經濟部中央標隼局員工消費合作社印裝 426515 A7 _______ _B7 五、發明説明（1 ) 發明背景 血纖維蛋白分解系統在維持正常的血液靜力學平衡 (hemostatic balance)之中扮有關鍵角色。在此系统中的—種 重要因子爲血纖維溶酶元活化劑抑制劑AI-1)，其可經 由抑制血纖維溶酶元活化劑例如組織型血纖維溶跨元活化 —劑（t P A )而減低内源脱除，血-纖維蛋白的能力。研究記載證 明PAI-1的提高與深部靜脈血栓形成的危險性增高有關聯 性。此外，在患有心肌梗塞和敗血病的病人體内也發明 P AI - 1的增高。因爲金纖維蛋白分解能力與心血管危險性 的增加有關聯，所以降低P AI、1應該可導致心臟保護作用 。事實上，最近在Framingham Offspring Study _對於停經 前和停經後的女人醴内PAI-1水平之分析研究証明停經後的 女人具有明顯較高的P AI - 1水平，其可經由雌激素治療而 減低到停經前水平a這種P AI - 1效應的減低據信對於雌激 素代替治療法對心疾病危險性減低的整體效應有所貢鈇。 雖然P AI - 1可在多種組織内產生，但其實質水平係由血 管内皮細胞所分泌的。血管内皮係構成在血液凝結的調節 ，發炎，及血管内室與實質組織之間的流體和介質之交換 中具有效用的主要器官。因此之故，内皮的恰當機能對於 整體止血具有重要性。因爲PAI-1可對應於某些刺激，包 括細胞激素而在内皮細胞中增加，所以其會助成官能障礙 狀態，而可能導致凝血缺陷’局部和系統性血管發炎，及 動脈粥樣硬化斑的進展和破裂之增進ύ這些效應可能進一 步導致包括下列之病況：心肌梗塞，深部靜脈血栓形成，及 本紙張尺度逋用中園國家棣準（CN'S ) A4规格（210 X 297公釐） ---------^--------IT------.^ - - (請先聞讀背面之注意事項再填寫本頁) A7 4 265 15 五、發明説明（2 ) ~~ '〜· 散侔性靜脈内J&L栓形成。 因爲在内皮細胞/'A漿介面的PAI- 1局部控制可能在許 病理學方法中扮有重大角色，所以可抑鈿ώ ； 』种制闪皮中p AI -；[表 現的藥劑可用來治療病況例如敗血病’損傷包括主要組織 的傷害和創傷’系統性炎性反應徵候蛘，敗血徵候群，敗 一血性休克和多發性器官官能障礙徵候群（包括〇〗c )以及心 肌梗塞’深部靜脈A栓形成’散佈性靜脈内血栓形成，動 脈粥樣硬化斑的破裂及其後發病。再者，因爲血織維蛋白 在腫瘤細胞生物學中的重要角色，可調制PA】· i的藥刻可 用爲抗-移位變化劑（anti-metastatic agents)。 發明概述 衣發明提出抑制血織維溶酶元活化劑抑制劑1之方法，其 包括給有此需要的人服用有效量的化合物Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 426515 A7 _______ _B7 V. Description of the Invention (1) Background of the Invention The fibrin breakdown system plays a key role in maintaining a normal hemostatic balance. An important factor in this system is the plasminogen activator inhibitor AI-1), which can be inhibited by a plasminogen activator such as a tissue-type plasmin transactivator (t PA) And reduce the ability of endogenous removal, blood-fibrin. Studies have shown that an increase in PAI-1 is associated with an increased risk of deep venous thrombosis. In addition, patients with myocardial infarction and septicemia have also been found to have increased P AI-1. Because the ability of gold fibrin to decompose is associated with increased cardiovascular risk, lowering P AI, 1 should lead to cardioprotective effects. In fact, a recent analysis in the Framingham Offspring Study _ analysis of PAI-1 levels in women before and after menopause proved that women after menopause have significantly higher levels of PAI-1, which can be reduced by estrogen therapy This reduction in P AI-1 effect to pre-menopausal levelsa is believed to contribute to the overall effect of estrogen replacement therapy on the reduced risk of heart disease. Although PAI-1 can be produced in a variety of tissues, its substantial level is secreted by vascular endothelial cells. Vascular endothelial system constitutes the main organ that is useful in the regulation of blood coagulation, inflammation, and the exchange of fluids and media between the intravascular compartment and parenchymal tissue. For this reason, the proper function of the endothelium is important for overall hemostasis. Because PAI-1 can be increased in endothelial cells in response to certain stimuli, including cytokines, it can contribute to a dysfunctional state, which can lead to coagulation defects, local and systemic vascular inflammation, and the progression of atherosclerotic plaques These effects may further lead to conditions including myocardial infarction, deep venous thrombosis, and the use of the China National Standard (CN'S) A4 size (210 X 297 mm) on this paper scale ----- ---- ^ -------- IT ------. ^--(Please read the notes on the back before filling out this page) A7 4 265 15 V. Description of the invention (2) ~ ~ '~ · Sanitary intravenous J & L thrombosis. Because