂肪酸衍生物,以此衍生物可使藥物或 脂肪酸產生共效性。 (iv) —種增進藥物在體内通過脂質膜的運送的方法,其 特點在給予上述形式的藥物。 (v) —種製造包括運送藥物通過體内脂質膜以改進治療 -26- 本紙張尺度適用中國國家標準(CNS ) A4規格、210X297公釐) (請先閱讀背面之注意事項再填寫本頁) •樣衣 訂 546138 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(24 ) 的藥劑的方法,其特點在於使藥劑中的藥物爲上述 形式。 (vi) —種製造供投送一或二種上表中(ii)之脂肪酸或供 投送上述一種脂肪酸及令一活性劑的藥劑的方法。 特定化合物的例已於上述;合成實例容後述。 一般功效與用途 本文中已於各處提及特定化合物的特定用途,今將13_ 丙烷二醇酯的用途敘述如下: 1 ·脂肪酸耐受性的改進:除了三酸甘油酯外,多數可給 予的脂肪酸的形式包括自由態的酸,鹽,乙基酯,及其他 甘油酯會導致某種程度的胃腸不適,如呕心,P區吐及腹寫 等。以鼠(rats)及小鼠(mice)等動物作研究發現丙燒二醇二 酯有極佳耐受性。例如,以10克/公斤的劑量給予鼠及小 鼠GLA-GLA及GLA-EPA二酯,爲發現有腹瀉。這表示二酯 是很可接受的給予生物活性的脂肪酸的方法。 2.藥物毒性的減少:非類固醇抗炎藥物如阿斯匹靈及消 炎痛是很有名的引起胃及腸潰瘍導致胃腸道出血的對胃腸 道具毒性的藥物。以引起胃腸潰的劑量的消炎痛(5-30毫 克/公斤)給予空腹的鼠,給予的形式一種是自由態的消炎 痛,一種是與另一位置上的GLA形成的1,3·丙烷二醇二酯 。24小時後將動物犧牲,檢查整個胃腸道的潰瘍情形。於 給予單獨消炎痛的動物發現嚴重的潰瘍,而於給予gLA-消炎痛的動物則只發現極小潰瘍或無潰瘍。 生物活性形式的脂肪酸的有效投送:GLA係以GLA_ -—_ -27- 本纸張尺細中國國家榡準(CNS一_ --- (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 546138 A7 B7 五、發明説明(25 ) GLA或GLA-EPA的形式給予,而EPA是以GLA-EPA或EPA· EPA的形式給予。此等二酯係以強飼經口給予或以靜脈内 給予,所給予者是20%的乳液,用2%的燕麥半乳糖脂作乳 化劑製成,給予劑量爲約0.1至2.0克/公斤。給予後1、2、 4、8及24小時將動物殺死,收取血漿,紅血球及肝。用高 效液體色譜法測定未代謝的二酯。由二酯衍生的脂肪酸及 此等脂肪酸的代謝物係這樣檢查:將肝、血漿及紅血球作 脂萃取,將脂不分以薄層色譜法分離出三酸甘油酯、磷脂 質、膽固醇酯幾自由態脂肪酸,再以由此等分離出的部分 衍生的脂肪酸行甲基化,再以氣體色譜法分析脂肪酸,以 上諸法都是標準敎科書上所述的方法。此等實驗顯示,在 經口給予後,約10%給予的二酯證實爲二酯形式。發現大 多數GLA或EPA爲自由態脂肪酸或磷脂質,只有少量爲見 於膽固醇酯及三酸甘油酯。此外,特別是於磷脂質部分, 發現GLA,DGLA及花生四烯酸的代謝物,以及EPA、二十 碳五晞及DHA的代謝物都增加。此等現象表示,脂肪酸易 於由二酯形式釋出,並進一步代謝成具生物活性的物質。 以二酯作靜脈内給予後也發現有類似結果,只是於一小時 時,約40%的二酯仍維持原始形式,24小時後脂肪酸才釋 出、代謝、並進入其他脂部分。此未改變的二酯形式本身 很可能即具生物活性。現已發現1,3-二酸甘油酯形式的亞 油酸有抗癌效果,且只對癌有抗性,對正常細胞並無抗性 ,而且此種抗性其他形式的亞油酸是沒有的(A. Matsuzaki et al,Cancer Res. 1989; 49: 5702-7)。可能這是因爲此種作 -28- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁)This paper size applies to Chinese National Standard (CNS) A4 ^ (21〇xl97 ^ F 546138 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (23) Lists the specific diols of the two fatty acids and the The fatty acids of GLA, DGLA, AA, SA, EPA, DHA, cLA, and CA are located in one position and the other positions are vitamins, amino acids, aromatic acids, steroids, antioxidants or glycols of other drugs, which are novel substances Fatty acid diesters have various uses. Can be used as medicine to treat or prevent diseases that have been proven to have abnormal fatty acids. It can also be added to food, or used in nutritional supplements to give specific fatty acids to treat or prevent diseases It can also be used for veterinary use by food or medicine. It can also be used for skin care. From the advantages and specific aspects included in the patent application, the present invention provides (i) for therapeutic or nutritional purposes, giving one or two kinds Convenient and safe method for unsaturated fatty acid group, or an unsaturated fatty acid and a biologically active substance which is not a fatty acid. (Ii) A biologically active substance has a 1,3-propanediol bond Derived from natural n-6 or η-3 series fatty acids and in particular derivatives on GLA or DGLA, AA, SA, EPA or DHA or related fatty acids cLA or CA, where the biologically active substance needs to pass through the lipid membrane in the body Into cells or through the skin, blood-brain disorders or other disorders to exert its effect 0 (iii) fatty acid derivatives of a drug with which the drugs or fatty acids are synergistic. (Iv)-a drug that enhances The method of transporting through the lipid membrane in vivo is characterized by administering the drug in the above-mentioned form. (V)-a method of manufacturing including transporting the drug through the lipid membrane in the body to improve the treatment-26- This paper applies Chinese National Standards (CNS) A4 size, 210X297 mm) (Please read the precautions on the back before filling out this page) • Sample order 546138 A7 B7 printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economy It is characterized in that the medicine in the medicament is in the above-mentioned form. (vi) A method for manufacturing one or two fatty acids of (ii) in the above table or a method for delivering one of the aforementioned fatty acids and an active agent. Examples of specific compounds have been described above; synthetic examples are described later. General efficacy and use The specific use of specific compounds has been mentioned throughout this article. The use of 13-propanediol esters is described as follows: 1. Improved fatty acid tolerance: In addition to triglycerides, most can be given Fatty acid forms include free-state acids, salts, ethyl esters, and other glycerides that can cause some degree of gastrointestinal discomfort, such as nausea, P-vomiting, and abdominal dissection. Animals such as rats and mice have found that propylene glycol diesters are extremely well tolerated. For example, GLA-GLA and GLA-EPA diesters were administered to rats and mice at a dose of 10 g / kg, and diarrhea was found. This indicates that diesters are a very acceptable method of administering biologically active fatty acids. 2. Reduction of drug toxicity: Non-steroidal anti-inflammatory drugs such as aspirin and indomethacin are well-known drugs that cause stomach and intestinal ulcers and cause gastrointestinal bleeding. Fasting rats were given indomethacin (5-30 mg / kg) in a dose that caused gastrointestinal ulcers, in the form of free indomethacin and 1,3 · propanedi with GLA at another site Alcohol diester. After 24 hours, the animals were sacrificed and examined for ulcers throughout the gastrointestinal tract. Severe ulcers were found in animals given indomethacin alone, while only minimal or no ulcers were found in animals given gLA-indomethacin. Effective delivery of biologically active forms of fatty acids: GLA is based on GLA_ -—_ -27- This paper size is based on Chinese national standards (CNS 一 _ --- (Please read the precautions on the back before filling this page) Order Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 B7 V. Description of Invention (25) GLA or GLA-EPA is given, and EPA is given in the form of GLA-EPA or EPA · EPA. These diesters are Gavage is given orally or intravenously. It is given as a 20% emulsion, made with 2% oat galactolipid as an emulsifier, and given at a dose of about 0.1 to 2.0 g / kg. Animals were killed at 4, 8, and 24 hours, and plasma, red blood cells, and liver were collected. High-performance liquid chromatography was used to determine unmetabolized diesters. Fatty acids derived from diesters and metabolites of these fatty acids were examined as follows: Extraction of lipids from plasma, red blood cells, and lipids. Triglycerides, phospholipids, and cholesterol esters are separated by thin-layer chromatography, and methylated with the partially-derived fatty acids isolated from these. Analysis of fatty acids by gas chromatography All methods are described in the standard monograph. These experiments show that after oral administration, about 10% of the diester administered is confirmed to be in the form of a diester. Most GLA or EPA are found to be free fatty acids or phospholipids Only a small amount is found in cholesterol esters and triglycerides. In addition, especially in the phospholipid part, metabolites of GLA, DGLA and arachidonic acid were found, as well as metabolites of EPA, eicosapentazone and DHA. These phenomena indicate that fatty acids are easily released from diesters and are further metabolized into biologically active substances. Similar results have been found after intravenous administration of diesters, but at about one hour, about 40% of The diester remains in its original form, and fatty acids are released, metabolized, and enter other lipid moieties after 24 hours. This unchanged diester form is likely to be biologically active by itself. The 1,3-diglyceride form has now been discovered Linoleic acid has anticancer effects, and is only resistant to cancer. It is not resistant to normal cells, and other forms of linoleic acid are not available (A. Matsuzaki et al, Cancer Res. 1989 49: 5702-7). This is because this can make -28- This paper scales applicable Chinese National Standard (CNS) A4 size (210X 297 mm) (Please read the back of the precautions to fill out this page)
、1T 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(26 ) 八他的作用需投送於1,3 _二酸甘油酯作間隔的二 刀的脂肪酸的關係。類似的間隔也可用13-丙烷二醇達 成,所以靜脈内給予某些丙烷二醇衍生物以確保其在完全 代謝前以二醇的形式循環一些時間會有特別的價値。 、、二在發明人及其他人的著作中曾詳述脂肪酸有多種生物及 口療活〖生四種脂肪酸,GLA,DGLA,SA及EPA,都有 廣泛的效果,此等效果包括: 1 ·對心血管的作用,包括血管擴張,降低血壓,抑制血 小板凝集,降低三酸甘油酯及LDL_膽固醇含量,升高 HDL·膽固醇含量,及抑制平滑肌增生。 2·抗火作用’包括前炎介質如細胞活素形成的降低,及 衍生自花生四烯酸的二十烷類生成的降低,減少中性白血 球的移動,中性白血球突發性呼吸之降低,局部發炎反應 的降低,對各種動物模型發炎的抑制,如對尿酸導致的發 炎及關節炎的抑制,對各種發炎性疾病如骨性關節炎及風 濕性關節炎的治療。 3·免疫調整功能,包括於動物模型阻止免疫及過敏的過 度反應’如實驗的過敏性腦脊髓炎及色素層炎,於致敏感 化的動物的氣管及皮膚過度反應,這導致於對人之由過度 免疫反應引起的疾病會有價値的觀念。 4 ·對呼吸的作用,包括氣管擴張及抑制氣管收縮的作用 〇 5.因鈣之吸收增加而改進鈣平衡,減少鈣的排出,增加 鈣於骨的沉著,減少鈣在組織(如動脈及腎)的異位沉著。 -29- ___________________ _ 本紙張尺度適用中國國家標準(CNS ) Μ規格(210'^7公釐) ~ ' (請先閱讀背面之注意事項再填寫本頁)Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the 1T A7 B7 V. Description of the invention (26) The role of his needs to be the relationship of fatty acids with 1,3-diglyceride as the interval between two knives. Similar intervals can also be achieved with 13-propanediol, so intravenous administration of certain propanediol derivatives to ensure that they circulate for some time in the form of diols before complete metabolism can be particularly costly. In the writings of the inventor and others, there are detailed descriptions of various biological and oral treatments of fatty acids. The four kinds of fatty acids, GLA, DGLA, SA and EPA, have a wide range of effects. These effects include: 1 · Cardiovascular effects include vasodilation, lowering blood pressure, inhibiting platelet aggregation, reducing triglyceride and LDL_cholesterol content, increasing HDL · cholesterol content, and inhibiting smooth muscle proliferation. 2 · Fire resistance 'includes reduction of proinflammatory mediators such as cytokine formation, and reduction of eicosanoids derived from arachidonic acid, reduction of neutrophil migration, and reduction of neutrophil sudden respiration Reduction of local inflammatory response, inhibition of inflammation in various animal models, such as inhibition of uric acid-induced inflammation and arthritis, treatment of various inflammatory diseases such as osteoarthritis and rheumatoid arthritis. 3. Immune adjustment function, including preventing immune and allergic overreactions in animal models, such as experimental allergic encephalomyelitis and uveitis, overreaction in the trachea and skin of sensitized animals, which results in Diseases caused by excessive immune responses can have a pricey notion. 4 · Respiratory effects, including tracheal dilatation and inhibition of tracheal contraction. 05. Improving calcium balance due to increased calcium absorption, reducing calcium excretion, increasing calcium deposition in bones, and reducing calcium in tissues such as arteries and kidneys. Ectopic calm. -29- ___________________ _ This paper size applies to Chinese National Standards (CNS) M specifications (210 '^ 7mm) ~' (Please read the precautions on the back before filling this page)
經濟部中央標準局員工消費合作社印製 546138 A7 f____ — Β7 五、發明説明(27 ) ^ ~ — 6·三種抗癌作用’於癌細胞(非正常細胞)有選擇性細胞 毒性損害及引起呑嗤作用,藉減少生長因子的活動及對生 長所需的第二信使系統的干擾而抑制生長,以各種作用抑 制細胞分裂,包括E -鈣依賴蛋白表現之增加及對蛋白分 解酶,如尿激酶、脂氧合酶及基質金屬蛋白酶,之抑制, 及對癌伴生之惡病質之抑制。 7·對神經細胞的作用,包括對正常神經膜構造及功能之 維持及對正常神經傳遞質節前-及節後_作用的維持。 此等所需的作用意謂,此組的脂肪酸可用於治療各種疾 病’包括多種型的心血管疾病,發炎疾病如類風濕關節炎 ,骨性關節炎,潰瘍性結腸炎及克羅漢氏病(Cr〇hn,s disease),呼吸疾病包括氣喘,精神疾病包括精神分裂, 酒精中毒’注意力不集中疾病,抑鬱及愛滋海默氏病,神 經疾病包括多發性硬化症及韓庭頓氏舞蹈症,腎及尿道疾 病包括各種腎炎及尿道舞結石,代謝疾病包括骨質疏鬆及 異位鈣化,及胃腸潰瘍及發炎疾病。雖則共軛亞油酸(cLA) 還未像GLA或EPA樣作普遍試驗,似乎也有廣泛作用,包 括對癌、心血管疾病及代謝疾病的治療價値。 GLA,DGLA,AA及加侖賓酸對皮膚有所需作用,在治 療如特應性濕疹,牛皮癣,蓴麻疹及過敏反應上有特別價 値。 AA常被認作是有害脂肪酸。但AA是所有正常細胞膜的 必需成分’於各種疾病,包括特應性濕療,精神分裂,常 發現有微量的增加(Horrobin et al,Schizophrenia Res 1994· -30- "i"紙張尺度適用中國國家$ ( A4規ϋ丨&297公釐)^'~~ ---- (請先閱讀背面之注意事項再填寫本頁) 衣· 一:填寫太Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 f____ — Β7 V. Description of the invention (27) ^ ~ — 6 · Three types of anti-cancer effects' selective cytotoxic damage to cancer cells (abnormal cells) and cause 呑 嗤Effect, by reducing the activity of growth factors and interfering with the second messenger system required for growth, inhibiting growth, inhibiting cell division by a variety of effects, including increased expression of E-calcium-dependent proteins and effects on proteolytic enzymes such as urokinase, Inhibition of lipoxygenase and matrix metalloproteinase, and inhibition of cachexia associated with cancer. 7. Effects on nerve cells, including maintenance of normal nerve membrane structure and function and maintenance of normal neurotransmitter pre-ganglion- and post-ganglion_ effects. These required effects mean that this group of fatty acids can be used to treat a variety of diseases, including many types of cardiovascular diseases, inflammatory diseases such as rheumatoid arthritis, osteoarthritis, ulcerative colitis and Crohn's disease ( Crohn, s disease), respiratory diseases including asthma, mental illness including schizophrenia, alcoholism 'inattention disease, depression and AIDS, and neurological diseases including multiple sclerosis and Hantington's dance Disease, kidney and urethral diseases include various nephritis and urethral calculi, metabolic diseases include osteoporosis and ectopic calcification, and gastrointestinal ulcers and inflammatory diseases. Although conjugated linoleic acid (cLA) has not been universally tested like GLA or EPA, it also appears to have a wide range of effects, including treatment costs for cancer, cardiovascular disease, and metabolic diseases. GLA, DGLA, AA, and galenbinic acid have the required effect on the skin, and are particularly valuable in the treatment of atopic eczema, psoriasis, measles and allergic reactions. AA is often considered a harmful fatty acid. However, AA is an essential component of all normal cell membranes. It is found in a variety of diseases, including atopic hygrotherapy, schizophrenia, and is often found to increase slightly (Horrobin et al, Schizophrenia Res 1994 · -30- " i " paper scales are applicable to China Country $ (A4 Regulations && 297 mm) ^ '~~ ---- (Please read the precautions on the back before filling out this page)
、1T 546138 Α7 Β7 經濟部中央標準局員工消費合作社印製 五、發明説明(28 ) l3: l95-2〇7),於心血管疾病也有微量之增加(H〇rr〇bin,1T 546138 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (28) l3: l95-2〇7) There is also a slight increase in cardiovascular disease (Horrbin,
Prostaglandins Leukotr· EFAs 1995; 53: 385-96)。於此等疾 病AA似乎有特別價値,於其他精神疾病如酒精中毒及注 意力不集中等AA含量減少的疾病也有價値。 DHA也有上述EFA的作用,但於細胞膜中有特多含量, 尤以心膜、視網膜及腦膜中含量爲多。DHA也有強力抗炎 及所需對心血管的作用。DHA似對心血管疾病、對視網膜 及視覺疾病包括色素性視網膜炎、老年斑退行性變化及閱 讀困難、對精神病及神經疾病包括精神分裂,注意力不集 中’抑鬱,酒精中毒,愛滋海默氏病及其他形式的精神障 礙與多發性硬化,有特別價値。 取近證實感染似乎也對脂膀酸有反應,特別是對Gla與 DGLA,EPA與DHA有反應。許多細菌可被此等脂肪酸殺 夕匕’包括對彳儿生素有南抗性的細菌。最近^一些研究室的報 告顯不’此等高度不飽和的脂肪酸對成功治療如癔疾及原 蟲疾病上是重要。 是以很明顯,各種脂肪酸似乎在疾病的治療及預防上, 以及在皮膚保養及營養上,能增加藥物及其他幾乎任何生 物活性物的效果,在以二醇的形式給予單一脂肪酸或與同 一分子内給予二種不同脂肪酸時也有治療效果。治療上的 特別價値是,在多數情形下脂肪酸是無毒的,可給予大劑 量而無重要副作用的危險。 作爲一酯治療功效的特定實例,以1,3 GLA-EPA丙烷二 醋治療ASPC-1人類胰臟癌作試驗,將此癌作皮下移植於 __- 31 - ^張尺度適^ -- (請先閱讀背面之注意事項再填寫本頁) 、1ΤProstaglandins Leukotr. EFAs 1995; 53: 385-96). AA seems to have special value in these diseases, and it also has value in other mental diseases such as alcoholism and reduced concentration of AA. DHA also has the effects of the above-mentioned EFA, but it is particularly abundant in the cell membrane, especially in the heart membrane, retina, and meninges. DHA also has potent anti-inflammatory and cardiovascular effects. DHA seems to be effective for cardiovascular disease, retina and visual diseases including pigmented retinitis, degenerative changes in senile plaques and dyslexia, and for psychiatric and neurological diseases including schizophrenia, inattention 'depression, alcoholism, AIDS Hemeri Diseases and other forms of mental disorders and multiple sclerosis are of particular value. Closer confirmation has confirmed that the infection also appears to be responsive to lipids, particularly to Gla and DGLA, and EPA and DHA. Many bacteria can be killed by these fatty acids, including bacteria that are resistant to dysbiotics. Recent reports from some laboratories have shown that these highly unsaturated fatty acids are important for successful treatments such as dysentery and protozoal diseases. It is clear that various fatty acids seem to increase the effect of drugs and almost any other biologically active substance in the treatment and prevention of diseases, as well as in skin care and nutrition. In the form of diols, a single fatty acid or the same molecule is given. There are also therapeutic effects when two different fatty acids are administered internally. The special therapeutic value is that fatty acids are non-toxic in most cases and can be given in large doses without the risk of significant side effects. As a specific example of the efficacy of monoester treatment, 1,3 GLA-EPA propanediacetate was used to test ASPC-1 human pancreatic cancer, and this cancer was subcutaneously transplanted at __- 31-^ 张 值 适 ^^ ( (Please read the notes on the back before filling out this page), 1T
