TW320562B - - Google Patents

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320562 A7 _B7 五、發明説明（1 ) 本發明麗藥理學、醫學與藥物化學的範_並搛供經腌予 氟色汀、芬拉法辛、米納西普蘭或杜洛色汀的病人臞部《 加5-羥色胺、正»上腺素輿多巴胺利用率之方法及姐合物 Ο 在過去廿年或更長的時間裡，蕖理學的研究特別專注於 人臞中包含一元胺的神經元之生理現象。在該範_中不斷 地發現並已經顬示在臑中5-羥色胺、正腎上臃索與多巴胺 輿多種受體作用並控制或影響可調節諸多身體器官及功能 之過程。特別是經發琨5-羥色胺為多種生理輿心理功能有 鼷之邊程的重要因素。 也許，最近幾年在蕖物化學上所做的最重大發現為戴色 汀-一種5-羥色胺再吸收之抑制_，是治療抑鬱極有效的 藥。因為是再吸收的抑制_，其可藕滅低5-羥色胺吸收載 體吸收5-羥色胺之作用Μ增加5-羥色胺在突觸部位之利用 率。因過度吸收導致之5-羥色胺神烴元之官能譚礙會引起 抑鬱、以及其他中樞神經系铳之病害。麵色汀不僅對抑響 特別有效、其在治療其他多種症害亦很有效。 經濟部中央橾準局員工消费合作社印製 (請先閲讀背面之注意事項再填寫本頁) 一種新一代的蕖物為杜洛色汀*其為5-羥色胺輿正腎上 腺素再吸收之抑制劑。目前在治療抑鬱與尿失禁，其為高 等的臨床試驗藥·同時亦很有效。芬拉法辛輿米納西彗蘭 亦為5-羥色胺輿正腎上腺素再吸收的抑制劑。 儘管氟色汀之最初作用乃是抑制5-羥色胺之再吸收，但 腦中一元胺«程之階梯作用將5-羥色胺與正》上睇素及多 巴胺連接起來。因而· 5-羥色胺利用率之增加亦等致正賢 -4- 本紙張尺度逍用中國國家#準（CNS )八4规格（210X297公釐） A7 B7 五、發明説明（2 ) 上腺素與多巴胺利用率 芬拉法辛與米纳西替Μ 收亦增加多巴胺之利用 本發明提供一種甚至 纳西普蘭和杜洛色汀之 胺的利用率比較皆更好 其乃《強化埴些轉的作 本發明提供一種壜強 輿杜洛色汀選出之第一 臃素輿多巴胺利用率的 里諾露（alprenolol)、 镰（spiperone)、品多 托 R (penbutolol)、普 多露（tertatolol)輿具 之增加。間樣地，藉杜洛色汀Μ及 Μ抑制5-羥色胺及正腎上腺素之吸 率。 是興一般鞴氟色汀、芬拉法辛、米 增加5-羥色胺、正鹜上腺素與多巴 的方法Μ增加前述三者之利用率* 用Μ行之。 由氰色汀、芬拉法辛、米納西替籣 類成份增加臞中5-羥色胺、正蹵上 方法、包括將第一類成份與由眄布 位 100135 (WAY 100135)、斯比波 » (Pindolol)、（S)-UH-301、餳布 嫌替蘭諾露（propranolol) 、S他 下式之化合物選出者共間旛用 OH I Ar-0-CH2CHCH2NHZ \_ j 1 1 V Ri (請先閲讀背面之注意事項再填寫本I) r>裝. 訂 經濟部中央棣準局貝工消費合作社印褽 其中Ar係320562 A7 _B7 Fifth, the description of the invention (1) The scope of pharmacology, medicine and medicinal chemistry of the present invention _ and provide for patients who have been marinated with flustine, fenlafaxine, minacipran or duloxetine "Methods and Sister Compounds for Adding Serotonin, N-Adrenaline and Dopamine Utilization Ο In the past 20 years or more, research in pharmacology has focused specifically on neurons containing monoamines in humans. Physiological phenomenon. It has been continuously discovered in this category and has been shown in serotonin, spleen, dopamine, and dopamine, and various receptors function and control or influence processes that can regulate many body organs and functions. In particular, menstrual serotonin is an important factor for many physiological and psychological functions. Probably, the most significant discovery made in the chemistry of the metabolites in recent years is dysstatin, an inhibitor of serotonin reuptake, which is an extremely effective medicine for treating depression. Because it is an inhibitor of resorption, it can eliminate the effect of the low serotonin absorption carrier to absorb serotonin. M increases the utilization rate of serotonin at the synaptic site. The functional disorder of serotonin neurons caused by excessive absorption can cause depression and other diseases of the central nervous system. Complexion is not only particularly effective in suppressing noise, it is also very effective in treating many other diseases. Printed by the Staff Consumer Cooperative of the Central Department of Economic Affairs of the Ministry of Economic Affairs (please read the precautions on the back before filling in this page) A new generation of propagule is duloxetine * which is an inhibitor of serotonin and norepinephrine reabsorption . It is currently an advanced clinical trial drug in the treatment of depression and urinary incontinence. It is also very effective. Venlafaxine and Minasset are also inhibitors of serotonin and norepinephrine reuptake. Although the initial role of flutein is to inhibit the reabsorption of serotonin, the staircase action of the monoamine in the brain connects serotonin with serotonin and dopamine. Therefore, the increase in the utilization rate of serotonin is also due to Zhengxian -4- This paper standard is used in China's national #quasi (CNS) 84 specifications (210X297 mm) A7 B7 5. Description of the invention (2) Epinephrine and dopamine Utilization of fenlafaxine and minaset for M also increases the use of dopamine. The present invention provides a better comparison of the utilization of amines of nalcitram and duloxetine. An increase in the use of linuolu (alprenolol), sickle (spiperone), pintoto R (penbutolol), and tertatolol, the first choice of doxorubicin and dopamine utilization rate. In an intermittent manner, the absorption of serotonin and norepinephrine was inhibited by dulostatin M and M. It is the method of increasing the use of serotonin, fenlafaxine, and rice to increase serotonin, norepinephrine, and dopa. Increase the utilization rate of the above three * Use M to do it. Add serotonin in cyanototin, fenlafaxine, and minaxite to the serotonin, the normal method, including combining the first type of ingredients with the 100% (WAY 100135), SPYBO »( Pindolol), (S) -UH-301, sugar cloth suspected propranolol (Proranolol), S and other compounds of the following formula were selected and used together OH I Ar-0-CH2CHCH2NHZ \ _ j 1 1 V Ri (please Read the precautions on the back first and then fill out this I) r > Pack. Ordered by the Ministry of Economic Affairs Central Bureau of Precision Industry Beigong Consumer Cooperative Printed by Ar Department

‘紙張尺度適用中國國家揉準（CNS ) Α4规格（210X297公釐） A7 B7 五、發明説明（3: 經濟部中央梂準局員工消費合作社印製 R3‘Paper scale is applicable to China National Standard (CNS) Α4 specifications (210X297mm) A7 B7 V. Description of invention (3: Printed by the Employee Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs R3

RaRa

R2.R2.

R2·R2 ·

R2· R2'R2 · R2 '

R2·R2 ·

或 R2· (請先閲讀背面之注意Ϋ項再填寫本頁) .裝· 訂 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 320562 A7 B7 五、發明説明（4 )Or R2 · (please read the note Ϋ on the back before filling in this page). Binding · Order This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297mm) 320562 A7 B7 V. Invention description (4)

!U為一可視需要在三個連接的碳原子其中之一進行取代 的甲基； 1?2為氫、Ci-“烷基、三氟甲基、羥基（Ci-CU烷基）-〇-、（Ca-“烷基）-S (0)»»-或鹵素， 1?3為（：3-(：«»環烷基或具下式之雙瑁烷基， (請先閲讀背面之注意事項再填寫本頁) G-! U is a methyl group that may be substituted on one of the three connected carbon atoms as required; 1 to 2 are hydrogen, Ci- "alkyl, trifluoromethyl, and hydroxyl (Ci-CU alkyl) -〇- , (Ca- "alkyl) -S (0)» »-or halogen, 1? 3 is (: 3-(:« »cycloalkyl or bis-alkyl group with the following formula, (please read the back Matters needing attention before filling this page) G-

經濟部中央標準局員工消費合作社印袋 其中a輿C為獨立的1-5，b為0-5，而（a + c)大於2; Z為直鍵或支鍵之“-(；1〇烷、烯或炔基、（C4-Ce瑁烷基 )可視需要以（Μ4烷基或苯基取代、一種具下式之雙環 烷基， G-The printed bags of the Employees Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs where a and C are independent 1-5, b is 0-5, and (a + c) is greater than 2; Z is a straight bond or a branch of "-(; 1〇 Alkanes, alkenes or alkynyl groups, (C4-Ce alkynyl) optionally substituted with (Μ4 alkyl or phenyl, a bicyclic alkyl group of the following formula, G-

