五、發明説明（/4 第83 102582號專利甶請案 A7 中文說明書修正頁（87年3月）B7 390875 總量250毫升含5.95克（30.1毫莫耳）實例1(a)化合掏 及4.8克（35.8毫莫耳）（S)-蘋果酸（99% )，限用 AldrMch化學公司）之丙酮溶液加熱至所有的固體溶解， 需要小量之甲醇使有效地完全溶解。將冷卻過程中形成之 固體收集起來，並由2 50毫升熱丙酮中再结晶兩次，再次 需要小量之甲醇使有效地完全溶解。將所產生之產物收集 起來，並在真空中乾燥，可產生2克之標題化合物。[α ]〇= +50.03° (c = 0.9563，CH30H，23Τ；);此胺部份之 鏡像純度99.8%。 雪m 研究實例1之標題化合物和（S) - α -苯基-2-吡啶乙胺 (S)-蘋果酸鹽對潮濕之穩^定度。前者在相對濕度為80%時 已溶化；而後者在相同之相對濕度下槿吸收其本身重量之 0 · 1 %之水。 C請先閲讀背面之注意事項再填寫本頁} 例 奮 擊 電 大. 最 由 鼠 老 對 時 物 合 化 題 標 之 2 例 實 用 施 眼 □ W' 法 述 r 見 性 活 防 預 之 展 伸 直 強 肢 後 之 發 為 經濟部甲央標準局員工消費合作社印製 斤 公 \ 克 毫 9 2 6 1 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） A6 B6 經濟部中央標準局員工消費合作社印製 五、發明説明（i ) 本發明係關於（s)-a -苯基-2-吡啶乙胺鹽（S)-蘋果酸鹽 在醫藥上-尤其在治療神經變性病變-之用途，它的產生 步驟及包含它的翳藥調配物。 用於治療神經變性病變之現存藥物的主要難題在濃度缺 乏可預知性，施用某一已知量之藥物後無法預測病人血漿 中藥物之濃度，亦即現存蔡物無法表現出線性藥物動力學 闞係。曾有人描述此範_之理想藥物在劑量和血漿濃度之 間表現出線性關係，亦即藥物之某一劑量之改變可預測血 中澹度將產生之改變[老、新及尚未發琨之抗攧麻藥物之 藥物動力學，R H Levy 及 B Kerr，癱 ®，vol 30，Supp 1 , S35-S411. 1989]。 歐洲專利案號356035揭示許多用於治療神經變性病變之 化合物，其中包括α-苯基-2-吡啶乙胺鹽[其中提到的為 i . 卜苯基-2- (2:吡啶基）乙基胺]。頃發規此化合物之（S)-鏡 像異構物，及其殺藥上可接受的酸加成鹽表現線性藥物動 力學，且此揭示於W093/20052 (國際專利案號N°PCT/GB93/ 00689)。 令人驚訝的是現在發現（S)-a -苯基-2-吡啶乙胺鹽之 (S)-蘋果酸鹽k有許多的優點，包括對濕氣之顯著穩定性 Ο 因此，根據本發明其限制為（S) - a -苯基-2-吡啶乙胺之 (S)-蘋果酸鹽 (請先閲讀背面之注意事項再填窝本頁) 〇 -裝. 訂 -線. -本紙張尺度適用中國國家標準（CNS)甲4規格(210X297公釐) A6 B6 五、發明説明（2 )V. Description of the Invention (/ 4 Patent No. 83 102582, Request for A7 Chinese Version Correction Sheet (March 1987) B7 390875 Total 250ml contains 5.95g (30.1mmol) Example 1 (a) Combined with 4.8 Gram (35.8 mmol) (S) -malic acid (99%), limited to AldrMch Chemical Co., in acetone solution. Heat all solids to dissolve. A small amount of methanol is required to effectively dissolve completely. The solids formed during cooling were collected and recrystallized twice from 2,50 ml of hot acetone, again requiring a small amount of methanol for effective and complete dissolution. The resulting product was collected and dried in vacuo to give 2 g of the title compound. [α] 〇 = + 50.03 ° (c = 0.9563, CH30H, 23T;); the mirror purity of this amine moiety was 99.8%. Snow m The stability of the title compound and (S) -α-phenyl-2-pyridineethylamine (S) -malate to humidity in Study Example 1. The former melts at 80% relative humidity; the latter absorbs 0.1% of its own weight of water at the same relative humidity. C Please read the precautions on the back before filling this page} Example of struggling with TV University. 2 examples of the most practical subject of the time-honored combination of the old mouse and the eye □ W 'Laws r Seeing extension of sexual activity prevention The post-strength issue is printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs \ 克 9 9 6 6 This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) A6 B6 Central Standard of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperatives V. Description of the Invention (i) The present invention relates to (s) -a-phenyl-2-pyridineethylamine salt (S) -malate in medicine-especially in the treatment of neurodegenerative diseases- Use, its production steps and peony formulations containing it. The main problem of the existing drugs used to treat neurodegenerative diseases is the lack of predictability of the concentration, and the concentration of the drug in the patient's plasma cannot be predicted after the administration of a known amount of drug, that is, the existing Cai Wu can not show linear pharmacokinetics. system. It has been described that the ideal drug of this range shows a linear relationship between dose and plasma concentration, that is, a change in a certain dose of the drug can predict the change in blood pressure [old, new, and not yet developed resistance Pharmacokinetics of Ramie Drugs, RH Levy and B Kerr, Paralysis®, vol 30, Supp 1, S35-S411. 1989]. European Patent No. 356035 discloses a number of compounds for the treatment of neurodegenerative diseases, including α-phenyl-2-pyridineethylamine salt [of which i. Phenylphenyl-2- (2: pyridyl) ethyl Amine]. The (S) -mirror isomer of this compound, and its pesticide-acceptable acid addition salt exhibit linear pharmacokinetics, and this is disclosed in W093 / 20052 (International Patent Case No. N ° PCT / GB93 / 00689). Surprisingly, it has now been found that (S) -malate k of (S) -a-phenyl-2-pyridineethylamine salt has many advantages, including significant stability to moisture. Therefore, according to the present invention, Its limitation is (S) -a-Phenyl-2-pyridineethylamine (S) -malate (please read the precautions on the back before filling this page) 〇-Binding. Staple-line.-This paper Standards apply to China National Standard (CNS) A4 specifications (210X297mm) A6 B6 V. Description of invention (2)
C〇2HHO、、H (請先閲讀背面之注意事项再填窝本頁) (下文中指“本發明之化合物 其鏡像純度大於90%C〇2HHO ,, H (Please read the notes on the back before filling this page) (hereinafter referred to as "the compound of the present invention whose mirror purity is greater than 90%