the local control of PAI-1 in the endothelial cells / 'A plasma interface may play a significant role in Xu pathological methods, it can be suppressed; "AI AI in the production of semi-skins; [the expressed agents can be used to treat Conditions such as septicemia 'injuries include major tissue damage and trauma' systemic inflammatory response symptoms, septicemia syndromes, septic shock and multiple organ dysfunction syndromes (including 0) c and deep myocardial infarction Venous A thrombosis' disseminated intravenous thrombosis, rupture of atherosclerotic plaques, and subsequent onset. In addition, because of the important role of hemoglobin in tumor cell biology, the drugs that can modulate PA] · i can be used as anti-metastatic agents. SUMMARY OF THE INVENTION The invention proposes a method for inhibiting plasminogen activator inhibitor 1, which comprises administering an effective amount of a compound to a person in need thereof
經濟部中央標準局員工消費合作社印製 〇 Ο 其中R1和R3獨立地爲氫，-CHS，故基），或j|：_Ar， 其中A r爲視情浞經取代的苯基； 本紙張尺度適财㈣家縣（CNS ) A4規格（2!GX 297公釐） 經濟部中央標準局員工消費合作杜印繁 426515 A7 ---------B7 五、發明説明（3 ) R2爲選自吡咯啶基，六亞甲基亞胺基’和六氫吡啶基之 中者：及其醫藥可接受的鹽和溶劑合物。 發明之詳細説明 本發明係有關一選擇组的2·苯基-3_芳醯基苯幷嘍吩（苯 幷嚷吩類）’即式I者，可用來抑制PAI-1之發現。 一 本發明所提使用方法係經由給有此需要的人服用—劑量 的式I化合物或其醫藥可接受鹽或溶劑合物，其可有效地抑 制P AI -1或與其超量相關的生理狀況。，,抑制,，一詞包括其 爲通常所接受的意義，其包括禁止，預防，約束：及減缓 ’停止或逆反進裝，嚴重性或所得徵狀或效應。 〜拉羅西！.(以IjjAifgne) ’爲本發明一化合物，其t其爲式I 中R和R3皆爲氫> 且R2爲1.六氩比咬基的化合物之鹽酸鹽， 爲種桂與知性分子（nuclear regulatory mo丨ecule)。拉羅西 吩經tE明可結合到雌激素受體且原先被認爲是一種其機能 和藥物學係屬抗-雌激素之分子，以其可阻斷雌激素所具活 化子言组織輿雌激素相關性乳癌的能力之故。的確，拉羅 西分確實可阻斷雌激素在某些細胞中的作用；不過，在其 他細胞類別中，拉羅西吩卻是活性化與雌激素所活化者相 同之基因且顯示出相同的藥物學，例如，骨質疏鬆，高脂 血症。其結果，拉羅西吩被稱爲是一種具有混合激動一拮 抗性質的抗-雌激素劑。拉羅西吩所顯示出且異於雌激素所 具者之獨特性徵至今被認爲是來自於拉羅西吩-雌激素受體 複合物對各種基因機能的獨特活化及/或壓抑係有別於雌激 素·雌激素受體複合物對諸基因的活化及/或壓抑。所以， -6- 本紙浪尺度適用中國國家榇孪（CNS Μ4現格UlOxm公楚) ---------裝------訂-------Λ (请先閲讀背面之注意事項再填寫本頁) 426515 經濟部中夬標隼局員工消费合作杜印策 A7 _________B7 五、發明説明（4 ) 雖然拉羅否吩和雌激素皆利用且競爭相同的受體，但這兩 者對基因調節所得藥物學結果卻不易預測且各具獨特之處 0 通常，該化合物係與常用的賦形劑，稀釋劑或載體調配 ，並塵製成錠’或調配成酏劑或溶液供方便的口服之用， /或經由肌肉内或靜脈内途徑給用。該化合物可透皮給用， 且可調配成持續释放性劑形等。 本發明方法所用化合物可根據確定程序製成，例如詳載 於美國專利第4，133,814號，4,418,068號，和4,380,635號之 中者，彼等全部併於本文作爲參考。概括而言，該方法係 用有6·羥基和2-(4-羥基苯基）基的苯幷ib],塞吩起始的。該 起始化合物經保護，醯化，及去保護而形成式I化合物。彼 等化合轴的製備例載於上引諸美國專利之中β視情況經取 代的苯基包括苯基及含有一或兩個下列取代基之苯基：Ci_c6 燒基’ CVC4規氧基，羥基，硝基，氣，氟，或三（氣或氟） 甲基= 本發明方法中所用化合物可與廣多種有機和無機酸和鹼 ’形成醫藥可接受的酸和鹼加成鹽且包括醫藥化學中常用 的生理可接受鹽。彼等鹽也構成本發明的一部份，用以形 成彼等鹽的典型無機酸包括鹽酸，氫溴酸，氫碘酸，硝酸 ，硫酸’磷酸，次磷酸等D也可以使用衍生自有機酸，例 如脂族一羧酸和二羧酸，笨基取代烷酸，羥基烷酸和羥基 二虼酸’芳族酸’脂族和芳族磺酸之鹽。彼等醫藥可接受 鹽因而包括匕酸鹽’笨乙酸鹽，三氟乙酸鹽，丙缔酸鹽， 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨OX 297公变）Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, where R1 and R3 are independently hydrogen, -CHS, base), or j |: _Ar, where Ar is phenyl substituted as appropriate; Shicai County (CNS) A4 size (2! GX 297 mm) Staff Consumer Cooperation of Central Standards Bureau of the Ministry of Economic Affairs Du Yinfan 426515 A7 --------- B7 V. Description of invention (3) R2 is It is selected from the group consisting of pyrrolidinyl, hexamethyleneimino 'and hexahydropyridyl: and pharmaceutically acceptable salts and solvates thereof. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a selected group of 2 · phenyl-3_arylfluorenylphenanthrenes (phenylphenants), i.e. those of formula I, which can be used to inhibit the discovery of PAI-1. A method for using the present invention is by administering to a person in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, which can effectively inhibit P AI -1 or a physiological condition related to its excess. . The term "inhibit" includes its commonly accepted meaning, which includes prohibition, prevention, restraint: and mitigation of 'stopping or retrograde loading, severity or resulting symptoms or effects. ~ La Rossi! (IjjAifgne) is a compound of the present invention, which is the hydrochloride salt of a compound of formula I in which both R and R3 are hydrogen > (Nuclear regulatory mo 丨 ecule). Larosithine binds to the estrogen receptor via tE and was originally considered to be an anti-estrogen molecule whose function and pharmacology department is used to block the activation of estrogen. The reason for the ability of estrogen-related breast cancer. It is true that larocetin can block the role of estrogen in some cells; however, in other cell types, larocetin is a gene that activates the same genes as those activated by estrogen and shows the same Pharmacology, for example, osteoporosis, hyperlipidemia. As a result, larosinphene is said to be an anti-estrogen agent with mixed agonistic-antagonistic properties. The unique characteristics of larosetin that are different from those of estrogen are considered to be from the unique activation and / or suppression of various gene functions by the larosetin-estrogen receptor complex. Different from the activation and / or suppression of genes by the estrogen-estrogen receptor complex. Therefore, -6- this paper wave scale is applicable to the Chinese national twin (CNS Μ4 is now UlOxm). --------- Installation ------ Order ------- Λ (please first (Please read the notes on the back and fill in this page) 426515 Employees ’cooperation with the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People ’s Republic of China Du Yince A7 _________B7 V. Description of the invention (4) Although laranophen and estrogen both use and compete for the same receptor, However, these two are not easy to predict the pharmacological results of gene regulation. Each has its own unique features. 0 Generally, the compound is formulated with commonly used excipients, diluents or carriers and made into tablets or tinctures. Or the solution is for convenient oral administration, and / or is administered via intramuscular or intravenous routes. The compound can be administered transdermally and can be formulated into a sustained release dosage form and the like. The compounds used in the methods of the present invention can be made according to certain procedures, such as those detailed in U.S. Patent Nos. 4,133,814, 4,418,068, and 4,380,635, all of which are incorporated herein by reference. In summary, the method is initiated with phenylhydrazine, a thiophene, having 6 · hydroxy and 2- (4-hydroxyphenyl) groups. The starting compound is protected, tritiated, and deprotected to form a compound of formula I. Examples of the preparation of their combined shafts are set out in the above cited U.S. patents. Β optionally substituted phenyl includes phenyl and phenyl containing one or two of the following substituents: Ci_c6 alkyl, CVC4 oxo, hydroxyl , Nitro, gas, fluorine, or tris (gas or fluorine) methyl = compounds used in the method of the present invention can form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases and include medicinal chemistry Commonly used physiologically acceptable salts. These salts also form part of the present invention. Typical inorganic acids used to form these salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid 'phosphoric acid, hypophosphorous acid, etc. D can also be derived from organic acids For example, aliphatic monocarboxylic acids and dicarboxylic acids, benzyl substituted alkanoic acids, hydroxyalkanoic acids and hydroxydiphosphonic acid 'aromatic acids' salts of aliphatic and aromatic sulfonic acids. Their pharmaceutically acceptable salts thus include dartrate ’stupid acetate, trifluoroacetate, and acrylic acid. The size of this paper applies to the Chinese National Standard (CNS) A4 specification (2 丨 OX 297)