ί 1 - I— I 經濟部中央標準局員工消費合作社印製 546138 A7 B7 五、發明説明(29 ) 裸鼠,此裸鼠缺乏胸腺功能可接受外來移植物而無拒絕反 應。將15隻鼠的每一支皮下注射五百萬懸浮於Matrigel and DMEM緩衝液中的ASPC-1細胞。所有動物内部發展成腫瘤 ,腫瘤的大小可用測徑器測量,腫瘤的容積可由線性向量 計算出。每一鼠的腫瘤每星期測定二次,連續測定五週。 將動物分成三組。5隻動物用作對照,每天只接受10克/公 斤玉米油。5隻鼠每天接受10克/公斤玉米油,另外每星期 還接受注射二次1.5克/公斤劑量的GLA-EPA二酯。此二酯 係以20%的乳液形式給予,乳液内用2%的燕麥半乳糖脂作 乳化劑;此靜脈注射的乳液耐受性良好,未引起血溶或血 栓性靜脈炎或其他任何形式的對動物的抑制。另外5隻鼠 除接受玉米油外,還接受10克/公斤/天GLA-EPA二酯。此 治療持續三星期,再讓腫瘤生長二星期,然後將動物犧牲 ,取出腫瘤測定其重量。腫瘤平均重量爲:對照組,1240 ±290毫克;靜脈内GLA-EPA組,820±180毫克;經口GLA-EPA組,490±160毫克。可看出,經口及靜脈内給予GLA-EPA二酯的動物的腫瘤生長實質上被抑制,而無任何副作 用或痛苦。這顯示,GLA-EPA二酯可有效地用於治療癌, 這和實驗室内分別使用GLA及EPA可殺死培養的人類癌細 胞的預期一致。所以二酯是給予各種脂肪酸的生物活性方 法。因此,可合理地期望二酯能發揮脂肪酸的多種所需效 果,這些效果見於許多已發表的文獻(例如:Horrobin DF, ed.? Omega-6 Essential Fatty Acids: Pathophysiology and Roles in Clinical Medicine: Wiley_Liss, New York,1990 o -32- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) :II—41— (請先閱讀背面之注意事項再填寫本頁) 訂 546138 A7 B7 五、發明説明(3〇 )ί 1-I—I Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 B7 V. Description of the invention (29) Nude mice, which lack thymus function and can accept foreign grafts without rejection. Each of 15 mice was injected subcutaneously with five million ASPC-1 cells suspended in Matrigel and DMEM buffer. All animals develop tumors internally. The size of the tumor can be measured with a caliper, and the volume of the tumor can be calculated from a linear vector. The tumors of each mouse were measured twice a week for five consecutive weeks. The animals were divided into three groups. Five animals served as controls and received only 10 g / kg corn oil per day. Five rats received 10 g / kg of corn oil per day, and received another injection of GLA-EPA diester at a dose of 1.5 g / kg twice a week. This diester is given in the form of a 20% emulsion with 2% oat galactolipid as an emulsifier in the emulsion; this intravenous emulsion is well tolerated and does not cause hemolysis or thrombophlebitis or any other Inhibition of animals. In addition to corn oil, the other 5 rats received 10 g / kg / day of GLA-EPA diester. This treatment lasted three weeks, the tumors were allowed to grow for another two weeks, then the animals were sacrificed and the tumors were removed to determine their weight. The average tumor weight was: control group, 1240 ± 290 mg; intravenous GLA-EPA group, 820 ± 180 mg; oral GLA-EPA group, 490 ± 160 mg. It can be seen that the tumor growth of the animals administered the GLA-EPA diesters orally and intravenously is substantially suppressed without any side effects or pain. This shows that GLA-EPA diesters can be effectively used to treat cancer, which is consistent with the expectation that using GLA and EPA in the laboratory to kill cultured human cancer cells, respectively. So diesters are a biologically active method for administering various fatty acids. Therefore, it is reasonable to expect that diesters can exert a variety of desired effects of fatty acids, which are found in many published literature (for example: Horrobin DF, ed.? Omega-6 Essential Fatty Acids: Pathophysiology and Roles in Clinical Medicine: Wiley_Liss, New York, 1990 o -32- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm): II—41— (Please read the notes on the back before filling this page) Order 546138 A7 B7 V. Invention description (30)
Simopoulos AP et al? eds, Health Efects of Omega-3 Polyunsaturated Fatty Acids in Seafoods, Karger, Basel, 1991 。Fats and Oils in Human Nutrition,World Health Organization,Rome, 1994 o Unsaturated Fatty Acids: Nutritional and Physiological Significance o British Nutrition Foundation,Chapman and Hall,London,1992) 0 特定1,3-丙烷二醇化合物的特異用途 1. 1,3-丙烷二醇衍生物含有:二種脂肪酸,其中脂肪 酸之一是 GLA或 DGLA,另一是 GLA,DGLA,SA,EPA, DHA,cLA (共軏亞油酸)或CA (加令賓酸),用於治療:- (a) 糖尿病併發症,特別是神經病及視網膜病;糖尿病 中及前糖尿病期,改善對胰島素的反應; (b) 癌; (c) 骨性關節炎; (d) 類風濕關節炎; (e) 其他發炎及自體免疫疾病,包括Sjogren氏徵候群, 系統性紅斑狼瘡,潰瘍性結腸炎,Crohn氏病,及 眼色素層炎; (f) 呼吸疾病,包括氣喘; 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) (g) 神經疾病包括多發性硬化,巴金森氏病,及韓廷頓 氏病; (h) 腎及尿道疾病; ⑴ 心血管疾病; (j) 眼的退行性疾病,包括色素性視網膜炎及老年斑退 -33 - 本紙張尺度適用中國國家檩準(21 〇 :)40丄 A7 --—---— B7 五、發明説明(31 ) ~~ ——一一 — - 行性病變; ()精神疾病’包括精神分裂,愛滋海默氏病,注意力 不集中,酒精中毒,及抑鬱; (l) 前列腺肥大及前列腺炎; (m) 陽萎及男性不孕症; (n) 乳腺痛; (〇)男性型禿頭; (P)骨質疏鬆; ⑷皮膚疾病,包括異位性濕疹,手濕疹,牛皮癖,蓴 麻療,及過敏疾病; (0 閱讀困難及其他學習障礙; (S) 癌惡病質。 2.含二種脂肪酸的Μ-丙烷二醇衍生物,其中一種脂 肪酸是AA,而另一種是AA,GLA,DHA,贱八或肌, 用於治療前⑴所述疾病,尤其是⑷,(g),⑴,⑴,(k), (q)及(r)項所述疾病。 經濟部中央標準局員工消費合作社印製 3·含二種脂肪酸的1,3-丙烷二醇衍生物,其中一種脂 肪酸是EPA而另一種是EPA或DHA,用於治療前(1)所述疾 病,尤其是(b),(c),(d),(e),(f),(g),⑻,⑴,⑴,(k) ,(p),(r)及(S)項所述疾病。 4· Μ-丙烷二醇衍生物,其中一個位置上是選自GLA ,DGLA,AA,SA,cLA,EPA或 DHA的脂肪酸,另一位 置上是選自下列的劑,此等劑的化學構造可使其藉下述的 键键合於1,3-丙烷二醇上: -34- 本纸張尺度適用中國國家標準(CNS ) A4規格(210:<297公釐) 經濟部中央標準局員工消費合作社印製 546138 A7 ---_ B7 ______ 五、發明説明(32 ) (a) 色胺酸,用於治療任何疾病,但特別適用於精神疾 病,神經疾病,行爲方面的疾病,疼痛及其他疾病 ’尤其是抑鬱,睡眠及偏頭痛; (b) 苯丙胺酸,用於治療任何疾病,但特別適於抑鬱, 多發性硬化,及慢性疲倦徵候群; (c) 精胺酸,用於治療任何疾病,但特別適用於有氧化 氮生產缺陷的疾病; (d) 肉毒鹼或肉毒鹼衍生物,用於治療任何疾病,但特 別適用於肌肉無力,心衰竭,慢性疲勞徵候群,愛 滋海默氏病,及週邊神經疾病; (e) 任何其他胺基酸或相關物質,用於治療任何疾病; 胺基乙醯丙酸或其衍生物,用於治療任可疾病,但 特別適用於癌; (f) 腺甞丁二酸鹽或相關物質,用於治療任何疾病,但 特別適用於肌萎縮,心衰竭,慢性疲勞徵候群,愛 滋海默氏病,及其他癡呆; (g) 阿斯匹靈,水楊酸,消炎痛(indomethacin),異丁苯 丙酸(ibuprofen)或其他非類固醇抗炎藥物,用於治 療任何疾病,但特別適用於疼痛的炎性疾病,愛滋 海默氏病及其他癡呆的炎性疾病,及其他任何應抑 制血小板凝集的疾病的炎性疾病; (h) 任何抗生素,用於治療任何合適的感染,特別是四 環素,氯林可黴素(clindamycin),二甲胺四環素 (minocycline),氯四環素及紅黴素,用於治療痤瘡 -35- ~本紙張尺度適中國國家標準(CNS ) 公釐) ~ ~ ~-- ^ — -疃|丨 (請先閱讀背面之注意事項再填寫本頁) 訂 546138 A7 B7 五、發明説明(33 ) , (i) 任何抗瘧疾及抗原蟲藥物,用於治療任何疾病,但 特另丨J是氯口奎(chloroquine),阿的平(mepacrine),p奎 那克林(quinacrine)及甲氟4 (mefloquine)用於治療癔 疾,原蟲疾病,發炎性疾病及精神分裂; (j) 任何抗眞菌藥物,用於治療任何疾病,特別是甲硝 塔咬(metronidazole)及抗眞菌咪峻與硝基咪峻與兩 性黴素(amphotericin),用於治療各種型態的眞菌感 染; (k) 任何抗炎類固醇,用於治療任何疾病,特別是氫合 可體松及Θ·米松,用於治療皮膚疾病,及氯地米 松(beclomethasone)與布敵松得(budesonide),用於 治療氣喘; (l) 任何性腺類固醇,用於治療任何疾病,特別是雌激 素及孕激素,用以治療卵巢功能不足及骨質疏鬆, 及雄激素,用以治療睪丸功能不足; (m) 任何腎上腺類固醇,用於治療任何疾病,特別是脱 氫表雄酮,用以治療與老化有關的疾病; 經濟部中央標準局員工消費合作社印製 :-IΙΦΤ, (請先閱讀背面之注意事項再填寫本頁) (η) 任何類視黃素,用於治療任何疾病,特別是維生素 Α酸及異維生素Α酸,用以治療皮膚疾病及用以保 護皮膚; (〇) 任何抗癌劑,用以治療癌; (P) 任何抗精神病劑,用以治療精神分裂及其他精神病 -36- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 經濟部中央標準局員工消費合作社印製 546138 A7 -^^一 _ B7 五、發明説明(34 ) (q) 任何抗抑鬱劑,用於治療任何疾病,特別是用以治 療抑參; (r) 任何抗焦慮劑,用於治療任何疾病,特別是用以治 療焦慮及恐慌發作; (S) 任何免疫抑制劑,用於治療任何疾病,特別是環跑 菌素及特羅里慕(tacrolimus),用以控制器官移植後 的免疫,並用以治療自體免疫及發炎疾病,包括牛 皮癖,濕疹,氣喘,類風濕性關節炎及炎性腸疾病 ⑴任何質子泵壓抑制劑或H2拮抗劑,用於治療任何 疾病,特別是用以治療與胃酸過多有關之疾病或對 胃酸防禦減少的疾病; (u) 任何利尿劑,用於治療任何疾病,特別是用以治療 與液體滯留有關的疾病及高血壓; (v) 任何#5拮抗劑,用於治療任何疾病,特別是用以治 療心血管疾病; (w) 任何血管緊張素轉化酶抑制劑或血管緊張素拮抗劑 ,用於治療任何疾病,特別是用以治療心血管疾病 (X) 任何卢-阻斷劑,用以治療任何疾病,特別是用以 治療心血管疾病; (y) 任何抗癲癇藥物,用以治療任何疾病,特別是苯妥 英(phenytoin),醯胺咪 _ (carbamazepine),丙戊酸 鹽(valproate),乙玻胺(ethosuximide),維格巴春 -37- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) ~~ ' -----------衣-- C請先閱讀背面之注意事項再填寫本頁} -訂_ 經濟部中央標準局員工消費合作社印製 546138 A7 B7 五、發明説明(35 ) (vigabatrin)或拉莫垂眞(lamotrigine),用以治療癲癇 9 (Z) 任何降血脂劑,用以治療任何疾病,特別是降脂纖 維酸醋(fibrates)及抑制素(statins),用以降低膽固醇 及膽固醇改質; (aa)任何口服降血糖劑或胰島素敏感化劑,用以治療糖 尿病; (bb)任何雙膦酸鹽,用以治療骨質疏鬆症,柏哲德氏 (Paget)病,或癌; (cc)任何放射術上用的顯影劑,包括泛影酸鹽化合物, 破肥胺(iodipamide),甘胺破苯酸鹽(ioglycamates), 破番酸鹽(iopanoates),破苯酉旨(iophendylate),破肽 酸鹽(iothalamate),ioxaglate,甲泛葡胺(metrizamide) 及相關化合物; (dd)任何肽或蛋白質,用於治療使用該肽或蛋白質,本 身之疾病,包括胰島素,降#5素,紅血球生成素, 及其他肽; (ee)任何維生素,用以治療任何疾病,或用於食物或營 養補充劑或食物添加物中,爲有效的維生素補充法 9 (ff)任何抗氧化劑,用以治療任何疾病,特別是抗氧化 劑特別有用的疾病,包括心血管疾病,癌或炎症, 以及任何用作食物或其他防腐劑的抗氧化劑,或作 爲食物、食物添加物或營養補充物的成分; -38 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) ! : I—Γ蝗—丨 (請先閱讀背面之注意事項再填寫本頁)Simopoulos AP et al? Eds, Health Efects of Omega-3 Polyunsaturated Fatty Acids in Seafoods, Karger, Basel, 1991. Fats and Oils in Human Nutrition, World Health Organization, Rome, 1994 o Unsaturated Fatty Acids: Nutritional and Physiological Significance o British Nutrition Foundation, Chapman and Hall, London, 1992) 0 Specific uses of specific 1,3-propanediol compounds1 1,3-propanediol derivatives contain: two fatty acids, one of which is GLA or DGLA, the other is GLA, DGLA, SA, EPA, DHA, cLA (co-linoleic acid) or CA (plus (Lingbinic acid) for the treatment of:-(a) complications of diabetes, especially neuropathy and retinopathy; improved response to insulin during and before diabetes; (b) cancer; (c) osteoarthritis; (d) rheumatoid arthritis; (e) other inflammatory and autoimmune diseases, including Sjogren's syndrome, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, and uveitis; (f) respiratory diseases , Including asthma; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) (g) neurological diseases include multiple sclerosis, Parkinson's disease, Huntington's disease; (h) Renal and urethral diseases; ⑴ Cardiovascular disease; (j) Degenerative diseases of the eye, including pigmented retinitis and senile plaque regression -33-This paper is in accordance with China's national standard (21 〇 :) 40 丄 A7 -------- B7 V. Explanation of the invention (31) ~~ —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— B7 V. Inconcentration, alcoholism, and depression; (l) Prostatic hypertrophy and prostatitis; (m) Impotence and male infertility; (n) Breast pain; (〇) Male baldness; (P) Osteoporosis; ⑷ Skin Diseases, including atopic eczema, hand eczema, psoriasis, ramie therapy, and allergic diseases; (0 dyslexia and other learning disabilities; (S) cancer cachexia. 2. M-propanedi containing two fatty acids Alcohol derivatives in which one fatty acid is AA and the other is AA, GLA, DHA, base eight or muscle, and is used for the treatment of the diseases mentioned above, especially ⑴, (g), ⑴, ⑴, (k), Diseases described in items (q) and (r). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Propanediol derivatives, one of which is EPA and the other is EPA or DHA, is used to treat the diseases described in (1) before, especially (b), (c), (d), (e), (f ), (G), ⑻, ⑴, ⑴, (k), (p), (r) and (S). 4. M-propanediol derivatives, in which one position is a fatty acid selected from GLA, DGLA, AA, SA, cLA, EPA or DHA, and at another position is an agent selected from the following, the chemical structure of these agents It can be bonded to 1,3-propanediol by the following bonds: -34- This paper size applies Chinese National Standard (CNS) A4 specification (210: < 297 mm) Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative 546138 A7 ---_ B7 ______ V. Description of the invention (32) (a) Tryptophan is used to treat any disease, but it is especially suitable for mental illness, neurological illness, behavioral illness, pain and Other diseases, especially depression, sleep and migraine; (b) Phenylalanine for the treatment of any disease, but particularly suitable for depression, multiple sclerosis, and chronic fatigue syndrome; (c) Arginine for the treatment Any disease, but especially for diseases with deficiencies in nitric oxide production; (d) Carnitine or carnitine derivatives, for the treatment of any disease, but especially for muscle weakness, heart failure, chronic fatigue syndrome, love Zheimer's disease and peripheral neuropathy (E) any other amino acid or related substance for the treatment of any disease; aminoacetic acid or its derivatives for the treatment of any disease, but especially for cancer; (f) adenine Acid salts or related substances for the treatment of any disease, but especially for muscular atrophy, heart failure, chronic fatigue syndrome, AIDS, and other dementias; (g) aspirin, salicylic acid, Indomethacin, ibuprofen, or other non-steroidal anti-inflammatory drugs, used to treat any disease, but especially suitable for painful inflammatory diseases, inflammatory diseases of AIDS and other dementias Disease, and any other inflammatory disease that should inhibit platelet aggregation; (h) any antibiotic for the treatment of any suitable infection, particularly tetracycline, clindamycin, minocycline , Chlorotetracycline and erythromycin for the treatment of acne -35- ~ This paper is suitable for Chinese National Standards (CNS) mm ~ ~ ~-^ —-疃 | 丨 (Please read the notes on the back before filling (This page) Order 546138 A7 B7 V. Description of the invention (33), (i) Any antimalarial and antiprotozoal drug used to treat any disease, but in particular, J is chloroquine, mepacrine, pquinacrine (Quinacrine) and mefloquine are used to treat dysentery, protozoan, inflammatory and schizophrenia; (j) any anti-bacillus drug used to treat any disease, especially metronidazole ) And anti-mycobacteria mijun and nitromizon and amphotericin (amphotericin), for the treatment of various types of bacillus infections; (k) any anti-inflammatory steroid for the treatment of any disease, especially hydrocodone Body pine and Θ · Mison, used to treat skin diseases, and beclomethasone and budesonide, used to treat asthma; (l) Any gonadal steroid, used to treat any disease, especially females Hormones and progestins for the treatment of ovarian insufficiency and osteoporosis, and androgens for the treatment of testicular insufficiency; (m) any adrenal steroids for the treatment of any disease, especially DHEA And aging Related diseases; Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs: -IΙΦΤ, (Please read the precautions on the back before filling this page) (η) Any retinoid used to treat any disease, especially vitamin A Acid and isovitamin A acid for treating skin diseases and protecting the skin; (〇) any anticancer agent for treating cancer; (P) any antipsychotic agent for treating schizophrenia and other mental illnesses -36- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7-^^ 一 _ B7 V. Description of the invention (34) (q) Any antidepressant For the treatment of any disease, especially for the treatment of antiseptics; (r) any anxiolytic agent for the treatment of any disease, especially for the treatment of anxiety and panic attacks; (S) any immunosuppressive agent for the treatment Any disease, especially cyclotoxin and tacrolimus, to control immunity after organ transplantation and to treat autoimmune and inflammatory diseases, including psoriasis, eczema, asthma, and similar Wet arthritis and inflammatory bowel disease: Any proton pump inhibitor or H2 antagonist for the treatment of any disease, especially for diseases related to hyperacidity or diseases with reduced defense against gastric acid; (u) any diuresis Agents for the treatment of any disease, especially for the treatment of fluid retention-related diseases and hypertension; (v) any # 5 antagonist for the treatment of any disease, especially for the treatment of cardiovascular disease; (w) Any angiotensin-converting enzyme inhibitor or angiotensin antagonist, for the treatment of any disease, especially for the treatment of cardiovascular disease (X) Any Lu-blocker, for the treatment of any disease, especially for the treatment Cardiovascular diseases; (y) Any antiepileptic drug for the treatment of any disease, especially phenytoin, carbamazepine, valproate, ethosuximide, Vig Bachun-37- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) ~~ '----------- Cloth-C Please read the notes on the back before filling This Page}-Order _ Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 546138 A7 B7 V. Description of Invention (35) (vigabatrin) or Lamotrigine (lamotrigine) for the treatment of epilepsy 9 (Z) Any hypolipidemic agent for the treatment of any disease, especially It is a lipid-lowering fibrates and statins for lowering cholesterol and cholesterol upgrading; (aa) any oral hypoglycemic agent or insulin sensitizer for treating diabetes; (bb) any bisphosphine Acid salts for the treatment of osteoporosis, Paget's disease, or cancer; (cc) any radiographic developer, including diatrizoate compounds, iodipamide, glycine Ioglycamates, iopanoates, iophendylate, iothalamate, ioxaglate, metrizamide and related compounds; (dd) any peptide Or protein for the treatment of diseases using the peptide or protein, including insulin, noretin # 5, erythropoietin, and other peptides; (ee) any vitamin for the treatment of any disease, or for food or nutrition Make up Supplements or food supplements that are effective vitamin supplements 9 (ff) Any antioxidant used to treat any disease, especially diseases where antioxidants are particularly useful, including cardiovascular disease, cancer or inflammation, and anything used as Antioxidants of food or other preservatives, or as ingredients of food, food additives or nutritional supplements; -38-This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm)!: I-Γ Locust — 丨 (Please read the notes on the back before filling this page)