Q “鏡像纯 鏡像純度大 應之（R )-鏡 本發明之 近100%更 结晶法_、偏 達成。 α -苯基-藉下述之實 本發明也 鹽之方法， .裝.. 度大於90% ”意指此鹽之每一個鏑像姐成物之 於9 0% ;也就是每一涸鏡像組成物含有之相對 像異構物Μ重量計小於10%。 化合物的鏡像純度大於9 9%較佳，鏡像純度接 佳，此可Μ已知之方法如光學純化法（如部分 光9色析法），偏光引發物質及/或偏光合成法 線. 2-吡啶乙胺鹽及（S>-〇f -苯基-2-吡啶乙胺鹽可 例1之方法製成。 提供製備（S) - α -笨基-2-吡啶乙胺（s>-蘋果酸 它包括： 經濟部中央標準局貝工消費合作社印製 (a) 由α -苯基-2-吡啶乙胺鹽；或一種其鹽類與鏡像純度 大於90%之（S)蘋果酸之混合物的溶液中沉澱而形成 :或 (b) 由（S) - ct -苯基-2-吡啶乙胺，或一種其鹽類與鏡像純 JS大於90%之（S)-蘋果酸之混合物的溶液中沉澱而形 - 本紙張尺度逋用中國國家標準（CNS)甲4规格（210X297公釐) 五、發明説明（3 ) 成 A6 B6 經 濟 部 中 央 標 準 局 貝 工 消 費 合 作 社 印 製 本發明之化合物適用於發藥上，尤其作為治療神經變性 病變之抗痙孿與神經保護劑。可能被提及之特定神經變性 病變包括中風（stroke)，大腦缺血（cerebral ischaemia) ，大腦性麻揮（cerebral palsy)，低血糖症 (hypoglycaemia)、顏痴、愛滋病引起之痴呆症*阿兹海 默症（Alzheimer’s disease)，漢亭頓氏無蹈症. (Huntington’s chorea) * 撤欖體橋體小腦萎縮（Olivo- ponto-cerebellar atrophy) * 週產期童息（perinatal asphyx 丨 a)，帕金森氏症（Parkinson’s disease) ，缺氧 (anoxia)，藥物濫用引起之神經缺損（如麻醉劑 (narcotics)或古柯驗（cocaine)，視網膜病變 (retinopathies)，精神分裂症（schizophrenia)，心臓 / 停止或外科丰術後之缺血狀態，中毒（intoxication)或奇 髓受傷及肌萎縮性側索硬化（anyotrophic lateral sclerosis)。其中癲痴之抗痙輋治療，及中風、大腦缺血 及缺氧之神經保護治療尤其令人感興趣。當不囿於理論之 限制時，神經變性被認為是由中樞神經系統可自然發現的 特定刺激性胺基酸所引起或加速變性。麩氨酸鹽 (Glutamate)係内源性胺基酸，它被認為是哺乳動物腦部 ϋ快速剌激性傳導物質。麩氨酸鹽也因其為強神經毒素而 著名，它在和中風及心臓休止相伴產生之特定病態下可殺 死中樞神經糸統之神經元。突觸後麩氨酸鹽受器之某些特 定拮抗劑已被認為可降低中樞神經元對缺氧和缺血之敏感 {請先閲讀背面之注意事项再填窝本頁} © •裝 .訂. -線- 本紙張尺度適用中國國家標準（CNS)甲4规格（210X297公釐） A6 B6 五、發明説明（4 ) 性。麩氨酸鹽之特色為在四種神經元剌激性胺基酸受器部 位皆具活性之廣效協同劑。瑄些受器部位κ可選擇性剌激 他們的胺基酸來命名，其名稱分別為海人酸盥（Kainate KA)* N -甲基-D-天門冬胺酸S(N-methyl-D- aspartate, NMDA)，奎士夸雷特 Uuis quatate, QUIS)及 2-胺基-4-碟酸丁酸鹽（2-aBino-4-phosphonolutyrate APB>。咸信挺 氨酸鹽係具有结合此四種受器全部並可刺激他們之混合性 協同劑。因此，可選擇性阻斷或拮抗麩氨酸遡在這些受器 之活動之藥劑就可預防和缺氧、氧不足或缺血所引起之神 經毒損害。特定言之•可和NMD A受器部位结合並且選擇性 阴斷麩氨酸鹽作用之化合物可用於預防和治療神經變性病 變。· 本發明之化合物的藥理活性可用下列之試驗測量。 / * 經濟部中夬樣準局員工消费合作社印製 {靖先閲讀背面之注意事項再填窝本頁) a) NMDA阻斷"活性之测量係經由評估一種化合物對老鼠根 據Czuczuar•等人所提[神經傳導物質，癱痴發作和癲 痴 III，(Neurotransmitters, Seizures and Epilepsy III), G. Histico 等人出販，Raven Press, New York 1986, p235-246]之步驟.靜脈施注 150毫克/公斤之NMD AK引發痙攣之保護作用而定。 已分好姐之老鼠在試驗三十分鐘前預先經由腹膜内路 經施用試驗化合物，然後再給HMDA。観察試驗動物是 否出現痙擎，痙孿之定義為喪失直立反射並出現強直 性 / 陣孿性癱痴（tonic/clonic seizure)。給 NMDA 後 觀察六十分鐘，並記錄死亡率。 本紙張尺度適用中國國家標準（CNS)甲4規格(210X297公釐) A6 B6 經濟部中央標準局員工消費合作社印製 五、發明説明（5 ) b) HMDA受器拮抗劑活性可做活體外測試，其係評估一種 化合物抑制受器拮抗劑：10, 11-二氫-5-甲基~5H-二 苯基[a，b]-環庚烯-5, 10-亞胺（ΜΚ8 01>(1〇,11-dihydro-5-methyl-5H-dibenzo[a,b]-cyclohepten-5, 10-iBine)之结合力之能力。這個方法之搶述請見 F〇ster及 Wong , Br J Pharmacol 91. 403-409 (1987)〇 c) NMDA及氨基乙酸受器親和力也可K依照Monaghan及 cotman , PNAS , 83 . 7532, (1986)及 Watson等人， Neurosu Res. Comm; 2_，169，（1988)之方法 M. [3H] L-麩氨酸鹽及[3H]-氨基乙酸结合分析法測試。 d) 抗缺氧活性可K很容易地用老鼠試驗。將老鼠分姐Μ 腹膜内注_法投與不同等級劑量之試驗化合物之後在 不同的時間試驗。在溫度控制下之缺氧環境（96%之 氮氣與4%之氧氣）中之動物存活時間記錄下來。將 同時以媒劑處理之動物和賁驗動物之结果用統計方法 比較。如此可得到化合物之劑量一反應之闞係和最小 活性劑量（minimum active dose) [A A Artu及 J D M i c h e n f e 1 d e r，麻醉及止痛，1 9 8 1 , QiL 8 6 7 ]。也可 M用其他之投藥法。 e) 抗癲痴活性也可Μ測量，此係藉著評估分組之試驗鼠 依據R J Porter等人出版之癲痴分支 （Epilepsy Branch) HINCDS, Cleve Clin Quarterly 1984, 5_L. 293中之步驟M 口眼，腹膜内，靜脈或皮下施用試驗 本紙張尺度逋用中國國家標準（CNS)甲4规格（210x297公釐) {諳先閲讀背面之注意事項再填窝本頁} © .装· •ΤΓ., 線. ， A6 _____B6__ 五、發明説明（6 ) ’ 化合物後*再K最大電擊法（maxiaal electroshock) 引發癲痴，視此化合物預防試驗動物出現後肢強直性 伸展之能力•並與標準抗癲麻藥物内醢脲酸二笨納 (dilantin)及苯基巴比妥（phenobarbital)互相比較 〇 f) 四條血管阻塞模式之中風係用來造成實驗鼠乏球性缺 血*且是評估化合物預防腦部選擇性易受損害部位[ 著名的為海禺（hippocampus)之CA1錐體神經元]之.損 害的有效性之必要技巧。此易受損害部位牽渉到實驗 動物和人類之短期記憶形成之路徑。此步驟包含在第 一天將實驗鼠之椎體動脈燒灼，且將其頸動脈分離並 保抟在麻醉的情形下。第二天時鉗住頸動脈不同的時 間*十分g就足Μ摧毀C A1神經元。移開紺子使血液 重新灌¥，並在灌流後不同之時間投與藥物。在整個 缺血及恢復期中體溫都維持在37 t：。經遇48-72小時 CA1神經元完全死亡，且通常實驗老鼠K藥物（腹腔 内，靜脈或注口）治療至少三天，且在第七天取出大 腦做組織學檢査。CA1之損害的分級係用兩種方法完 成：即計算能存活的CA，神經元及外観病變程度之計 分[W A Pulsinelli 及 A Buchan, "HMDA 受器 / 離子 通道：它對選擇性易受損神經之活體內缺血損害很重 要，大腦缺血之藥物學，由J KrUglstein Η及 Oberp. ichler·編輯，Wissenschaftliche、 Verlagsgesellschaft, Stuttgart出，1990 p169]。 -8 - 尺度適用中國ΐ家樣準（CNS)甲4規格（210X297公釐} (請先閲讀背面之注意事項再填寫本頁) © .裝 -訂.. -線. 經濟部中央標準局員工消费合作社印製， A6 B6 經濟部中央標準局負工消费合作社印製 五、發明説明（7 ) g) 在局部中風模式中，用自發性高血壓鼠做試驗動物， 因為他們之大腦的側枝循環相對較差。在麻醉的情形 下紺住自發性高血壓鼠之中大腦動脈及同側之頸動脈 ，可造成兩小時之局邰缺血。可在紺住動脈之前（通 常ip)成立後各個不同時間給藥，也可在二個小時重 新灌流時給藥。實驗.後二十四小時取出腦部，冷凍並 切片，且用一傳统方法建立之定量糸统 [A Μ Buchan, D Xue 及 A Slivka,中風，1992，2JL, 27 3]來測量藥物對降低大腦皮質之梗塞體積的效果。 本發明之化合物的毒性可用下述試驗测量。 a) 劑量範圍研究係根據NW Spur ling及P F Carey所描 述之“重覆劑量毒性試驗之劑量選擇方法”，此為毒 物學學會冬年會之974篇發表之文章，西雅圖，美國 ，23-2/Feb. 1992。 每天逐漸增加試驗化合物之劑 量Μ靜脈注射至鼠體内，直到找到最大可重覆劑量， 超過此劑量痙攀和其他不正常之臨床徵候就無法接受 Ο b) 反.向屏蓁試驗[L L Cougenour，J R _1<<:1^31»，及_ R B Parker, Pharmacol. Biochem. Behav, 1977 6_, 351]。 給予試驗鼠某劑量之試驗化合物三十分鐘後， 將其置於一個經180°弧度倒轉之小鐵絲平臺。若老 鼠無法在三十秒内爬到直立的位置則將其歸於失敗姐 。使用足夠的劑量及動物，則可Μ很容易測出恰當之 TDs〇 ( 50%之試驗鼠失效之劑量）° {請先閲讀背面之注意事項再填窝本頁} © .裝 .訂. .線· 本紙張尺度適用t國國家標準（CNS)甲4規格（210X297公釐) 經濟部中央標準局貝工消费合作社印製. A6 ________B6_ 五、發明説明（3 ) c) 根據S Irwin[精神藥理學· 1968，L1，222]之28種行 為徵候之觀察試驗。將三隻試驗鼠分成一組，每姐之 試驗劑量相同* Μ 25-400毫克/公斤之範圍逐漸增加 試驗化合物的劑量，並在給藥後，三十分鐘，三小時 與二十四小時後觀察28種徴候出現的情形。 d) Phencycl idine (PCP)類似行為之試驗。PCP類似行 為係強效競爭性與非競爭性NMD A受器拮抗劑之一種副 作用。