(请先閱讀背面之注意事項再填寫本頁J .裝 I-5 泉 4 2 651 5 A7 B7 五、發明说明（5 ) 抗壞血酸鹽，苯甲酸鹽，氣苯甲酸鹽，二硝基苯〒酸鹽， 羥基苯甲酸鹽，甲氧基苯甲酸鹽，甲基笨甲酸鹽，鄰_乙酿氧 基苯甲酸鹽，蓁-2-苯甲酸鹽，溴化物，異丁酸建，苯丁酸 鹽，万-羥基丁酸鹽，丁炔-1，4-二酸鹽，己決_丨，4_二酸 鹽’己酸鹽，辛酸鹽，氣化物，肉桂酸鹽，棒樣酸幾，甲 一酸鹽’反丁烯二酸鹽，乙醇酸鹽，庚酸鹽，馬尿酸逸，乳 酸鹽’蘋果酸鹽，順丁烯二酸鹽，羥基順丁埽二酸鹽，丙 二酸鹽，扁桃酸鹽，甲續酸鹽，於给酸鹽，異於給酸鹽， 硝酸致，草酸幾’政酸鹽’對苯二甲酸建，辟酸鹽，.碍酸 一氫鹽，磷酸二氩鹽，偏磷酸鹽，焦磷酸鹽，丙炔酸鹽， 两酸鹽’苯丙酸鹽’柳酸鹽，癸二酸發，丁二酸鹽，辛二 酸鹽，硫酸鹽，疏酸氩鹽，焦繞酸鹽，亞藏酸鹽，亞硫酸 氫鹽，磺酸鹽，苯磺酸鹽，對-溴苯磺酸鹽，氣苯磺酸鹽， 乙烷磺酸鹽，2 -羥基乙烷磺酸鹽，甲烷績酸鹽，茬-丨_績酸 鹽，苯-2-磺酸鹽，對-甲苯磺酸鹽，二甲苯磺酸鹽，酒石 酸鹽等3較佳的鹽爲鹽酸鹽。 醫藥可接受的酸加成鹽典型地係經由用式I化合物與等莫 耳量或超量的酸反應而形成的。諸反應物通常是在雙溶劑 例如乙绽或苯中組合的。該鹽一般是在約一小時至1 〇天之 間從溶液沉澱出來且可過濾分離出或可用習用手段滌除溶 劑。 鹽形成所常用的鹼包括氫氧化銨及鹼金屬和鹼土金屬的 氫氧化物’碳酸鹽’以及腊族和第―，第二與第三胺，脂 族一胺。特別可用來製備加成鹽的鹽包括氫氣化按，碳酸 本紙張足度賴中職家縣（CNS) A4規格（2!()><297公 ---------^------1T------.A. (請先閱讀背*之注意事項再填寫本頁) 經濟部中夬標準局員工消費合作社印裝 ΑΊ 426515 __________Β7 五、發明説明（6 ) 鉀，甲胺，二乙胺，乙二胺，和環己胺。 藥物可接受鹽通常具有比衍生彼等的化合物較爲増進的 /谷解特性因而常更易於調配成液體或乳液。 醫藥調配物可用技藝中已知的程序予以製備3則如，該 化合物可與常用的織形劑，稀釋劑或載劑調配並形成錠劑 膝囊，懸浮液’散料ώ適料彼等調配物的賦形劑， 稀釋劑和m子包括τ列：填料和增充辭丨如激粉，糖 ，甘露糖醇，和矽衍生物；黏合劑例如羧甲基纖維素和其 他纖維素衍生场，海漢酸盈，明跟，和聚乙缔基咕洛坡嗣 二濕化劑例如甘油；崩解劑例如碳酸鈣和碳酸氫鈉；滯緩 溶解齊』〜如石壤，吸收加速劑則如四級按化合物；界面活 性刺例如鮮料，甘油—硬脂酸醋：吸附性載體例如高嶺 土和政土，及,間滑劑例如滑石，硬脂酸劈和錢，與固體聚 乙二醇。 4化合物也可，經帛配成跳劑心容液供彳便口服或爲適合 經腸給藥的溶液，例如經由肌肉内，皮下或靜胳内諸途 後者此外’该化合物很適合於調配成持續釋放性劑形等 魏物:該等調配场可以構成得使彼等只在或優先在腸道 =特殊部份釋放a活性成份^可能在_段_内釋放。其 塗被層’包封’和保護性基質可以用例如聚合物質或域製 成〇 人抑制PAI-1 ’或本文所揭示的任何其他用途所需的式[化 二物特殊Μ 1，根據本發明，係決定於病沉嚴重性，給藥 途，和由主治醫師所決定的相關因素。概括而言，可接 ---------裝------訂------..Α (請先閒諳背面之注意事項再填寫本頁) 經濟部中央標準局員工消费合作社印製 I -0* 經濟部中央標準局員工消費合作社印策 A7 B7 五、發明説明（7 ) 受且有效的每曰劑量爲約〇.1至約1 0 0 0毫克/天’且更典型 者爲約5 0至約2 0 0毫克/天°彼等劑量係給有其需要的患者 每日給用一次至約三次，或視需要更頻者以有效抑制卩八卜 1，或本文所揭示的任何其他用途3 通常最好以酸加成建形式的式I化合物依載有鹼基，例如 六氫吡啶基環的醫藥之習用給藥方式來服用。此外有利者 係經由口服途徑給用彼等化合物3對於彼等目的可以使用 下列口服劑形》 ' 調配物 於下面所述調配物中，”活性成份”意指式I化合物 調配物1 :明膠膠囊劑 成份 量（毫克/膠囊） 活性成份 0.1-1000 澱粉，NF 0-650 激粉流動性粉末 0-6 50 聚矽氧流體3 5 0厘史 0-15 將彼等成份摻合，通過45號篩目美國篩’並裝填到硬質 明膠膠囊内。 已製成的拉羅西吩膠囊劑調配物之特殊例子包括下面所 示者： 成份 量（毫克/膠囊） 拉羅西吩 .1 殿粉，NF 1 12 澱粉，流動性粉末 2 2 5.3 聚矽氧流體3 5 0厘史 1.7 -10- 本紙張尺度適用中國國家標準（CMS ) A4規格（2丨0.X 297公釐） ---------私衣------1T------忒 . - {請先聞讀背面之注意事項再填寫本頁} 426515 A7 B7五、發明説明（S ) 調配物3 :拉羅西吩膠囊劑 成份 量（毫克/膠囊） 拉羅西吩 5 、 澱粉，NF 108 澱粉，流動性粉末 22 5.3 聚矽氧流體3 5 0厘史 ^ I . 7 調配物4 :拉羅西吩膠囊劑 成餘 量（毫克/醪囊） 拉羅西吩 10 澱粉，NF 103 :殿粉，流動性粉末 ; 225.3 聚矽氧流體3 5 0厘史 1.7 調配物5:拉羅西吩膠囊劑 成份 量（毫克/膠囊） 拉羅西吩 5 0 澱粉，NF 15 0 澱粉，流動性粉末 3 9 7 聚矽氧流體350厘史 3.0 ---------^------—ΐτ------Λ. (請先閱讀背面之注意事項再填寫本頁) 經濟部中央揉準局員工消費合作社印製 上述特殊調配物可依所提出的合理變異而予以變更。 用下面成份製備錠劑調配物： 調配物6 :錠劑 本紙張尺度適用中國國家橾準（CNS ) Α·4規格（210X297公釐） 426515 A7 B7 五、發明説明（9(Please read the notes on the back before filling in this page. J. I-5 spring 4 2 651 5 A7 B7 V. Description of the invention (5) Ascorbate, benzoate, gas benzoate, dinitrobenzene Gallate, hydroxybenzoate, methoxybenzoate, methylbenzate, o-ethyloxybenzoate, hydrazone-2-benzoate, bromide, isobutyl Acid building, phenylbutyrate, 10,000-hydroxybutyrate, butyne-1,4-diacid, hexadecane, 4-diacid'hexanoate, caprylate, gaseous, cinnamate , Stick-like acid, formamate 'fumarate, glycolate, heptanoate, heuronic acid, lactate' malate, maleate, hydroxymaleate Salt, malonate, mandelate, formic acid, to acid salt, different from acid salt, caused by nitric acid, oxalic acid, a few 'political acid salts', terephthalic acid, acid