、1T 經濟部中央標隼局員工消費合作社印裂 546138 A7 _ B7 五、發明説明(36 ) 一~ (gg)任何以卟啉氯(porphyrin chlorin)或以細菌氯 (bacteriochlorin)爲主的藥物,特別是其肆(羥基苯 基)衍生物,用於癌的光動力療法。 合成的簡易 甘油酯之合成 特別疋與二故甘油自旨相比’使用1,3 -丙燒二醇有如下優 點。 特足地説,在酯化脂肪酸方面,建議用i,%丙烷二醇代 替甘油,尤以只有一個脂肪酸(例如r _亞麻酸)要聯於三碳 鍵支架時爲然。雖然二@旨與三酸甘油自旨的化學特點非常 相似,一酯之製造可在很溫和的條件下進行,幾小時即可 7D成。要製造二酸甘油酯時,需強烈的條件,要不就需使 用脂肪醯基氯化物,或需要生物催化劑(此法需幾天的時 間)。 酸甘油酯的合成方法的概要署: 1 ·化學反應以金屬,金屬氣化物,或有機酸作催化劑。 2. 使用脂肪醯基氯。 3 · 使用固定的酶。 所有方法都使用酸,金屬,金屬氯化物,或有機酸作催 化劑’非常相似’其優點和缺點也相同。許多問題是此等 方法所固有的,即酸性條件及高溫(140°C至i80°c )。卜 TSA法的問題可能最少,因爲此法係於最溫和條件(U(rc ) 進行。甘油於脂肪醯基氯之反應係在”冷"條件完成,但會 排出毒性氣體,而且如果不小心監視,反應會不能控制。 _-39- 本紙張尺度適用中國國家檩準(CNS ) A4規^11^297公釐) :—I疃— (請先閱讀背面之注意事項再填寫本頁) 、11 經濟部中央標準局員工消費合作社印製 546138 A7 B7 五、發明説明(37 ) 此法還有一缺點,即必須先製成脂肪醯基氯本身;此一多 出的步驟降低此法的總效率。可用特定的酶系,脂防酶, 在溫和條件(例如60°C )下催化酯化反應,此種酶可能是使 用多不飽和脂肪酸時的最佳催化劑。但是,多數酶對甘油 的1-及3-位反應最有效。將脂肪酸加於2-位上是慢的,且 常依賴"醯基轉移”,即脂肪酸必須先聯於1-或3-位,然後 再轉移至需要聯上的2-位。是以,以酶催化的三酸甘油酯 的合成常需數日之久才能完成反應。 理論上,使用於甘油的同樣的酯化方法也可使用於13_ 丙烷二醇的酯化。但是在考慮及酶較易在甘油的1_及3_位 加上脂肪酸時,很明顯地,此等酶可有效地用於製造二酯 。事實正是如此,和三酸甘油酯的合成相比,此反應可在 幾小時之間且甚至在低溫(例如45°C至60°C )完成。四個小 時後即無脂肪酸,八個小時後二酯的產出率即超過95%, 剩餘的是單酯。 特定三酸甘油酯的合成的另一複雜性是甘油内有初級及 一級經基及中心碳上有前對掌性中心的存在。這些問題可 用小心選出的保護基及對掌性合成解決。但是這又增加合 成的步驟,減少產出率,每一步驟的純度也降低。相反的 ,1,3-丙烷二醇只有初級羥基,也沒有前對掌性中心。此 合成可減少至最多需二個步驟,總產出率增加,不純度降 總之,與對應的三酸甘油酯的合成相比,以多不飽和脂 膀酸及1,3-丙燒二醇製備二酯的反應較快,且可在溫和條 ________ -40- 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇 X 297公釐) :-I—疃 II (請先閱讀背面之注意事項再填寫本頁)1. 1T Consumer Insurance Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs prints 546138 A7 _ B7 V. Description of the invention (36) a ~ (gg) Any drug mainly composed of porphyrin chlorin or bacteriochlorin, In particular, its derivatives (hydroxyphenyl) are used for photodynamic therapy of cancer. Synthetic simple synthesis of glycerides Compared with the purpose of glycerol, the use of 1,3-propanediol has the following advantages. In particular, in terms of esterified fatty acids, it is recommended to replace glycerol with i,% propanediol, especially when only one fatty acid (such as r_linolenic acid) is to be attached to the three-carbon bond scaffold. Although the chemical characteristics of bisphenol and triglyceride are very similar, the manufacture of monoester can be carried out under very mild conditions, and it can be 7D in a few hours. Strong conditions are required to make diglycerides, or fatty fluorenyl chloride is required, or a biocatalyst is required (this process takes several days). An outline of the synthesis method of acid glyceride: 1. The chemical reaction uses metal, metal vapor, or organic acid as catalyst. 2. Use fatty ammonium chloride. 3 · Use immobilized enzymes. All methods use acids, metals, metal chlorides, or organic acids as catalysts " very similar " The advantages and disadvantages are the same. Many problems are inherent to these methods, namely acidic conditions and high temperatures (140 ° C to i80 ° c). The TSA method may have the fewest problems, because this method is performed under the most mild conditions (U (rc)). The reaction of glycerol with fatty methyl chloride is completed under "cold" conditions, but it will emit toxic gases, and if you are not careful Surveillance and response will not be controlled. _-39- This paper size applies to China National Standards (CNS) A4 ^ 11 ^ 297 mm): —I 疃 — (Please read the precautions on the back before filling this page), 11 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 B7 V. Description of the invention (37) There is also a disadvantage of this method, that is, it must be made into fatty amidyl chloride itself; this extra step reduces the overall efficiency of this method The esterification reaction can be catalyzed under mild conditions (such as 60 ° C) with a specific enzyme system, lipid-preventing enzymes. This enzyme may be the best catalyst for the use of polyunsaturated fatty acids. However, most of the -And 3-position reactions are the most effective. Adding fatty acids to the 2-position is slow, and often depends on "quoting", that is, the fatty acids must first be attached to the 1- or 3-position, and then transferred to the 2-digit on. Therefore, it takes several days for the synthesis of the triglyceride to be catalyzed by the enzyme to complete the reaction. In theory, the same esterification method used for glycerol can also be used for the esterification of 13-propanediol. However, when considering that it is easier to add fatty acids to the 1_ and 3_ positions of glycerol, it is clear that these enzymes can be effectively used to make diesters. This is indeed the case. Compared to the synthesis of triglycerides, this reaction can be completed between several hours and even at low temperatures (e.g. 45 ° C to 60 ° C). After four hours, there is no fatty acid, and after eight hours, the yield of the di-ester is more than 95%, and the remaining is the mono-ester. Another complication of the synthesis of specific triglycerides is the presence of primary and primary mesogens in the glycerol and the presence of a front palm center on the central carbon. These problems can be solved with carefully chosen protecting groups and with palm synthesis. However, this increases the number of synthetic steps, reduces the yield, and reduces the purity of each step. In contrast, 1,3-propanediol has only a primary hydroxyl group and does not have a pro palmar center. This synthesis can be reduced to a maximum of two steps, the total yield is increased, and the purity is reduced. In short, compared with the corresponding triglyceride synthesis, polyunsaturated fatty acids and 1,3-propanediol are used. The reaction to prepare the diester is fast, and it can be used in mild strips. ________ -40- This paper size is applicable to China National Standard (CNS) A4 specification (21〇X 297 mm): -I— 疃 II (Please read the back (Please fill in this page again)
、1T 546138 A7 B7 五、發明説明(38 件下進行。這導致更經濟的更少浪費的生產方法,並且將 反應物或產品在生產過程中變質的危險降至最低。 調配物 此等化合物可以精於藥品、皮膚保養產物或食物製造者 所知的任何合適的方法調配。此等調配物可經口給予,經 腸給予,局部給予,非經口給予(皮下,肌肉内,靜脈内) ’ t直財給予’經陰道給予,或經任何適宜的途徑給予。 像二酸甘油酯一樣,1,3-丙烷二醇二酯,特別是含二個 脂肪酸的,可用磷脂質或特別是半乳糖脂乳化劑乳化。此 種乳液特別適用於經口給予,經腸給予,及靜脈内給予。 例如,像自由流動的油樣的脂肪酸(UFA)二酯可如下調 配:- L 與EPA與1,3-丙烷二醇成的二酯的乳液的 製備 以高壓均質化製備經口給予的乳液。顆粒大小分佈及製 成的乳液的~電勢係於室溫以動力光散射測定。顆粒大小 的測足係於室溫進行(Zetasizer 4 Malvern Instruments Limited) 〇 製成含如下成分的水包油乳液(批量200克): 成分 乳化劑(半乳糖脂)* 二酯(GLA-EPA) 棕櫚酸抗壞血酸@旨(AP) 維生素E 水 -41 - 本紙張尺度適财關家標準(CNS ) M規格(21QX297公董) (請先閱讀背面之注意事項再填寫本頁) 、言 經濟部中央標準局員工消費合作社印製 % 2.00 20.00 0.02 0.5 100.00 ^ 67 _________ ^ 67 _________ 經濟部中央標準局員工消費合作社印製 546138 A7 五、發明説明(39 ) * Scotia LipidTeknik專利"水包油乳液 ’’。PCT/SE95/00115 (WO95/20943) 將乳化劑半乳糖酯分散於二酯内,將維生素E,AP及水 混合。將油相在高剪混合(Ultraturrax)下以4速加於水相内 ,並混合數分鐘。將此前乳液於80 MPA在50°C均質化6個 循環(mini-Lab 8.30 H; APV Rannie As,Denmark)。製成的乳 液之平均小滴大小爲230納米。 抗微生物防腐劑山梨酸鉀及調味劑可加於上述經口給予 乳液中。 2.靜脈内給予的20%的由GLA與EPA與1,3-丙烷二醇成的 二酯的乳液的製備 以類似方式製成200克含如下成分的水包油乳液: 成分 % 乳化劑 2.0 二酯(GLA-EPA) 20.0 甘油 2.0 水,加至 100.00 上述乳液,以高壓均質化6分鐘製成,之平均小滴大小 爲211納米,/9電勢-40毫伏。此等靜脈内給予的乳液可用 孔大小爲0.22微米的膜過濾,也可高壓消毒,小滴大小有 變化。 此活性物的給予劑量可從每天1亳克至200克,較佳是10 毫克至10克,更佳是10毫克至3克,視其種類而定。治療 癌時,較佳劑量可爲2-150克/天。製劑合適時也可作局部 -42- 本紙張尺度適用中國國家標準(CNS ) A4規核^( 27^297公釐) ~ — ---------^^衣-- (請先閱讀背面之注意事項再填寫本頁)1T 546138 A7 B7 V. Description of the invention (under 38 pieces. This leads to a more economical and less wasteful production method and minimizes the risk of reactants or products spoiling during production. Formulations These compounds can Specialized in pharmaceuticals, skin care products or any suitable method known to food manufacturers. These formulations can be administered orally, enterally, topically, parenterally (subcutaneously, intramuscularly, intravenously) ' Straight-line administration 'is given by vaginal administration, or by any suitable route. Like glyceryl diacid, 1,3-propanediol diesters, especially those containing two fatty acids, can be phospholipids or especially galactose Fatty emulsifier. This emulsion is especially suitable for oral, enteral, and intravenous administration. For example, fatty acid (UFA) diesters like free-flowing oils can be formulated as follows:-L with EPA and 1, Preparation of 3-propanediol diester emulsions Oral emulsions were prepared by high-pressure homogenization. The particle size distribution and the ~ potential of the prepared emulsions were determined at room temperature using dynamic light scattering. Foot measurement of size was performed at room temperature (Zetasizer 4 Malvern Instruments Limited). 〇Oil-in-water emulsion (200 g batch) was prepared with the following ingredients: Ingredient emulsifier (galactose) * diester (GLA-EPA) Palm Acid Ascorbic Acid @ Purpose (AP) Vitamin E Water -41-This paper is suitable for financial standards (CNS) M specifications (21QX297 public director) (Please read the precautions on the back before filling this page), the central standard of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperatives% 2.00 20.00 0.02 0.5 100.00 ^ 67 _________ ^ 67 _________ Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 V. Description of Invention (39) * Scotia LipidTeknik Patent " Oil-in-water emulsion ''. PCT / SE95 / 00115 (WO95 / 20943) Disperse the emulsifier galactose in the diester, mix vitamin E, AP and water. Add the oil phase to the water phase at 4 speeds under Ultraturrax And mix for several minutes. The previous emulsion was homogenized at 80 MPA at 50 ° C for 6 cycles (mini-Lab 8.30 H; APV Rannie As, Denmark). The average droplet size of the prepared emulsion was 230 nm. Antimicrobial Prevent Potassium sorbate and flavoring agent can be added to the above oral administration emulsion. 2. An intravenously administered 20% emulsion of a diester of GLA and EPA with 1,3-propanediol is prepared in a similar manner. 200 grams of oil-in-water emulsion containing the following ingredients: Ingredient% Emulsifier 2.0 diester (GLA-EPA) 20.0 Glycerin 2.0 water, added to 100.00 above emulsion, made by high pressure homogenization for 6 minutes, the average droplet size is 211 nm, / 9 potential -40 mV. These intravenously administered emulsions can be filtered with a membrane having a pore size of 0.22 micron, or they can be autoclaved, and the droplet size may vary. The amount of the active to be administered may be from 1 g to 200 g per day, preferably 10 mg to 10 g, more preferably 10 mg to 3 g, depending on the kind. When treating cancer, the preferred dose may be 2-150 g / day. It can also be used as a local preparation when the formulation is suitable. -42- This paper size is applicable to China National Standard (CNS) A4 regulation ^ (27 ^ 297mm) ~---------- ^^ clothing-(please first (Read the notes on the back and fill out this page)
、1T 546138 經濟部中央標準局員工消費合作社印掣 Α7 Β7 五、發明説明(4〇 ) 給予,此種製劑活性物佔局部給予製劑的〇 001%至50〇/〇, 較佳是0·05%至20%,更佳是0.1%至1〇〇/0。 實例 NSAID聯於脂肪' 酸上的合成見前述以公佈的ΕΡΑ-0 675 103。將脂肪酸通過1,3-丙燒二醇殘基聯於其他一般説明性 物料上的説明性合成如下。 實例1 1,3·(二·ζ,ζ,ζ·十八基_6,9,12·三晞酿基氧基)丙燒 (GLA與1,3_丙烷二醇之二酯) 將1,3-二環己基碳化二亞醯胺(1.07克)及4-(Ν,Ν-二甲基胺 基)吡啶(0.59克)於二氯甲烷(5毫升)内之溶液加於1,3-二羥 基丙烷(0.152克)及2,2,2-十八基_6,9,12_三烯酸(95%,1.36 克)於二氯甲烷(15毫升)内之溶液中。將此反應物於室溫在 氮氣下攪拌至以tic (薄層色譜分析)測定已反應完全。於此 反應物内加己烷(8〇毫升)。過濾移除沉澱物,用己烷徹底 洗。將合併之濾過物濃縮’作閃色譜分析純化’製得1,3_( 二-z,z,z-十八基-6,9,12-三烯醯基氧基)丙燒,爲灰黃色自 由流動油體。 實例2 l-(z,z,z-十八基-6,9,12-三烯醯基氧基)-3_(ζ·十八基-9-烯醯 基氧基)丙烷 (GLA及油酸與1,3_丙烷二醇之二酯) 部分1 : 將ζ,ζ,ζ-十八基_6,9,12-三烯酸(150克)於二氯甲燒(500毫 -43- 本紙張尺度適用巾酬家標準(CNS ) Α4規格(21(3X 297公釐) :IIΓ_ΐ (請先閱讀背面之注意事項再填寫本頁) 、1Τ 經濟部中央標準局員工消費合作社印製 546138 A7 B7 ____ 五、發明説明(41 ) 升)内之溶於室溫在氮氣下滴加於丨,3-二經基丙坑(205克) ,1,3·二環己基碳化二亞醯胺(130克)及4-(N,N-二甲基胺基) 吡啶(87克)於二氯甲烷(2500毫升)之混合物内。在tlc顯示 反應已完全後,將反應混合物過濾。濾過物用稀鹽酸’水 ,及飽和氯化鈉溶液洗。將溶液乾燥,濃縮,作乾柱色譜 分析純化,製得l_(z,z,z-十八基-6,9,12-二晞Si基氧基)-3-經基丙烷,爲灰黃色油體。 部分2 : 將1,3-二環己基碳化二亞醯胺(23.7克)及4-(队>1-二甲基胺 基)吡啶(15.9克)於二氯甲烷(200毫升)内之溶液在氮氣下於 室溫加於l-(z,z,z-十八基-6,9,12-三晞酿基氧基)-3_經基丙 烷(3 3.6克)及z-十八基-9-烯酸(30克)於二氯甲烷(400毫升) 内之溶液中。以tic測定已反應完全後,此溶液用己燒稀釋 ,過濾,濃縮,作乾柱色譜分析純化,製得l_(z,z,z-十八 基-6,9,12-三烯醯基氧基)-3-(z-十八基-9-烯醯基氧基)丙烷 ,爲自由流動的灰黃色油體。 實例3 l-(z,z,z_十八基-6,9,12-三晞醯基氧基)_3_(z,z,z,z,z_二十基- 5,8,11,14,17-五烯醯基氧基)丙烷 (GLA與EPA及1,3-丙烷二醇之二酯) 製備如實例2部分2,但用ζ,ζ,ζ,ζ,ζ·二十基 ΐ 烯酸 代替 z-十八基 _9_晞酸 。以 色譜分 析製得 1_(ζ,ζ,ζ· 十 八基-6,9,12·三烯醯基氧基)_3-(z,z,z,z,z_: + S-5,8,ll,14, 17·五烯醯基氧基)丙烷,爲灰黃色油體。 -44 - 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210X297公釐1 ~~一 " I!: IIΓ 疃—丨 (請先閲讀背面之注意事項再填寫本頁)1T 546138 Consumption Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperative Association A7 B7 V. Description of the invention (40) The active substance of this preparation accounts for 0.0001% to 50/0 of the locally administered preparation, preferably 0.05 % To 20%, more preferably 0.1% to 100/0. For the synthesis of example NSAIDs linked to fatty acids, see the aforementioned EPA-0 675 103. An illustrative synthesis of fatty acids via 1,3-propanediol residues on other general illustrative materials is as follows. Example 1 1,3 · (di · ζ, ζ, ζ · octadecyl-6,9,12 · trimethylamino) propane (GLA and 1,3-propanediol diester) will be 1 A solution of 1,3-dicyclohexylcarbodiimideamine (1.07 g) and 4- (N, N-dimethylamino) pyridine (0.59 g) in dichloromethane (5 ml) was added to 1,3 -A solution of dihydroxypropane (0.152 g) and 2,2,2-octadecyl-6,9,12-trienoic acid (95%, 1.36 g) in dichloromethane (15 ml). The reaction was stirred at room temperature under nitrogen until the reaction was complete as determined by tic (thin layer chromatography). To the reaction was added hexane (80 ml). The precipitate was removed by filtration and washed thoroughly with hexane. The combined filtrates were concentrated and 'purified by flash chromatography' to obtain 1,3_ (di-z, z, z-octadecyl-6,9,12-trienyloxy) propene as a grayish yellow. Free flowing oil body. Example 2 l- (z, z, z-octadecyl-6,9,12-trienyloxy) -3_ (ζ · octadecyl-9-alkenyloxy) propane (GLA and oil Diesters of acids and 1,3-propanediol) Part 1: Put ζ, ζ, ζ-octadecyl-6,9,12-trienoic acid (150 g) in dichloromethane (500 mmol-43 -This paper size applies CNS standard A4 (21 (3X 297 mm)): IIΓ_ΐ (Please read the precautions on the back before filling out this page), 1T Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 B7 ____ V. Description of the invention (41 liters) Dissolved in room temperature under nitrogen and added dropwise to 丨, 3-dimethyacryl (205g), 1,3 · dicyclohexylcarbodiimide (130 g) and 4- (N, N-dimethylamino) pyridine (87 g) in a mixture of dichloromethane (2500 ml). After tlc showed that the reaction was complete, the reaction mixture was filtered. The filtrate Wash with dilute hydrochloric acid 'water and saturated sodium chloride solution. The solution was dried, concentrated, and purified by dry column chromatography to obtain l_ (z, z, z-octadecyl-6,9,12-difluorene Si Alkoxy) -3- via propane, as a gray-yellow oil. Fraction 2: Place 1,3-dicyclohexylcarbodiimide (23.7 g) and 4- (Team> 1-dimethylamino) pyridine (15.9 g) in dichloromethane (200 ml). The solution was added at room temperature under nitrogen to l- (z, z, z-octadecyl-6,9,12-triamyloxy) -3-propanylpropane (3 3.6 g) and z-deca Octyl-9-enoic acid (30 g) in dichloromethane (400 ml). After the reaction was determined by tic, the solution was diluted with hexane, filtered, concentrated, and purified by dry column chromatography. L_ (z, z, z-octadecyl-6,9,12-trienyloxy) -3- (z-octadecyl-9-alkenyloxy) propane was obtained, which was free flowing Gray-yellow oil. Example 3 l- (z, z, z_octadecyl-6,9,12-trimethyloxy) _3_ (z, z, z, z, z_icosyl- 5,8,11,14,17-pentaenyloxy) propane (the diester of GLA with EPA and 1,3-propanediol) was prepared as in Example 2, part 2, but using ζ, ζ, ζ, ζ , Ζ eicosyl enoic acid instead of z-octadecyl-9_fluorenic acid. 1_ (ζ, ζ, ζ octadecyl-6,9, 12 · trienyloxy) was prepared by chromatographic analysis. ) _3- (z, z, z, z, z_: + S-5,8,11,14,17 · pentaenyloxy) propane, a gray-yellow oil body. -44-This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X297 mm 1 ~~一 " I !: IIΓ 疃 — 丨 (Please read the precautions on the back before filling this page)