筛檢某一化合物是否具有這種副作用之可能性 的方法係Μ 口眼方式給老鼠試驗化合物（K保護最大 電擊試驗之口服EDBO之倍數表達），並將其放置於單 獨之透明塑膠簾内，觀察四個小時，看和PCP有翮之 S種特殊行為：即過動（hyperactivity)、運動失調 (ataxia) ' 繞圈子（circling)、頭搌動（head .ft weaving)&_後移（retropulsion)出現之頻率。觀察每 一治療姐之五隻老鼠的行為，並和接受PCP之控制姐 比較。發生率總分數為25，即五隻試驗鼠都表現五種 行為。PCP為EDB〇之10倍時會產生25分[W Koek . J H Woods，P, Ornstein, 1987，精神藥理學，SX· 297]。. e) 眺板逃逸試驗（Gang Plank Escape Test)係测量老鼠 之神經缺損[GE Gar ske et a丨.，癲痴研究，1991， 9_，161]。 將老鼠置於照明良好之入口方格之窄板上 (寬度篇1.25公分，懸掛於平台頂上40公分），它通 往逐漸變暗之盒中，此盒之另一邊連接黑暗之逃逸方 -10 - 本紙張尺度適用中國國家標準+(CNS)甲4规格(210x297公釐） (請先閲讀背面之注意事項再蜞窝本頁) -裝 訂· 線， Α6 Β6 經濟部中央標準局黃工消费合作社印製 五、發明説明（9 ) . 格（此板63公分長）。若試驗鼠無法通過跳板則認為 其神經有缺損，此試驗考慮到老鼠之兩種著名行為， 即懼高與喜愛黑暗的環境。 線性藥物動力學可用老鼠測得，其係藉著評估血漿濃度 v乘KK靜脈施注逐漸增加劑量之單一劑量試驗化合物所 得.之曲線所得到之面積（Smith et al, Xenobiotica,.20, 1 187-1 1 99，1990)。在二十四小時內之各個不同時點由頸 靜脈插管中取血。用離心法將血漿分離出來· Μ高效液態 色析紫外線色析法測量試驗化合物之湄度。在圖表上盡上 每一劑量之血漿湄度ν值•並且估計其下之面積。若有線 性藥物動力學關係，則每一劑量之血漿濃度！/時間曲線下 之面積將和所給之劑量成正比。若在試驗鼠上出現線性藥 物動力學關係\暗示人體上也會出現線性藥物動力學闞係 (Leander et al,掘 SI，3 3. 696-704, 1992, ·ρ703) ° 根據本發明之另一個特點，它可提供治療神經變性病變 之方法*此方法包含施用有治療效果之劑量之本發明之化 合物於病人身上。此方法特別令人感興趣之處為腌用之化 合物的劑量和所要之此化合物之血漿濃度呈線性比例。 當然，上面所提到之用途所施用之劑量將視所使用之化 合物*施用之途徑*與所要治療之疾病而不同。然而，一 般說來，當每天施用之本發明之化合物的劑量為每公斤動 物體重從約0.1毫克至約20毫克，即可獲得令人滿意之结 果，此劑量一天分成一至四次給，或用持續釋放型之方式 給較佳。對人類來說，每天之總劑量範圍從5毫克至1400 -11 - 本紙張尺度適用中國國家標準（CNS)甲4規格（210X297公釐) (請先閲婧背面之注意事項再填窝本頁} ο .裝 .訂. -線- 五、發明説明Ο0 A6 B6 毫克，Μ10毫克至100毫克較佳，且適合口眼施用之單一劑 型包含2毫克至1 400毫克之試驗化合物，與固態或液態豁藥 載劑或稀釋液混合。 本發明之化合物可Μ其本身使用，或Κ適當之腸道或非 經腸道联槩製備之方式施用。根據本發明之更進一步特點 *其可提供之輅藥配方包括含本發明之化合物以重里計小 於80»，且小於50¾更佳，並混合轚藥上可接受的佐劑，稀 釋劑或載劑。 稀釋劑及載劑之實例為： 錠劑和糖衣錠者有：乳糖、澱粉、滑石粉、硬脂酸； 膠囊劑者有：酒石酸或乳糖； 注射用溶液：水、酒精、甘油、蔬菜油； 栓劑者有：天然油或硬油或石蟈。 / 當使Μ本發明之化合物於治療帕金森氏症時，特別令人 感興趣之佐劑為L-多巴（L-dopa>。 根據本發明之更進一步特點，它提供本發明之化合物作 為製造治療神經變性病變之輅藥品的活性成分。 本發明之化合物具有之優點為較以前用於前面提到之治 療範圃之化合物更無毒性、更有效、較長效、作用範圍更 廣、更強效、產生較少之副作用、較易吸收或有其他有用 請 先 閲 € 背 之 注 意 事 項 再 填 窝 本 δ 經濟部中央標準局員工消费合作社印製 明 說 步 1 進 例 實 列 下 。 藉 性可 特明 理發 藥本 之 2 11 本紙張尺度逋用中國國家標準（CNS)甲4规格（210X297公釐） 390875 A6 B6_ 五、發明説明（】〗） {请先閲請背面之注意事項再堞窝本頁) 啻例1 (S)-ry -笼某-2-吡晾7,胺二氡仆氩之郸備法 a ) a -¾ 某胺二氡化氩 在 600 毫升之苯甲醛（benzaldehyde)(34.23 克，0.323 莫 耳）的四氫呋喃冷（0°C)溶液中，K三十分鐘的時間一滴滴 地加入雙（三甲基矽烷基）-醢胺鋰[LithiUB bis (triraethylsilyU-amide] (LHMDS) ( 323毫升之 1M的四氫 呋喃溶液，0. 323奠耳）。將此混合物在下攪拌三小時 0 在一含有 2-甲基吡啶（2-picoline) (30.0克，0.323莫 耳）之四氫呋喃（ 600毫升）冷溶液（-78 "0)之獨立圓底 燒瓶中Μ二十分鐘以上的時間加入η-丁基鋰（ n-butyl 1 ithiu^) ( 1 29.2毫升之 2.5M己烷溶液）。 經濟部中央標準局員工消费合作社印鬣 使第一個反應混合物加溫至Ot：，.並再維持此溫度四十 分鐘。將第二個反應混合物（含2-甲基吡啶之鋰化陽離子 )Μ二十分鐘以上的時間用管子滴入第一個反應混合物内 。再三十分鐘後除去冷浴，並使此混合物加溫至室溫。再 一個小時後，將反應混合物傾倒入含有冰（1升> 及12«鹽 酸（ 200毫升）之獨立漏斗中。水溶液層Κ 200毫升乙醚冲 洗三次，然後水25¾¾ NaOH水溶液鹸化。水溶液層Μ 200毫 升氯仿萃取兩次，氛仿之萃出物Κ硫酸鎂乾煉，過濾後在 真空中濃縮。將殘餘物溶解於乙酸乙酯中，並Κ鹽酸/乙 酸乙酯之飽和溶液酸化。將此溶液Μ乙醚稀釋*所產生之 白色固體在真空中過滅並乾燥後可得到副標題化合物（ -13 - _本紙張尺度逍用中國國家標準（CNS.)甲4規格(210x297公釐) ' — 390875 A6 B6 經濟部t央標準局員工消费合作社印# 五、發明説明（12 ) 37.08克，43»!)，熔點=206-208\：。 b) (S) - α -苯基-2-吡晾脓二氲化氫 在外濟旋ot-苯基-2-吡啶乙胺鹽（係步驟（a)之產物的自 由態鐮*可藉著Μ 25X氫氧化納溶液與步驟（a)產物的水溶 液中和*並Μ氛仿萃取而獲得）（10.96克，0.05 53莫耳 )之乙酸乙酯（400毫升）溶液中加入S( + )-苯乙醇酸[ Si + )-mandelic acid](8.41 克，0.0553莫耳）之乙酸乙醋 (300奄升）溶液。使所產生之沉澱物再由熱乙酸乙酯（500 毫升）中再结晶三次。此鹽Μ 25%氫氧化纳溶液鐮化，以 100毫升氯仿萃取三次，Κ硫酸鎂乾堞，並在真空中過漶 及濃縮。將殘餘物溶解於乙酸乙酯（300毫升）中，且Μ鹽 酸/乙酸乙酯飽和溶液酸化。所產生之白色固體在真空中 過濾和乾堞，f得到（-)-α -苯基-2-吡啶乙胺二氯化氫（ 5.5克），熔ά = 220-222Ό，[ct ]D= - 87.3。 （c =1.0, CH3〇H) ° 最初沉澱所得到之過濾物M25%.氬氧化納水溶液中和， 250毫升氛仿萃取兩次，Μ硫酸鎂乾燦，在真空中過.濾及 濃縮。殘餘物溶解於乙酸乙酯（500毫升）中，並加r (-)-苯乙酵酸（6.5克，0,043莫耳）之乙酸乙醋（500毫升） 溶液到此溶液中。將沉澱物過濾出來，並再结晶三次。此 鹽M2 5%之氫氧化納溶液鹼化，Κ 1〇〇毫升之氛仿萃取三 次，Κ硫酸鎂乾燥，在真空中遇濾及濃縮。將殘餘物溶解 於乙酸乙酯（300毫升）中，並Μ鹽酸/乙酸乙酯之飽和溶 液酸化。將所產生之白色固體在真空中過滤及乾燦，可得 -14 - _本紙張尺度適用中困國家標準（CNS)甲4规格(210X297公釐) r ,®. ................................................................Γ.;Λ...........裝........................ΤΓ.....................線 (誇先閲請背面之运意亊項年填窝本頁) ⑷ I 390815 A6 B6 五、發明説明（13 ) 到標題化合物（3.84克），熔點=220-222 Ό，[ a ]D = ♦87.1。 （ c = 1. 1，CH3OH)。 其鏡像純度可藉著苯乙醇酸或二氯化氫鹽與甲基苯基異 氰酸之鏡像純體（大於99.5% )衍化而測知，然後用K乙 醇己烷[6:9 4]為溶劑之正常相柱之高效液態色析法分析。 由上述方法得到之鏡像異構物之鏡像純度大於99 · 5%。 X-光結晶學顯示此（ + )-鏡像異構物具有鈍- (S)立體化學 0 阳·.畦乙胺之方法 在含3.0克声例1之標題化合物之100毫升乙酸乙醋溶 液中，加入（S)-蘋果酸（99%，限用Aldrich化學公司之 產品）之乙酸乙酯飽和溶液，直到所產生之混合物變成酸 性。加入甲醇使所產生之沉澱物溶解*且加乙醚可使之再 沉澱。將產生之白色固體在真空中過濾並乾煉可得到3.85 克之標題化合物，熔點=134-136¾ ; [ a ]D = +51.02° ( c=0.99 57 vCH3〇H，23勺）；此胺厚子團之鏡像纯度 >99.999%。 , ® ) .......................................................................,............裝...................…-訂.....................線； (請先閲讀背面之注意事項再填窝本頁} 經濟部中央標準局員工消费合作社印製 俐 窨 備 0 HCTTΜ 氬 二 胺 .乙 哇0 * 2 釋 某 ί本 - 由 啶0- 2 續 某 笼 a 法 方 之 翰 餓 果 額 5 1Λ 適 度 尺 張 紙 本 準 標 家 讀Q "mirror pure mirror image purity (R) -mirror of the present invention is nearly 100% more crystallized, it is achieved. Α-phenyl- the following method of the present invention is also a salt method. "More than 90%" means that each salt of the salt is less than 90% of the adult product; that is, the relative image isomer M of each salt image composition is less than 10% by weight. Compounds with a mirror image purity greater than 9 9% are preferred, and mirror image purity is better. This can be known by methods such as optical purification (such as partial light 9-color analysis), polarized light-initiating substances, and / or polarized light synthesis normals. 