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） A7 B7 經濟部中央梂準局員工消費合作社印裝 五、發明説明（5 ) 情況亦可為苯基取代之C2-C1〇烷基、其中之苯基可視情況 Μ先前定義之取代•或（Ci-“次烷基^-T-iCi-C^烷基） 。其中 T 為-0- 、-S- 、-so-或-s〇2-; 其中 毎個G為一種獨立的鐽結或Ci-CU次烷基； X為-H、-COY、-CH或匕吖*烷基； Y 為-OH、-O-iCi-C* 烷基）或-NHz; R·與R·.為獮立地«或G-Cs烷基或與其所依附之碳原 子一起形成一儀C3-Ce環烷的環； P 為 0 、1 、或 2 ； A 為-0-、-S-、-NH-或-KCHS-;而且 為0 、1 、2或3 、或一種其B蕖上可接受的鼸。 本發明亦提供包括第一類成份協同如上名稱之一種第二 類成份之醫_姐合物。甚且•其搮供治療因滅低的5-羥色 胺、多色胺或正腎上腺素利用率所引起之病害，包括施予 需此治療的病人一種包括第一類成份輿上述名稱之一種第 二類化合物之輔助治療。 本發明亦攞供可增強第一類成份的化合物之作用的上述 蕖物组合之用法輿使用上述姐合製造相同目的之藥物的方 法。 此外，其提供治療因5-羥色胺、正腎上腺素或多巴胺利 用率滅低而引起之病害輿製造為庇目的之蕖物的方法。 甚且，本發明提供一完成上述輔助治療的方法之較佳方 式，其中第二類成份的施用可供給其在血中實霣穩定的量 -8- 本紙張尺度逍用中國國家橾準（CNS ) Α4规格（210Χ297公釐） (請先閱讀背面之注意事項再填寫本頁)This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 Printed by the Employee Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economy V. Description of invention (5) The case can also be C2-C10 alkanes substituted by phenyl Group, the phenyl group of which may be substituted as previously defined • or (Ci- “Subalkyl ^ -T-iCi-C ^ alkyl). Where T is -0-, -S-, -so- or- s〇2-; where each G is an independent Kj or Ci-CU subalkyl group; X is -H, -COY, -CH or dagger * alkyl; Y is -OH, -O-iCi- C * alkyl) or -NHz; R · and R ·. Are cerebrum «or G-Cs alkyl or the carbon atom to which they are attached to form a ring of C3-Ce cycloalkane; P is 0, 1, Or 2; A is -0-, -S-, -NH- or -KCHS-; and it is 0, 1, 2, or 3, or one of its kind that is acceptable on the B plant. The present invention also includes the first category The ingredients are synergistic with the second category of the name of the above-mentioned medicine. It is even available for the treatment of diseases caused by the low utilization of serotonin, polytryptamine or norepinephrine, including the need for administration The patients under treatment include the first type of ingredients and the above names An adjunct treatment of a second type of compound. The present invention also provides a method of using the above-mentioned lotion combination that can enhance the action of the first type of compound and the method of using the above-mentioned sister to manufacture a drug for the same purpose. In addition, it provides a treatment Diseases caused by low utilization of serotonin, norepinephrine, or dopamine and methods for manufacturing aspirants. Furthermore, the present invention provides a better way to complete the above-mentioned adjuvant therapy, of which the second category The application of the ingredients can provide a stable amount in the blood -8- The standard of this paper is the Chinese National Standard (CNS) Α4 specification (210Χ297 mm) (please read the precautions on the back before filling this page)

V "裝·V " suit ·

、1T A7 B7 經濟部中央梂準局貝工消費合作社印裝 五、發明説明（6 ) ，此量足以供給第一類成份的作用實質穩定的»強程度， 亦提供經改變以完成本發明之較佳方式的組合物。 本文中•所有的溫度皆為攝氏溫度，而所有的*·量的 比值輿瀠度若非特刖說明皆K重量單位表示。 市售之氟色汀，N-甲基-3-(對-三氟甲基苯氧基）-3-苯 基丙胺為氯化氫《形式且為其兩種鏡形異構物之消旋混合 物。美國專利4,314,081為該化合物的一篇早期參考資料 。Robertson 等人 * 在 J. Med. Che·. 31. 1412 (1988) 中教導吾人分離蠹色汀之R與S鏡形異構物的方法並指出 其做為5-羥色胺吸收抑制劑之活性彼此相近*在本文中 ”氟色汀”造届辭將用Μ表示任何酸加成Μ或游鐮齡且亦包 括消旋混合物或R或S型的鏑型異構物。 杜洛色汀· Η-甲基-3-(1 -萊基氧基）_3-(2-噻唑基）丙胺 施用時通常為氱化氫《(輿（+ )鏡型異構物型式。美國専利 4,956,38 8首先告知吾人其高蕖效。”杜洛色汀”道個辭在 本文中意指任何酸加成釀或該分子之游雕_。 文獻中常可見芬拉法辛且在美圓專利4,761,501中亦教 導吾人其合成法及其做為5-羥色胺與正罾上腺素吸收的抑 制劑之活性。在該專利中將芬拉法辛命名為化合物A 。 美國専利4,478,836教導吾人米納西普籣（Ν,Ν-二乙基 -2-胺基甲基-卜苯基瓖丙烷羧醵胺）並訂其為實例4之製 備物。該專利將其化合物描述成抗抑鬱繭。Moret等人* 1¾ Mje.iLT_Q.PhajaacolQKy ZL·, 1211-19 (1985)中說明其蕖理 活性。 -9- 本紙張尺度適用中國國家梂準（CNS ) A4規格（210X297公釐） (請先閏讀背面之注項再填寫本X ) f 裝., 1T A7 B7 Printed by the Beigong Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs 5. Description of the invention (6), this amount is sufficient to provide a substantially stable effect of the first type of ingredients, and also provides changes to complete the invention The composition of the preferred mode. In this article, all temperatures are in degrees Celsius, and all ratios of * · quantities and degrees are expressed in K weight units unless otherwise specified. The commercially available fluorochrome, N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine, is in the form of hydrogen chloride and is a racemic mixture of its two mirror isomers. US Patent 4,314,081 is an early reference for this compound. Robertson et al. * In J. Med. Che .. 31. 1412 (1988) taught us the method of separating the R and S mirror isomers of calastatin and pointed out that their activities as serotonin absorption inhibitors Similar * The term "flusetine" in this article will use M to denote any acid addition M or tourmaline age and also includes racemic mixtures or R or S dysprosium isomers. Durostatin · Η-methyl-3- (1-lylyloxy) _3- (2-thiazolyl) propylamine is usually a hydrogenated hydrogen chloride ((+) mirror isomer type. USA専 利 4,956,38 8 First of all, let me know its high efficiency. "Durosertine" in this article means any acid addition brew or the molecule's engraving_. Venlafaxine is often seen in the literature and in US Patent 4,761,501 I was also taught about its synthesis and its activity as an inhibitor of the absorption of serotonin and epinephrine. In this patent, venlafaxine was named compound A. U.S. Patent 4,478,836 teaches me Minasep Ν, Ν-diethyl-2-aminomethyl-phenylphenylpropanecarboxamide) and is designated as the preparation of Example 4. The patent describes its compound as an antidepressant cocoon. Moret et al. * 1¾ Mje.iLT_Q.PhajaacolQKy ZL ·, 1211-19 (1985) describes its lapping activity. -9- This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) (please read the note on the back first Fill in this item X) f Install.