、1T 546138 經濟部中央標準局員工消費合作社印製 Α7 Β7 五、發明説明(42 ) 實例4 1,3-二〇,十八基-6,9,12_三烯醯基氧基)丙烷 (GLA與1,3-丙烷二醇之二酯) 製備如實例2部分2,但用z,z,z•十八基_6,9,12-三烯酸代 替z-十八基-9-烯酸。以色譜分析製得13-二(z,z,z_十八基· 6,9,12-三烯醯基氧基)丙燒,爲灰黃色油體。 實例5 (+)-1-(1,2-一 硫院-3-戊酿基氧基)_3_(;2,2;,2;-十八基-6,9,12-三 烯醯基氧基)丙烷 (硫辛酸及GLA與1,3-丙烷二醇之二酯) 將1,3-二環己基碳化二亞醯胺(720毫克,3.45毫莫耳)及 4-(Ν,Ν·二甲基胺基)吡啶(480毫克,3.98毫莫耳)於三級丁 基甲基醚(15毫升)内之溶液加於硫辛酸(645毫克,3.12毫 莫耳)及1·(ζ,ζ,ζ-十八基_6,9,12-三烯醯基氧基)_3_羥基丙烷 (1克,3毫莫耳)於三級丁基甲基醚(3〇毫升)内之混合物中 。此混合物於室溫在氮氣下攪掉5小時,以tic (40%醋酸乙 酯/己烷)監視反應之進行。反應完全後,將混合物過濾, 濃縮,以閃色譜分析純化(己燒,2%醋酸乙酯/己燒,5% 醋酸乙酯/己烷,最後用1〇〇/0醋酸乙酯/己烷),製得(士)4-(1,2-二硫烷-3_戊醯基氧基)_3_(z,z,z_十八基_6,9,12_三烯醯 基氧基)丙貌,爲枯性黃色油體。 實例6 1_([Ζ]·5_氟甲基·ΐ_[4-(甲基亞磺醯基)亞芊基]莽弁_3-乙 醯基氧基)-3-(z,z,z_十八基·6,9,12_三烯醯基氧基)丙燒 -45- 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐) :I—Γ鍾! (請先閱讀背面之注意事項再填寫本頁) 、1Τ 經濟部中央標準局員工消費合作衽印製 546138 A7 ____ B7 五、發明説明(43 ) (蘇靈大及GLA與1,3_丙烷二醇之二酯) 將1,3-二環己基碳化二亞醯胺(720毫克,3.45毫莫耳)於 三級丁基甲基醚(30毫升)内之溶液加於蘇靈大(1.12克, 3.15毫莫耳),4-(N,N-二甲基胺基)吡啶(480毫克,3.9毫莫 耳)及l-(z,z,z_十八基-6,9,12-三烯醯基氧基)-3_羥基丙烷(1 克,3毫莫耳)於三級丁基甲基醚(i 5毫升)内之混合物中。 此混合物於室溫在氮氣下攪拌5小時,以tic (40%醋酸乙酯 /己烷)監視反應之進行。反應完全後,將混合物過濾,濃 縮,以閃色譜分析純化(40%醋酸乙酯/己烷,50%醋酸乙酯 /己烷,最後用60%醋酸乙酯/己烷),製得1-([Ζ]-5-氟-2-甲 基-1-[4·(甲基亞磺醯基)亞芊基]茚幷-3_乙醯基氧基)_3-(ζ,ζ,ζ-十八基·6,9,12_三烯醯基氧基)丙燒,爲躐樣黃色固 體。 實例7 l_([R)-3·乙醯氧基_4·[三甲基胺基]丁醯基氧基)-3_(ζ,ζ,ζ_ + 八基-6,9,12-三烯醯基氧基)丙烷 (乙酿基肉毒鹼及GLA與1,3_丙烷二醇之二酯) 將新蒸餾出的亞硫醯氯(1.5毫升)緩慢加於梨形燒瓶内的 (R)·乙醯基肉毒鹼〇克)内。注意在成爲澄清溶液前各試劑 應在燒瓶底部。於室溫過4小時後,減壓除去過量的亞硫 驗氯(維持燒瓶溫度低於3〇°C )。所產生的醯基氯爲高度吸 濕的白色固體,此產品立即使用不必純化。於此燒瓶内加 l-(z,z,z-十八基_6,9,12_三烯醯基氧基)_3經基丙烷Q 4克, 4· 17毫莫耳)及無水thf (4毫升)。任此混合物於室溫靜置 __ ___ -46- 本紙張尺度適用中國國家榡準(CNS ) A4規2】〇>< 297公餐) (請先閲讀背面之注意事項再填寫本頁) 衣 _ 、·ιτ 經濟部中央標準局員工消費合作社印製 546138 A7 ___ B7 五、發明説明(44 ) 過夜。tic分析(40%醋酸乙酯/己烷)顯示反應已完全。將反 應混合物滴加於己烷(250毫升)内,同時強烈攪拌。形成 細灰白色沉澱,離心收取此沉澱。除去漂浮物,將固體再 懸浮於己烷内並離心。再以己烷洗,製得乙醯氧 基·4·[二甲基胺基]丁醯基氧基)-3-(z,z,z-十八基·6,9,12-三 烯醯基氧基)丙烷。 實例8 1-(3,3-二甲基_7-氧基-6-([苯氧基乙醯基)胺基]_4-17塞-;[>_氮雙 環[3.2.0]庚·2·醯基氧基)-3·(ζ,ζ,ζ-十八基_6,9,12_三晞醯基 氧基)丙燒 (青黴素V及GLA與1,3·丙燒二醇之二酯) 將青黴素V(1克,2.9毫莫耳),1_(ζ,ζ,ζ十八基_6,9,12_三 烯醯基氧基)-3-經基丙燒(860毫克,2.6毫莫耳),1,3_二環 己基碳化二亞醯胺(620毫克,3毫莫耳)及4-(Ν,Ν-二甲基胺 基)吡啶(催化劑)於二氯甲烷(30毫升)内之混合物於室溫授 拌過夜。反應混合物用己烷(50毫升)稀釋,過濾並濃縮至 乾。殘餘物用己烷(3x50毫升),洗,除去未反應的 十八基-6,9,12-三烯醯基氧基)-3-羥基丙烷。將半固體殘餘 物溶於乙醚(150毫升)内,用水(1〇〇毫升)洗,乾燥。酸溶 液用己(125毫升)稀釋’以二氧化秒床(4公分χ4公分)過 濾溶液。將濾過物濃縮,製得1-(3,3_二甲基-7·氧基_6·([苯 氧基乙醯基)胺基]-4-嘧-1-氮雙環[3.2.0]庚_2-醯基氧基 (z,z,z_十八基-6,9,12_二婦S蠢基氧基)丙力兄,爲枯性無色油 體0 -47- 本紙張尺度適用中國國家標準(CNS ) Α·4規格(210X 297公釐) I : IIι#τ, (請先閱讀背面之注意事項再填寫本頁) 、11 經濟部中央標準局員工消費合作社印製 546138 A7 ________ B7 五、發明説明(45 ) — ~ 實例9 1-(2,2,2_十八基-6,9,12-三烯醯基氧基)-3_(1-(4-氯苯甲醯基 )-5 -甲氧基-2_甲基-哨嗓-3 -乙酸基氧基)丙燒 (消炎痛及GLA與1,3_丙烷二醇之二酯) 將1,3-二環己基碳化二亞醯胺(58毫克,0.28毫莫耳)及4_ (N,N-二甲基胺基)吡啶(37.9克,0.31莫耳)於二氯甲烷(800 毫升)内之溶液於室溫在氮氣下在攪:摔下加於1 -(z,z,z-十八 基-6,9,12-三烯醯基氧基)-3-羥基丙烷(79.5克,0.24莫耳)及 消炎痛(93.2克’ 0.26莫耳)於二氯甲燒(4 00毫升)内之溶液 中。繼續攪拌3小時。將混合物過濾,濃縮,以乾柱色譜 分析純化(醋酸乙酯/己燒)。收集產物並濃縮,製得i_ (z,z,z-十八基-6,9,12_三晞酿基氧基)-3-(1-(4-氯苯甲酸基)-5_甲氧基-2-甲基丨噪-3 -乙醯基氧基)丙燒,爲淺黃色枯性 油體。 實例10 1-(ζ,ζ,ζ·十八基-6,9,12_三晞醯基氧基)-3-(2-^洛貌羧基)丙 坑 (脯胺酸及GLA與1,3_丙烷二醇之二酯) 部分1 : 將1,3-二環己基碳化二亞醯胺(674毫克,.3.3毫莫耳)及4-(N,N-二甲基胺基)吡啶(472毫克,3.9毫莫耳)於二氯甲燒 (20毫升)内之溶液於室溫在氮氣下在攪拌下加於十 八基-6,9,12-三晞醯基氧基)-3-¾基丙燒(1克,2.97毫莫耳) 及N-tBOC-脯胺酸(671毫克,3.12毫莫耳)於二氯甲烷(20毫 -48 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297^^7 一 " ~ ---------衣-- (請先閱讀背面之注意事項再填寫本頁) 、11 546138 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(46 ) 升)内之溶液中。繼續攪拌7小時,將混合物儲於〇°C過夜 。將混合物過濾,作柱色譜分析(甲醇/二氯甲烷)純化,製 得1·(ζ,ζ,ζ-十八基-6,9,12·三烯醯基氧基)-3-(N_tBOC-2-吡咯 烷羧基)丙烷,爲黃色油體。 部分2 : 將保護的產物溶於10%容積/容積茴香醚/三氟醋酸(1〇毫 升)内,在氮氣下置於室溫30分鐘。在tic分析顯示去保護 已完全後,將混合物作柱色譜分析(8〇/〇甲醇/42%二氯甲烷 /50%醋酸乙酯)純化,製得i-(z,z,z-十八基_6,9,12·三晞酸基 氧基)-3-(2-ρ比洛燒羧基)丙燒,爲枯性橘色油體。 實例11 1-(2,2,2_十八基-6,9,12-三烯醯基氧基)_3<2-胺基_3_啕哚基 丙醯基氧基)丙燒 (色胺酸及GLA與1,3-丙烷二醇之二酯) 部分1 : 將1,3-二環己基碳化二亞醯胺(674毫克,.3.3毫莫耳)及4_ (Ν,Ν-二甲基胺基)吡啶(472毫克,3.9毫莫耳)於二氯甲烷 (20¾升)内之:谷液於Α溫在氮氣下在揽摔下加於ι·(ζ,ζ,ζ_ + 八基-6,9,12-三烯醯基氧基)-3-羥基丙烷(1克,2.97毫莫耳) 及N-tBOC-色胺酸(950毫克,3·12亳莫耳)於二氯甲烷(20毫 升)内之溶液中。繼續攪拌7小時,將混合物儲於〇〇C過夜 。將混合物過濾,作柱色譜分析(甲醇/二氯甲烷)純化,製 得l-(z,z,z-十八基_6,9,12_三烯醯基氧基)小(N_tB〇c_2胺基 -3丨哚基丙醯基氧基)丙烷,爲黃色油體。 -49- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) I :丨丨Γ疃丨丨 (請先閱讀背面之注意事項再填寫本頁) 訂 546138 經濟部中央標準局員工消費合作社印製 A7 ___________ B7 五、發明説明(47 ) 部分2 : 將保護的產物溶於10%容積/容積茴香醚/三氟醋酸(61毫 升)内,在氮氣下置於室溫15分鐘。在tic分析顯示去保護 已完全後’將混合物作柱色譜分析(8%甲醇/42%二氯甲燒 /50%醋酸乙酯)純化,製得卜(2,2,2_十八基_6,9,12_三烯醯基 氧基)-3-(2-胺基-3-吲哚基丙醯基氧基)丙烷,爲粘性紅色 蠟樣物。 實例12 l-(z,z,z-十八基-6,9,12·三烯醯基氧基)-3-(從·胺基-卢·苯基 丙醯基氧基)丙烷 (苯丙胺酸及GLA與1,3 -丙燒二醇之二酯) 部份1 : 將1,3·二環己基碳化二亞醯胺(ι·77克,8.57毫莫耳)及4-(N,N_一甲基胺基)吨遗(1.24克’ 10.13蒙莫耳)於二氣甲燒 (30毫升)内之溶液於室溫在氮氣下在攪拌下加於十 八基-6,9,12-二晞醯基氧基)_3_遵基丙貌(2·62克,7·79毫莫 耳)及N-tBOC-苯丙胺酸(2.17克,8.18毫莫耳)於二氯甲燒 (30¾:升)内之溶液中。繼續攪拌7小時,將混合物儲於〇。^ 過夜。將混合物過濾,作柱色譜分析(甲醇/二氯甲烷)純化 ,製得l-(z,z,z-十八基·6,9,12-三烯醯基氧基)_3_(N_tB〇c_ α -胺基- yS-苯基丙酸基氧基)丙燒,爲黃色油體。 部分2 : 將保護的產物溶於10%容積/容積茴香醚/三氟醋酸(丨7毫 升)内,在氮氣下置於室溫30分鐘。在tlc分析顯示去保護 -50· _本紙張尺度適f中國國家標準([NS ) A4規格(210X297公釐^ - ' -----:!Γ_τ— (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 546138 A7 B7 - ^ 一 ~ "" ’ — -~—丨1 —— -- 五、發明説明(48 ) 已完全後,將混合物作柱色譜分析(8%甲醇/42%二氯甲烷 /50%醋酸乙酯)純化,製得l-(z,z,z-十八基-6,9,12_三晞醯基 氧基)-3-(以-胺基-卢-苯基丙醯基氧基)丙燒,爲枯性黃色油 體。 實例13 l-(z,z,z-十八基·6,9,12_三烯醯基氧基)_3-(4·胺基-丁醯基氧 基)丙燒 (GABA及GLA與1,3·丙烷二醇之二酯) 部分1 : 將1,3-二環己基碳化二亞醯胺(0.84克,4.06毫莫耳)及4-(N,N-二甲基胺基)吡啶(0·59克,4.79毫莫耳)於二氯甲燒 (10毫升)内之溶液於室溫在氮氣下在攪拌下加於1_(ζ,ζ,ζ_十 八基-6,9,12-二晞酿基氧基)-3-¾基丙燒(1.24克,3.69毫莫 耳)及N-tBOC-GABA(0.75克,3.69毫莫耳)於二氯甲燒(15 毫升)内之溶液中。繼續攪拌7小時,將混合物儲於過 夜。將混合物過濾,作柱色譜分析(甲醇/二氯甲燒)純化, 製得1-(ζ,ζ,ζ·十八基_6,9,12_三烯醯基氧基)_3_(N-tB〇c_4_胺 基-丁醯基氧基)丙烷,爲無色油體。 部分2 ·· 將保護的產物溶於10%容積/容積茴香醚/三氟醋酸(1〇 5 毫升)内,在氮氣下置於室溫30分鐘。在tic分析顯示去保 護已完全後,將混合物作柱色譜分析(8%甲醇/42%二氣甲 烷/50%醋酸乙酯)純化,製得l-(z,z,z-十八基_6,9,12_三晞醯 基氧基)-3-(4-胺基-丁醯基氧基)丙規,爲黃色油體。 -51 - 本紙張尺度適用中國國家標準(CNS ) Α4ϋ 2ί〇Τΐ97公釐)— ~~ '—· ;———4II (請先閱讀背面之注意事項再填寫本頁) 、11 經濟部中央標準局員工消費合作社印製 546138 A7 ____ B7 五、發明説明(49 ) 一~ ^~ 實例14 3,3’-硫基二-(卜丙醯基氧基)·(3_(ζ,ζ,ζ_十八基ία三婦 醯基氧基)丙烷)) (GLA與1,3 -丙跪二醇及3,3’-硫代二丙酸之雙二醋) 將二環己基碳化二亞醯胺(660毫克,3.22亳莫耳)及 4_(N,N-二甲基胺基风啶(料5毫克,3·64亳莫耳)於二氯甲 烷(10毫升)内之溶液於室溫在氮氣下在攪拌下加於2 _(ζ,ζ,ζ_ 十八基·6,9,12·三晞醯基氧基)-3-¾基丙燒(940毫克,2.8毫 莫耳)及3,3··硫代丙酸(250毫克,1.4毫莫耳)於二氯甲垸(3〇 毫升)内之溶液中。繼續攪拌4小時。將混合物用己燒(5〇 毫升)稀釋,過濾,濃縮,作閃色譜分析(醋酸乙酯/己烷) 純化。收集產物部分,濃縮,製得3,3,_硫基-二_(1_丙醯基 氧基)-(3-(z,z,z-十八基-6,9,12-三晞酿基氧基)丙燒)),爲無 色油體。 實例15 l-(l-(z,z,z-十八基·6,9,12_三烯醯基氧基>3·丙基Μ_(ζ ζ,ζ_ 十八基_6,9,12-三烯基)丁烷-丨,‘二酸酯 ((GLA單酯與1,3-丙燒二醇)及GLA醇與丁二酸)之二酯) 部分1 : 將1_(ζ,ζ,ζ_十八基_6,9,12-三烯醯基氧基)_3_羥基丙烷(1〇 克,3〇毫莫耳)及丁二酸酐(3克,3〇毫莫耳)於無水THF (100毫升)内之混合物於室溫攪拌至成澄清溶液。將此溶 液冷至0°C,滴加u —二氮雙環[5·4.0]十一碳烯(45毫升 ,30毫莫耳)於無水THF (50毫升)内之溶液。3小時後^顯 _ ^ -52- 本紙張尺度適用中國國家檩準(CNS ) A4規格(21〇χ 297公羡) I : ί—衊|丨 (請先閱讀背面之注意事項再填寫本頁) 、1Τ 經濟部中央榡準局員工消費合作社印製 546138 A7 -___ B7______ 五、發明説明(5〇 ) 示大多數單酯已反應。再加少許丁二酸酐結晶,繼續攪拌 30分鐘。反應混合物用乙醚(250毫升)稀釋,用2M的鹽酸 (2x250毫升),水(250亳升)及鹽水(250毫升)洗。然後乾燥( 硫酸鈉)並濃縮至乾。此物質直接使用,不必純化。 部分2 : 將草醯氯(3.9毫升,45毫莫耳)加於部分1產物(13克,30 毫莫耳)於二氯甲烷(75毫升)内之溶液中。此混合物於室溫 在氮氣下攪拌2小時,濃縮至乾。加己烷(75毫升),再將 此混合物濃縮至乾。再以二份己貌(各75亳升)重複此過程 。此物質直接使用,不必純化。 部分3 : 將部分2製得之醯基氣(1克,2.2毫莫耳)於二氯甲烷(1〇毫 升)内之溶液於室溫滴加於z,z,z_十八基_6,9,12_三晞醇(635 毫克,2.4毫莫耳),三乙基胺(1亳升,7.2毫莫耳)及4-(N,N-二甲基胺基)p比淀(催化量)於二氯甲垸(2〇毫升)内之溶 液中。反應完全後,將混合物濃縮,作閃色譜分析純化( 醋酸乙酯/己烷),製得1_(ζ,ζ,ζ·十八基_6,9,12-三烯醯基氧 基)_3_丙基)_4·(ζ,ζ,ζ-十八基-6,9,12_三晞基)丁嫁],4_二酸 酉旨,爲無色油體。 實例16 1-(2,3,5·三破苯甲醯基氧基)-3_(ζ,ζ,ζ_十八基_6,9,12-三締酿 基氧基)丙烷 (2,3,5-三碘苯甲酸及GLA與1,3-丙烷二醇之二醋) 將2,3,5-三破苯甲酿氯(1.54克’ 3.〇8亳莫耳)加於卜(ζ,ζ ζ_ -53- Ρ氏張I度適用中國國家標準(CNS~) A4規格(27^77公釐 ~~ -----:———疃|丨 (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央標隼局員工消費合作杜印製 546138 A7 B7 五、發明説明(51 ) ~ 十八基-6,9,12-三烯醯基氧基)-3-輕基丙燒(J克,297毫莫 耳)及三乙基胺(1毫升)於二氯甲烷(80亳升)内之溶液中, 此混合物於室溫在氮氣下攪掉過夜。將混合物濃縮,作閃 色譜分析(醋酸乙酯/己烷)純化,製得1-(2,3,5-三破苯甲驢 基氧基)-3-(z,z,z-十八基-6,9,12-三烯醯基氧基)丙燒。 實例17 (土)-1-(1,2_ 二硫烷·3_ 戊醯基氧基)_3_(z,z,z,z,z,z-二十二基一 4,7,10,13,16,19-六烯醯基氧基)丙烷 (DHA及硫辛酸與1,3-丙烷二醇之二酯) 部分1 : 將 2,2,2,2,2,2-二十二基_4,7,10,13,16,19-六烯酸(64克, 19.5毫莫耳)於二氯甲燒(225毫升)内之溶液於_i〇°c滴加於 1,3-丙烷二醇(7.5克,99毫莫耳),1,3_二環己基碳化二亞 醯胺(4.65克,20毫莫耳)及4-(Ν,Ν·二甲基胺基)吡啶(21克 ,17毫莫耳)於二氯甲烷(225毫升)内之溶液中。將此反應 混合物攪拌過夜,升至室溫。將混合物過濾,濃縮,作閃 色譜分析(醋酸乙酯/己烷)純化,製得1-(ζ,ζ,ζ,ζ,ζ,ζ•二十二 基_4,7,10,13,16,19-六烯醯基氧基)-3-經基丙燒,爲灰黃色 油體。 部分2 : 將1,3-二環己基碳化二亞醯胺(720毫克,3_45毫莫耳)及 4-(Ν,Ν_二甲基胺基)峨淀(4 80毫克,3.9¾莫耳)於二氯甲燒 (30毫升)内之溶液加於 1·(ζ,ζ,ζ,ζ,ζ,ζ_二十二基 _4,7,1〇,13,16, 19-六晞酿基氧基)-3-¾基丙燒(1.16克,3¾莫耳)及硫辛酸 _ -54- 本紙張尺度適用中國國家標準(CNS ) 公釐1 '一~ "一"- ! : ί ι#τ — (請先閱讀背面之注意事項再填寫本頁) -訂1T 546138 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (42) Example 4 1,3-Dioxo, octadecyl-6,9,12_trienyloxy) propane ( GLA and 1,3-propanediol diester) Prepared as in Example 2, Part 2, but replacing z-octadecyl-9- with z, z, z-octadecyl-6,9,12-trienoic acid Enoic acid. Chromatographic analysis yielded 13-bis (z, z, z-octadecyl · 6,9,12-trienyloxy) propane as a gray-yellow oil. Example 5 (+)-1- (1,2-monothiol-3-pentyloxy) _3 _ (; 2,2;, 2; -octadecyl-6,9,12-trienefluorenyl Oxy) propane (lipoic acid and the diester of GLA and 1,3-propanediol) 1,3-dicyclohexylcarbodiimide (720 mg, 3.45 mmol) and 4- (Ν, Ν A solution of dimethylamino) pyridine (480 mg, 3.98 mmol) in tert-butyl methyl ether (15 ml) was added to lipoic acid (645 mg, 3.12 mmol) and 1. (ζ, ζ , Zeta-octadecyl-6,9,12-trienyloxy) -3-hydroxypropane (1 g, 3 mmol) in a mixture of tertiary butyl methyl ether (30 ml). The mixture was stirred at room temperature under nitrogen for 5 hours, and the progress of the reaction was monitored by tic (40% ethyl acetate / hexane). After the reaction was completed, the mixture was filtered, concentrated, and purified by flash chromatography (hexane, 2% ethyl acetate / hexane, 5% ethyl acetate / hexane, and finally 100/0 ethyl acetate / hexane ) To obtain (±) 4- (1,2-disulfane-3_pentamyloxy) _3_ (z, z, z_octadecyl_6,9,12_trienyloxy) ) The appearance of C is a yellow oily body. Example 6 1 _ ([Z] · 5-fluoromethyl · fluorene_ [4- (methylsulfinylfluorenyl) fluorenyl] manganyl-3-ethylethoxy) -3- (z, z, z _18 octadecyl, 6,9,12_trienyloxy) propane-45- This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm): I-Γ Zhong! (Please read the precautions on the back before filling this page) 、 Printed by the staffing cooperation agreement of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 ____ B7 V. Description of the invention (43) (Su Lingda and GLA with 1,3_propane II Alcohol diester) A solution of 1,3-dicyclohexylcarbodiimide (720 mg, 3.45 mmol) in tertiary butyl methyl ether (30 ml) was added to Sulinda (1.12 g, 3.15 Millimoles), 4- (N, N-dimethylamino) pyridine (480 mg, 3.9 millimoles) and l- (z, z, z-octadecyl-6,9,12-triene Fluorenyloxy) -3-hydroxypropane (1 g, 3 mmol) in a mixture of tertiary butyl methyl ether (i 5 ml). The mixture was stirred at room temperature under nitrogen for 5 hours, and the progress of the reaction was monitored with tic (40% ethyl acetate / hexane). After the reaction was completed, the mixture was filtered, concentrated, and purified by flash chromatography (40% ethyl acetate / hexane, 50% ethyl acetate / hexane, and finally 60% ethyl acetate / hexane) to obtain 1- ([Z] -5-Fluoro-2-methyl-1- [4 · (methylsulfinamilide) fluorenyl] indene-3-ethylethynyloxy) _3- (ζ, ζ, ζ -Stearyl, 6,9,12-trienyloxy) propane, as a pyrene-like yellow solid. Example 7 l _ ([R) -3 · Ethyloxy-4 · [trimethylamino] butyryloxy) -3_ (ζ, ζ, ζ_ + octyl-6,9,12-trienefluorenyl (Oxy) propane (Ethyl Carnitine and GLA and 1,3-propanediol diester) Slowly add freshly distilled thionyl chloride (1.5 ml) to the (R) · in a pear-shaped flask Acetylcarnitine (0 g). Note that each reagent should be at the bottom of the flask before becoming a clear solution. After 4 hours at room temperature, excess sulfur was removed under reduced pressure and the chlorine test was maintained (maintain the flask temperature below 30 ° C). The fluorenyl chloride produced was a highly hygroscopic white solid, and this product was used immediately without purification. Into this flask were added l- (z, z, z-octadecyl-6,9,12_trienyloxy) -3 propionyl Q (4 g, 4.17 mmol) and anhydrous thf ( 4 ml). Let the mixture stand at room temperature __ ___ -46- This paper size is applicable to China National Standard (CNS) A4 Regulation 2] 〇 > < 297 meals) (Please read the precautions on the back before filling this page ) _ 、 · Ιτ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 ___ B7 V. Invention Description (44) Overnight. Tic analysis (40% ethyl acetate / hexane) showed that the reaction was complete. The reaction mixture was added dropwise into hexane (250 ml) with vigorous stirring. A fine off-white precipitate formed and was collected by centrifugation. The float was removed and the solid was resuspended in hexane and centrifuged. Then washed with hexane to obtain ethoxyl · ··························································································································· (Oxy) propane. Example 8 1- (3,3-Dimethyl-7-oxy-6-([phenoxyethylfluorenyl) amino] -4-17 plug-; [> _nitrobicyclo [3.2.0] heptane · 2 · fluorenyloxy) -3 · (ζ, ζ, ζ-octadecyl_6,9,12_trifluorenyloxy) propane (penicillin V and GLA with 1,3 · propane) Alcohol diesters) Penicillin V (1 g, 2.9 mmol), 1_ (ζ, ζ, ζoctadecyl-6,9,12_trienyloxy) -3-ylpropane ( 860 mg, 2.6 mmol), 1,3-dicyclohexylcarbodiimide (620 mg, 3 mmol) and 4- (N, N-dimethylamino) pyridine (catalyst) The mixture in methyl chloride (30 ml) was stirred at room temperature overnight. The reaction mixture was diluted with hexane (50 ml), filtered and concentrated to dryness. The residue was washed with hexane (3x50 ml) to remove unreacted octadecyl-6,9,12-trienyloxy) -3-hydroxypropane. The semi-solid residue was dissolved in ether (150 ml), washed with water (100 ml) and dried. The acid solution was diluted with hexane (125 ml) and the solution was filtered through a bed of dioxide (4 cm x 4 cm). The filtrate was concentrated to obtain 1- (3,3_dimethyl-7 · oxy_6 · ([phenoxyethylamyl) amino] -4-pyrim-1-azabicyclo [3.2.0 ] Heptan-2-yloxy (z, z, z_octadecyl-6,9,12_di-methyl-s-stilyloxy) propylene, a bleached colorless oil body 0 -47- This paper Standards are applicable to Chinese National Standards (CNS) Α · 4 specifications (210X 297 mm) I: IIι # τ, (Please read the precautions on the back before filling out this page), 11 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 ________ B7 V. Explanation of the invention (45) — ~ Example 9 1- (2,2,2_octadecyl-6,9,12-trienyloxy) -3_ (1- (4-chlorobenzene Methenyl) -5 -methoxy-2_methyl-whistle-3 -acetoxy) propane (indomethacin and the diester of GLA and 1,3-propanediol) 1,3- Dicyclohexylcarbodiimide (58 mg, 0.28 mmol) and 4- (N, N-dimethylamino) pyridine (37.9 g, 0.31 mole) in dichloromethane (800 ml) Stir under nitrogen at room temperature: add to 1- (z, z, z-octadecyl-6,9,12-trienyloxy) -3-hydroxypropane (79.5 g, 0.24 mo Ear) and indomethacin 93.2 g '0.26 mole) in dichloromethane (400 ml). Stirring was continued for 3 hours. The mixture was filtered, concentrated, and purified by dry column chromatography (ethyl acetate / hexane). The product was collected And concentrated to obtain i_ (z, z, z-octadecyl-6,9,12_trimethylamino) -3- (1- (4-chlorobenzoate) -5_methoxy -2-methyl 丨 Noise-3 -ethenyloxy) propane is a pale yellow cumulant oil body. Example 10 1- (ζ, ζ, ζ Octadecyl-6, 9, 12_trifluorene Fluorenyloxy) -3- (2- ^ Lomaline carboxyl) propanone (proline and diesters of GLA and 1,3-propanediol) Part 1: Carbodiimide of 1,3-dicyclohexyl A solution of amidine (674 mg, .3.3 mmol) and 4- (N, N-dimethylamino) pyridine (472 mg, 3.9 mmol) in dichloromethane (20 ml) in a chamber Under stirring under nitrogen, add octadecyl-6,9,12-trimethyloxy) -3-¾propane (1 g, 2.97 mmol) and N-tBOC-proline (671 mg, 3.12 mmol) in dichloromethane (20 mmol-48-this paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 ^^ 7 a " ~ ----- ---- Cloth-(Please read the precautions on the back before filling this page), 11 546138 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 (5, Invention Description (46 liters)). Stirring was continued for 7 hours, and the mixture was stored at 0 ° C overnight. The mixture was filtered and purified by column chromatography (methanol / dichloromethane) to obtain 1 · (ζ, ζ, ζ-octadecyl-6,9,12 · trienyloxy) -3- (N_tBOC -2-Pyrrolidine carboxy) propane, as a yellow oil. Part 2: The protected product was dissolved in 10% vol / vol anisole / trifluoroacetic acid (10 ml) and placed at room temperature under nitrogen for 30 minutes. After tic analysis showed that deprotection was complete, the mixture was purified by column chromatography (80/0 methanol / 42% dichloromethane / 50% ethyl acetate) to obtain i- (z, z, z-eighteen The group _6,9,12 · trisanoic acidoxy group) -3- (2-ρ bilocarbon carboxyl) propanone is a fuming orange oil body. Example 11 1- (2,2,2_octadecyl-6,9,12-trienyloxy)) 3 < 2-amino_3_oxolinylpropanyloxy) propane (color Amino acids and diesters of GLA and 1,3-propanediol) Part 1: 1,3-Dicyclohexylcarbodiimide (674 mg, .3.3 mmol) and 4- (N, N-di Methylamino) pyridine (472 mg, 3.9 mmol) in dichloromethane (20¾ liters): Valley fluid at A temperature under nitrogen and added to ι · (ζ, ζ, ζ_ + eight -6,9,12-trienyloxy) -3-hydroxypropane (1 g, 2.97 mmol) and N-tBOC-tryptophan (950 mg, 3.12 mmol) Methyl chloride (20 ml) in solution. Stirring was continued for 7 hours, and the mixture was stored at 00C overnight. The mixture was filtered and purified by column chromatography (methanol / dichloromethane) to obtain l- (z, z, z-octadecyl-6,9,12-trienyloxy) small (N_tBocc_2 Amino-3 (indolylpropionyloxy) propane is a yellow oil. -49- This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) I: 丨 丨 Γ 疃 丨 丨 (Please read the precautions on the back before filling this page) Order 546138 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the cooperative A7 ___________ B7 V. Description of the invention (47) Part 2: Dissolve the protected product in 10% volume / volume anisole / trifluoroacetic acid (61 ml) and place it at room temperature under nitrogen for 15 minutes. After tic analysis showed that the deprotection was complete, the mixture was purified by column chromatography (8% methanol / 42% dichloromethane / 50% ethyl acetate) to obtain (2,2,2_octadecyl_ 6,9,12-trienyloxy) -3- (2-amino-3-indolylpropionyloxy) propane, a viscous red waxy substance. Example 12 l- (z, z, z-octadecyl-6,9,12 · trienefluorenyloxy) -3- (from · amino-lu · phenylpropionyloxy) propane (amphetamine Acid and the diester of GLA and 1,3-propanediol) Part 1: 1,3 · Dicyclohexylcarbodiimide (ι · 77 g, 8.57 mmol) and 4- (N, N_monomethylamino group) (1.24 g '10 .13 monmor) solution in digas methylbenzene (30 ml) at room temperature under nitrogen with stirring under octadecyl-6,9, 12-Difluorenyloxy) _3_ Zynyl Propionate (2.62 g, 7.79 mmol) and N-tBOC-phenylalanine (2.17 g, 8.18 mmol) in dichloromethane ( 30¾: liter). Stirring was continued for 7 hours, and the mixture was stored at 0. ^ Overnight. The mixture was filtered and purified by column chromatography (methanol / dichloromethane) to obtain l- (z, z, z-octadecyl · 6,9,12-trienyloxy) _3_ (N_tBOC_ α-Amino-yS-phenylpropanoyloxy) propane is yellow oil. Part 2: Dissolve the protected product in 10% vol / vol anisole / trifluoroacetic acid (7 ml) and place at room temperature under nitrogen for 30 minutes. Analysis at tlc shows that deprotection -50 · _ This paper is suitable for China National Standard ([NS) A4 size (210X297 mm ^-'-----:! Γ_τ— (Please read the precautions on the back before filling (This page) Order printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 B7-^ 一 ~ " " '—-~ — 丨 1 ——-5. When the description of the invention (48) is complete, the mixture is used as Purification by column chromatography (8% methanol / 42% dichloromethane / 50% ethyl acetate) to obtain l- (z, z, z-octadecyl-6,9,12_trimethylamino) 3- (Amino-L-phenyl-propionyloxy) propane is a flaky yellow oil. Example 13 l- (z, z, z-octadecyl · 6,9,12_ Trienyloxy) _3- (4 · amino-butyryloxy) propane (GABA and GLA and the diester of 1,3 · propanediol) Part 1: Carbide 1,3-dicyclohexyl Solution of iminomine (0.84 g, 4.06 mmol) and 4- (N, N-dimethylamino) pyridine (0.59 g, 4.79 mmol) in dichloromethane (10 ml) Add 1- (ζ, ζ, ζ-octadecyl-6,9,12-diamidinooxy) -3-¾yl under stirring at room temperature under nitrogen. Propylene (1.24 g, 3.69 mmol) and N-tBOC-GABA (0.75 g, 3.69 mmol) in dichloromethane (15 ml). Stirring was continued for 7 hours and the mixture was stored overnight The mixture was filtered and purified by column chromatography (methanol / dichloromethane) to obtain 1- (ζ, ζ, ζ octadecyl_6,9, 12_trienyloxy) _3_ (N -tB〇c_4-Amine-butyryloxy) propane, a colorless oil. Part 2 ·· Dissolve the protected product in 10% volume / volume anisole / trifluoroacetic acid (105 ml) under nitrogen The mixture was left at room temperature for 30 minutes. After tic analysis showed that deprotection was complete, the mixture was purified by column chromatography (8% methanol / 42% digasmethane / 50% ethyl acetate) to obtain l- (z, z, z-octadecyl_6,9,12_trifluorenyloxy) -3- (4-amino-butylfluorenyloxy) propane gauge is a yellow oil body. -51-This paper size applies to China National Standard (CNS) Α4ϋ 2ί〇Τΐ97mm) — ~~ '— ·; ——— 4II (Please read the precautions on the back before filling out this page), 11 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 ____ B7 Explanation of the invention (49) One ~ ^ ~ Example 14 3,3'-thiodi- (bupropenyloxy) · (3_ (ζ, ζ, ζ_octadecyl α α-trisyloxy) propane) ) (GLA with 1,3-propanediol and 3,3'-thiodipropionic acid bisdiacetate) Dicyclohexylcarbodiimide (660 mg, 3.22 mol) and 4_ (N Of N-dimethylaminopyridine (5 mg, 3.64 mol) in dichloromethane (10 ml) at room temperature under nitrogen and added to 2 _ (ζ, ζ , Ζ-octadecyl · 6,9,12 · trisyloxy) -3-¾propylpropane (940 mg, 2.8 mmol) and 3,3 ·· thiopropionic acid (250 mg, 1.4 Mol) in a solution in methylene chloride (30 ml). Stirring was continued for 4 hours. The mixture was diluted with hexane (50 ml), filtered, concentrated, and purified by flash chromatography (ethyl acetate / hexane). The product fractions were collected and concentrated to obtain 3,3, _thio-di_ (1-propanyloxy)-(3- (z, z, z-octadecyl-6,9,12-trifluorene) Bake based oxy) propylene)), is a colorless oil body. Example 15 l- (l- (z, z, z-octadecyl · 6,9,12_trienefluorenyloxy > 3.propylM_ (ζ ζ, ζ_octadecyl-6,9, 12-trienyl) butane- 丨 'diester ((GLA monoester and 1,3-propanediol) and GLA alcohol and succinic acid) diester) Part 1: Put 1_ (ζ, ζ, ζ_octadecyl_6,9,12-trienyloxy) _3-hydroxypropane (10 g, 30 mmol) and succinic anhydride (3 g, 30 mmol) The mixture in anhydrous THF (100 ml) was stirred at room temperature until a clear solution was obtained. This solution was cooled to 0 ° C, and u-diazabicyclo [5 · 4.0] undecene (45 ml, 30 mmol) was added dropwise. Moore) solution in anhydrous THF (50 ml). After 3 hours ^ show _ ^ -52- This paper size applies to China National Standards (CNS) A4 specifications (21〇χ 297 public envy) I: ί— 蔑| 丨 (Please read the precautions on the back before filling this page), 1546 printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs, 546138 A7 -___ B7______ 5. The invention description (50) shows that most of the monoesters have reacted. Add a little succinic anhydride to crystallize and continue stirring for 30 minutes. The reaction mixture was treated with ether (250 ml) Dilute, wash with 2M hydrochloric acid (2x250 ml), water (250 ml), and brine (250 ml). Then dry (sodium sulfate) and concentrate to dryness. This material is used directly without purification. Part 2: The grasshopper Chlorine (3.9 ml, 45 mmol) was added to a solution of Part 1 product (13 g, 30 mmol) in dichloromethane (75 ml). The mixture was stirred at room temperature under nitrogen for 2 hours and concentrated. Add to dryness. Add hexane (75 ml), and concentrate the mixture to dryness. Repeat this process with two portions (75 liters each). This material is used directly without purification. Part 3: Prepare part 2 A solution of the obtained hydrazone gas (1 g, 2.2 mmol) in dichloromethane (10 ml) was added dropwise to z, z, z_octadecyl_6,9,12_trifluorene at room temperature. Alcohol (635 mg, 2.4 mmol), triethylamine (1 liter, 7.2 mmol) and 4- (N, N-dimethylamino) p ratio (catalytic amount) in chloroform溶液 (20 ml) in solution. After the reaction was completed, the mixture was concentrated and purified by flash chromatography (ethyl acetate / hexane) to obtain 1_ (ζ, ζ, ζ · 18 _6,9,12-trienyloxy) _3_propyl) _4 · (ζ, ζ, ζ-octadecyl-6,9,12_trimethyl) butyrate], 4_diacid Purpose is a colorless oil body. Example 16 1- (2,3,5 · Trispobenzyloxy) -3_ (ζ, ζ, ζ_octadecyl-6,9,12-trienyloxy) propane (2, 3,5-triiodobenzoic acid and GLA with 1,3-propanediol diacetate) 2,3,5-tribenzyl chloride (1.54 g '3.08 mol) added to the cloth (ζ, ζ ζ_ -53- P-sheet I degree is applicable to Chinese National Standard (CNS ~) A4 specification (27 ^ 77 mm ~~ -----: ——— 疃 | 丨 (Please read the note on the back first) Please fill in this page again for the matters) Order the consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs, printed 546138 A7 B7 V. Description of the invention (51) ~ octadecyl-6,9,12-trienyloxy) -3- A solution of light propylene (J g, 297 mmol) and triethylamine (1 ml) in dichloromethane (80 ml), the mixture was stirred at room temperature under nitrogen overnight. The mixture was stirred. Concentrate and purify by flash chromatography (ethyl acetate / hexane) to obtain 1- (2,3,5-trispobenzyloxy) -3- (z, z, z-octadecyl- 6,9,12-trienyloxy) propane. Example 17 (Earth) -1- (1,2-disulfane · 3_pentamyloxy) _3_ (z, z, z, z, z , Z-twenty-two base one 4,7,10,1 3,16,19-Hexenyloxy) propane (DHA and the diester of lipoic acid and 1,3-propanediol) Part 1: Put 2,2,2,2,2,2-2.2 A solution of phenyl 4,7,10,13,16,19-hexaenoic acid (64 g, 19.5 mmol) in dichloromethane (225 ml) was added dropwise at -1 ° C to 1,3 -Propanediol (7.5 g, 99 mmol), 1,3-dicyclohexylcarbodiimide (4.65 g, 20 mmol) and 4- (N, N · dimethylamino) pyridine (21 g, 17 mmol) in dichloromethane (225 ml). The reaction mixture was stirred overnight and warmed to room temperature. The mixture was filtered, concentrated, and analyzed by flash chromatography (ethyl acetate / hexane). Alkane) purification to obtain 1- (ζ, ζ, ζ, ζ, ζ, ζ docosyl_4,7,10,13,16,19-hexaenyloxy) -3-mer It is sintered as a gray-yellow oil. Part 2: Carrying 1,3-dicyclohexylcarbodiimide (720 mg, 3-45 mmol) and 4- (N, N_dimethylamino) Edo (4 80 mg, 3.9¾ mol) in dichloromethane (30 ml) was added to 1 · (ζ, ζ, ζ, ζ, ζ, ζ_tcosyl_4, 7, 1〇 , 13 16, 19-Hexadecyloxy) -3-¾-propane (1.16 g, 3¾ mol) and lipoic acid_ -54- This paper size applies to Chinese National Standard (CNS) mm 1 '一 ~ " 一 "-!: Ί ι # τ — (Please read the notes on the back before filling this page) -Order
經濟部中央標準局員工消費合作社印I 546138 A7 -----— _B7 五、發明説明(52 ) 一 ^〜--- Γ:=νΛ12毫莫耳)及二氣甲烷05毫升)之混合物内。 …皿在氮軋下過2.5小時後,將混合物過濾,濃縮,作 閃色4分析(醋酸乙酯/己烷)純化,製得(土),二硫烷_ 基)_3_(ζ,ζ,ζ,ζ,ζ,ζ二十二基·WWW,:;· 酿基氧基)丙抗,爲黃色油體。 甲基-二(ζ,ζ,ζ_十八基_6 9,12_三烯醯基氧基丙基)磷酸酯 (2分子GLA的3 -羥基丙基酯及!分子甲醇所成之磷三酯 部分1 : 1三乙基胺(3.74亳升,26.8亳莫耳)滴加於新蒸餘出的鱗 醯氯(2.74毫克,17.9毫莫耳)於無水THF(15亳升)内之冷的 (0 C )溶液中,於此混合物中滴加入十八基·6,9,ΐ2_ 晞酿氧基)·3·^基丙燒(5克,14.9毫升)於無水thF(15毫升) 中之溶液。將溫度維持於10。(:之下,反應係在氮氣下進行 。15分鐘後以tlc測定已完全無起始物質。將混合物過遽, 濃縮。再加甲苯(5〇毫升),將混合物濃縮。再加另一份甲 苯(50毫升)並再移除。 部分2 : 將1·(ζ,ζ,ζ-十八基·6,9,12·三烯醯基氧基)_3_羥基丙烷(3克 ,9毫莫耳)於無水THF (10毫升)内之溶液於室溫在氮氣下 滴加於粗製磷醯氯(7·5毫莫耳)(上部分2所製之半量)及三 乙基胺(3.2亳升,22.5毫莫耳)於無水THF(20毫升)内之溶 液中。此反應物於低於l〇°C存放3天。加甲醇(15毫升)將 反應物存於室溫至tic測定磷醯氯已完全反應生成所需的磷 •55- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) :ί Γ 衊! (請先閱讀背面之注意事項再填寫本頁) -訂 546138 A7 B7 53 五、發明説明( ------------ (請先閱讀背面之注意事項再填寫本頁) 三酯。作閃色譜分析(醋酸乙酯/己烷)純化,製得甲基-二 (z,z,z-十八基-6,9,12-三烯醯基氧基丙基)嶙酸酯,爲無色 油體。 實例19 二(z,z,z-十八基- 6,9,12-三晞醯基氧基丙基)骑酸酉旨 (2分子GLA的3-¾基丙基醋的磷二酉旨) 訂 將甲基乙基酮(1毫升)内之漠化裡(104毫克,1.13毫莫耳) 加於甲基二(z,z,z_十八基_6,9,12·三烯醯基氧基丙基)磷酸 酉曰(0·85克,1.13¾莫耳)(如實例18所製備)於甲基乙基酮(1 耄升)内之溶液中’此混合物回流加熱1小時。冷卻後,將 混合物溶於乙醚(3毫升)内,用水(3毫升)萃取。加幾滴甲 醇使形成的乳液破壞。分離有機層,乾燥(硫酸鈉),濃縮 ,作閃色譜分析(甲醇/氯仿)純化,製得二(z,z,z__十八基_ 6,9,12-二烯醯基氧基丙基)嶙酸酯,爲犧樣白色固體。 實例20 (2_胺基乙基)-(ζ,ζ,ζ·十八基_6,9,12-三烯醯基氧基丙基鴻酸 酉§ (乙醇胺及GLA的3_羥基丙基酯的磷二酯) 部分1 : 經濟部中央標準局員工消費合作社印製 將乙醇胺(0.5毫升,8 25毫莫耳)及三乙基胺(42毫升, 3〇毫莫耳)之混合物加於粗製磷氯化物(7 5毫莫耳X實例工8 部分i所製之半量)於無水THF(2〇毫升)内之溶液中,、維持 溫度低於i〇°C。以tic監滿方處士以、/ 皿視反應〈進行。此混合物於低於5 C存放3天。然後過遽,濃縮,用己烷⑼毫升)稀釋,再 -56 -Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs I 546138 A7 ------ _B7 V. Description of the invention (52) a ^ ~ --- Γ: = νΛ12mmol) and dichloromethane (05ml) . … After 2.5 hours under nitrogen rolling, the mixture was filtered, concentrated, and purified by flash color 4 analysis (ethyl acetate / hexane) to obtain (soil), disulfanyl) _3_ (ζ, ζ, ζ, ζ, ζ, ζ Twenty-two bases · WWW,:; · Dimethyloxy) propionate is a yellow oil body. Methyl-bis (ζ, ζ, ζ_octadecyl_6 9,12_trienyloxypropyl) phosphate (2 molecules of 3-hydroxypropyl ester of GLA and! Molecule of phosphorus formed by methanol Triester part 1: 1 Triethylamine (3.74 liters, 26.8 mol) was added dropwise to freshly distilled squid chloride (2.74 mg, 17.9 mmol) in anhydrous THF (15 liters) To a cold (0 C) solution, to this mixture was added dropwise octadecyl · 6,9, ΐ2_ hydrazone oxy) · 3 · ^ propylpropane (5 g, 14.9 ml) in anhydrous thF (15 ml) In solution. Maintain the temperature at 10. (Under, the reaction was carried out under nitrogen. After 15 minutes, the starting material was completely free from tlc measurement. The mixture was purged and concentrated. Toluene (50 ml) was added and the mixture was concentrated. Add another portion Toluene (50 ml) and remove again. Part 2: Put 1 · (ζ, ζ, ζ-octadecyl · 6,9,12 · trienyloxy) _3-hydroxypropane (3 g, 9 mmol) Moore) solution in anhydrous THF (10 ml) was added dropwise at room temperature under nitrogen to crude phosphonium chloride (7.5 mmol) (half of the amount prepared in Part 2) and triethylamine (3.2 (12.5 liters, 22.5 mmol) in a solution of anhydrous THF (20 ml). The reactant was stored at less than 10 ° C for 3 days. Add methanol (15 ml) and store the reactant at room temperature until tic determination. Phosphonium chloride has completely reacted to produce the required phosphorus • 55- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm): ί Γ! (Please read the precautions on the back before filling this page)- Order 546138 A7 B7 53 V. Description of the invention (------------ (Please read the precautions on the back before filling in this page) Triester. For flash chromatography analysis (acetic acid Ethyl ester / hexane) was purified to obtain methyl-bis (z, z, z-octadecyl-6,9,12-trienyloxypropyl) phosphonate as a colorless oil. 19 Bis (z, z, z-octadecyl-6,9,12-trisyloxypropyl) ridine acid (Phosphonium diphosphonate of 2-¾-propylpropyl acetate of 2 molecules of GLA) Add methyl ethyl ketone (1 ml) to desertification (104 mg, 1.13 mmol) and add methyl di (z, z, z_octadecyl_6,9,12 · triene 醯The solution of alkoxypropyl) phosphonium phosphate (0.85 g, 1.13¾ mole) (prepared in Example 18) in methyl ethyl ketone (1 liter) was heated under reflux for 1 hour. After cooling, the mixture was dissolved in ether (3 ml) and extracted with water (3 ml). A few drops of methanol were added to destroy the emulsion formed. The organic layer was separated, dried (sodium sulfate), concentrated, and analyzed by flash chromatography (methanol / Chloroform) was purified to obtain bis (z, z, z_octadecyl-6,9,12-dienyloxypropyl) phosphonate as a white solid. Example 20 (2-amino Ethyl)-(ζ, ζ, ζ · octadecyl-6,9,12-trienyloxypropyl Hong acid 酉 § (Phosphodiesters of ethanolamine and 3-hydroxypropyl esters of GLA) Part 1: Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, ethanolamine (0.5 ml, 8 25 mmol) and triethylamine (42 ml, 30 millimoles) was added to a solution of crude phosphorous chloride (7.5 millimoles X half of the amount prepared in Example 8 part i) in anhydrous THF (20 milliliters), maintaining the temperature below i 〇 ° C. The reaction was carried out with a tic supervise and a plate. This mixture was stored at less than 5 C for 3 days. Then 遽, concentrated, diluted with hexane ⑼ml), and then -56-
‘紙張尺度適用中國國家標準(CNsI A4規格(21 Οχ297公羞 • !- - ! 經濟部中央標準局員工消費合作社印製 546138 A7 ____— ___ B7 五、發明説明(54 ) 一 濃縮。 部分2 : 將邵分1所得產物溶於異丙醇(100毫升),醋酸(1〇毫升) 及水(4〇毫升)内,此溶液於室溫在氮氣下靜置。在tic顯示 反應已冗全時將混合物濃縮,於乙腈(5〇毫升)及己烷(5〇毫 升)間分開。分離己烷層,濃縮,作閃色譜分析(甲醇/氯仿 /水)純化。收集純化部分,濃縮。加醋酸乙醋打碎,製得 (2·胺基乙基)·(ζ,ζ,ζ-十八基-6,9,12_三烯醯基氧基丙基)磷酸 酯’爲壤樣奶色固體,以離心收取。 實例21 (ζ,ζ,ζ_十八基_6,9,12-三烯醯基氧基丙基)_(2-(Ν,Ν,Ν-三甲基 銨)乙基)磷酸酯 (膽鹼及GLA的3-羥基丙基酯的嶙二酯) 部分1 ·· 將2_氯-1,3,2_二氧磷虎·2_氧化物(430毫克,3.4毫莫耳)於 甲苯(5毫升)内之溶液加於l-(z,z,z-十八基-6,9,12-三烯醯基 氧基)-3·羥基丙烷(1克,2·98毫莫耳)及三乙基胺(0.57毫升 ,4.1毫莫耳)於甲苯(45毫升)内之冷的(0°C )溶液中。將此 混合物揽摔過夜’同時升至室溫。tl c分析顯示反應已完全 。再加三乙基胺(0.3毫升)及2_氯-1,3,2_二氧磷烷-2-氧化 (200毫克)(於甲苯(5毫升)内之溶液),再繼續任反應過夜。 此時tic顯示反應已完全,將混合物濃縮。 部分2 : 將部分1之粗產物溶於乙腈(60毫升)内。將四分之一的此 -57- 本紙張尺度適用中國國家標準(CNS ) A4規格(2⑴X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 546138 A7 __—一 ___ B7 五、發明説明(55 ) 溶液(15毫升)及三乙基胺(1〇毫升)於封閉管内於6〇°C加熱5 小時(當心)。將反應物冷卻,在氮氣下濃縮,製得(z,z,z-十八基-6,9,12-三烯醯基氧基丙基)·(2_(Ν,Ν,Ν_5甲基銨)乙 基)磷酸酯。 實例22 (ζ,ζ,ζ-十八基-6,9,12·三烯醯基氧基丙基)嶙酸酯 (GLA的3-羥基丙基酯的磷單酯) 將1-(ζ,ζ,ζ_十八基·6,9,12_三烯醯基氧基)·3_羥基丙烷(1.95 克,5.8毫莫耳),吡啶(1.4亳升,17.3毫莫耳)及無水THF (15毫升)之溶液在揽掉下滴加於鱗醯氯(1.02克,6.6毫莫耳) 於爲水THF (5毫升)内之冷(〇°C )的溶液中,此混合物於〇°C 存置3小時。反應混合物内加碳酸氫鈉水溶液(10%重量/重 量,10毫升)。攪拌20分鐘後將混合物倒入冰/水(30毫升) 内,此溶液内滴加2M的鹽酸酸化至pH 1。此混合物用乙 醚(2 X 3 0毫升)萃取。合併醚萃取物’乾燥,濃。所得油 體與無水1"比淀共沸,製得(z,z,z-十八基-6,9,12-三晞驢基氧 基丙基)磷酸酯,爲粘性黃色固體。 實例23 甲基-(z,z,z-十八基-6,9,12-三晞酿基氧基丙基)-(α-生育酉分 基)辨酸酉旨 (從-生育酚,甲醇及GLA的3_羥基丙基酯的磷三酯) 部分1 : 將三乙基胺(7.5毫升)於加於新蒸餾出的磷醯氯(1.26 克,8.25毫莫耳)於無水THF (7.5毫升)内之溶液中。15分鐘 -58- 中國國家標準(CRS )Ί^ϋΤ2】〇κ 297公釐) (請先閱讀背面之注意事項再填寫本頁) -、1Τ 經濟部中央標準局員工消費合作社印製 546138 A7 __________ B7__ 五、發明説明(56 ) 後,於〇°C用30分鐘以上的時間滴加卜(z,z,z-十八基-6,9,12-三烯醯基氧基)-3·羥基丙烷(2.5克,7.5毫莫耳)於無水THF (7.5毫升)内之溶液。加烷後,於此溫度繼續攪拌30分鐘。 再於10Ό滴加π -生育酚(3.23克,7.5毫莫耳)於無水THF (5 毫升)内之溶液,所得混合物於l〇°C攪摔1小時,然後升至 室溫攪拌過夜。 部分2 ·· 將部分2四分之一混合物,三乙基胺(〇·8毫升,6毫莫耳) 及甲醇(10毫升)於室溫在氮氣下攪拌過夜。將此反應混合 物濃縮,在醋酸乙酯(30毫升)及水(20毫升)間分開,同時 加氯化鈉及甲醇使乳液破裂。將醋酸乙酯層乾燥,濃縮, 作閃色譜分析(氯仿)純化,製得甲基-(z,z,z_十八基-6,9,12-三烯醯基氧基丙基)-(心生育酚基)磷酸酯。 實例24 (z,z,z-十八基-6,9,12-三晞醯基氧基丙基)(仪-生育紛基)嶙 酸酯 (心生育酚及GLA的3·羥基丙基酯的磷二酯) 將三乙基胺(2毫升)及水(5毫升)加於四分之一實例23部 分1所製得的反應混合物内。此混合物在氮氣下於冰浴内 攪拌1小時,用2M的鹽酸酸化至pH 1,在萃取入醋酸乙酯 (20毫升)及甲醇(5毫升)内。將萃取物乾燥,濃縮,作閃色 譜分析(氯仿)純化,製得(z,z,z-十八基-6,9,12-三烯醯基氧 基丙基Η心生育酚基)磷酸酯。 實例25 -59- 本纸張尺度適用中國國家標準(CNS ) Α4規格(210X29?公釐) (請先閱讀背面之注意事項再填寫本頁) -1¾. 訂 經濟部中夹標準局員工消費合作社印製 546138 A7 _B7 __________ 五、發明説明(57 ) 1-(2,2,2-十八基_6,9,12-三烯醯基氧基)_5_(2,2,2,2,2-二十基- 5,8,11,14,17-五烯醯基氧基)戊烷 (GLA及EPA與1,5_戊烷二醇之二酯) 部分1 : 將z,z,z_十八基_6,9,12-三烯醯氯(2克)滴加於1,5-二羥基戊 烷(3.5克),三乙基胺(〇·94毫升)及4-(Ν,Ν_二甲基胺基)吡啶 (0.2克)於二氯甲烷(50毫升)内之溶液中,同時於〇°C在氮 氣下攪:摔。tic顯示反應完全後,反應混合物用稀鹽酸及水 洗,乾燥,作柱色譜分析純化,製得l-(z,z,z_十八基_ 6,9,12-三烯酿基氧基)-5-輕基戊坑,爲灰黃色油體。 部分2 : 以實例2邵分2方法,但用l_(z,z,z_十八基-6,9,12·三烯醯 基氧基)-5-¾基戊燒代替ΐ-(ζ,ζ,ζ-十八基-6,9,12·三晞醯基 氧基)-3_羥基丙烷,用ζ,ζ,ζ,ζ,ζ_二十基_5,8,11,14,17-五晞酸 代替ζ-十八基-9-烯酸。色譜分析製得h(z,z,z_十八基· 6,9,12·三烯醯基氧基)-5_(z,z,z,z,z-二十基 _5,8,11,14,17-五 烯醯基氧基)戊烷,爲灰黃色油體。 實例26 l-(z,z,z-十八基 _6,9,12·三烯醯基氧基)_4-(z,z,z,z,z_二十基_ 5,8,11,14,17-五烯醯基氧基)苯 (GLA及EPA與1,4-二羥基苯之二酯) 以實例25部分1及2方法,但於部分j中用υ-二超基苯代 替1,5-二邊基戊烷,且於部分i中以四氫呋喃代替二氯甲 烷作溶劑。色譜分析製得l-(z,z,z_十八基_6,9,12•三烯醯基 _______ _60_ 本紙張尺度適ϋϊϋ標準(--—__ (請先閱讀背面之注意事項再填寫本頁)'The paper size applies to the Chinese national standard (CNsI A4 specification (21 〇χ297 public shame •!--! Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 ____ — ___ B7 V. Description of the invention (54)) Condensed. Part 2: The product obtained from Shaofen 1 was dissolved in isopropanol (100 ml), acetic acid (10 ml) and water (40 ml). The solution was left at room temperature under nitrogen. When tic showed that the reaction was complete The mixture was concentrated and separated between acetonitrile (50 ml) and hexane (50 ml). The hexane layer was separated, concentrated, and purified by flash chromatography (methanol / chloroform / water). The purified portion was collected and concentrated. Acetic acid was added Ethyl vinegar was crushed to obtain (2 · aminoethyl) · (ζ, ζ, ζ-octadecyl-6,9,12_trienyloxypropyl) phosphate, which was a soil-like milk color. Solid, recovered by centrifugation. Example 21 (ζ, ζ, ζ_octadecyl_6,9,12-trienyloxypropyl) _ (2- (N, N, N-trimethylammonium) Ethyl) phosphate ester (choline diester of choline and 3-hydroxypropyl ester of GLA) Part 1 ··· 2-Chloro-1,3,2_dioxophosphate · 2_ oxide (430 mg, 3.4 mo ) The solution in toluene (5 ml) was added to l- (z, z, z-octadecyl-6,9,12-trienyloxy) -3 · hydroxypropane (1 g, 2.98 Mmol) and triethylamine (0.57 ml, 4.1 mmol) in a cold (0 ° C) solution in toluene (45 ml). This mixture was stirred overnight while warming to room temperature. Tl c. The analysis shows that the reaction is complete. Add triethylamine (0.3 ml) and 2-chloro-1,3,2_dioxophane-2-oxidation (200 mg) (toluene (5 ml) in solution ), And then allowed to react overnight. At this time tic showed that the reaction was complete, the mixture was concentrated. Part 2: The crude product of Part 1 was dissolved in acetonitrile (60 ml). A quarter of this -57-paper Standards are applicable to China National Standard (CNS) A4 specifications (2⑴X 297 mm) (Please read the precautions on the back before filling out this page). Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 __— 一 ___ B7 5. Description of the invention (55) The solution (15 ml) and triethylamine (10 ml) were heated in a closed tube at 60 ° C for 5 hours (beware). The reaction was cooled and the reaction mixture was cooled under nitrogen. Concentrated under gas to obtain (z, z, z-octadecyl-6,9,12-trienyloxypropyl) · (2- (N, N, N_5methylammonium) ethyl) phosphate Example 22 (ζ, ζ, ζ-octadecyl-6,9,12 · trienyloxypropyl) phosphonate (phosphoric monoester of 3-hydroxypropyl ester of GLA) 1- ( ζ, ζ, ζ_octadecyl · 6,9,12_trienyloxy) · 3-hydroxypropane (1.95 g, 5.8 mmol), pyridine (1.4 mg, 17.3 mmol) and A solution of anhydrous THF (15 ml) was added dropwise to a solution of squama chloride (1.02 g, 6.6 mmol) in a cold (0 ° C) solution in water THF (5 ml). Store at 0 ° C for 3 hours. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution (10% w / w, 10 ml). After stirring for 20 minutes, the mixture was poured into ice / water (30 ml), and the solution was acidified to pH 1 with 2M hydrochloric acid dropwise. This mixture was extracted with ether (2 X 30 ml). The combined ether extracts were dried and concentrated. The obtained oil body was azeotroped with anhydrous 1 " Bide Lake to obtain (z, z, z-octadecyl-6,9,12-trisyldonyloxypropyl) phosphate as a viscous yellow solid. Example 23 Methyl- (z, z, z-octadecyl-6,9,12-triammonyloxypropyl)-(α-tocopheryl radical) Phosphotriester of 3-hydroxypropyl esters of methanol and GLA) Part 1: Triethylamine (7.5 ml) was added to freshly distilled phosphorous chloride (1.26 g, 8.25 mmol) in anhydrous THF ( 7.5 ml). 15minutes-58- Chinese National Standard (CRS) Ί ^ ϋΤ2] 〇κ 297 mm) (Please read the notes on the back before filling out this page)-1T Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperative 546138 A7 __________ B7__ V. After description of the invention (56), add (z, z, z-octadecyl-6,9,12-trienyloxy) -3 · at 30 ° C for more than 30 minutes. A solution of hydroxypropane (2.5 g, 7.5 mmol) in anhydrous THF (7.5 ml). After the addition of alkane, stirring was continued at this temperature for 30 minutes. Then, a solution of π-tocopherol (3.23 g, 7.5 mmol) in anhydrous THF (5 ml) was added dropwise at 10 ° C, and the resulting mixture was stirred at 10 ° C for 1 hour, and then raised to room temperature and stirred overnight. Part 2 · Part 2 of a quarter mixture of triethylamine (0.8 ml, 6 mmol) and methanol (10 ml) was stirred at room temperature under nitrogen overnight. The reaction mixture was concentrated and separated between ethyl acetate (30 ml) and water (20 ml), and the emulsion was broken by adding sodium chloride and methanol at the same time. The ethyl acetate layer was dried, concentrated, and purified by flash chromatography (chloroform) to obtain methyl- (z, z, z-octadecyl-6,9,12-trienyloxypropyl)- (Cardiotocopheryl) phosphate. Example 24 (z, z, z-octadecyl-6,9,12-trisyloxypropyl) (yi-tocopheryl) phosphonate (cardiol tocopherol and GLA 3-hydroxypropyl Phosphodiesters of the ester) Triethylamine (2 ml) and water (5 ml) were added to a quarter of the reaction mixture prepared in Example 23, Part 1. The mixture was stirred in an ice bath under nitrogen for 1 hour, acidified to pH 1 with 2M hydrochloric acid, and extracted into ethyl acetate (20 ml) and methanol (5 ml). The extract was dried, concentrated, and purified by flash chromatography (chloroform) to obtain (z, z, z-octadecyl-6,9,12-trienyloxypropylsulfonyl tocopheryl) phosphate ester. Example 25 -59- This paper size applies the Chinese National Standard (CNS) Α4 size (210X29? Mm) (Please read the notes on the back before filling this page) Printing 546138 A7 _B7 __________ V. Description of the invention (57) 1- (2,2,2-octadecyl_6,9,12-trienyloxy) _5_ (2,2,2,2,2 -Eicosyl- 5,8,11,14,17-pentaenyloxy) pentane (GLA and EPA diester with 1,5-pentanediol) Part 1: z, z, z Octadecyl_6,9,12-trienephosphonium chloride (2 g) was added dropwise to 1,5-dihydroxypentane (3.5 g), triethylamine (0.94 ml) and 4- (N , N-dimethylamino) pyridine (0.2 g) in a solution of dichloromethane (50 ml), while stirring at 0 ° C under nitrogen: drop. After tic showed that the reaction was complete, the reaction mixture was washed with dilute hydrochloric acid and water, dried, and purified by column chromatography to obtain l- (z, z, z_octadecyl_ 6,9,12-trienyloxy). -5-Light pentyl pit, a gray-yellow oil body. Part 2: The method of Example 2 is used, but l_ (z, z, z_octadecyl-6,9,12 · trienyloxy) -5-¾ylpentanyl is used instead of ΐ- (ζ , Ζ, ζ-octadecyl-6,9,12 · trisyloxy) -3-hydroxypropane, using ζ, ζ, ζ, ζ, ζ eicosyl_5, 8, 11, 14 , 17-pentapic acid replaces z-octadecyl-9-enoic acid. Chromatographic analysis yields h (z, z, z_octadecyl · 6,9,12 · trienyloxy) -5_ (z, z, z, z, z-eicosyl_5,8, 11,14,17-pentaenyloxy) pentane as a gray-yellow oil. Example 26 l- (z, z, z-octadecyl-6,9,12 · trienyloxy) _4- (z, z, z, z, z_eicosyl_ 5,8,11 , 14,17-pentaenyloxy) benzene (GLA and EPA diesters with 1,4-dihydroxybenzene) Example 25 Part 1 and 2 method, but υ-disuperylbenzene in part j In place of 1,5-dimeric pentane, tetrahydrofuran was used in place of methylene chloride as the solvent in part i. Chromatographic analysis yields l- (z, z, z_octadecyl_6,9,12 • trienefluorenyl _______ _60_ This paper is suitable for the standard (---__ (Please read the precautions on the back before (Fill in this page)
、1T 546138 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(58 ) 氧基)-4_(2,2,2,2,2-二十基_5,8,11,14,17-五烯醯基氧基)苯, 爲灰黃色油體。 實例27 1,4-二(2;,2,2-十八基-6,9,12_二婦基)_丁坑-1,4-^一 酸酉旨 (GLA醇與丁二酸之二酯) 部分1 : 將1,8-二氮雙環[5.4.0]十一碳_7_烯(0.54毫升)於無水四氫 吱喃(10毫升)内之溶液滴加於z,z,z_十八基_6,9,12-三烯醇(1 克)及丁二酸酐(0.3 6克)無水四氫呋喃(20毫升)内之冷的(〇 °C )溶液中。tic顯示反應完後,反應混合物用乙醚稀釋’ 用稀鹽酸,水及鹽水洗。將有機層乾燥,濃縮,直接用於 部分2反應。 部分2 : 將1,3-二環己基碳化二亞醯胺(0·83克)及4-(N,N-二甲基胺 基)吡啶(0.55克)於二氯甲烷(20毫升)内之溶液加於卜(z,z,z-十八基-6,9,12-三烯基)_丁烷-1,4-二酸酯(1.32克)及z,z,z-十 八基_6,9,12_三烯醇(0.98克)於二氯甲烷(40毫升)内之溶液 中。tic測定反應完全後,反應混合物用己烷稀釋,過濾, 濃縮,作柱色譜分析純化’製得1,4-二(z,z,z-十八基-6,9,12-三烯基)-丁烷-1,4-二酸酯’爲灰黃色油體。 實例28 2_(2_甲基-5-硝基咪唑基)乙基-z,z,z_十八基_6,9,12_三烯酸 酯 (甲硝嗒唑與GL A之酯) -61 - 本紙張尺度適用中國國家標準(CNS ) Α4規格(21〇Χ297公釐) 疃—— (请先閱讀背面之注意事項存填寫本頁)、 1T 546138 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy 17-pentaenyloxy) benzene as a gray-yellow oil. Example 27 1,4-bis (2;, 2,2-octadecyl-6,9,12_dioxyl) _butan-1,4- ^ monocarboxylic acid (GLA alcohol and succinic acid Diester) Part 1: Add a solution of 1,8-diazabicyclo [5.4.0] undec-7_ene (0.54 ml) in anhydrous tetrahydrocran (10 ml) to z, z, z_octadecyl_6,9,12-trienol (1 g) and succinic anhydride (0.3 6 g) in a cold (0 ° C) solution in anhydrous tetrahydrofuran (20 ml). After tic showed that the reaction was completed, the reaction mixture was diluted with ether 'and washed with dilute hydrochloric acid, water and brine. The organic layer was dried, concentrated and used directly in Part 2 reaction. Part 2: 1,3-Dicyclohexylcarbodiimide (0.83 g) and 4- (N, N-dimethylamino) pyridine (0.55 g) in dichloromethane (20 ml) The solution was added to (z, z, z-octadecyl-6,9,12-trienyl) -butane-1,4-diester (1.32 g) and z, z, z-octadecyl A solution of stilbene-6,9,12-trienol (0.98 g) in dichloromethane (40 ml). After the tic measurement reaction was completed, the reaction mixture was diluted with hexane, filtered, concentrated, and purified by column chromatography to obtain 1,4-bis (z, z, z-octadecyl-6,9,12-trienyl ) -Butane-1,4-diester 'is a gray-yellow oil. Example 28 2- (2-methyl-5-nitroimidazolyl) ethyl-z, z, z_octadecyl-6,9,12_trienoate (ester of metronidazole and GL A) -61-This paper size applies Chinese National Standard (CNS) Α4 size (21〇 × 297 mm)
、1T 經濟部中央標準局員工消費合作社印製 546138 A7 _______ B7 五、發明説明(59 ) 方法A : 於甲硝嗒唑(206克)於無水乙腈(2300毫升)及無水吡啶 (107毫升)内之懸浮液中於室溫在氮氣下於攪拌中加z,z,z-十八基-6,9,12_三烯醯氯(373克),費時30分鐘。加醯基氯 短時間後即形成澄清溶液,繼續攪拌2小時。此混合物於 室溫靜置過夜,眞空(50°C/20毫米汞柱)除去溶劑。殘餘物 内加醋酸乙酯(1000毫升),濾除任何沉澱的固體,醋酸乙 酯溶液相繼用鹽水,2M的鹽酸,飽和碳酸氫鈉水溶液洗 ’最後再用鹽水洗。乾燥(硫酸鈉)後,除去溶劑得橘色油 體。以此物質作乾色譜分析,製得2-(2-甲基-5_硝基咪唑 基)乙基-z,z,z-十八基-6,9,12-三烯酸酯,爲灰黃色非蒸餾 1生油體。 方法B : 將甲硝嗒唑(1·9克)懸浮於甲苯(30毫升)内,在攪拌下將 此混合物於回流用Dean and Stark head加熱20分鐘,除去 可能有的水分。於此沸騰溶液内在氮氣下滴加z,z,z•十八 基_6,9,12-三烯醯氯(2.96克),費時20分鐘。此混合物繼續 於回流攪拌加熱2小時,成爲暗色反應混合物。冷卻後將 混合物作乾柱色譜分析,製得2_(2_甲基-5-硝基咪唑基)乙 基-ζ,ζ,ζ·十八基-6,9,12-三烯酸酯,爲灰黃色非蒸餾性油體 〇 皇例29 2_(2-甲基-5-硝基咪唑基)乙基_z,z_十八基-9,12-二烯酸酯 (甲硝嗒唑與LA之酯) 一 —__ -62- 本紙張尺度適用中國國家標準(CNS )八4規1「2「0^7公釐_ (請先閱讀背面之注意事項再填寫本頁}Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 546138 A7 _______ B7 V. Description of the Invention (59) Method A: In metronidazole (206 g) in anhydrous acetonitrile (2300 ml) and anhydrous pyridine (107 ml) To this suspension was added z, z, z-octadecyl-6,9,12-trienephosphonium chloride (373 g) under stirring at room temperature under nitrogen for 30 minutes. A short period of time after the addition of fluorenyl chloride formed a clear solution, and stirring was continued for 2 hours. The mixture was allowed to stand at room temperature overnight, and the solvent was removed by evacuating (50 ° C / 20 mmHg). Ethyl acetate (1000 ml) was added to the residue, and any precipitated solid was filtered off. The ethyl acetate solution was washed successively with brine, 2M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and finally with brine. After drying (sodium sulfate), the solvent was removed to obtain an orange oil. Using this material for dry chromatography analysis, 2- (2-methyl-5_nitroimidazolyl) ethyl-z, z, z-octadecyl-6,9,12-trienoate was obtained as Grayish yellow non-distilled 1 crude oil body. Method B: Suspend metronidazole (1.9g) in toluene (30ml), and heat the mixture under reflux with Dean and Stark head for 20 minutes under stirring to remove possible moisture. In this boiling solution, z, z, z-octadecyl-6,9,12-trienephosphonium chloride (2.96 g) was added dropwise under nitrogen for 20 minutes. This mixture was stirred and heated under reflux for 2 hours to obtain a dark reaction mixture. After cooling, the mixture was subjected to dry column chromatography to obtain 2- (2-methyl-5-nitroimidazolyl) ethyl-ζ, ζ, ζ octadecyl-6,9,12-trienoate, It is a gray-yellow non-distillable oil body. Example 29 2_ (2-methyl-5-nitroimidazolyl) ethyl_z, z_octadecyl-9,12-dienoate (metronidazole Ester with LA) I —__ -62- This paper size is applicable to Chinese National Standard (CNS) Regulation 8 "1" 2 "0 ^ 7 mm_ (Please read the precautions on the back before filling this page}
、1T 經濟部中央標準局員工消費合作社印製 546138 A7 _____ B7 五、發明説明(6〇 ) —- 於甲硝嗒唑(1.9克)於無水二氯甲烷(20毫升)内之懸浮液 中相繼加4_(N,N-二甲基胺基)吨啶(1·22克),環己基 碳化二亞驢胺(2.2克)及亞油酸(2.8克)。此混合物予^溫授 摔過夜。於此反應物中加2M的鹽酸(2〇毫升),繼續授摔。 過遽後分離有機層’用50%飽和的鹽水洗,再用飽和碳酸 氫鈉水溶液洗。將此二氯甲烷溶液乾燥(硫酸鈉),眞空蒸 發(30°C /20毫米汞柱)。於此殘餘物中加汽油(沸點3〇-6(rc ,20毫升),將混合物於室溫置2小時,沉澱出剩餘的腸。 過遽除去脉,滤過物使用乾柱上,製得2-(2-甲基_5_确基 咪峻基)乙基-z,z-十八基-9,12-二晞酸酯,爲灰黃色非蒸鶴 性油體。 實例30 2·(2-甲基-5-硝基咪峻基)乙基-z,z,z-二十基-8,11,14-三缔酸 酯 (甲硝嗒唑與DGLA之酯) 以類似方式但用需要量的z,z,z-二十基-8,11,14_三晞酸代 替亞油’製得2-(2_甲基-5-硝基味峻基)乙基-z,z,z -二十 基_8,11,14-三晞酸酯。 實例31 2_(2_甲基_5_硝基味峻基)乙基_2:,2,2,2,2,2-二十二基-4,7,1〇, 13,16,19-六烯酸酯 (甲硝嗒唑與DHA之酯) 以類似方式但用需要量的z,z,z,z,z,z_二十二基_4,7,1〇,13, 16,19-六烯酸代替亞油酸,製得2-(2-甲基-5-硝基咪唑基) -63- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) ^ ' (請先閱讀背面之注意事項再填寫本頁)1,1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 _____ B7 V. Description of the invention (60) --- Suspension of metronidazole (1.9 g) in anhydrous dichloromethane (20 ml) Add 4- (N, N-dimethylamino) xanthene (1.22 g), cyclohexylcarbodidonylamine (2.2 g) and linoleic acid (2.8 g). This mixture was allowed to fall overnight. To this reaction was added 2M hydrochloric acid (20 ml), and teaching was continued. The organic layer was separated after washing, washed with 50% saturated brine, and then with a saturated aqueous sodium hydrogen carbonate solution. This dichloromethane solution was dried (sodium sulfate) and evaporated in vacuo (30 ° C / 20 mmHg). To this residue was added gasoline (boiling point 30-6 (rc, 20 ml)), and the mixture was left at room temperature for 2 hours to precipitate the remaining intestines. The veins were removed by filtration, and the filtrate was applied to a dry column to obtain 2- (2-Methyl_5_acidimidyl) ethyl-z, z-octadecyl-9,12-diphosphonate, a grayish yellow non-steamed oil body. Example 30 2 · (2-methyl-5-nitroimidyl) ethyl-z, z, z-icosyl-8,11,14-triassociate (ester of metronidazole and DGLA) in a similar manner However, the required amount of z, z, z-icosyl-8,11,14_trisuccinic acid was used instead of linolein 'to obtain 2- (2-methyl-5-nitroamido) ethyl-z , Z, z-icosyl_8,11,14-tris (triacetate). Example 31 2_ (2_methyl_5_nitroamido) ethyl_2:, 2,2,2,2 , 2-Doccosyl-4,7,10,13,16,19-hexaenoate (ester of metronidazole and DHA) in a similar manner but with the required amount of z, z, z, z , Z, z_docosalyl_4,7,10,13,16,19-hexaenoic acid instead of linoleic acid to obtain 2- (2-methyl-5-nitroimidazolyl) -63 -This paper size is applicable to China National Standard (CNS) A4 (210X 297mm) ^ '(Please read the back first (Please fill out this page again)
546138 A7 —------ B7 ___ 五、發明説明(ei ) 乙基_2,2,2,2,冗,2_二十二基-4,7,10,13,16,19-六晞酸酯。 4-[3-[2_(三氟甲基)1〇11_吩p塞畊_ι〇_基]]·1·六氫吡p井乙基· ζ,ζ,ζ_十八基-Hu·三烯酸酯 (氟奮乃靜與GL Α之酉旨) 以類似方式但用需要量的4-[3-[2-(三氟甲基)10H-吩嘧畊 •10-基]]_1_六氫峨畊乙醇(氟奮乃靜)之自由態的驗代替甲 硝嗒唑,並以需要量的GLA代替亞油酸,製得4_[3_[2_(三 氟甲基)10H-吩喳畊_1〇_基]]-1-六氫吡畊乙基_z,z,z-十八基-6,9,12-三婦酸酯。 4,4、(雙z,z,z_十八基-6,9,12-三烯醯基胺基)二苯基颯 (胺苯颯與GLA之雙醯胺) 以類似方式但用需要量的4,4,-二胺基二苯基颯(胺苯颯) 代替甲硝嗒唑,並以需要量的GLA代替亞油酸,製得4,4·-( 雙ζ,ζ,ζ-十八基_6,9,12-三烯醯基胺基)二苯基砜。 34 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) N-甲基-3-苯基三氟-對位-甲苯基]丙基;ζ,ζ,ζ·十 八基·6,9,12-三晞醯胺 (氟苯氧丙胺與GLA之醯胺) 以類似方式但用需要量的Ν-甲基-3-苯基-3 [從,〜從-三氟-對位-甲苯基]丙基胺(氟苯氧丙胺)代替甲硝嗒唑,並以需 要量的GLA代替亞油酸,製得Ν-甲基-3-苯基三 氟-對位-甲苯基]丙基;ζ,ζ,ζ-十八基-6,9,12-三烯酿胺。 -64- 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ 297公釐) 546138 經濟部中央標準局員工消費合作社印製 Α7 Β7 五、發明説明(62 ) 反式-l_(z,z,z-十八基-6,9,12·三烯醯基胺基)-2·苯基環丙烷 (反苯環丙胺與GLA之醯胺) 以類似方式但用需要量的反式-i-胺基-2-苯基環丙烷代 替甲硝嗒唑,並以需要量的gla代替亞油酸,製得反式-1-(z,z,z_十八基-6,9,12·三晞醯基胺基)-2-苯基環丙烷。 6-[(胺基苯基乙醯基)胺基]_3,3,·二甲基·7_氧基_4_噻-卜氮雙 環[3.2.0]庚烷_2_羧酸_z,z,z-十八基-HU-三烯醯胺 (胺苄青黴素與GLA之醯胺) 將三乙基胺(0.3毫升)在氮氣下加於胺苄青黴素(〇.7克)於 無水DMF (120毫升)内之攪拌的懸浮液中。於此澄清溶液 中加ζ,ζ,ζ·十八基·6,9,12-二烯,N-羥基丁二亞醯胺酯(0.75 克),同時維持反應於0-10Χ:。此反應物於此溫度再攪拌 一小時’然後置於室溫過夜。此時tlc分析(4〇%THF/己烷) 顯示幾乎所有的丁二亞醯胺酯已反應。燒瓶内加水(4〇毫 升)’攪拌内容物。然後將此溶液中和,用醋酸乙酯萃取 。萃取物用水洗,乾燥(硫酸鈉),濃縮至乾,得粗製產物 ,爲黃色玻璃樣。用己烷研磨,製得6_[(胺基苯基乙醯基) 胺基]-3,3·-二甲基-7-氧基-4-噻-1-氮雙環[3.2.0]庚烷_2_羧酸 -ζ,ζ,ζ-十八基-6,9,12-三晞醯胺,爲黃色粉。 實例37 ζ,ζ,ζ_十八基_6,9,12-二晞基_ζ,ζ,ζ_十八基_6,9,12·三晞酸酉旨 (GLA與GLA醇的酯) -65- 本紙張尺度適用中國國家標準(CNS ) Α4規格(27^297公釐) -----IIΜ4Ι. (請先閱讀背面之注意事項再填寫本頁) 訂 546138 經濟部中央標準局員工消費合作社印製 Α7 Β7 五、發明説明(63 ) 將1,3-二環己基碳化二亞醯胺(〇·82克)及4-(N,N_二甲基胺 基)吡啶(0.48克)於二氯甲烷(5亳升)内之溶液於室溫在氮氣 下加於z,z,z-十八基_6,9,12-三烯醇(0.95克)及ζ,ζ,ζ·十八基-6,9,12-三烯酸(1克)於二氯甲烷(10毫升)内之溶液中,同時 攪掉。tic證明反應完全後,反應混合物内加己烷,然後過 濾,並作柱色譜分析純化,製得z,z,z-十八基-6,9,12-三烯 基_ζ,ζ,ζ·十八基- 6,9,12-三晞酸酯,爲灰黃色油體。 實例38 z,z,z-十八基 _6,9,12·三烯基-z,z z,z z_二十基-5,8,11,14,17- 五烯酸酯 (EPA與GLA醇的酯) 以實例37所述方法製備,但用z,z,z,z,z-二十基_5,8,11,14, 17-五烯酸代替z,z,z-十八基_6,9,12_三烯酸。 實例39 2-甲基 _3-(2,2,2,2,2-二十基_5,8,11,14,17-五烯醯基氧基)_4- 甲醯基-5-〇,^2-二十基_5,8,11,14,17-五烯醯基氧基)甲 基峨淀 (吡哆醛之二EPA酯) 於峨$酸鹽酸鹽克)於二氯甲烷(20毫升)内之懸浮液 中加三乙基胺(2.0毫升)。形成澄清黃色溶液。於冰内冷卻 下加2,2,2,2,2-二十基-5,8,11,14,17-五烯醯氣(1_73克)(以丑?八 與草醯氯在二氯甲烷内製備)。此混合物在氮氣下攪拌過 夜,同時升至室溫。以等容量的二氯甲烷稀釋後,此混合 物用2M的鹽酸(2〇毫升)萃取,用水(3 χ 2〇毫升)洗,乾燥 ___ -66· 本紙張尺度適用^公釐·—— (請先閱讀背面之注意事項再填寫本頁) 訂 546138 經濟部中央榡準局員工消費合作衽印製 Α7 Β7 五、發明説明(64 ) 並濃縮。作閃色譜分析(醋酸乙酯/己烷)純化,製得2-甲基 -3-(2,2,2,2,2-二十基-5,8,11,14,17_五烯醯基氧基)-4_甲醯基-5-(2,2,2,2 3-二十基_5,8,11,14,17_五烯醯基氧基)甲基峨啶, 爲澄清油體。 實例40 2·甲基_3_羥基·4_甲醯基-5-(z,z,z-十八基_6,9,12_三烯醯基 氧基)甲基吡啶 (吡哆醛的GLA酯) 將z,z,z_十八基_6,9,12_三烯醯氯(800毫克,2.7毫莫耳)於 二氯甲烷(10毫升)内之溶液於〇°C在氮氣下緩慢滴加於吡 哆趁鹽酸鹽(500毫克,2.45毫莫耳),三乙基胺(1毫升,7.2 毫莫耳)及4-(Ν,Ν·二甲基胺基)吡啶(數毫克,催化量)於二 氯甲烷(20毫升)内之混合物中。