2-pyridine Ethylamine salt and (S > -〇f-phenyl-2-pyridineethylamine salt can be prepared by the method of Example 1. Provide (S) -α-benzyl-2-pyridineethylamine (s > -malic acid) It includes: Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (a) a salt of α-phenyl-2-pyridineethylamine; or a mixture of its salt with (S) malic acid having a mirror purity of greater than 90% Formed by precipitation in solution: (b) In a solution of (S) -ct-phenyl-2-pyridineethylamine, or a mixture of (S) -malic acid whose salt and mirror pure JS is greater than 90% Precipitation and Shape-This paper uses Chinese National Standard (CNS) A4 specification (210X297 mm) 5. Description of the invention (3) A6 B6 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs In medicine, it is especially used as an antispasmodic and neuroprotective agent for the treatment of neurodegenerative diseases. Degenerative lesions include stroke, cerebral ischaemia, cerebral palsy, hypoglycaemia, facial dementia, dementia caused by AIDS * Alzheimer's disease ), Huntington's chorea. (Huntington's chorea) * Olivo-ponto-cerebellar atrophy * perinatal asphyx 丨 a, Parkinson's disease ), Hypoxia (anoxia), neurological deficits caused by substance abuse (such as narcotics or cocaine, retinopathy, schizophrenia, palpitations / stops, or postoperative surgeries) Ischemic state, intoxication or pith injury, and amyotrophic lateral sclerosis. The antispasmodic treatment of epilepsy, and the neuroprotective treatment of stroke, cerebral ischemia and hypoxia are particularly attractive. Interested. When not limited by theory, neurodegeneration is thought to be caused by a specific stimulating amino acid that is naturally found in the central nervous system or Accelerated Denaturation. Glutamate is an endogenous amino acid, which is considered to be a fast stimulating conductive substance in the mammalian brain. Glutamate is also known for its strong neurotoxin, which kills neurons of the central nervous system in specific pathologies associated with stroke and palpitations. Certain specific antagonists of post-synaptic glutamate receptors have been considered to reduce the sensitivity of central neurons to hypoxia and ischemia {Please read the precautions on the back before filling this page} © • Binding. Order . -Line-This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) A6 B6 5. Description of invention (4). The glutamate is a broad-spectrum synergist that is active in all four neuronal stimulating amino acid receptor sites. Some receptor sites κ can selectively stimulate their amino acids, which are named Kainate KA * N -methyl-D-aspartic acid S (N-methyl-D -aspartate, NMDA), Uuis quatate, QUIS) and 2-amino-4-phosphonolutyrate APB >. Salty and tyrosine salts have a combination of this All four receptors can stimulate their mixed synergistic agents. Therefore, agents that can selectively block or antagonize the activity of glutamate in these receptors can prevent and cause hypoxia, hypoxia or ischemia Neurotoxic damage. In particular • Compounds that can bind to the NMD A receptor site and selectively block glutamate can be used to prevent and treat neurodegenerative diseases. · The pharmacological activity of the compounds of the present invention can be tested as follows Measured. / * Printed by the Consumers' Cooperatives of the Ministry of Economic Affairs of the Chinese People's Republic of China. (Jing first read the precautions on the back and then fill in this page) a) The measurement of NMDA blocking " activity is based on the evaluation of a compound on mice according to Czuczuar • Mentioned by [Nerve Conducting Substances, Paralysis and Epilepsy III, (Neurotransmitters, Seizures and Epilepsy III), published by G. Histico, et al., Raven Press, New York 1986, p235-246]. Depending on the protective effect of intravenous administration of 150 mg / kg NMD AK on spasticity . Thirty minutes prior to the test, the rats were pre-administered with the test compound by intraperitoneal route, and then HMDA. Check the test animals for spasms. Spasticity is defined as loss of upright reflexes and tonic / clonic seizure. Observe NMDA for sixty minutes and record mortality. This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) A6 B6 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (5) b) HMDA receptor antagonist activity can be tested in vitro, It evaluates a compound inhibitor receptor antagonist: 10, 11-dihydro-5-methyl ~ 5H-diphenyl [a, b] -cycloheptene-5, 10-imine (ΜΚ8 01 > (1 〇, 11-dihydro-5-methyl-5H-dibenzo [a, b] -cyclohepten-5, 10-iBine). For a quick description of this method, see Foster and Wong, Br J Pharmacol 91 403-409 (1987) 0c) NMDA and glycine receptor affinity can also be K according to Monaghan and cotman, PNAS, 83. 