11T A7 B7 經濟部中央樣準局員工消费合作社印製 五、發明説明（7 ) 已知杜洛色汀與氟色汀K及其餘第一類成份可増加5-羥 色胺（5-HT)、多巴胺（DA)輿正S上腺素（HE)之利用率*而 第二成份藥物增強該寶貴的特性。第二類成份蕖物具共同 的特性即皆可做為5-羥色胺1A受«之拮抗物。 (S)-UH-301 ((S)-5-氟-8-羥基-2-二丙胺基-四氬萘） 廣為藥理學家輿蕖化學家所熟知。Hillver等人.，在 M^jj^Che·,.......13-, 1541-44 (1990)中教導吾人其合成法而 Moreau等人.，在 Brain Res. Bull. 29. 901-04 (1992)¾ 供很多有闞該化合物之活髓内資料。 8^11<^1^〇1等人，在美國專利3,466,325中揭示轲布里 諾露（1-(1-甲基乙基）胺基-3-[2-(2-丙烯基）-笨氧基]-2-丙酵），並指示其做為實例5之製備物。 VAY 100135 (N-(第三-丁基）-3-[4-(2-甲氧苯基）吡耕 -1-基]-2-苯基丙醣胺）》Abou-Gharbia等人，於美國専利 4,988,814中掲»，其並指出該化合物具5-HT1Ag醱之親 和力。Cl iffe等人· ·# ·Κ Kfid. Che·. 3ft. 1509-10 (1993)中指出該化合物為5-ΗΤα a之拮抗物。 斯比波篛（8-[4-(4-氟苯基）-4-氧丁基]-：1-笨基-1,3,8 -三氮螵[4,5]癸-4-酮）為一種廣為人知之化合物，在美國 専利3,155,669輿3 , 155,670中可見。其做為5-HT1A拮抗 物的活性者’可#考Middleiiss等人，Neurosci. and B-LiLb.£-hay-._Rev . 1 fi r 75-82 (1992) ° 忑他多K(8-(3-第三-丁基胺基-2-羥基丙氧基）-疎苯 并二氫哌哺經Ma len等人，於美國専利3 , 960 , 891揭示， -10- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） tl . (請先閱讀背面之注意事項再填寫本頁) f 裝. 訂 知· 32056? A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明（8 ) 並告知吾人其可做心臓貝他-轚上腺素受體。它的其他活 性包括此處之5-HT1A拮抗物活性、自其原始專利出現後皆 巳經發規。 普羅普蘭諾® (1-異丙基胺基-3-U-萘基氧基）-2-丙酵 經0〇»1;»^1*等人*於美_專利3,337,628中掲示為類似忑 他多霣之貝他-阻断麵。再者，其別的性霣亦為藥理學家 所熟知。 «布托霣（1-(第三-丁基胺基>-2-羥基-3-(2-環戊基-苯氧基）丙烷）由Ruschig等人•於美鼷専利4,551，493中 告知吾人，並將之描述成貝他阻賺鳎。其（-)興（+ )的鏑 形異構物皆有效益，（-)的鏑形異構物對本發明之目的而 言較佳，但在本文中兩種»形異構物與消旋混合物皆包括 在"偏布托K"此用辭的範園。 品多霣（4-(2-羥基-3-異丙基胺基丙氧基）-吲哚）由 Troxler等人，於美鼷專利3,471,515中掲霣並描述此化 合物為貝他-阻•劑。該化合物施用時通常為濟旋混合物 但有人將兩種鏞形混合物分鐮出且若在設定的》用情形使 用單獨異構物產品時（-）的鏡形異構物較佳。在本文中 ”品多露"此一用辭包括兩種鏞形異構物與消旋混合物。 式I的化合物纆由Beedle等人，在美B専利5,013,761 中公告周知，其說明併列於本文K供參考。該化合物的合 成與特性包括5H T, a拮抗物活性在該專利中皆已列出。 特佳的式I化合物包括，例如下列之僩別化合物。吾人 應了解下列化合物只是式I化合物的典型但此類化合物包 -11- 本紙張尺度逍用中國國家標準（CNS ) A4規格（210X297公釐） ^ (請先閱讀背面之注意事項再填寫本頁) 裝·11T A7 B7 Printed by the Employee Consumer Cooperative of the Central Bureau of Samples of the Ministry of Economic Affairs 5. Description of the invention (7) Known that duloxetine, flutatin K and other first-class ingredients can be added with 5-hydroxytryptamine (5-HT) and dopamine (DA) Utilization rate of Eugenic S Adrenaline (HE) * and the second component drug enhances this precious property. The second type of ingredients, which have common characteristics, can be used as antagonists of serotonin 1A receptors. (S) -UH-301 ((S) -5-fluoro-8-hydroxy-2-dipropylamino-tetrahydronaphthalene) is widely known by pharmacologists and chemists. Hillver et al., In M ^ jj ^ Che ·, ............ 13-, 1541-44 (1990), taught me the synthesis method and Moreau et al., In Brain Res. Bull. 29. 901 -04 (1992) ¾ Provides many intramedullary materials with the compound. 8 ^ 11 < ^ 1 ^ 〇1 et al. Disclosed in U.S. Patent 3,466,325 Kebrinolu (1- (1-methylethyl) amino-3- [2- (2-propenyl) -stupid Oxy] -2-propanase), and instruct it as the preparation of Example 5. VAY 100135 (N- (Third-Butyl) -3- [4- (2-Methoxyphenyl) pyrrol-1-yl] -2-phenyltrisamine)》 Abou-Gharbia et al., United States, 4,988,814 Zhonghe », which also pointed out that the compound has 5-HT1Ag affinity. Cliffe et al. · # · K Kfid. Che .. 3ft. 1509-10 (1993) indicated that the compound was an antagonist of 5-HTα. Spirobole (8- [4- (4-fluorophenyl) -4-oxobutyl]-: 1-benzyl-1,3,8-triazole [4,5] dec-4-one ) Is a widely known compound, which can be seen in U.S. 3,155,669 and 3,155,670. Its activity as an antagonist of 5-HT1A's can be tested by Middleiiss et al., Neurosci. And B-LiLb. £ -hay -._ Rev. 1 fi r 75-82 (1992) ° Tataduo K (8- (3-Third-Butylamino-2-Hydroxypropoxy) -Dibenzodihydroperazine was fed by Ma len et al., US 3, 960, 891, -10- This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) tl. (Please read the notes on the back before filling in this page) f Pack. Ordered knowledge · 32056? A7 B7 Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy V. Inventions Explain (8) and inform us that it can be used as a beta-epinephrine receptor. Its other activities include the 5-HT1A antagonist activity here, and it has been issued since its original patent. Propland Nuo® (1-isopropylamino-3-U-naphthyloxy) -2-propanase via 0〇 »1;» ^ 1 * et al. * In the United States_Patent 3,337,628 is shown to be similar to dotaxol霣 之 beta-blocking surface. In addition, other sex 霣 is also well known to pharmacologists. «Butuo 霣 (1- (third-butylamino> 2-hydroxy-3- ( 2-cyclopentyl-phenoxy) propane) by Ruschig et al. • Yumei専 利 4,551,493 tells me and describes it as beta-learning sole. Its (-) Xing (+) dysprosium isomers are beneficial, (-) dysprosium isomers are for the purpose of the present invention It is better, but in this article, both of the "isomers" and racemic mixtures are included in the "Yuanbu Tuo K" "Fan Fan." Pin Duo (4- (2-hydroxy-3- Isopropylaminopropyloxy) -indole) was described by Troxler et al. In U.S. Patent 3,471,515 and described this compound as a beta-blocker. This compound is usually administered as a beta-mixture but some people will Two kinds of yin-shaped mixtures are divided and if the single isomer product is used in the set "use case", the mirror-shaped isomer of (-) is better. In this article, "Pindolu" includes two Y-shaped isomers and racemic mixtures. The compound of formula I is known by Beedle et al., Published in U.S. Patent 5,013,761, and its description is listed in K for reference. The synthesis and properties of this compound include 5H T, a Antagonist activities are listed in this patent. Particularly preferred compounds of formula I include, for example, the following compounds. People should understand that the following compounds are only typical of the compounds of formula I, but this kind of compound package -11- This paper scale uses the Chinese National Standard (CNS) A4 specifications (210X297mm) ^ (Please read the precautions on the back before filling this page ) Outfit