resistance, acid resistance Monohydrogen salt, diargon phosphate, metaphosphate, pyrophosphate, propionate, bis-'phenylpropionate 'salicylate, sebacate, succinate, suberate, Sulphate, argon salt, pyrograte, Tibetan acid salt, bisulfite, sulfonate, benzenesulfonate, p-bromobenzenesulfonate, gas benzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonic acid Salts, succinates, benzene-2-sulfonates, p-toluenesulfonates, xylenesulfonates, tartrates, etc. 3 The preferred salts are the hydrochloride salts. Pharmaceutically acceptable acid addition Salt formation is typically formed by reacting a compound of formula I with an equimolar or excess acid. The reactants are usually combined in a dual solvent such as ethyl acetate or benzene. The salt is typically in about one hour It can be precipitated from the solution within 10 days and can be separated by filtration or can be removed by conventional means. The bases commonly used for salt formation include ammonium hydroxide and hydroxide 'carbonates' of alkali and alkaline earth metals, as well as wax and The first, second, and third amines are aliphatic monoamines. Salts that are particularly useful for the preparation of addition salts include hydrogenation. Carbonated paper is based on Zhongshanjiajia County (CNS) A4 specifications (2! () &Gt); < 297 male --------- ^ ------ 1T ------. A. (Please read the notes on the back * before filling this page) Ministry of Economic Affairs Chinese Standard Board member Printed by a consumer cooperative AΊ 426515 __________B7 V. Description of the invention (6) Potassium, methylamine, diethylamine, ethylenediamine, and cyclohexylamine. Pharmaceutically acceptable salts usually have a higher yield than the compounds from which they are derived. Solution properties are often easier to formulate into liquids or emulsions. Pharmaceutical formulations can be prepared using procedures known in the art. 3 For example, the compound can be formulated with commonly used textures, diluents or carriers to form lozenge knee capsules. , Suspensions, bulk materials, excipients suitable for their formulations, thinners and formulas include τ columns: fillers and supplements 丨 such as powder, sugar, mannitol, and silicon derivatives; adhesives Examples include carboxymethylcellulose and other cellulose-derived fields, sea han acid, gluten, and polyethylene glycol poloxamer dihumidifying agents such as glycerin; disintegrating agents such as calcium carbonate and sodium bicarbonate; retardation Dissolve all the way ~ like stone soil, absorption accelerators are like four-level compounds; interfacial active thorns such as fresh materials, glycerol-stearic acid vinegar: adsorptive carriers such as kaolin and political soil, and interstitial agents such as talc, Fatty acid split and money, polymer with solid Diol. The compound 4 is also acceptable. It can be formulated into a heartbeat solution for oral administration or a solution suitable for enteral administration, for example, intramuscularly, subcutaneously or intracellularly. The latter is also suitable for formulating into Sustained-release dosage forms, etc .: These formulation fields can be constructed so that they release the active ingredient only or preferentially in the intestinal tract = a special part ^ may be released within _ paragraph _. Its coating layer 'encapsulation' and protective matrix can be made with, for example, polymeric substances or domains. Human inhibition of PAI-1 'or any other use disclosed herein is required by the formula [Chemical