以tic測定反應完全後,將 混合物濃縮,作閃色譜分析(醋酸乙酯/己烷)純化,製得2一 甲基-3-¾基-4-甲醯基-5·(ζ,ζ,ζ-十八基-6,9,12-三晞醯基氧 基)甲基吡啶,爲無色油體,此油體再加固化。 實例41 '—------ 2_甲基_3_羥基-4,5·二(ζ,ζ,ζ·十八基_6,9,12_三烯醯基氧基)甲 基峨咬 (吡哆醇之雙GLA酯) 將ζ,ζ,ζ-十八基-6,9,12-三烯醯氣(650毫克,2.2毫莫耳)於 二氯甲烷(10毫升)内之溶液於〇。(:在氮氣下緩慢滴加於吡 今醇鹽酸鹽(206毫克,1毫莫耳),三乙基胺(〇·7毫升,5毫 莫耳)及4_(Ν,Ν-二甲基胺基)ρ比淀(數毫克,催化量)於二氣 _ -67- 本紙張尺度適用中國國家標準(CNS ) 格(210X 297公漦) " '~ :II—41— (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 546138 A7 —---------------B7 五、發明説明(65 ) “ 甲烷(20毫升)内之混合物中。以❿測定反應完全後(4小時) ,將混合物濃縮,作閃色譜分析(醋酸乙酯/己烷)純化,製 得2-甲基-3·羥基·4,5_二(ζ,ζ,ζ·十八基_6,9,12三烯醯基氧基) 甲基吡啶爲無色油體。 實例42 1_(2-(2•甲基硝基咪唑醯基)乙基)_4_(ζ,ζ,ζ_十八基_6,9,12_ 三烯基)丁烷_1,4·二酸酯 (甲硝嗒唑及GLA醇與丁二酸之二酉旨) 將1,3-二環己基碳化二亞醯胺(780亳克,3.8毫莫耳)及4-(Ν,Ν-二甲基胺基)吡啶(530毫克,4.3毫莫耳)於二氯甲燒 (15¾升)内之溶液於室溫在氮氣下於授摔中加於醇丁 二酸單酯(1.25克,3.3毫莫耳)(如實例27部分1所製備)及甲 硝嗒吃(620毫克,3.6毫莫耳)於二氯甲烷(3〇毫升)内之溶液 中。tic證明反應完全後,混合物用己燒稀釋,過滤,濃縮 ’作閃色潘分析(醋酸乙g旨/己燒)純化。收集產物部分並濃 縮’製得1-(2_(2-甲基_5_硝基咪咬醯基)乙基)_4-(z,z,z-十八 基-6,9,12-三晞基)丁燒-1,4·二酸醋,爲無色油體。 實例43 反式-1-(ζ,ζ,ζ-十八基-6,9,12_三烯基氧基羰基丁基氧基胺基) -2-苯基環丙烷 (丁二酸,1-GLA醇酯,4-反苯環丙胺醯胺) 將1,3-二環己基碳化二亞醯胺(315毫克,L52毫莫耳)及 4-(Ν,Ν-二甲基胺基)说淀(210毫克,1.72亳莫耳)於二氯甲 烷(10毫升)内之溶液於室溫在氮氣下於攪掉中加於GLA醇 -68- 本紙張尺度適用中國國家標準(CNS ) Α4規$( 210X 297公釐) ~~~~ ~— :IIΓ衊—丨 (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 546138 A7 ______ B7 五、發明説明(66 ) ~~ ^ — 丁二酸單酯_毫克,m毫莫耳χ如實例27部分ι所製備) 及反苯環丙胺(225毫克,i.32毫莫耳)於二氯甲燒(2〇毫升) 内之溶液中。tic證明反應完全後,混合物用己烷稀釋,過 濾,濃縮,作閃色譜分析(醋酸乙酯/己烷)純化。收集產物 部分並濃縮,製得反式_HZ,Z,Z_十八基·6,912_三烯基氧基 羧基丁基氧基胺基)-2-苯基環丙垸,爲無色油體。 實例44 (土)-2,5,7,8_四甲基-2·(4,,8,,12,_三甲基癸基)_6_氧雜萘滿基_ 2,2,十八基-6,9,12-三烯酯 〇·生育紛之GLA酯) 將2,2十十八基_6,9,12-三烯醯氯(2.96克,1〇毫莫耳)在氮 氣下於·5°(:在攪拌中用2-3分鐘時間滴加於(± )_從_生育酚 (4.3克,10亳莫耳)及吡啶(0 885毫升,η毫莫耳)於二氯甲 烷(35毫升)内之溶液中。將混合物攪拌過夜,同時升至室 溫。tic顯示反應已實質完全。反應混合物用水(1〇〇毫升) ,2M的鹽酸(1〇毫升於1〇〇毫升水内)及水(4χ ι〇〇毫升)洗。 將有機層乾燥(硫酸鈉)並濃縮。作閃色譜分析(醋酸乙酯/ 己烷)純化,製得(±)_2,5,7,8-四甲基-2-(4’,8,,12,-三甲基癸 基)-6-氧雜莕滿基_ζ,ζ,ζ_十八基4,932-三烯酯,爲灰黃色 油體。 實例45 雄(甾)-5-烯-17·酮·3-(ζ,ζ,ζ,ζ,ζ,ζ-二十二基-4,7,10,13,16,19- 六烯酸酯) (脱氫表雄酮之DHA酯) -69- 本紙張尺度適用中國國家標準(CNS ) A4規格(21^97公ΪΤ (請先閱讀背面之注意事項再填寫本頁) •噃· 訂 546138 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(67 ) 於脱氫表雄酮(1克)及三乙基胺(1毫升)於二氯甲烷(20毫 升)内之冷(〇C )混合物中,加z,z,z,z,z,z_:十二基_ 4,7,10,13,16,19_六晞醯氯(I·33克)(以DHA與草醯氯在二氯 甲烷内反應製備)。將混合物攪拌過夜,同時升至室溫。 用二氯甲烷(20毫升)稀釋,用2M的鹽酸(20毫升)萃取,用 水(2 X 20毫升)洗,乾燥並濃縮。作閃色譜分析(醋酸乙酯/ 己烷)純化,製得脱氫表雄·5·烯_17·酮·3(ζ,ζ,ζ,ζ,ζ,ζ-: + : 基-4,7,10,13,16,19-六烯酸酯),爲澄清油體。 實例46 ζ,ζ,ζ·十八基_6,9,12-三烯基_(2_(ζ,ζ,ζ-十八基_6,9,12_三烯基 氧基)醋酸酯) (GLA及GLA醇與乙醇酸之二酉旨) 部分1 : 將氯乙醯氯(0.4毫升,5毫莫耳)於二氯甲烷(10毫升)内之 落液於0C滴加於ζ,ζ,ζ-十八基·6,9,12·三烯醇(1克,3.8毫莫 耳)及三乙基胺(1.4毫升,1〇毫莫耳)於二氣甲烷(2〇毫升)内 之洛液中。以tic監視反應之進行。再加幾滴氯乙醯氣。5 分鐘内tic顯示反應已完全。此混合物用水(2 χ 5〇毫升)及 鹽水(50亳升)洗,乾燥(硫酸鈉),濃縮。加甲苯亳升)共 沸除去最後的微量水。製得GLA醇的氯乙醯基酯,爲暗棕 色油體,不必純化直接使用。 部分2 : 將z,z,z-十八基_6,9,12_三烯酸(7〇〇毫克,2.5毫莫耳)及碳 酸铯(410毫克,1_25毫莫耳)於甲醇内攪拌至成澄清溶液。 _____ - 70 - 本紙張尺i適用準 :IIΓ衊—丨 (請先閱讀背面之注意事項再填寫本頁) 、11 經濟部中央標隼局員工消費合作社印製 546138 A7 B7 _ _ ............. —;—-1 —一 -----— -----————____ 五、發明説明(68 ) 然後將此溶液濃縮,並在高眞空下於40°C維持1小時。製 得GLA的铯鹽,不必純化直接使用。 部分3 : 於含有部分2所製的GLA的铯鹽的燒瓶内加GLA醇的氯乙 醯基酯(部分1)(500毫克,1.5毫莫耳)及爲水DMF (15亳升) 。將此反應物於室溫在氮氣下攪拌。90分鐘後,tic分析顯 示反應已完全。此反應混合物用己烷(2 X 40毫升)萃取, 己燒萃取物用鹽水(2 X 50毫升)及水(50毫升)洗,乾燥(疏 酸鈉),濃縮,製得z,z,z-十八基-6,9,12_三烯基-(2·(ζ,ζ,ζ-十 八基·6,9,12·三稀基氧基)醋酸醋),爲無色油體。 實例47 氫化可體松-21-(ζ,ζ,ζ_十八基·6,9,12-三烯酸酯) (氫化可體松之GLA酯) 將ζ,ζ,ζ-十八基-6,9,12·三烯醯氯(450毫克,1.52毫莫耳) 於二氯甲烷(10毫升)内之溶液於〇°C在氮氣下緩慢滴加於 氫化可體松(500毫克,1.38毫莫耳),三乙基胺(420微升, 3毫莫耳)及4_(N,N-二甲基胺基)吡啶(數毫克,催化量)於二 氯甲烷(20亳升)内之混合物中。4小時後tic分析測出反應 已完全。將混合物濃縮,作閃色譜分析(醋酸乙酯/己烷)純 化,製得氫化可體松-21·(ζ,ζ,ζ-十八基_6,9,12_三烯酸酯), 爲無色油體。 實例48 ζ,ζ,ζ·十八基-6,9,12-三晞基- (2-(1-(4-氯苯甲酿基)-5-甲氧基 -2-甲基啕哚-3-乙醯基氧基)醋酸酯) -71 - I紙張尺度適用中國國家標準(CNS ) 公釐厂 一~ 一 :IIΓ讀! (請先閱讀背面之注意事項再填寫本頁〕 -訂 經濟部中央標準局員工消費合作社印製 Α7 ______Β7 五、發明説明(69 ~~— ―一 ^~ G肖炎痛及GLA與乙醇酸之二酯) 部分1 : 古知消炎痛(895毫克,2.5毫莫耳)及碳酸铯(41〇毫克,125 毛莫耳)之混合物於甲醇内攪拌至成澄清溶液。然後將此 溶液;辰縮’並在高眞空下於40°C維持1小時。製得消炎痛 的絶鹽,爲淺黃色固體。 邵分2 : 於含有部分1所製的消炎痛的铯鹽的燒瓶内加gla醇的 氣乙醯基酯實例46部分1製備)(500毫克,1.5亳莫耳)及爲 水DMF (15亳升)。將此反應物於室溫在氮氣下攪拌,以tlc 刀析監視反應之進行。於冰箱過夜後,tlc分析顯示反應已 完全。此反應混合物於水(50毫升)及醋酸乙酯(5〇毫升)間 分開。加幾毫升鹽水破壞乳液。醋酸乙酯層用水(3 X 5〇毫 升)洗,乾燥(硫酸鈉),用二氧化矽膠墊過濾,濃縮,製得 z,z,z_十八基-6,9,12_三烯基-(2_(1_(4-氣苯甲醯基)_5_甲氧基 -2-甲基啕哚-3-乙醯基氧基)醋酸酯),爲淺黃色油體。 實例49 l-(z,z,z-十八基-6,9,12-三晞醯基氧基)-3-(4-苯基丁醯基氧 基)丙垸 (4-苯基丁酸及GLA與1,3_丙烷二醇之二酯) 將1,3-二環己基碳化二亞醯胺(710毫克,3.45毫莫耳)及 4-(Ν,Ν·二甲基胺基)吡啶(475亳克,3.9毫莫耳)於二氯甲烷 (10毫升)内之溶液加於1_(ζ,ζ,ζ-十八基·6,9,12-三晞醯基氧 基)-3-羥基丙烷(1克,3毫莫耳)及4-苯基丁酸(520毫克, -72- 本紙張尺度適用中國國家標準(CNS ) Α4規格(2!0Χ 297公釐) 丨丨1 I衊-丨 (請先閱讀背面之注意事項再填寫本頁)546138 A7 ------- B7 ___ V. Description of the Invention (ei) Ethyl_2,2,2,2, Redundant, 2_Ocosyl-4,7,10,13,16,19- Hexanoate. 4- [3- [2_ (trifluoromethyl) 1〇11_pheno-sepogen_ι〇_yl]] · 1 · hexahydropyridine p-ethyl · ζ, ζ, ζ-octadecyl-Hu · Trienoates (the purpose of fluphenazine and GL Α) in a similar manner but with the required amount of 4- [3- [2- (trifluoromethyl) 10H-phenpyrimidine • 10-yl]] _1_ The free state test of hexahydroecohol ethanol (fluphenazine) replaced metronidazole, and the required amount of GLA was used instead of linoleic acid to obtain 4_ [3_ [2_ (trifluoromethyl) 10H- Phenomenone_10_yl]]-1-hexahydropyroxyethyl_z, z, z-octadecyl-6,9,12-trihydrate. 4,4, (bis-z, z, z-octadecyl-6,9,12-trienylamidoamino) diphenylphosphonium (diphenylphosphonium and bisphosphoniumamine of GLA) in a similar manner but with the need The amount of 4,4, -diaminodiphenylphosphonium (aminophenylhydrazone) was used in place of metronidazole and the required amount of GLA was used in place of linoleic acid to obtain 4,4 ·-(bisζ, ζ, ζ -Octadecyl-6,9,12-trienylaminoamino) diphenylsulfone. 34 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) N-methyl-3-phenyltrifluoro-para-tolyl] propyl; ζ, ζ, ζ Octadecyl 6,9,12-trisaminol (fluorophenoxypropylamine and glutamidine GLA) in a similar manner but with the required amount of N-methyl-3-phenyl-3 [from, ~ from -Trifluoro-p-tolyl] propylamine (fluorophenoxypropylamine) in place of metronidazole and the required amount of GLA in place of linoleic acid to prepare N-methyl-3-phenyltrifluoro- Para-tolyl] propyl; ζ, ζ, ζ-octadecyl-6,9,12-trienylamine. -64- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 546138 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (62) trans-l_ (z, z, z-octadecyl-6,9,12 · trienylamidoamino) -2 · phenylcyclopropane (transphenylcyclopropylamine and glutamine of GLA) in a similar manner but with the required amount of trans-i- Amino-2-phenylcyclopropane was used in place of metronidazole, and linoleic acid was replaced by the required amount of gla to obtain trans-1- (z, z, z_octadecyl-6,9,12 · Trimethylamino) -2-phenylcyclopropane. 6-[(Aminophenylethylaceto) amino] _3,3, · dimethyl · 7_oxy_4_thia-pyrazinebicyclo [3.2.0] heptane_2_carboxylic acid_z , Z, z-octadecyl-HU-trienamidine (Ampicillin and GLA amidine) Triethylamine (0.3 ml) was added to ampicillin (0.7 g) under anhydrous nitrogen in anhydrous DMF (120 ml) in a stirred suspension. To this clear solution was added ζ, ζ, ζ octadecyl 6,9, 12-diene, N-hydroxysuccinimide (0.75 g), while maintaining the reaction at 0-10X :. The reaction was stirred at this temperature for another hour 'and then left at room temperature overnight. At this time tlc analysis (40% THF / hexane) showed that almost all of the succinimide ester had reacted. Water (40 ml) was added to the flask 'and the contents were stirred. This solution was then neutralized and extracted with ethyl acetate. The extract was washed with water, dried (sodium sulfate), and concentrated to dryness to give the crude product as a yellow glass. Trituration with hexane yielded 6-[(aminophenylethylethyl) amino] -3,3 · -dimethyl-7-oxy-4-thia-1-azabicyclo [3.2.0] heptane Alkan-2-carboxylic acid-ζ, ζ, ζ-octadecyl-6,9,12-trimethylamine is a yellow powder. Example 37 ζ, ζ, ζ_octadecyl_6,9,12-diamidyl_ζ, ζ, ζ_octadecyl_6,9,12 · trisuccinate (GLA and GLA alcohol ester ) -65- This paper size applies Chinese National Standard (CNS) Α4 size (27 ^ 297mm) ----- IIM4Ⅰ. (Please read the precautions on the back before filling this page) Order 546138 Central Bureau of Standards, Ministry of Economic Affairs Printed by employee consumer cooperative A7 B7 V. Description of the invention (63) 1,3-Dicyclohexylcarbodiimide (0.82 g) and 4- (N, N-dimethylamino) pyridine (0.48 G) A solution in dichloromethane (5 liters) was added to z, z, z-octadecyl-6,9,12-trienol (0.95 g) and ζ, ζ at room temperature under nitrogen. Zetadecyl-6,9,12-trienoic acid (1 g) in a solution of dichloromethane (10 ml) while stirring. After tic proved that the reaction was complete, hexane was added to the reaction mixture, and then filtered and purified by column chromatography to obtain z, z, z-octadecyl-6,9,12-trienyl_ζ, ζ, ζ -Octadecyl-6,9,12-trimethyl ester, a grayish yellow oily body. Example 38 z, z, z-octadecyl-6,9,12 · trienyl-z, zz, z zicocosyl-5,8,11,14,17-pentaenoate (EPA and GLA alcohol ester) was prepared as described in Example 37, but using z, z, z, z, z-eicosyl-5,8,11,14,17-pentaenoic acid instead of z, z, z-deca Octyl-6,9,12-trienoic acid. Example 39 2-methyl-3- (2,2,2,2,2-eicosyl-5,8,11,14,17-pentaenyloxy) -4-methylamidino-5- , ^ 2-Eicosyl_5,8,11,14,17-pentaenyloxy) methyl eodolide (dipyridoxal diEPA) in diacetate) in dichloride To the suspension in methane (20 ml) was added triethylamine (2.0 ml). A clear yellow solution formed. Add 2,2,2,2,2-eicosyl-5,8,11,14,17-pentafluorene gas (1_73g) under cooling in ice. Prepared in methane). This mixture was stirred under nitrogen overnight while warming to room temperature. After diluting with an equal volume of dichloromethane, the mixture was extracted with 2M hydrochloric acid (20 ml), washed with water (3 x 20 ml), and dried ___ -66 · This paper is suitable for ^ mm · —— ( Please read the precautions on the back before filling out this page.) Order 546138 Consumption Cooperation between Employees of the Central Bureau of the Ministry of Economic Affairs, print A7, B7 5. Description of Invention (64) and condensed. Purified by flash chromatography (ethyl acetate / hexane) to obtain 2-methyl-3- (2,2,2,2,2-icosyl-5,8,11,14,17_pentene Fluorenyloxy) -4_methylfluorenyl-5- (2,2,2,2 3-eicosyl_5,8,11,14,17_pentaenyloxy) methyleridine, To clarify the oil body. Example 40 2 · methyl_3_hydroxy · 4_methylamidino-5- (z, z, z-octadecyl-6,9,12_trienyloxy) methylpyridine (pyridoxal GLA ester) A solution of z, z, z_octadecyl-6,9,12_trienephosphonium chloride (800 mg, 2.7 mmol) in dichloromethane (10 ml) at 0 ° C at Slowly add pyridinium hydrochloride (500 mg, 2.45 mmol), triethylamine (1 ml, 7.2 mmol), and 4- (N, N · dimethylamino) pyridine under nitrogen. (A few mg, catalytic amount) in a mixture of dichloromethane (20 ml). After the reaction was determined to be complete by tic, the mixture was concentrated and purified by flash chromatography (ethyl acetate / hexane) to obtain 2-methyl-3-¾yl-4-methylfluorenyl-5 · (ζ, ζ, ζ-octadecyl-6,9,12-trimethyloxy) methylpyridine is a colorless oil body, and this oil body is further cured. Example 41 '------- 2_methyl_3_hydroxy-4,5 · bis (ζ, ζ, ζ · octadecyl-6,9,12_trienyloxy) methyl Ebbitate (bis-GLA ester of pyridoxine) ζ, ζ, ζ-octadecyl-6,9,12-triene tritium (650 mg, 2.2 mmol) in dichloromethane (10 ml) The solution was at 0. (: Slowly added pimerolol hydrochloride (206 mg, 1 mmol), triethylamine (0.7 ml, 5 mmol) and 4- (N, N-dimethyl) under nitrogen. Amine) ρ Bidian (a few milligrams, catalytic amount) in two gases _ -67- This paper size applies Chinese National Standard (CNS) grid (210X 297 cm) " '~: II—41— (Please read first Note on the back, please fill out this page again) Order printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 —--------------- B7 V. Description of Invention (65) “Methane (20 Ml). After measuring the reaction to completion (4 hours), the mixture was concentrated and purified by flash chromatography (ethyl acetate / hexane) to obtain 2-methyl-3 · hydroxy · 4,5. _Bis (ζ, ζ, ζ · octadecyl-6, 9, 12 trienylfluorenyloxy) methylpyridine is a colorless oil body. Example 42 1_ (2- (2 • methylnitroimidazolyl) Ethyl) _4_ (ζ, ζ, ζ_octadecyl_6,9,12_trienyl) butane_1,4 · diester (Metronidazole and GLA alcohol and succinic acid) ) 1,3-Dicyclohexylcarbodiimide (780 g, 3.8 mmol) A solution of 4- (N, N-dimethylamino) pyridine (530 mg, 4.3 mmol) in dichloromethane (15¾ liters) was added to succinic acid under nitrogen at room temperature under nitrogen. Acid monoester (1.25 g, 3.3 mmol) (as prepared in Example 27, Part 1) and metronidazole (620 mg, 3.6 mmol) in dichloromethane (30 mL) .tic After the reaction was proved to be complete, the mixture was diluted with hexane, filtered, and concentrated to be purified by flash color analysis (ethyl acetate / hexane). The product portion was collected and concentrated to obtain 1- (2_ (2-methyl_5) _Nitroimidino) ethyl) 4- (z, z, z-octadecyl-6,9,12-trimethyl) butan-1,4 · dicarboxylic acid, which is a colorless oily body. Example 43 trans-1- (ζ, ζ, ζ-octadecyl-6,9,12-trienyloxycarbonylbutyloxyamino) -2-phenylcyclopropane (succinic acid, 1 -GLA alcohol ester, 4-transphenylcyclopropylamine sulfonamide) 1,3-dicyclohexylcarbodiimide (315 mg, L52 mmol) and 4- (N, N-dimethylamino) A solution of the precipitate (210 mg, 1.72 mol) in dichloromethane (10 ml) was stirred at room temperature under nitrogen. For GLA Alcohol-68- This paper size applies Chinese National Standard (CNS) A4 $ (210X 297 mm) ~~~~ ~ —: IIΓΓ— 丨 (Please read the notes on the back before filling this page) Order Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 ______ B7 V. Description of the invention (66) ~~ ^ — Succinic acid monoester _ mg, m millimoles (as prepared in Example 27 part ι) and transphenyl ring A solution of propylamine (225 mg, i.32 mmol) in dichloromethane (20 ml). After tic proved that the reaction was complete, the mixture was diluted with hexane, filtered, concentrated, and purified by flash chromatography (ethyl acetate / hexane). The product portion was collected and concentrated to obtain trans-HZ, Z, Z-octadecyl · 6,912-trienyloxycarboxybutyloxyamino) -2-phenylcyclopropanefluorene as a colorless oil. Example 44 (Earth) -2,5,7,8_tetramethyl-2 · (4,8,12, _trimethyldecyl) _6_oxanaphthyl_2,2,18 -6,9,12-trienyl ester GLA ester of tocopherol) Put 2,2 octadecyl-6,9,12-trienephosphonium chloride (2.96 g, 10 mmol) in nitrogen Below 5 ° (: add 2-3 minutes to (±) _from_tocopherol (4.3g, 10 亳 mol) and pyridine (0 885ml, ηmmol)) while stirring. In a solution in methyl chloride (35 ml). The mixture was stirred overnight while warming to room temperature. The tic showed that the reaction was substantially complete. The reaction mixture was water (100 ml), 2M hydrochloric acid (10 ml in 100 ml). Wash with water (4 ml) and water (4 × 100 ml). The organic layer was dried (sodium sulfate) and concentrated. Purified by flash chromatography (ethyl acetate / hexane) to obtain (±) _2,5,7 , 8-tetramethyl-2- (4 ', 8,12, -trimethyldecyl) -6-oxapyridinyl_ζ, ζ, ζ-octadecyl 4,932-trienyl ester, as Gray-yellow oil. Example 45 Androsta-5-ene-17 · one · 3- (ζ, ζ, ζ, ζ, ζ, ζ-docosalyl-4, 7, 10, 13, 16, 19- Saturday Ethyl acrylate) (DHA ester of dehydroepiandrosterone) -69- This paper size applies to Chinese National Standard (CNS) A4 specification (21 ^ 97 public ΪΤ (Please read the precautions on the back before filling this page) • 噃· Order 546138 Printed by A7 B7, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (67) in dehydroepiandrosterone (1 g) and triethylamine (1 ml) in dichloromethane (20 ml) To the cold (0C) mixture, add z, z, z, z, z, z_: dodecyl_ 4,7,10,13,16,19_hexamethyl chloride (1.33 g) (to Prepared by reacting DHA with chloramphenicol in dichloromethane). The mixture was stirred overnight while warming to room temperature. Diluted with dichloromethane (20 mL), extracted with 2M hydrochloric acid (20 mL), and water (2 X 20 Ml), washed, dried and concentrated. Purified by flash chromatography (ethyl acetate / hexane) to obtain dehydroepiandrosterene-5 · ene-17-one · 3 (ζ, ζ, ζ, ζ, ζ, ζ -: +: -4,7,10,13,16,19-hexaenoate), which is a clear oil body. Example 46 ζ, ζ, ζ Octadecyl-6,9,12-trienyl _ (2_ (ζ, ζ, ζ-octadecyl_6,9,12_trienyl Base) Acetate) (GLA and GLA alcohols and glycolic acid two purposes) Part 1: Drop chloroacetamyl chloride (0.4 ml, 5 mmol) in dichloromethane (10 ml) at 0 C drop Add ζ, ζ, ζ-octadecyl · 6,9,12 · trienol (1 g, 3.8 mmol) and triethylamine (1.4 ml, 10 mmol) to methane ( 20 ml). Monitor the progress of the reaction with tic. Add a few more drops of chloroacetam. Within 5 minutes tic showed that the reaction was complete. The mixture was washed with water (2 x 50 ml) and brine (50 ml), dried (sodium sulfate), and concentrated. Add toluene (l) and azeotropically remove the last trace of water. The chloroethenyl ester of GLA alcohol was obtained as a dark brown oil body and used without purification. Part 2: Stir z, z, z-octadecyl-6,9,12-trienoic acid (700 mg, 2.5 mmol) and cesium carbonate (410 mg, 1-25 mmol) in