，tT 經濟部中央棣準局員工消費合作社印装 A7 B7五、發明説明（9 ) 括麵數其他如先前提及的美_専利中之寶賁的種類。吾人 應進一步了解*儘管下述俚別的蘧與某些情形下鏑型異構 物特別有效益，其他鹽、鏡形異構物，立Μ異構物輿消旋 混合物依此仍是很賣資的且亦包含於式I的化合物，做為 本發明的藥m。 1-(4-吲基氧基）-3-環己基胺基-2-丙酵•顚丁烯二酸 鼸； 顏_-1-(4-«|哚基氧基）-3-(4-苯基瑁己基-胺基）-2-丙 酵，草酸》; 哚基氧基）-3-(2-苯基乙基胺基）-2-丙酵，草酸 麵； 1-(4-吲哚基氧基）-3-(3-苯基乙基胺基）-2-丙酵，草酸 鹽； 1-(4-吼哚基氧基）-3-(4-苯基乙基胺基）-2-丙酵•草酸m ； 1-(4-吲基氧基）-3-環戊基胺基-2-丙_，顆丁烯二酸 蘧； 1-(4-β丨哚基氧基）-3-瑁庚基胺基-2-丙_ ; (S)-(-)-l-(4-吲哚基氧基）-3-環己基胺基-2-丙酵，顚 丁烯二酸Μ ; (0-1-(4-0¾哚基氧基）-3-瓖庚基胺基-2-丙酵·顒丁烯 二酸鹽； 1-(4-吲哚基氧基）-3-(3-甲基環己基胺基）-2-丙酵； 1-(4-吲哚基氧基）-3-(4-甲基瑁己基胺基）-2-丙醇； (請先閲讀背面之注意事項再填寫本頁) 裝·, TT Ministry of Economic Affairs, Central Bureau of Precinct Employee Consumer Cooperative Printed A7 B7 V. Description of invention (9) Including the number of faces, as mentioned earlier, the types of beauty and beauty in the ben. I should further understand that * Although the following alternatives and dysprosium isomers are particularly beneficial in some cases, other salts, mirror isomers, Li isomers and racemic mixtures are still very popular The compound of formula I is also used as the drug m of the present invention. 1- (4-Indenyloxy) -3-cyclohexylamino-2-propanase • Mubutenedioic acid salt; Yan_-1- (4- «| indolyloxy) -3- (4 -Phenyloxyhexyl-amino) -2-propanase, oxalic acid >>; indolyloxy) -3- (2-phenylethylamino) -2-propanase, oxalate; 1- (4- Indolyloxy) -3- (3-phenylethylamino) -2-propanase, oxalate; 1- (4-oxolyloxy) -3- (4-phenylethyl Amino) -2-propanase • oxalic acid m; 1- (4-indenyloxy) -3-cyclopentylamino-2-propane_, butadiene acid hydride; 1- (4-β 丨Indolyloxy) -3- 瑁 heptylamino-2-propane_; (S)-(-)-l- (4-indolyloxy) -3-cyclohexylamino-2-propanase , Oxobutenedioic acid M; (0-1- (4-0¾ indolyloxy) -3-oxoheptylamino-2-propanase · oxobutenedioate; 1- (4-indole Yloxy) -3- (3-methylcyclohexylamino) -2-propanase; 1- (4-indolyloxy) -3- (4-methylxenylamino) -2- Propanol; (Please read the precautions on the back before filling this page)

、1T Κ -12- 本紙張尺度適用中國國家揉準（CNS ) Α4规格（210X297公釐） A7 B7 經濟部中央橾準局員工消費合作社印製 五、發明説明（10 ) 1-(4 -吲哚基氧基）-3-(5 -苯基戊基胺基）-2 -丙酵，草酸 醱； 1-(4-吲跺基氧基）-3-(6-苯基己基胺基）-2-丙酵，草酸 SR ； 1-(4-吲B采基氧基）-3-(2,3-二甲基瓖己基-胺基）-2-丙 酵，單酸_ ; (+ )-1-(4-蚓哚基氧基）-3-(3-戊基胺基）-2-丙酵； (R>-( + )-l-(4-蚓哚基氧基卜3-環己基胺基-2-丙酵，丁 二酸鹽； 哚基氧基）-3-環己基胺基-2-丙酵，丁 二酸Μ ; 1-(2-三氟甲基-4-苯咪唑基）-3-(4-苯基丁基胺基）-2-丙_ ; (外）-1-(4-吲基氧基）-3-(正萡基胺基）-2-丙醇； (内）-1-(4-吲哚基氧基）-3-(正宿基胺基）-2-丙酵； 1-(1-莱基氧基）-3-環庚基胺基-2-丙酵，草酸鹽； 1-(2-環戊基苯氧基）-3-環庚基胺基-2 ~丙_，草酸馥； 1-(2-瓖己基笨氧基）-3-瑁辛基胺基-2-丙酵，草酸鼸； 1-(2-環庚基苯氧基）-3-(1,2,3-三甲基-2-丙基胺基）-2-丙醇，草酸鹽；與 1-(2-環丙基笨氧基）-3-(1,1-二甲基丁基-胺基）-2-丙 酵，草酸》° 式I的逭類化合物其中該Ar基為基或經取代的吲哄 基者構成5-HT1A拮抗物之較佳族類，且式I的化合物，其 -13- 本紙張尺度逍用中國國家標準（CNS ) A4规格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 裝-、 1T Κ -12- This paper scale is suitable for China National Standard (CNS) Α4 specification (210X297mm) A7 B7 Printed by the Consumer Cooperative of Central Central Bureau of Economics of the Ministry of Economy V. Description of invention (10) 1- (4-Ind Indolyloxy) -3- (5-phenylpentylamino) -2-propanase, oxalate; 1- (4-indenyloxy) -3- (6-phenylhexylamino) -2-Propylase, oxalic acid SR; 1- (4-Indoxybenzyloxy) -3- (2,3-dimethylhexyl-amino) -2-propanase, monoacid_; (+ ) -1- (4-lumenolyloxy) -3- (3-pentylamino) -2-propanase; (R >-( +) -l- (4-lumenolyloxy 3 -Cyclohexylamino-2-propanase, succinate; indoyloxy) -3-cyclohexylamino-2-propanase, succinic acid M; 1- (2-trifluoromethyl-4 -Benzimidazolyl) -3- (4-phenylbutylamino) -2-propanyl;; (outer) -1- (4-indenyloxy) -3- (n-conylamino) -2 -Propanol; (internal) -1- (4-indolyloxy) -3- (n-subsylamino) -2-propanase; 1- (1-lesyloxy) -3-cycloheptan Aminoamino-2-propanase, oxalate; 1- (2-cyclopentylphenoxy) -3-cycloheptylamino-2 ~ propane, oxalate; 1- (2- 瓖 Hexyl Oxy) -3-oxooctylamino-2-propane , Oxalate; 1- (2-cycloheptylphenoxy) -3- (1,2,3-trimethyl-2-propylamino) -2-propanol, oxalate; and 1- (2-Cyclopropylbenzyloxy) -3- (1,1-dimethylbutyl-amino) -2-propanase, oxalic acid》 ° Wain compounds of formula I where the Ar group is based or The substituted indole groups constitute a better family of 5-HT1A antagonists, and the compound of formula I, the -13- paper size of the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read (Notes on the back then fill out this page)

*tT -h £ * 經濟部中央橾準局貝工消費合作社印裝 A7 B7 五、發明説明（11 ) 中Z為（c4-c89烷基）且視情況以g-Ca烷基或苯基取代 者’或Z代表視情況由苯基取代之c2-C10烷基，其中笨基 可視情況MR2取代者，進一步構成可用於本發明的化合物 之特佳族類。 所有上述的美國専利輿本發明所用化合物有鼷連者皆併 列於本文Μ供參考。 儘管所有第一類成份與第二類成份化合物的姐合皆很有 用且寶貴*但某些组合特別有價值且較佳，玆述之如下： 氟色汀/品多》 杜洛色汀/品多霣 氟色汀/偏布托露 杜洛色汀/偏布托霣 氟色汀/替羅普《諾露 杜洛色汀/替羅替《諾霱 氟色汀/忑他多露 杜洛色汀/忑他多露 氟色汀/ 4-(2-羥基-3-環己基胺基丙氧基）-«!哚 杜洛色汀/ 4-(2-羥基-3-環己基胺基丙氧基）-吲0朵 通常使用氟色汀或杜洛色汀為第一類成份之姐合與治療 方法較佳。 技術熟練的讀者會了解本發明所用之所有化合物皆能形 成SK類且通常會使用其》類做為藥物，因其常較游雛鐮易 形成結晶輿純化。在所有情形下，使用上述鹽類做為蕖物 皆涵蓋於本文的說明且通常較佳，且所有化合物之翳蕖上 -14- 本紙張尺度適用中國國家標準（CNS ) A4规格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 裝.* tT -h £ * A7 B7 printed by Beigong Consumer Cooperative of Central Central Bureau of Economic Affairs of the Ministry of Economy V. Description of Invention (11) Z is (c4-c89 alkyl) and may be substituted with g-Ca alkyl or phenyl as appropriate The 'or Z' represents a C2-C10 alkyl group optionally substituted by phenyl, and a phenyl group may optionally be substituted by MR2, which further constitutes a particularly good class of compounds that can be used in the present invention. All of the above-mentioned compounds used in the present invention and those of the present invention are listed in this document for reference. Although all the first-class and second-class compounds are very useful and valuable *, some combinations are particularly valuable and better. Here are the following: flusetin / pindol》 duloxetine / pin Dodecetine / Partebutirol Duloxetine / Partebutor Flutsetin / Tirop "Noruduloxetine / Tirotti" Norfluxetine / Dotaduroduro Satin / tatadoroflustine / 4- (2-hydroxy-3-cyclohexylaminopropoxy)-«! Indodurostatin / 4- (2-hydroxy-3-cyclohexylamino) Propoxy) -Indodo usually uses flusetin or dulostatin as the first component and the best treatment method. Skilled readers will understand that all compounds used in the present invention can form SK and usually use its》 as a medicine, because it is often easier to form crystals and purify than You Hickard. In all cases, the use of the above-mentioned salts as edible substances is covered in the description of this article and is generally preferred, and all compounds of yi yi shang -14- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm ) (Please read the precautions on the back before filling out this page).