II Special M 1, according to this The invention depends on the severity of the disease, the route of administration, and related factors determined by the attending physician. In general, you can connect --------- install ------ order ------ .. Α (please fill in the precautions on the back of the page before filling in this page) Central Standard of the Ministry of Economy Printed by the Consumer Cooperatives of the Bureau I-0 * Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (7) The accepted and effective dose is about 0.1 to about 100 mg / day 'And more typically about 50 to about 200 mg / day. Their dosages are given to patients in need once to about three times a day, or more frequently as needed to effectively inhibit carbuncle 1. Or any other use disclosed herein 3 It is generally best to take a compound of formula I in acid addition form in accordance with conventional pharmaceutical administration methods that contain a base, such as a hexahydropyridyl ring. In addition, it is advantageous to administer their compound 3 via the oral route. For their purpose, the following oral dosage forms can be used. "Formulations are described in the formulations below," active ingredient "means compound of formula I Formulation 1: gelatin capsules Amount of agent (mg / capsule) Active ingredient 0.1-1000 Starch, NF 0-650 Stirrable powder 0-6 50 Silicone fluid 3 5 0% history 0-15 Blend them with No. 45 Sieve mesh 'US sieve' and fill into hard gelatin capsules. Specific examples of prepared larosetin capsule formulations include the following: Ingredients (mg / capsule) Larosetin. 1 Dianfen, NF 1 12 Starch, Flowable Powder 2 2 5.3 Polysilicon Oxygen fluid 3 5 0% history 1.7 -10- This paper size applies the Chinese National Standard (CMS) A4 specification (2 丨 0.X 297mm) --------- Private clothing ------ 1T ------ 忒.-{Please read the precautions on the reverse side before filling out this page} 426515 A7 B7 V. Description of the Invention (S) Formulation 3: Ingredients of Laroxifen Capsules (mg / capsule) ) Larosetin 5, starch, NF 108 starch, fluid powder 22 5.3 polysilicone fluid 3 50 centimeters ^ I. 7 Formulation 4: Larosetin capsules remaining amount (mg / capsule) Larocetin 10 Starch, NF 103: Palace powder, flowable powder; 225.3 Polysiloxane fluid 3 5 0% history 1.7 Formulation 5: Larocetin capsule ingredient content (mg / capsule) Larocetin 5 0 Starch, NF 15 0 Starch, flowable powder 3 9 7 Polysiloxane fluid 350 centimeters 3.0 3.0 --------- ^ ---------- ΐτ ------ Λ. (Please Read the notes on the back before filling This page) Central Bureau of Ministry of Economic Affairs rub prospective employees consumer cooperatives be changed for printing reasonable variation of the above-mentioned special formulations proposed to follow. The following ingredients are used to prepare lozenge formulations: Formulation 6: Lozenges This paper size applies to China National Standard (CNS) A · 4 specifications (210X297 mm) 426515 A7 B7 V. Description of the invention (9