7532, (1986) and Watson et al., Neurosu Res. Comm; 2_, 169, (1988 ) Method M. [3H] L-glutamate and [3H] -glycolic acid binding assay test. d) Antihypoxic activity can be easily tested in mice. Mice were administered intraperitoneally with different doses of test compounds after intraperitoneal injection. Animal survival time was recorded in a temperature-controlled hypoxic environment (96% nitrogen and 4% oxygen). The results of animals treated with vehicle and test animals were compared statistically. In this way, the dose-response system and the minimum active dose of the compound [A Artu and J D M i c h e n f e 1 de r r, anesthesia and analgesia, 1981, QiL 8 6 7] can be obtained. Other methods of administration can also be used. e) The anti-epileptic activity can also be measured. This is done by evaluating the experimental mice according to the steps in the epilepsy branch published by RJ Porter et al. HINCDS, Cleve Clin Quarterly 1984, 5_L. 293. , Intraperitoneal, intravenous or subcutaneous application test This paper size uses the Chinese National Standard (CNS) A4 specification (210x297 mm) {谙 Read the precautions on the back before filling this page} ©. 装 · • ΤΓ., Line., A6 _____B6__ 5. Description of the invention (6) 'After the compound *, then the maxiaal electroshock method will cause epilepsy, depending on the ability of the compound to prevent the development of hindlimb extension in the test animals. • In combination with standard antiepileptic drugs Dilantin and phenobarbital are compared with each other. (F) Four vascular occlusion patterns are used in the stroke system to cause ischemic ischemia in experimental mice * and to evaluate compounds to prevent brain selection Sexually vulnerable sites [known as the CA1 pyramidal neurons of hippocampus]. Essential skills for the effectiveness of the damage. This vulnerable site is involved in the path of short-term memory formation in laboratory animals and humans. This step involves cauterizing the vertebral arteries of the experimental rats on the first day, separating their carotid arteries and keeping them under anesthesia. On the second day, the carotid artery was clamped at different times * ten grams to destroy the C A1 neuron. Remove the mule to re-perfusion the blood and administer the drug at different times after the perfusion. Body temperature was maintained at 37 t throughout the ischemia and recovery periods. After 48-72 hours of CA1 neuron death, rats are usually treated with K drug (intraperitoneal, intravenous or mouth) for at least three days, and the brain is removed for histological examination on the seventh day. The grading of CA1 damage is accomplished by two methods: scoring the degree of viable CA, neurons and lemma lesions [WA Pulsinelli and A Buchan, " HMDA Receptor / Ion Channel: It is vulnerable to selectivity Ischemia in vivo is important for nerve damage. The pharmacology of cerebral ischemia is edited by J KrUglstein Η and Oberp. Ichler ·, Wissenschaftliche, Verlagsgesellschaft, Stuttgart, 1990 p169]. -8-The scale is applicable to China National Family Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) ©. Binding-booking .. -line. Staff of Central Bureau of Standards, Ministry of Economic Affairs Printed by the Consumer Cooperative, A6 B6 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (7) g) In the local stroke mode, spontaneously hypertensive rats are used as experimental animals because of the collateral circulation of their brains Relatively poor. Clamping the cerebral arteries and ipsilateral carotid arteries in spontaneously hypertensive rats under anesthesia can cause local ischemia for two hours. It can be given at various times before the artery is pinched (usually ip), or it can be given at two hours after reperfusion. Experiment. After 24 hours, the brain was removed, frozen and sliced, and the quantitative system established by a traditional method [A Buchan, D Xue and A Slivka, Stroke, 1992, 2JL, 27 3] was used to measure the reduction of drug pairing. Effect of cerebral infarct volume. The toxicity of the compound of the present invention can be measured by the following test. a) The dose range study is based on the "Dose Selection Method for Repeated Dose Toxicity Tests" described by NW Spurling and PF Carey. This is an 974 article published by the Winter Conference of the Toxicology Society, Seattle, USA, 23-2 / Feb. 1992. Increasing the dose of the test compound M intravenously into rats every day until the maximum reproducible dose is found, beyond which the spasm and other abnormal clinical signs are unacceptable. 