'1T Α7 Β7 經濟部中央標準局員工消費合作社印裝 五、發明説明（12) 可接受的鹽皆包括在其名下。 本發明所用的蕖物劑最最後分析起來皆必須由負貴的轚 生使用藥物的知識依藥物的性霣_合路床試驗所定性質輿 病人特徴包括該翳生所治療的病人之其他疾病來設定。此 處亦將提供劑量輿某些較佳_量之一般說明。首先將分別 給予某些藥物之爾量指導，K削造任何必要姐合之指導· 使每人皆可《取此指導K施用每種成份藥物。 氟色汀：由約1〜約80毫克一次/天* Μ由約10〜約 40奄克一次/天較佳，較佳者是治療食食症輿強迫症，由 約20〜約80毫克一次/天； 杜洛色汀：由約1〜約30毫克一次/天，Κ由約5〜約 20毫克一次/天較佳； 芬拉法辛：由約10〜約150奄克1〜3次/天，Κ由25〜 約125 «克三次/天較佳； 米納西普Μ :由約10〜約100毫克1〜2次/天，Μ由約 25〜約50«克二次/天較佳； 品多霣：由約1〜約60奄克1〜3次/天，Μ由約5〜約 6 0毫克1〜3次/天較佳，由約1〜約1〇奄克二次/天亦佳 9 鴒布托露：由約2〜約80毫克一次/天，以由約10〜約 80奄克一次/天較佳，由約2〜約20爾克一次/天亦佳； 普羅普蘭諾》:由約10〜約240毫克1〜2次/天，以由 約10〜約120毫克二次/天較佳，由約40〜約240毫克1 〜2次/天亦佳； -15- 本紙張尺度逍用中國國家揉準（CNS ) Α4规格（210Χ297公釐） (請先閲讀背面之注意事項再填寫本頁) •Γ 裝_'1T Α7 Β7 Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy V. Description of the invention (12) Acceptable salts are included in its name. The final analysis of the medicine used in the present invention must be based on the expensive knowledge of the use of the medicine according to the nature of the medicine_health bed test and the characteristics of the patient and other diseases including the patients treated by the physique. set up. Here also a general description of the dose and certain better amounts will be provided. First of all, we will give guidance on the amount of certain medicines separately, and K will create any necessary guidance for the sisters, so that everyone can take this instruction K to administer each component of the medicine. Flusetine: from about 1 to about 80 mg once / day * M is preferably from about 10 to about 40 mg once / day, preferably from about 20 to about 80 mg once for the treatment of eating disorder and obsessive-compulsive disorder / Day; Durostatin: from about 1 to about 30 mg once / day, K is preferably from about 5 to about 20 mg once / day; Venlafaxine: from about 10 to about 150 mg 1 to 3 times / Day, Κ is from 25 to about 125 «g three times / day; Minasep M: from about 10 to about 100 mg 1 to 2 times / day, M from about 25 to about 50« g twice per day Good; Pinduo: from about 1 to about 60 g 1 to 3 times / day, M from about 5 to about 60 mg 1 to 3 times / day, preferably from about 1 to about 10 times g / Day Yi Jia 9 鸰 Butuoluo: from about 2 to about 80 mg once per day, preferably from about 10 to about 80 mg once per day, preferably from about 2 to about 20 Erke once per day; "Proplano": from about 10 to about 240 mg 1 to 2 times / day, preferably from about 10 to about 120 mg twice / day, preferably from about 40 to about 240 mg 1 to 2 times / day; -15- The size of this paper is in accordance with China National Standard (CNS) Α4 specification (210Χ297mm) (please read the notes on the back before filling This page) • Γ equipment _