將諸成儉接合並塵製成鍵3 另外，依下述製成各含〇.]·〗〇〇〇毫克活性成份的艘劑 調配物7:錠劑 成份 活性成份 纖維素，微晶 二氧化矽，發煙 硬脂酸 成份 活性成份 澱粉 纖維素，微晶 聚乙埽基-吡咯烷酮 (1 0 %水中溶液） 羧甲基纖維素鈉鹽 硬脂酸鎂 滑石 量（毫克/錠） 量（毫克/錠） 0.1-1000 45 3 5 4 4.5 0.5 I--------裝-------訂------术 • - (請先聞讀背面之注意事項再填寫本頁) 經濟部中夬標準局員工消費合作社印製 將活性成份，澱粉，和纖維素通過45號篩目美國知並充 分地混合。將聚乙晞基吡咯烷酮溶液輿所得粉末混合後， 通過1 4號篩目美國篩β所製得的顆粒在5 0 ° -60 °C下乾燥後 ，通過18號篩目的美國篩《然後將事先通過60號篩目美國 篩的羧甲基纖維素鈉鹽，硬脂酸鎂，和滑石加到該顆粒物 ，於混合後，在製錠機上壓製成錠。 •12- 本紙乐尺度適用中國國家標皁（（^)六4規格（2丨0乂 297公嫠） 經濟部中央標準局員工消費合作社印裂 4 2651 5 A7 A7 ___B7 五、發明説明（i〇) 依下述製備各含0.1 - 1 0 0 0毫克醫藥的懸浮液: 調配物8 :懸浮液 成份 量（毫克/5毫井） 活性成份 0.1-1000 毫克 羧甲基纖維素鈉鹽 50 毫克 糖槳 ^ 1.25 毫克 苯甲酸溶液 0.10 毫升 香料 多少 隨便 色料 多少 隨便 純水至 5 毫升 將醫藥通過45號篩目的美國篩並輿羧甲基纖維素鈉鹽和 糖漿混合形成均勻糊，將苯甲酸溶液，香料和色料用一些 水稀釋後挽拌加入〇然後加入足量的水以產生所需體積。 内皮細胞P AI -1檢定 用5xl04人類内皮細胞（HUVEC.)/洞在增補2 〇/〇 F B S的 Clonetics1内皮細胞生長培養基（EGM)中製備96洞组織培養 板。於37°C下培育整碼臀上後’將培養基更換成有或無化 合物@其中R1和R3皆處$基，且R2爲吡咯啶基），及有或 無1 nM IL-；l-bera的無血清培養基（DMEM/：F-12培養基， 20 mM-HEPES，pH 7.5, 50微克/毫升慶大衡素，i微克/毫 升人類轉鐵蛋白和1微克/毫升牛胰島素）。於371下培育過 夜後’用 Imubind Plasma PAI-1 ELISA (American DiagnosticThe various components are combined and formed into a bond 3. In addition, a boat formulation 7 containing 0.00 mg of the active ingredient is prepared as follows: a tablet ingredient, an active ingredient, cellulose, and microcrystalline dioxide. Silicon, fuming stearic acid ingredient Active ingredient starch cellulose, microcrystalline polyvinylacetinyl-pyrrolidone (10% solution in water) Carboxymethyl cellulose sodium salt Magnesium stearate (mg / tablet) Amount (mg) / Ingot) 0.1-1000 45 3 5 4 4.5 0.5 I -------- installation ------- order ------ operation •-(Please read the precautions on the back before filling (This page) Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs. Active ingredients, starch, and cellulose are passed through a No. 45 mesh in the United States and fully mixed. The obtained powder was mixed with the polyethylpyrrolidone solution, and the granules prepared through a No. 14 mesh U.S. sieve β were dried at 50 ° -60 ° C, and then passed through a No. 18 mesh U.S. sieve. Carboxymethylcellulose sodium salt, magnesium stearate, and talc passed through a No. 60 mesh U.S. sieve were added to the granules, and after mixing, they were pressed into ingots on a tablet mill. • 12- This paper music scale is applicable to the Chinese National Standard Soap ((^) 6 4 specifications (2 丨 0 乂 297 gong)) Employees' cooperatives of the Central Standards Bureau of the Ministry of Economy 4 2651 5 A7 A7 ___B7 V. Description of the invention (i〇 ) Prepare each suspension containing 0.1-1000 mg of medicine as follows: Formulation 8: Suspension content (mg / 5 milliwell) Active ingredient 0.1-1000 mg carboxymethyl cellulose sodium salt 50 mg sugar Paddle ^ 1.25 mg benzoic acid solution 0.10 ml as much spice as you want, as much color as you want, pure water to 5 ml. Pass the medicine through a No. 45 mesh US sieve and mix the sodium carboxymethyl cellulose and syrup to form a homogeneous paste. Flavors and colorants are diluted with some water and then added to 0 and then added a sufficient amount of water to produce the required volume. Endothelial cell PAI-1 assay is supplemented with 5xl04 human endothelial cells (HUVEC.) / Hole at 2/0 Prepare 96-well tissue culture plates in FBS's Clonetics1 endothelial cell growth medium (EGM). After incubating whole yards at 37 ° C, change the medium to the presence or absence of compounds @ wherein R1 and R3 are in $ groups, and R2 is pyrrolidine ), And serum-free medium with or without 1 nM IL-; l-bera (DMEM /: F-12 medium, 20 mM-HEPES, pH 7.5, 50 μg / ml gentamicin, i μg / ml human transfer iron Protein and 1 μg / ml bovine insulin). After overnight incubation at 371 ’, Imubind Plasma PAI-1 ELISA (American Diagnostic