0 b) Reverse. Screening test [LL Cougenour , JR _1 < <: 1 ^ 31 », and _ RB Parker, Pharmacol. Biochem. Behav, 1977 6_, 351]. Thirty minutes after giving a dose of test compound to test rats, it was placed on a small wire platform inverted by 180 ° arc. If the old rat cannot climb to an upright position within thirty seconds, it will be attributed to the failed sister. With sufficient doses and animals, it is easy to measure the appropriate TDs (50% of the test mouse failure dose) ° {Please read the precautions on the back before filling the nest page} ©. Line · This paper size is applicable to National Standard (CNS) A4 specifications (210X297 mm) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. A6 ________B6_ V. Description of the invention (3) c) According to S Irwin [Psychopharmacology · 1968, L1, 222] observational test of 28 behavioral symptoms. The three test mice were divided into a group, each sister's test dose was the same * Μ 25-400 mg / kg gradually increased the dose of the test compound, and after administration, thirty minutes, three hours and twenty-four hours Observe the appearance of 28 kinds of weather. d) Phencyclidine (PCP) similar behavior test. PCP similar behavior is a side effect of potent competitive and non-competitive NMD A receptor antagonists. The method for screening a compound for the possibility of such side effects is to test the compound (multiple expression of oral EDBO of K to protect the maximum electric shock test) in mice by oral and eye methods, and place it in a separate transparent plastic curtain and observe For four hours, I saw that there are S special behaviors with PCP: hyperactivity, ataxia 'circling', head .ft weaving & retropulsion Frequency of occurrence. The behavior of each of the five treated sisters was observed and compared with the control sisters who received PCP. The total incidence score was 25, meaning that all five rats exhibited five behaviors. A PCP of 10 times EDB0 yields 25 points [W Koek. J H Woods, P, Ornstein, 1987, Psychopharmacology, SX · 297]. e) The Gang Plank Escape Test measures nerve defects in mice [GE Gar ske et a 丨., Epilepsy Research, 1991, 9_, 161]. Place the mouse on a narrow plate with a well-lit entrance grid (width 1.25 cm, hanging from the top of the platform 40 cm). It leads to a box that gradually darkens. -This paper size applies Chinese National Standard + (CNS) A4 specification (210x297 mm) (please read the precautions on the back before digging into this page)-binding, thread, Α6 Β6 Huang Gong Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs 5. The description of the invention (9). The grid is printed (the board is 63 cm long). If the test rat fails to pass the springboard, the nerve is considered defective. This test takes into account two well-known behaviors of the rat, namely fear of heights and love of the dark environment. The linear pharmacokinetics can be measured in mice, which is obtained by assessing the plasma concentration v multiplied by a single dose of a test compound administered intravenously over KK. The area obtained from the curve (Smith et al, Xenobiotica, .20, 1 187 -1 1 99, 1990). Blood was taken from the jugular vein cannula at various points in time within 24 hours. The plasma was separated by a centrifugation method. The high-efficiency liquid color chromatographic ultraviolet chromatographic method was used to measure the mammary degree of test compounds. Indicate the plasma meridian value ν for each dose on the chart and estimate the area under it. If there is a linear pharmacokinetic relationship, then the plasma concentration per dose! The area under the / time curve will be proportional to the dose given. If a linear pharmacokinetic relationship appears in a test mouse \ It is implied that a linear pharmacokinetic system will also appear in humans (Leander et al., SI, 3 3. 696-704, 1992, · ρ703) ° According to another aspect of the present invention A feature which provides a method for treating a neurodegenerative disease * This method comprises administering a therapeutically effective amount of a compound of the invention to a patient. This method is particularly interesting because the dose of the compound to be cured is linearly proportional to the desired plasma concentration of the compound. Of course, the dosage to be used for the above-mentioned uses will vary depending on the compound used * the route of administration * and the disease to be treated. Generally, however, satisfactory results are obtained when the compound of the present invention is administered daily at a dose of from about 0.1 mg to about 20 mg per kilogram of animal body weight. This dose is divided into one to four times a day, or Sustained release is better. For humans, the total daily dose ranges from 5 mg to 1400 -11-This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (please read the precautions on the back of Jing before filling this page) } ο. Binding.