'ST Α7 Β7 經濟部中央揉準局負工消费合作社印製 五、發明説明（B) 4-(2-羥基-3-環己基胺基丙氧基）吲哚：由約1〜約50奄 克1〜2次/天，K由約1〜約10毫克二次/天較佳。 使用更常用用語言，吾人可根據上述指南之精神選取第 一類成份的_量並選取第二類成份的劑悬且設範圏由約1 〜約250毫克/劑，K削造本發明的一種姐合。依化合物 而言，較佳爾量可由約1〜約100毫克/麵，甚或可發現 更佳劑量範園為由約1〜約50毫克/劑，以由約1〜約 25«克/劑較理想。 本發明之輔助治療乃《任何方式施用第一類成份輿一種 第二類成份Μ便在身體中同一時間内提供有故量之兩種化 合物。所有有闞的化合物皆可口版、正常時亦皆口腹掩用 •故輔助姐合物Κ 口脹較佳。其可Μ單一麵躉形式一起施 用亦可分別豳用。 然而•口服非唯一途徑、甚或是唯一較佳途徑。例如， 穿皮方式豳用對健忘或討厭口眼藥者也許是更需要的。可 Μ用一種方式施用其中一種藥，諸如口 Κ，而另一種則可 穿皮、經皮嫌、靜鼷內、肌内、鼻内、或直腸內施用*視 特定瓌境而定。施用途徑可採任何方式、依藥物物性、病 人方便、病患照顧者之方便而言。 然而，對轜助姐合而言特佳者則是Μ單一翳蕖姐合物施 用，因此合併一種第一類成份與一種第二類成份的翳藥姐 合物是本發明之重要具體實施例。此類组合物可Κ是任何 醫蕖可接受的物理型式但Κ可口服之醫藥组合物特佳。此 類輔肋的醫蕖姐合物含有有效量的每種化合物，該有效量 -16 — 本紙張尺度逍用中國國家梂準（CNS ) A4规格（210X297公釐） (請先閲讀背面之注$項再填寫本頁) f 裝· 訂 經濟部中央梂準局貝工消费合作社印製 320562 A7 _B7 五、發明説明（以） 與欲腌用之化合物的毎日劑量有W。每一輔肋劑最單位可 含阐種化合物之毎日钃量或可含每日謂1之一部份，諸如 三分之一劑量。另外，毎一劑Μ單位可包含一種化合物之 全部劑量，輿另種化合物之_量的部份。此種情形下·病 人將毎天腹用一種姐合朗I量單位，與一僅含另一化合物之 一或多個單位。每一爾量單位中含有的每種_的量依選用 於治療的藥物之性霣Κ及其他因子，諸如對給予的_助治 療之指示而定。 將第二類成份化合物*做同一類看，其在《内效性很短 且據此只在每個鳎*後提供短暫的活性。例如，品多露在 先前用法中例行性地施用兩次/天，甚且》用頻率更高。 因此在本發明範園内施用第二類成份化合物時Κ可實貿上 維持第二類成份於病人血中之穩定量並高到足Κ提供增強 第一類成份作用之實霣的穩定程度之方式較佳。 當然*本發明或任何治療病人的方法皆非Μ提供真正地 高血中含量輿增強程度為目檷。生物邊程通常不同並會胆 礙準確地穩定结果。”實質上嫌定”逭一用語在本文中意指 會導致血中的含量輿》強程度至足夠穩定以在一治療日中 *與單獨的第一種成份化合物的效率比較提供連續的改逸 效率。另一種考盧實質上檯定的增強性之方式乃藉由比較 病人腦中5-羥色胺、正腎上胨素輿多巴胺的利用率。Μ” 實質上穩定”逭種用語意指在一治療日中利用率的最高與 最低點之差異不_ 10的2次方之情況。另種考處”寘質上 穩定”的方式之情況為最高與最低點之差距不逾10的1. 5 -17- 本紙張尺度逍用中國國家標率（CNS ) Α4规格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) Γ 經濟部中央橾準局員工消费合作社印装 A7 _B7 五、發明説明（15 ) 次方或其差距範為約10的1.5〜約3次方。 此類施用第二種成份的方法可由轚蕖學家K熟知的方法 行之。例如，可將第二種成份之每日總鼸量調配物成可提 供病人實霣上穩定的化合物流量之方式。只考處品多霣時 •至少下列參考資料教辱持纜性稼放的調配物：徳國専利 3632201 、膠囊；瑙士《利634990、綻第；德國専利 3237945 、頰膠片；镰_専利2732335 、綻麵；美國専利 52 60 0 66 、冷膠；歐洲専利公告361894、脂質«;日本専 利84-66710、穿皮貼Η。«藥學家熟悉規代技術之K調整 持續性釋放調配物的方式Μ提供給定的化合物之必要的施 藥速率且製備該調配物時可藉此處做為第二類成份之用的 化合物之翳蕖技術。 此類第二類成份化合物的調配物可與選定之第一類成份 化合物结合成簞一蘭量型式。例如，可將調配物成可提供 穩定的第二類成份的化合物之利用率之小錠劑或小粒與第 一類成份化合物組合成，例如膠囊。另外，可製備具能相 對地快速釋放第一類成份之厪域與相當慢地釋放第二類成 份的區域之穿皮貼片。甚且，可製備第一類成份呈規純化 合物顆粒而第二類成份顆粒經a塗覆μ便在《内提供持續 性釋放之懸浮液。在此方式中，可調整第二類成份之利用 率以提供血中所需的實質穩定的量輿*因此對第一類成份 之實霣棰定的增強作用。因而*經過改變κ提供第一類成 份之實霣穩定增強作用的姐合物為本發明較佳的姐合物。 除存在第一類成份與第二類成份化合物的姐合外*輔助 本紙張尺度適用中國國家揉準（CNS ) A4规格（210X297公釐） (請先閲讀背面之注意Ϋ項再填寫本頁) 裝. 訂 Α7 Β7 經濟部中央梂準局員工消費合作社印裝 五、發明説明（1€ ) 的B槩姐合物之惰性成份與調配物方式皆是傅铳的。一般 醫藥學所用的調配物方式亦可用於此處。全部的一般形式 的姐合物皆可使用，包括綻麵、可嚼绽01、膠囊、溶液、 非經腸溶液、鼻内曠爾或粉末、片劑、栓麵、穿皮貼片輿 懸浮液。通常，依所需劑量輿所用組合物型戆而定，姐合 物包含蟪最由約0.5〜約5 0%的化合物。然而，化合物的 量最好Μ有效逢表示，亦即，提供給需此種治療的病人所 需之毎一化合物的量。因輔助姐合的活性非頼姐合物 之特性，故選定姐合物與製成調配物時，僅頼方便性與纆 濟性。可將任何姐合調成任何姐合物之必要型式。吾人在 提供不同姐合物之討論後·將搮示某些典型的調配物。 製備膠囊時乃將化合物與逋當稀釋劑混合並將遴當量的 混合物充填入膠囊中。一般的稀釋謂包括惰性的粉末物霣 ，諸如很多不圃種類的澱粉、粉末纖維素、特別是结晶與 微結晶孅維素，糖、諸如果糖、甘霣糖酵輿蔗糖、粒狀麵 粉及類似的可食粉末。 綻劑乃經直接壓縮、溼性顥粒化或乾性糴粒化製成。其 調Κ物通常合併稀釋麵、结合W、濶滑劃輿分解_以及該 化合物。典型稀釋劑包括例如不間型態的澱粉、乳糖、甘 霱耱酵、高嶺土、磷酸鈣或硫酸鈣、無檐鹽諸如氣化納與 耱粉。亦可用粉末狀之期維素衍生物。典型的綻劑结合物 為諸如澱粉、明膠之物質與耱諸如乳糖、果糖、蔔萄糖輿 類似物。天然與合成的膠亦很方便，包括***膠、蒲酸 _、甲基嫌維素、聚乙烯吡咯啶及類似物。聚乙二酵、乙 -19- 本紙張尺度逋用中鬮國家梯準（CNS ) A4規格（210X297公釐） (請先W讀背面之注$項再填寫本頁) 裝· 、?τ -h 經濟部中央樣準局員工消費合作社印裂 A7 B7五、發明説明（1?) 基纖雉素輿匾亦可做结合劑。 錠劑諝配物中須要瀾滑薄Μ防錠麵與打印器黏於棋具。 涠滑劑乃遘自諸如滑石之滑的固髑、硬脂酸鎂輿鈣、硬胞 酸與氢化蔬萊油。 錠劑分解劑為當溼濶後會臃脹Μ破壊錠_並釋放化合物 者。其包括澱粉、黏土、纖維素、藻膠輿膠。更特別者甚 且可用玉米興馬妗薯澱粉、甲基纖維素、瓊脂、矽酸ίβ、 木材纖維素、粉末狀天然海綿陽雕子交換樹脂、薄酸、黃 耆謬、柑橘類漿肉輿羧甲基纖維素以及十二_磙酸納。 通常使用腸道調配物Μ保護有效成份免於霣的強酸破壊 。吾人薄塗覆一在酸性環境中不溶解而溶於鐮性環《的聚 合物膜於固«爾量型式Μ製造此類調配物。可做典型的联 者為鄰苯二甲酸乙酯纖維素、邮笨二甲酸聚乙烯乙_、鄰 笨二申酸羥基丙基甲基纖維素與琥珀酸乙酯羥基丙基甲基 鑛維素。將杜洛色汀與含杜洛色汀的姐合物調S物成腸道 組合物較佳，甚至將之調配物成腸道小粒更佳。 一種較佳的杜洛色汀腸道姐合物為包括a)—種由杜洛色 汀輿醫蕖可接受的赋型劑姐成之核心b)—種視情況分離的 層c) 一種包括琥珀酸乙酯羥基丙基甲基纖維素<HPMC AS)與 一種醫蓁可接受的《型劑之腸道餍d)—種視情況而加的拥 飾層之小丸調配物。下列實例顯示此類較佳調配物之製劑 (請先閲讀背面之注$項再填寫本頁) 裝.'ST Α7 Β7 Printed by the Consumer Labor Cooperative of the Central Bureau of Economic Development of the Ministry of Economy V. Description of the invention (B) 4- (2-hydroxy-3-cyclohexylaminopropoxy) indole: from about 1 to about 50 μm 1 to 2 times per day, K is preferably from about 1 to about 10 mg twice per day. Using more commonly used language, we can select the amount of the first type of ingredients and select the second type of ingredients according to the spirit of the above guidelines and set the range from about 1 to about 250 mg / dose. A kind of sister-in-law. Depending on the compound, the preferred amount may be from about 1 to about 100 mg / facet, and it may even be found that the preferred dosage range is from about 1 to about 50 mg / dose, and from about 1 to about 25 mg / dose. ideal. The adjuvant therapy of the present invention is "administration of the first type of component and one of the second type of component M in any manner provides two compounds in the body in the same amount at the same time. All kang compounds are available in a palatable version, and they are also used for normal application. Therefore, it is better for the auxiliary sister compound K to swell. It can be applied together in a single-sided form or separately. However, oral administration is not the only way, or even the only better way. For example, it may be more necessary for people who are forgetful or hate oral medicine. One of these drugs can be administered in one way, such as oral K, while the other can be administered transdermally, transdermally, intra-statically, intramuscularly, intranasally, or intrarectally. * Depending on the particular circumstance. The route of administration can be any method, depending on the physical properties of the drug, the convenience of the patient, and the convenience of the patient's caregiver. However, the best one for the sister-in-law combination is the application of a single tortoise compound. Therefore, the combination of a first-type component and a second-type component is a significant specific embodiment of the present invention. . Such a composition may be any medically acceptable physical form, but K is an orally acceptable pharmaceutical composition. This kind of auxiliary rib medicine composition contains an effective amount of each compound, the effective amount of -16 — This paper standard is used in China National Standards (CNS) A4 specifications (210X297 mm) (please read the note on the back $ Item and then fill out this page) f Packing and ordering 320562 A7 _B7 printed by the Beigong Consumer Cooperative of the Central Bureau of Economics of the Ministry of Economy V. Description of the invention (in) and the daily dosage of the compound to be marinated is W. The most unit of each supplementary agent may contain the daily amount of the compound described, or it may contain a portion of one day, such as a third dose. In addition, each dose of M unit may contain the total dose of one compound and the amount of another compound. In this case, the patient will use one sister unit for each day and one or more units containing only another compound. The amount of each _ contained in each ul unit depends on the sex K and other factors of the drug used for treatment, such as instructions for the _ help treatment given. Looking at the second category of component compounds * as the same category, it has a short internal effect and accordingly only provides short-lived activity after each sole *. For example, Pintolu was routinely applied twice per day in the previous usage, and even more frequently. Therefore, when the second-type component compound is administered within the scope of the present invention, K can practically maintain a stable amount of the second type component in the patient's blood and be high enough to provide a way to enhance the stability of the actual effect of the first type component. Better. Of course * Neither the present invention nor any method of treating patients is intended to provide truly high blood levels and enhancement levels. Biological margins are usually different and can prevent accurate results from being stabilized. The term "substantially disagreeable" in this article means that the content of the blood will be strong enough to be stable enough to provide continuous improvement efficiency in comparison with the efficiency of the first component compound alone within a treatment day . Another way in which Kaulu actually substantiates the enhancement is by comparing the utilization of serotonin, norepinephrine and dopamine in the patient's brain. The term “substantially stable” means that the difference between the highest and lowest utilization rates on a treatment day does not differ to the power of 10. Another way to test the "stabilization in quality" is 1. 