Inc. #8 2 2/IS)檢定培養基樣品中所含分泌出的pAil。 結果 -13· 本紙張尺度適用_國國家標準（CNS ) A4規2]〇x297公釐)--- I--------^------—1T------Λ * * (請先閔讀背面之注意事項再填寫本頁) A7 426515 ______ B7_ 五、發明説明（11 ) 在用IL-1誘導PA1-1的同時，用化合物！處理人類臍靜脈 内皮細胞（HUVEC)。於用得自商品供應商（cionetics)的幾 批細胞所作初始實驗中’我們發現並非所有批都對1 7_点雌 二醇有反應’因而在測定化合物1對ρΑΙ_丨分泌的影響之實 驗中不使用這些批料的細胞〇如表1所示者，在使用雌激素 一反應性細胞時，我們觀察到濃度〇 . 5 η Μ的化合物1可明顯 地減低I L - 1對P AI - 1的誘發。又如表2中所示者，使用不同 批的雌激素反應性細胞時，化合物1係以濃度相關性方式抑 制IL-1誘導的分泌作用。這些數據顯示化合物1對於p AI· i 自活化内皮細孢的誘發係一種非常強力的抑制劑且應該可 導致心保護作用，亦即，因增加的血纖維蛋白分解潛能而 減少心血管事故的發生率。此外，化合物1對於減低PAhi 的正面效應可在其增高水平係與病理相關的病況中提供緊 急用途。 表1 化合物1對於人類内皮細胞的PAI-1分泌之影響 處理 PAI-1水平（奈克/毫升） __________________________________^—^値上/二雙_準誤差，n = 4) 無 11 -1 對照組 · 3 28 +/- 46 IL-1 735+/-11 IL-1& ·5ηΜ 化合物 1 521 +/-52 表2 化合物1對於人類内皮細胞的P AI - 1分泌之影響的泼 度反應 -14- 本紙張尺度適用中國國家標隼（CNS ) A4規格（2丨OX 297公釐） I - «^^1 - I Ιϋ. I 1 I -I I - ! 士良 I In —--I. -I . -I X# -* • , (請先閲讀背面之注意事項再填寫本頁) 經濟部中夬標準局員工消費合作衽印裳 426515 A7 B7 五、發明説明（1: 處理 (M) PAI - 1水平（％抑制率） 5 X 1 0 · 9 Μ化合物1 5 X 1 CT 1 ΰ Μ化合物1 5 X 1 0·1 1 Μ化合物1 5 X 1 0·1 : Μ化合物1 5 X 1 0 ·1 3 Μ化合物1 5 X 1 0’1 4 Μ化合物1 82 +/- 17 6 5 +/- 8 4 8 +/ - 11 2 2+/-4 0 / <請先閔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 -15- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）Inc. # 8 2 2 / IS) assayed the secreted pAil contained in the media sample. Result-13 · This paper size applies _ National Standard (CNS) A4 Regulation 2] 〇297mm) --- I -------- ^ ------- 1T ----- -Λ * * (Please read the notes on the reverse side before filling out this page) A7 426515 ______ B7_ V. Description of the invention (11) While inducing PA1-1 with IL-1, use compounds at the same time! Processing of human umbilical vein endothelial cells (HUVEC). In an initial experiment with several batches of cells from a commercial supplier, 'we found that not all batches respond to 17-point estradiol', and therefore an experiment to determine the effect of Compound 1 on ρΑΙ_ 丨 secretion The cells that do not use these batches are shown in Table 1. When using estrogen-reactive cells, we observed that Compound 1 at a concentration of 0.5 ηM can significantly reduce IL-1 to PAI-1 Of induction. Also as shown in Table 2, when different batches of estrogen-responsive cells were used, Compound 1 inhibited IL-1 induced secretion in a concentration-dependent manner. These data show that compound 1 is a very potent inhibitor of the induction of p AI · i autoendothelial endothelial spores and should lead to cardioprotective effects, ie, reduce the occurrence of cardiovascular accidents due to increased fibrinolytic potential rate. In addition, the positive effects of Compound 1 on reducing PAhi may provide emergency use in its elevated levels in pathologically related conditions. Table 1 Effect of Compound 1 on PAI-1 secretion in human endothelial cells. Treatment of PAI-1 levels (neck / ml) __________________________________ ^ — ^ 値 上 / 二 双 _quasi error, n = 4) No 11 -1 control group · 3 28 +/- 46 IL-1 735 +/- 11 IL-1 & 5ηΜ Compound 1 521 +/- 52 Table 2 Compound 1 response to the effect of P AI-1 secretion by human endothelial cells -14- This paper size applies to China National Standards (CNS) A4 (2 丨 OX 297 mm) I-«^^ 1-I Ιϋ. I 1 I -II-! Shiliang I In --- I. -I. -IX #-* •, (Please read the notes on the back before filling out this page) Employees' Co-operation and Co-operation of the Bureau of Standards, Ministry of Economic Affairs 衽 515515 A7 B7 V. Description of the invention (1: Processing (M) PAI-1 level (% Inhibition rate) 5 X 1 0 · 9 Μ compound 1 5 X 1 CT 1 ΰ Μ compound 1 5 X 1 0 · 1 1 Μ compound 1 5 X 1 0 · 1: Μ compound 1 5 X 1 0 · 1 3 Μcompound 1 5 X 1 0'1 4 Μcompound 1 82 +/- 17 6 5 +/- 8 4 8 + /-11 2 2 +/- 4 0 / < Please read the notes on the back before filling (This page) Printed by Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs-15- This paper size applies to China National Standard (CNS) A4 (210X 297 mm)