methanol To a clear solution. _____-70-This paper rule i is applicable: IIΓ 蔑 — 丨 (Please read the precautions on the back before filling this page), 11 Printed by the Ministry of Economic Affairs Central Standards Bureau Employees' Cooperatives 546138 A7 B7 _ _ .... ......... —; —-1 — 一 -----— -----————____ 5. Description of the invention (68) Then the solution was concentrated and placed under high air Maintain at 40 ° C for 1 hour. The cesium salt of GLA was prepared and used without purification. Part 3: A flask containing the cesium salt of GLA prepared in Part 2 was charged with the chloroethenyl ester of GLA alcohol (Part 1) (500 mg, 1.5 mmol) and DMF in water (15 L). The reaction was stirred at room temperature under nitrogen. After 90 minutes, tic analysis showed that the reaction was complete. The reaction mixture was extracted with hexane (2 X 40 ml). The hexane extract was washed with brine (2 X 50 ml) and water (50 ml), dried (sodium sulphate), and concentrated to give z, z, z. -Octadecyl-6,9,12_trienyl- (2 ((ζ, ζ, ζ-octadecyl · 6,9,12 · tridiyloxy) acetate)) is a colorless oil body. Example 47 Hydrocortisone-21- (ζ, ζ, ζ_octadecyl · 6,9,12-trienoate) (GLA ester of hydrocortisone) ζ, ζ, ζ-octadecyl A solution of -6,9,12 · trienephosphonium chloride (450 mg, 1.52 mmol) in dichloromethane (10 ml) was slowly added dropwise to hydrocortisone (500 mg, 1.38 mmol), triethylamine (420 μl, 3 mmol) and 4_ (N, N-dimethylamino) pyridine (several mg, catalytic amount) in dichloromethane (20 μl) Inside the mixture. After 4 hours, tic analysis showed that the reaction was complete. The mixture was concentrated and purified by flash chromatography (ethyl acetate / hexane) to obtain hydrocortisone-21 · (ζ, ζ, ζ-octadecyl-6,9,12_trienoate), It is a colorless oil body. Example 48 ζ, ζ, ζ · octadecyl-6,9,12-trimethyl- (2- (1- (4-chlorobenzyl) -5-methoxy-2-methylpyridine -3-Ethyloxy) acetate) -71-I Paper size applies to China National Standards (CNS) Millimeter Factory I ~ One: IIΓ Read! (Please read the precautions on the back before filling this page]-Order printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Α7 ______ Β7 V. Description of the invention (69 ~~ — ― 一 ^ ~ G Xiao Yantong and GLA and glycolic acid Diester) Part 1: A mixture of Guzhi indomethacin (895 mg, 2.5 mmol) and cesium carbonate (41 mg, 125 mmol) was stirred in methanol until a clear solution was obtained. Then this solution was used; 'And maintained at 40 ° C for 1 hour under high altitude. An indomethacin absolute salt was obtained as a pale yellow solid. Shaofen 2: In a flask containing the indomethacin cesium salt prepared in Part 1, gla alcohol was added. Preparation of Gas Ethyl Ester Example 46 Part 1) (500 mg, 1.5 mol) and DMF (15 liter) in water. The reaction was stirred at room temperature under nitrogen, and the progress of the reaction was monitored by tlc knife analysis. After overnight in the refrigerator, tlc analysis showed that the reaction was complete. The reaction mixture was separated between water (50 ml) and ethyl acetate (50 ml). Add a few milliliters of saline to destroy the emulsion. The ethyl acetate layer was washed with water (3 × 50 ml), dried (sodium sulfate), filtered through a silica pad, and concentrated to obtain z, z, z_octadecyl-6,9,12_trienyl. -(2_ (1_ (4-Gasbenzylidene) _5_methoxy-2-methylpyridin-3-ethenyloxy) acetate) is a pale yellow oil. Example 49 l- (z, z, z-octadecyl-6,9,12-trifluorenyloxy) -3- (4-phenylbutylfluorenyloxy) propanyl (4-phenylbutanoic acid and Diester of GLA and 1,3-propanediol) 1,3-Dicyclohexylcarbodiimide (710 mg, 3.45 mmol) and 4- (N, N · dimethylamino) pyridine (475 g, 3.9 mmol) in dichloromethane (10 ml) was added to 1_ (ζ, ζ, ζ-octadecyl · 6,9,12-trisyloxy) -3 -Hydroxypropane (1g, 3mmol) and 4-phenylbutanoic acid (520mg, -72-) This paper size applies to China National Standard (CNS) A4 (2! 0 × 297mm) 丨 丨 1 -丨 (Please read the notes on the back before filling in this page)
、1T 經濟部中央標準局員工消費合作社印製 546138 A7 _— ___ B7 五、發明説明(7〇 ) 3.15亳莫耳)於二氯甲烷(15毫升)内之溶液中。此混合物於 室溫在氮氣下攪拌至以tic測定反應已完全。將混合物過濾 ’濃縮,作閃色譜分析純化,製得l-(z,z,z-十八基_6,9,12_ 三烯醯基氧基)-3-(4-苯基丁醯基氧基)丙烷。 實例50 ------ l-(z,z,z_十八基_6,9,12_三烯醯基氧基)_3_(苯基乙醯氧基)丙 烷 (苯基醋酸及GLA與1,3-丙烷二醇之二酯) 以類似實例49之方法,但用苯基醋酸(430毫克,3.15毫 莫耳)代替4_苯基丁酸,製得ΐ-(ζ,ζ,ζ·十八基_6,9,12·三晞醯 基氧基)-3-(苯基乙酿氧基)丙院D 實例51 l_(z,z,z_十八基_6,9,12_三烯醯基氧基y气反式肉桂醯基氧 基)丙烷 (反式肉桂酸及GL A與1,3·丙規二醇之二酯) 以類似實例49之方法,但用反式肉桂酸(470毫克,3.15 毫莫耳)代替4·苯基丁酸,製得i-(z,z,z_十八基_6,9,12_三烯 醯基氧基)-3-(反式肉桂醯基氧基)丙烷。 此處並未提出包含菸殮酸之化合物之申請專利範圍,該 化合物爲同日申請的另一申請案的主題。 本發明除未請求上述申請專利範圍外,並不受前述之一 般限制,而陳述本發明申請專利範圍如后。 -73- 本紙張尺度適用中國國家標準(CNS ) Μ規格(210x57公釐) 丨_. .——Μ4Ι— (請先閱讀背面之注意事項再填寫本頁) 訂 申請曰期 85. 6. 13 案 號 085107127 類 別 (以上各欄由本局填註) 中 文 、《名稱 英 文 A4 C4 中文說明書替換頁(92·年5用) 546138 具1,3-丙垸二醇鍵合構造的化合物及1,3-丙燒二醇衍生物 ’丨COMPOUNDS WITH 1,3-PR0PANE DI〇L LINKED STRUCTURE AND 1,3-PROPANE DIOL DERIVATIVES' 姓 名 1.大衛·佛萊得瑞克·哈洛賓2.莫哈·曼谷 國 籍 3.奥斯丁 ·麥克莫迪 5·安得瑞·皮特 7.保羅·華克菲德 1·至7.均英國8.加拿大 4.菲力普·諾斯 6.保羅·布拉德利 8.彼得·瑞登 人 住、居所 1·英國史考蘭郡史堤林市卡索商業公園史谷迪大廈 史谷迪製藥有限公司 2-7.均英國卡力索市金斯頓工業區金斯頓路 史谷迪製藥有限公司研究發展中心 !和拿太諾瓦史谷迪省肯堤維爾市818號鄭政信笳 英商史谷迪製藥(喬西)有限公司 國 籍 英國 申請人 f事務 £表 人 名 英屬海峽群島澤西郡海樂街科儉比瑞區22號 馬歇爾DE費格雷多 本紙張尺度適用 國國家標準(CNS) A4規格(210 X 297公釐) 546138 第0851〇7丨27號專利申請案 中文說明書替換頁(92年3月)Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 546138 A7 _ — ___ B7 V. Description of the invention (70) 3.15 mol) in a solution in methylene chloride (15 ml). This mixture was stirred at room temperature under nitrogen until the reaction was complete as determined by tic. The mixture was filtered and concentrated, and purified by flash chromatography to obtain l- (z, z, z-octadecyl-6,9,12_trienyloxy) -3- (4-phenylbutyryloxy) ) Propane. Example 50 --- l- (z, z, z_octadecyl_6,9,12_trienyloxy) _3_ (phenylethoxy) propane (phenylacetic acid and GLA Diester with 1,3-propanediol) In a manner similar to Example 49, but using phenylacetic acid (430 mg, 3.15 mmol) in place of 4-phenylbutyric acid, ΐ- (ζ, ζ, ζ · octadecyl_6,9,12 · trisynyloxy) -3- (phenylethynyloxy) propanone D Example 51 l_ (z, z, z_octadecyl_6,9 , 12_trienyloxyl, trans-cinnamonyloxy) propane (trans-cinnamic acid and the diester of GL A and 1,3-propanediol) In a similar manner to Example 49, but using Trans-cinnamic acid (470 mg, 3.15 mmol) instead of 4 · phenylbutyric acid to obtain i- (z, z, z_octadecyl_6,9,12_trienyloxy)- 3- (trans-cinnamonyloxy) propane. The scope of patent application for a compound containing nicotinic acid is not proposed here, which is the subject of another application filed on the same day. The present invention is not subject to the foregoing general restrictions except for the scope of the above-mentioned patent applications, and states that the scope of patent application for the present invention is as follows. -73- This paper size applies Chinese National Standard (CNS) M specifications (210x57 mm) 丨 _. .—— Μ4Ι— (Please read the precautions on the back before filling this page) Order application date 85. 6. 13 Case No. 085107127 Category (the above columns are filled out by the Bureau) Chinese, "Name English A4 C4 Chinese Manual Replacement Page (for 92 · year 5) 546138 Compounds with 1,3-propanediol bonding structure and 1,3 -Propanediol derivatives '丨 COMPOUNDS WITH 1,3-PR0PANE DI〇L LINKED STRUCTURE AND 1,3-PROPANE DIOL DERIVATIVES' Name 1. David Frederick Harobin 2. Moha Bangkok nationality 3. Austin McMurdie 5. Andreas Pitt 7. Paul Wakefield 1. to 7. Both British 8. Canada 4. Philip North 6. Paul Bra Deli 8. Living and residence of Peter Ryden 1. Shigudi Building, Shigudi Building, Cassow Commercial Park, Stirling, Scotland, UK 2-7. Both are Kingston, Calisso, UK Research and Development Center of Scottie Pharmaceutical Co., Ltd., Kingston Road, Industrial Zone! Zheng Zhengxin, Yingying Scotty Pharmaceuticals (Josie) Limited Nationality UK Applicant f Matters Name Name British Marshall De Fagredo No. 22 Cogbirry District, Haile Street, Jersey, British Channel Islands National Standard (CNS) A4 Specification (210 X 297 mm) 546138 Patent Application for Patent No. 0851〇7 丨 27 Replacement Page (March 1992)
因此障礙而難以在腦内達到適宜的濃度。另一障礙是皮 膚··直到幾年以前,藥物還只能為作用於皮膚而使用=皮 膚。但現已知道,皮膚也可給予藥物以發揮系統性作用的 途徑,現在已有越來越多的藥物以各種貼片技術控制。 所有這三種形式的障礙,細胞膜及細胞内膜,血·腦障 礙,以及皮膚,都有共同的重要特點.,即都由脂質構成。 這意謂,除非藥物藉受體或運送系統通過膜,水溶性的藥 物是不能滲透過的。相反的,親脂性物質則能不需任何特 定受體或運送系統而通過此等障礙。 需通過脂質障礙通路的生物活性物的種類 其藥物動力學變化可藉增進親脂性而改進的藥物,按其 進入途徑分類,是: 1.進入細胞的:特別受益的藥物是主要在細胞内作用的 藥物。包括: a. 所有的抗炎藥物,包括類固醇或非類固醇; b. 所有用於治療癌症的細胞毒性藥物; c. 所有抗病毒藥物; d·所有須進入細胞以發揮適宜效果的其他藥物,特別 是作用於DNA或RNA的藥物,作用於位於細胞内的 酶的藥物,作用於第二信使系統的藥物,或作用於 微管、線粒體、溶酶體、或任何其他細胞内小器官 的藥物; e.類固醇激素或其他與細胞内作用的激素,如雌數 素,孕激素,雄激素及脫氫表雄g同。 -6 ·Therefore, it is difficult to reach a suitable concentration in the brain. Another obstacle is the skin ... Until a few years ago, drugs could only be used to act on the skin = skin. However, it is now known that the skin can also be administered with drugs to exert a systemic effect, and now more and more drugs are controlled by various patch technologies. All three types of barriers, cell membranes and inner cell membranes, blood and brain barriers, and skin have common important characteristics. They are all composed of lipids. This means that water-soluble drugs are impermeable unless they pass through the membrane via a receptor or delivery system. In contrast, lipophilic substances can pass through these obstacles without any specific receptors or delivery systems. Types of biologically active substances that need to pass through the lipid barrier pathway. Drugs whose pharmacokinetic changes can be improved by increasing lipophilicity, are classified according to their pathway of entry, and are: 1. Entering the cell: Drugs that specifically benefit are mainly acting in the cell Drug. Including: a. All anti-inflammatory drugs, including steroids or non-steroids; b. All cytotoxic drugs used to treat cancer; c. All antiviral drugs; d. All other drugs that need to enter the cell to exert appropriate effects, especially Drugs that act on DNA or RNA, drugs that act on enzymes located in cells, drugs that act on the second messenger system, or drugs that act on microtubules, mitochondria, lysosomes, or any other small organ in the cell; e. Steroid hormones or other hormones acting intracellularly, such as estrogen, progesterone, androgens and dehydroepiandrosterone. -6 ·
裝 ηΗ
本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公爱) 546138 第085107127號專利申請案 中文說明書替換頁(92年3月) 4 五、發明説明( :改進:;Γ 作用於中樞神經系統的藥物可藉此技 術改進其運輸。此包括用於精神科的所有藥物,用於 何微生物導致的腦感染的所有藥物,或用於腦癌的藥物, =及其他所有作用於神經細胞的藥物,如抗癲癇藥物,及 其他作用於神經疾病如多發性硬化,轉_硬化,韓庭 頓氏舞蹈症等的藥物。 3.皮膚^如同血_腦^章礙一樣,所有需透過皮膚以達系統 性效果的藥物都會因轉化成脂肪酸衍生物而受益。 例如,前述的進步可用於胺基酸。特別有利的藥物是那 些在調整細胞功能上起作用的藥物,以及有蛋白質成分作 用的藥物。其例包括色胺酸(5_羥基色胺[5_ΤΗ]前體,神經 及肌肉功能的關鍵調整劑),苯丙胺酸(兒茶酚胺前體)及精 胺酸(氧化氮合成調整劑,在控制細胞活動上也有重要作 用)。 一般賦予的性質 一般而言,此處所提出的化合物除了其親脂性外還有許 多優點。給予脂肪酸的二個基或甚至一個基可以下述形式 投送’作為經口'非經口或局部使用的調配物,易於進入 身體;耐受性良好,無副作用,例如自由態脂肪酸所發生 的副作用;不會太安定以至不能有效利用;不需對掌中 心;較聯有三個相同脂肪酸的對應的三酸甘油酯易於合 成。雖則三酸甘油酯也耐受性良好並普遍使用,但較此處 提出的化合物為差,因為三酸甘油酯難以合成且可能有對 掌中心致有多種異構物。而且,三酸甘油酯的脂肪酸較易由 j紙張尺度適财g @家標準(CNS) Μ規格(謂χ挪公寶) 546138 第085107127號專利申請案 中文說明書替換頁(92年3月) A7 B7 32年、月ViThis paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 public love) 546138 No. 085107127 Patent Application Chinese Specification Replacement Page (March 1992) 4 V. Description of the invention (: Improvement:; Γ acting on the center Drugs for the nervous system can improve their transport with this technology. This includes all drugs used in psychiatry, all drugs used in microbial-induced brain infections, or drugs used in brain cancer, and all other drugs that act on nerve cells Drugs, such as anti-epileptic drugs, and other drugs that act on neurological diseases such as multiple sclerosis, transsclerosis, Hantington's chorea, etc. 3. Skin ^ Like blood _ brain ^ obstacles, all need to pass through the skin Drugs that achieve systemic effects all benefit from conversion to fatty acid derivatives. For example, the aforementioned advances can be applied to amino acids. Particularly beneficial drugs are those that work to regulate cell function, as well as those that have a protein component. Drugs. Examples include tryptophan (5-hydroxytryptamine [5_ΤΗ] precursor, a key regulator of nerve and muscle function), phenylalanine (catecholamine precursor), and essence Acid (a regulator of nitric oxide synthesis that also plays an important role in controlling cell activity). Properties generally imparted In general, the compounds presented here have many advantages in addition to their lipophilic properties. Two or even one bases are given to fatty acids The base can be delivered 'as an oral' formulation for non-oral or topical use in the following form, easy to enter the body; well tolerated, without side effects, such as the side effects of free-state fatty acids; not too stable or effective Utilization; no need for palm center; easier to synthesize the corresponding triglyceride with three identical fatty acids. Although triglyceride is also well tolerated and commonly used, it is inferior to the compounds proposed here because Glycerides are difficult to synthesize and may have multiple isomers at the center of the palm. In addition, the fatty acids of triglycerides are easier to adapt to the paper size g @ 家 standard (CNS) Μ specifications (referred to as χ Norwegian public treasure) 546138 No. 085107127 Patent Application Chinese Specification Replacement Page (March 1992) A7 B7 32 years, Vi
五、發明説明(11 ) — 或各種混合物供應,較佳是在營養及治療上能供應特定分 子的脂肪酸。在多數情形下,在給予EFA或其他脂肪酸時 同時也給予胺基酸,維生素,藥物或其他本身有所需性質 的分子。 現在有人建議,同時給予二種脂肪酸時可以特定的三酸 甘油酯代替,其理論根據是必需脂肪酸常以三酸甘油酯的 形式出現。但三酸甘油酯,除非是對稱於2 -碳,是對掌性 的,而且偶合的醯基會在α及/3位間移動,致使合成特定 的三酸甘油i旨十分困難。此種移動在合成後也會發生,在 藥物管理上也是問題。當二個脂肪酸出現於同一三酸甘油 酯分子時,特異性的缺乏在合成、藥理學、調配及安定性 上也構成問題。此外,三酸甘油酯的合成是慢而困難的。 在同樣條件下,丙烷二醇衍生物則容易合成。 為要方便地同時給予不同的脂肪酸或大量給予一種脂肪 酸而又要有良好耐受性時,所以須用二醇的酯。 根據本揭示生成的活性物的化學性質 本發明包括生物活性物的脂肪酸(或脂肪醇)衍生物,此 生物活性物有羧基,醇或胺基,可生成單一的意義明確的 化學實體。此偶合可直接生成二分化合物(bipartate compounds),或以合適的鍵合基隔開,生成三分化合物 (tripartate compounds),此係指化合物分裂成的部分的數 而言。 生物活性物的化學分類 化合物的分類如下所示,其中η是1至3。此處申請專利 本纸張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐)5. Description of the invention (11)-or various mixtures, preferably fatty acids that can supply specific molecules in nutrition and therapy. In most cases, amino acids, vitamins, drugs or other molecules with the desired properties are also given when EFA or other fatty acids are given. It has now been suggested that specific triglycerides can be substituted when two fatty acids are given at the same time, based on the theory that essential fatty acids often appear in the form of triglycerides. However, triglycerides, unless symmetrical to the 2-carbon, are palm-like, and the coupled fluorenyl groups will move between the α and / 3 positions, making it difficult to synthesize specific triglycerides. Such movements also occur after synthesis and are also a problem in drug management. When two fatty acids are present in the same triglyceride molecule, the lack of specificity also poses problems in terms of synthesis, pharmacology, formulation, and stability. In addition, the synthesis of triglycerides is slow and difficult. Under the same conditions, propanediol derivatives can be easily synthesized. In order to conveniently administer different fatty acids simultaneously or to administer one fatty acid in large amounts with good tolerance, esters of diols must be used. Chemical properties of actives produced according to the present disclosure The present invention includes fatty acid (or fatty alcohol) derivatives of biologically active materials. The biologically active materials have carboxyl, alcohol, or amine groups and can form a single chemical entity with a clear meaning. This coupling can directly generate bipartate compounds, or separate them with suitable bonding groups to generate tripartate compounds. This refers to the number of parts into which the compound is split. Chemical classification of biologically active compounds The classification of compounds is shown below, where η is 1 to 3. Apply for a patent here The paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm)
Claims (1)
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Application Number | Priority Date | Filing Date | Title |
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ZA963360A ZA963360B (en) | 1995-05-01 | 1996-04-26 | Presentation of bioactives |
IL11806196A IL118061A (en) | 1995-05-01 | 1996-04-29 | 1,3-propanediol diesters for use in therapy and some novel such diesters |
PCT/GB1996/001053 WO1996034846A1 (en) | 1995-05-01 | 1996-05-01 | 1,3-propane diol derivatives as bioactive compounds |
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TW546138B true TW546138B (en) | 2003-08-11 |
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TW085107127A TW546138B (en) | 1996-04-26 | 1996-06-13 | Compounds with 1,3-propane diol linked structure and 1,3-propane diol derivatives |
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