5 -17- the difference between the highest and lowest points is less than 10. 5-17- This paper scale uses the Chinese National Standard Rate (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling out this page) Γ A7 _B7 Printed by the Employees ’Consumer Cooperative of the Central Department of Economics of the Ministry of Economic Affairs A. _B7 5. Description of the invention (15) The power or the gap range is about 10 to 1.5 to about 3 . Such a method of applying the second ingredient can be performed by a method well-known to metalogist K. For example, the total daily mule amount of the second ingredient can be formulated to provide a way for the patient to achieve stable compound flow. Only test when there are many products • At least the following reference materials teach the insults of cable-bearing preparations: Germany 3635201, capsules; Naussie "Lee 634990, Zhandi; Germany Zheli 3237945, buccal film; sickle_Xinli 2732335 , Zhanmian; American special 52 60 0 66, cold glue; European special notice 361894, lipid «; Japan special 84-66710, wear leather stickers Η. «Pharmacists are familiar with the regulation technique K to adjust the sustained release formulations. M provides the necessary application rate of a given compound and can be used here as a second type of compound when preparing the formulation. Technology. The formulations of such second type component compounds can be combined with the selected first type component compounds to form a blue-and-white type. For example, the formulation can be combined into small lozenges or granules that provide a stable utilization rate of the compound of the second component, and the compound of the first component, such as a capsule. In addition, a transdermal patch can be prepared that has a relatively rapid release of the first-type component and a relatively slow-release area of the second-type component. Moreover, it is possible to prepare particles of the first type of components in the form of regular purification while particles of the second type of components are coated with a to provide a continuous release suspension. In this way, the utilization rate of the second-type component can be adjusted to provide the substantially stable amount of blood required in the blood * and thus the definite enhancement of the first-type component. Therefore, the sister compound that provides the first class of components with a strong stability-enhancing effect after changing κ is the preferred sister compound of the present invention. Except for the presence of the first-class components and the second-class components compounds * The auxiliary paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297mm) (please read the note Ϋ on the back before filling this page) Binding. Order Α7 Β7 Printed and printed by the Employee Consumer Cooperative of the Central Bureau of Economics of the Ministry of Economic Affairs. 5. The description of the invention (1 €) for the inert ingredients and formulations of the B compound are all by Fu Zheng. The formulation methods used in general medicine can also be used here. All general forms of sister compounds can be used, including noodles, chewable noodles 01, capsules, solutions, parenteral solutions, intranasal Kuanger or powder, tablets, suppositories, transdermal patches and suspensions . Generally, depending on the desired dosage and the type of composition used, the sister compound contains the compound from about 0.5% to about 50%. However, the amount of the compound should preferably be expressed, that is, the amount of each compound required to provide to patients in need of such treatment. Because the activity of the auxiliary sister compound is not the characteristics of the sister compound, the choice of the sister compound and the formulation is only convenient and economical. Any sister can be blended into the necessary form of any sister compound. After discussing the different sister compounds, we will show some typical formulations. When preparing capsules, the compound is mixed with diluent and the equivalent amount of the mixture is filled into the capsules. Common dilutions include inert powdered materials such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars, sugars, sugar cane, granulated flour and the like. Edible powder. The bleaching agent is made by direct compression, wet granulation or dry granulation. The K-regulated substance usually incorporates the diluted surface, combined with W, slipped and decomposed, and the compound. Typical diluents include, for example, uninterrupted types of starch, lactose, cantina, kaolin, calcium phosphate or calcium sulfate, non-branched salts such as sodium carbamide and silt. Powdered vitamin derivatives can also be used. Typical combinations of agents are substances such as starch and gelatin and analogues such as lactose, fructose, and glucose. Natural and synthetic gums are also very convenient, including gum arabic, citric acid, methyl thyroxine, polyvinylpyrrolidine and the like. Polyethylene Glycerine, B-19- This paper uses the National Standards (CNS) A4 specifications (210X297mm) (please read the $ item on the back and then fill in this page) Pack ·,? Τ- h A7 B7 printed by the Consumer Cooperative of the Central Bureau of Samples of the Ministry of Economic Affairs V. Description of the invention (1?) The base fiber pheasant can also be used as a binding agent. In the lozenge compound, it is necessary to stick the thin M surface and the printer to the chess set. The slip agent is made from slippery talc, magnesium stearate and calcium, stearic acid and hydrogenated vegetable oil. Lozenge disintegrants are those that will swell and break the lozenge and release the compound when wet. It includes starch, clay, cellulose, alginate and gum. More special ones can even use corn starch, starch, methyl cellulose, agar, silicic acid β, wood cellulose, powdered natural sponge Yang Diaozi exchange resin, thin acid, yellow paradox, citrus pulp and carboxyl Methyl cellulose and sodium dodecanoate. The intestinal formulation Μ is usually used to protect the active ingredients from the strong acids. We thinly coat a polymer film that is insoluble in an acidic environment and soluble in a sickle ring in a solid type M to make such formulations. Typical couplers are ethyl phthalate cellulose, polyethylene glycol dicarboxylate, hydroxypropyl methylcellulose phthalate and ethyl hydroxypropyl methyl succinate . It is better to convert duloxetine and duloxetine-containing sister compounds into intestinal compositions, and even to formulate them into intestinal granules. A preferred intestinal composition of dulostatin includes a) —a core made of excipients acceptable by dulostatin and b) —an optionally separated layer c) Ethyl succinate hydroxypropyl methylcellulose < HPMC AS) and a medically acceptable "Drug Intestine" d)-a pill formulation with a supporting layer added as appropriate. The following examples show the preparation of such better formulations (please read the item on the back of $ before filling in this page).