-Line-V. Description of the invention 00 A6 B6 mg, M10 mg to 100 mg is preferred, and a single dosage form suitable for oral and oral administration contains 2 mg to 1 400 mg of test compound, and solid or liquid The drug carrier or diluent is mixed. The compound of the present invention can be used by itself, or it can be administered by appropriate intestinal or parenteral preparation. According to the further features of the present invention * it can provide Pharmaceutical formulations include compounds containing the compounds of the invention that are less than 80 », and more preferably less than 50¾ by weight, and are mixed with an adjuvant, diluent or carrier acceptable on peony. Examples of diluents and carriers are: tablets and Sugar-coated tablets are: lactose, starch, talc, stearic acid; capsules are: tartaric acid or lactose; solutions for injection: water, alcohol, glycerin, vegetable oil; suppositories are: natural oil or hard oil or stone tincture. / When making M of the present invention In the treatment of Parkinson's disease, a particularly interesting adjuvant is L-dopa. According to a further feature of the present invention, it provides the compound of the present invention for the manufacture of a neurodegenerative disease.辂 Active ingredients of pharmaceuticals. The compounds of the present invention have the advantages of being less non-toxic, more effective, longer-lasting, broader in scope, more potent, and producing less than the compounds previously used in the aforementioned therapeutic paradigms. Side effects, easier to absorb or have other useful, please read the notes before you fill in the note δ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, the first step is listed in the examples. 2 11 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 390875 A6 B6_ V. Description of the invention ()〗 {Please read the precautions on the back first, and then read this page) Example 1 (S) -ry-cage-2-pyridine7, amine dihydrazine preparation method a) a -¾ benzaldehyde (34.23 g, 0.323 Moore) Tetrahydrofuran (0 ° C), add bis (trimethylsilyl) -phosphonium amide [LithiUB bis (triraethylsilyU-amide] (LHMDS) (323 ml of 1M tetrahydrofuran solution, 0. 323 Moore). The mixture was stirred for three hours 0 in a cold solution of tetrahydrofuran (600 ml) containing 2-picoline (30.0 g, 0.323 mole) (-78 " 0 ) In a separate round-bottomed flask, n-butyl lithium (n-butyl 1 ithiu ^) (1 29.2 ml of a 2.5 M hexane solution) was added for more than twenty minutes. The Consumers' Cooperative of the Central Standards Bureau, Ministry of Economic Affairs, printed the first reaction mixture to Ot :, and maintained this temperature for another 40 minutes. The second reaction mixture (the lithiated cation containing 2-methylpyridine) was dripped into the first reaction mixture for more than twenty minutes. After another thirty minutes, the cold bath was removed and the mixture was allowed to warm to room temperature. After another hour, the reaction mixture was poured into a separate funnel containing ice (1 liter) and 12 «hydrochloric acid (200 ml). The aqueous layer was washed three times with 200 ml of ether, and then water 25¾¾ NaOH aqueous solution was decanted. The aqueous layer M 200 It was extracted twice with ml of chloroform, and the extract of KNO was dried, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and acidified with a saturated solution of hydrochloric acid / ethyl acetate. This solution was acidified. The white solid produced by diluting with ethyl ether * can be sub-titled after extinguishing in vacuum and drying (-13-_ this paper size is in accordance with Chinese National Standard (CNS.) A4 specification (210x297 mm) '-390875 A6 B6 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs # V. Description of the Invention (12) 37.08 g, 43 »!), Melting point = 206-208 \: b) (S)-α-phenyl-2-pyridine Pyronium dihydrogen in ot-phenyl-2-pyridineethylamine salt (the free state of the product of step (a)) can be obtained by the M 25X sodium hydroxide solution and the aqueous solution of the product of step (a) Obtained by extraction with acetaminophen) (10.96 g, 0.05 53 mole) Ethyl ester (400 ml) was added a solution of S (+) - mandelic acid [Si +) -mandelic acid] (8.41 g, 0.0553 mole) of acetic acid ethyl ester (300 Om L) was added. The resulting precipitate was recrystallized three times from hot ethyl acetate (500 ml). The 25% sodium hydroxide solution of this salt was sickled, extracted three times with 100 ml of chloroform, dried over magnesium sulfate, dried in vacuo and concentrated. The residue was dissolved in ethyl acetate (300 ml), and a saturated solution of hydrochloric acid / ethyl acetate was acidified. The resulting white solid was filtered and dried in vacuo to obtain (-)-α-phenyl-2-pyridineethylamine dichloride (5.5g), melting = 220-222Ό, [ct] D =-87.3 . (C = 1.0, CH3OH) ° The filtrate obtained in the initial precipitation was M25%. The solution was neutralized with sodium argon aqueous solution and extracted twice with 250 ml of chloroform. The magnesium sulfate was dried, filtered in vacuo and concentrated. The residue was dissolved in ethyl acetate (500 ml), and a solution of r (-)-phenylacetic acid (6.5 g, 0,043 mol) in ethyl acetate (500 ml) was added to the solution. The precipitate was filtered off and recrystallized three times. This salt M2 was basified in a 5% sodium hydroxide solution, and K 100 ml of trichloromethane was extracted three times. K magnesium sulfate was dried, filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate (300 ml) and acidified with a saturated solution of hydrochloric acid / ethyl acetate. The white solid produced is filtered and dried in a vacuum to get -14-_ This paper size is applicable to the National Standard (CNS) A4 specification (210X297 mm) r, ® ........ ........................................ ....... Γ.; Λ ................ Installation ............ ΤΓ .. ...... Line (please read the intent on the back, please fill in this page on the back of the year) ⑷ I 390815 A6 B6 V. Description of the invention (13) to The title compound (3.84 g), melting point = 220-222 Ό, [a] D = ♦ 87.1. (C = 1.1, CH3OH). Its mirror-image purity can be determined by derivatizing mirror-image pure body (greater than 99.5%) of phenylglycolic acid or hydrogen dichloride and methylphenyl isocyanate, and then use K ethanol hexane [6: 9 4] as the solvent Efficient liquid chromatography analysis of normal phase columns. The mirror image purity of the mirror image isomers obtained by the above method is greater than 99.5%. X-ray crystallography showed that this (+)-mirror isomer has blunt- (S) stereochemistry. 0. · 畦 ethylamine method in 100 ml of ethyl acetate solution containing 3.0 g of the title compound of Example 1. Add a saturated solution of (S) -malic acid (99%, limited to Aldrich Chemical Co., Ltd.) in ethyl acetate until the resulting mixture becomes acidic. Methanol was added to dissolve the resulting precipitate * and ether was added to reprecipitate. The resulting white solid was filtered in a vacuum and dried to obtain 3.85 g of the title compound, melting point = 134-136¾; [a] D = + 51.02 ° (c = 0.99 57 vCH3OH, 23 spoons); this thick amine cluster The mirror purity is> 99.999%. , ®) ............................... ..................................... .............- Order .............. line; (Please read the notes on the back before filling in this page} Central Ministry of Economic Affairs Standard Bureau employee consumer cooperative prints 0 HCTTM argon diamine. Ewa 0 * 2 releases a copy of this-from the pyridine 0-2 to a certain cage a French hungry fruit amount 5 1 Λ moderate size paper standard Home reading
五、發明説明（/4 第83 102582號專利甶請案 A7 中文說明書修正頁（87年3月）B7 390875 總量250毫升含5.95克（30.1毫莫耳）實例1(a)化合掏 及4.8克（35.8毫莫耳）（S)-蘋果酸（99% )，限用 AldrMch化學公司）之丙酮溶液加熱至所有的固體溶解， 需要小量之甲醇使有效地完全溶解。將冷卻過程中形成之 固體收集起來，並由2 50毫升熱丙酮中再结晶兩次，再次 需要小量之甲醇使有效地完全溶解。將所產生之產物收集 起來，並在真空中乾燥，可產生2克之標題化合物。[α ]〇= +50.03° (c = 0.9563，CH30H，23Τ；);此胺部份之 鏡像純度99.8%。 雪m 研究實例1之標題化合物和（S) - α -苯基-2-吡啶乙胺 (S)-蘋果酸鹽對潮濕之穩^定度。前者在相對濕度為80%時 已溶化；而後者在相同之相對濕度下槿吸收其本身重量之 0 · 1 %之水。 C請先閲讀背面之注意事項再填寫本頁} 例 奮 擊 電 大. 最 由 鼠 老 對 時 物 合 化 題 標 之 2 例 實 用 施 眼 □ W' 法 述 r 見 性 活 防 預 之 展 伸 直 強 肢 後 之 發 為 經濟部甲央標準局員工消費合作社印製 斤 公 \ 克 毫 9 2 6 1 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）V. Description of the Invention (/ 4 Patent No. 83 102582, Request for A7 Chinese Version Correction Sheet (March 1987) B7 390875 Total 250ml contains 5.95g (30.1mmol) Example 1 (a) Combined with 4.8 Gram (35.8 mmol) (S) -malic acid (99%), limited to AldrMch Chemical Co., in acetone solution. Heat all solids to dissolve. A small amount of methanol is required to effectively dissolve completely. The solids formed during cooling were collected and recrystallized twice from 2,50 ml of hot acetone, again requiring a small amount of methanol for effective and complete dissolution. The resulting product was collected and dried in vacuo to give 2 g of the title compound. [α] 〇 = + 50.03 ° (c = 0.9563, CH30H, 23T;); the mirror purity of this amine moiety was 99.8%. Snow m The stability of the title compound and (S) -α-phenyl-2-pyridineethylamine (S) -malate to humidity in Study Example 1. The former melts at 80% relative humidity; the latter absorbs 0.1% of its own weight of water at the same relative humidity. C Please read the precautions on the back before filling this page} Example of struggling with TV University. 2 examples of the most practical subject of the time-honored combination of the old mouse and the eye □ W 'Laws r Seeing extension of sexual activity prevention The post-strength issue is printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs \ grams gram 9 2 6 1 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)