，1T Κ4 -20- 本紙張尺度適用中國國家揉準（CNS ) Α4规格（210Χ297公釐） A7 B7 五、發明説明（1现 經濟部中央標準局貞工消費合作社印策 10毫克杜洛色汀基質/膠囊 材料―崖置― 粒狀物 蔗糖-極品的澱粉，20-25網目 60.28毫克 杜洛色汀曆 杜洛色汀 11.21 羥基丙基甲基纖維素 3.74 分離曆 羥基丙基甲基纖維素 2.51 蔗糖 5.00 滑石，500網目 10.03 腸道暦 HPHCAS, LF趿，Sh in-Etsu Chemical 25.05 Co., Tokyo, Japan 檸樺酸三乙酯 5.00 滑石* 500纗目 7 . 52 潤飾暦 羥基丙基甲基钃維素 8.44 二氧化肽 2.81 潸石 少優 141 . 60毫克 藉將杜洛色汀懸浮於4 %重量/ 重量之羥基丙基甲基蠼 21- (請先閲讀背面之注意Ϋ項再填寫本頁) r 訂 本紙張尺度逍用中國國家梂準（CNS ) A4规格（210X2S»7公嫠） 經濟部中央梯準局員工消費合作社印裝 A7 B7 五、發明説明（19 ) 維素水溶液並KMS-12型CoBall研膺機（Fryia Hashinen AG, Rhe inf el den，瑙士）研究該懸浮麵以製成該杜洛色汀 曆。吾人使用每批量為1公斤之具Vurs ter管柱的流體床 乾煉器K製此產物。由亦溶有蔗糖於其中之溶於水中之4 %重量/重量的羥基丙基甲基纖維索的溶液之加入Μ形成 分離曆。 為製儎矚道塗覆的懸浮液*吾人將纯水冷卻至101並加 入聚山梨駿、三乙基檸«酸輿矽乳化劑並使分散或溶解。 然後加入HPMC AS與滑石並攪動直至均質化、並加氮氧化》 Μ完全中和HP MC AS、直至聚合物的溶液完成止。将0.5 % 重量/重量之羧甲基纖維索水瘠液加至此懸浮液並完全混 合。在塗覆«程中維持腸道懸浮液於20 υ。然後維持入口 的氣溫於50 υ，並將腸道懸浮液Ml 5«升/分喷霧*率加 至位於Wur st er管柱中之部份完成的小粒。當腸道》浮液 完全加入時*在Wurster中M50t：乾燦產物，然後在乾嫌 室中M 601C置於托盤上乾嫌3小時。然後將由含有二氣化 钛輿丙二酵做為塑型繭之45%重量/重ft的羥基丙基甲基 纖維素溶液之靥加入。在流《床乾燦器中將小丸完全乾燥 然後充填入3號尺寸之明膠膠囊中。 绽劑通常塗覆耱以為調味及做密封劑或塗覆會形成膜的 保謂劑Μ修飾绽劑之溶解性霣。亦可諝配物該化合物成可 皭錠爾•其乃如現今設立良好的規«般*藉添加大量諸如 甘R糖酵之良好風味的物質於調配物中。目前•亦常使用 即溶類似錠魍的調配物以使消费綻_型式的病人安心並避 -22- 本紙張^度逋用中國國家橾準（CNS ) Α4規格（210X297公釐） (請先閲饋背面之注意事項再填寫本頁) ·(-裝. 訂 320562 A7 B7 五、發明説明（2° ) 免困擾某些病人之呑_固《物的困難發生。 當需要施用姐合物做為栓麵時，可用一般的基質。可可 脂是一種傅統栓爾基質，其可鞴添加覼之修飾以稍提高其 溶黏。水可溶的栓_基質包括，特別是，亦經廣泛使用之 不同分子量的聚乙二醉。 最近穿皮貼Η愈見観迎。其典型的包括可溶藥物或部份 溶解藥物於其中之樹脂姐合物，其藉一«保謂該姐合物的 膜輿皮虜接觸。此範_中最近有很多專利。目前亦有人用 其他更褸雜之貼Η姐合物，特別是彼有打很多洞並可藉灌 透壓經此晴取藥物的_。 吾人提供下列典型調配物供醫藥學家做資料輿滿足好奇 心0 讕g物 1 使用下列成份Μ製備硬明膠謬囊： (請先聞讀背面之注意事項再填寫本頁) η 裝. 、1Τ 經濟部中央梂準局員工消费合作社印策 量 f臺克/ g囊） 氟 色 汀 ， 消 旋混合物，氣化氳藤 20毫 克 m 多 两 30 澱 粉 9 乾 埭 的 200 硬 腊 m 鎂 1SL 級 置 260* 克 -23- 本紙張尺度逍用中國國家橾準（CNS ) Α4规格（210X297公釐） 五、發明説明（21) Α7 Β7 m mm 使用如下成份κ製備錠劑 氟色汀，消旋混合物 (-)-僱布托》 纗維素，微结晶 二氣化矽*發煙的 硬脂酸 總《 氛化氫Μ ft (毫克/ g囊） 10 40 400 10 __5 465毫克 混合成份並壓縮之K形成毎届重46 5橐克之绽麵< 製備含下列成份之氣溶_成份： ( + )-杜洛色汀，氣化氫匾 品多露 乙酵 推進麵22 10 10 25.75 (請先聞讀背面之注意事項再填寫本頁), 1T Κ4 -20- This paper scale is applicable to the Chinese National Standard (CNS) Α4 specification (210Χ297 mm) A7 B7 V. Description of invention (1 is now printed by the Central Bureau of Standards of the Ministry of Economic Affairs Zhengong Consumer Cooperative Society 10 mg duloxetine Matrix / capsule material ―Yazhi― Granular sucrose-superior starch, 20-25 mesh 60.28 mg duloxetine duloxetine 11.21 hydroxypropyl methylcellulose 3.74 isolated hydroxypropyl methylcellulose 2.51 Sucrose 5.00 talc, 500 mesh 10.03 Intestinal tract HPHCAS, LF FU, Sh in-Etsu Chemical 25.05 Co., Tokyo, Japan Triethyl citrate benzylate 5.00 talc * 500 纗 目 7. 52 Retouching hydroxypropyl methyl Paclofen 8.44 Dioxide Peptide 2.81 Lu Shaoyou 141. 60 mg Suspension of duloxetine in 4% w / w hydroxypropyl methyl sulfone 21- (please read the note Ϋ on the back before filling in this Page) r The standard size of the paper used in the Chinese National Standard (CNS) A4 (210X2S »7 public daughter) Printed A7 B7 by the Employee Consumer Cooperative of the Central Escalation Bureau of the Ministry of Economy V. Description of the invention (19) Vitamin solution and KMS -12 CoBall Research Machine Fryia Hashinen AG, Rheinf el den (Nauze) studied the suspension surface to make the Durostatin calendar. I used a fluid bed dryer K with a Vurs ter column of 1 kg per batch to make this product. The separation calendar is formed by adding Μ of a 4% w / w solution of hydroxypropyl methylcellulose in water, in which sucrose is also dissolved, to form a separation calendar. The suspension coated for the production of glazes * I will cool the pure water To 101 and add polysorbate, triethyl lemon «acid and silicon emulsifier and disperse or dissolve. Then add HPMC AS and talc and stir until homogenized, and add nitrogen oxidation》 M and completely neutralize HP MC AS, until The polymer solution is complete. Add 0.5% w / w carboxymethylcellulose aqueous solution to this suspension and mix it thoroughly. Maintain the intestinal suspension at 20 υ during the coating process. Then maintain the inlet temperature At 50 υ, and add the intestinal suspension Ml 5 «L / min spray * rate to the partially completed pellets in the Wurst er column. When the intestinal》 float is completely added * M50t in Wurster : Dry Can products, then place M 601C on the tray in the dry room for 3 hours Then add 45% weight / weight ft of hydroxypropyl methylcellulose solution containing titanium dioxide and malonan as the shaping cocoon. The pellets are completely dried in the flow dryer and filled. Put into size 3 gelatin capsules. The blooming agent is usually coated with flavoring and used as a sealant or coated with a preservative M that forms a film to modify the solubility of the blooming agent. The compound can also be conjugated into a cocoon. It is as well-established today as it is * by adding a large amount of substances with good flavors such as glucomannan to the formulation. At present, it is also often used to dissolve the formulations similar to ingots to make the consumer _ type of patients at ease and avoid -22- This paper uses the Chinese National Standard (CNS) Α4 specifications (210X297 mm) (please first (Please read the precautions on the back of the feed and then fill out this page) · (-installation. Order 320562 A7 B7 V. Description of the invention (2 °) Avoid troubles that may disturb some patients _ solid "things difficult. When you need to use sister compound to do For the suppository, a general base can be used. Cocoa butter is a general-purpose suppository base, which can be modified by adding scorpions to slightly increase its viscosity. Water-soluble suppository bases include, in particular, the widely used difference The molecular weight of polyethylene is drunk. Recently, it is more and more popular to wear a leather patch. It typically includes a soluble resin or a partially dissolved drug in the resin compound, which is borrowed from a film Skinny contact. There are many patents in this category recently. Some people are also using other more complex stickers Η sister compound, especially he has a lot of holes and can take drugs through osmotic pressure through this clear _. Provide the following typical formulations for medical scientists to do data and satisfy curiosity 0 g Item 1 Use the following ingredients Μ to prepare hard gelatin pouches: (please read the notes on the back before filling in this page) η pack. 、 1Τ The Ministry of Economic Affairs Central Bureau of Accreditation Employee Consumer Cooperatives printed an amount of f gram / g pouch ) Flusertin, racemic mixture, gasified Ganoderma lucidum 20 mg m more than 30 starch 9 dried vine 200 m wax m magnesium 1SL grade set 260 * g-23- This paper scale is used by the Chinese National Standard (CNS) Α4 specification (210X297mm) V. Description of the invention (21) Α7 Β7 mm mm Preparation of lozenge flustine, racemic mixture (-)-Zhubuto using the following ingredients κ 溗 维素, microcrystalline silicon dioxide * Total fuming stearic acid "Hydrogenated hydrogen M ft (mg / g capsule) 10 40 400 10 __5 465 mg of mixed ingredients and compressed K to form a weight of 46 5 5 grams of velvet face < prepare the following ingredients Air-soluble _ Ingredients: (+) -Durostatin, Hydrogenated Plaque Product Exposed Ethanol Propulsion 22 10 10 25.75 (Please read the precautions on the back before filling this page)

I 訂 經濟部中央橾準局貝工消費合作社印製 (二氟一氰甲烷） 70.00 總 Μ 115.75 將有效成份混Μ乙酵且將此琨合物加至一份的推進劑 22、冷卻至-30 t：並轉移至充填装置。然後將需要量裝入 不辨鋼容器並K_餘推進劑稀釋。然後將控制閥接合於此 容器。 -24- 本紙張尺度逍用中國國家橾準（CNS ) A4规格（210X297公釐） 320562 A7 ___B7五、發明説明（22 ) 钃配物 4 製備如下之每β含80毫克有效成份的錠_ : ( + )-杜洛色汀，氣化氫Μ 20毫克 (-)-«布托》 60毫克 濉粉 45毫克 撖纖維素 35奄克 聚乙烯吡咯啶酮 (10%水溶液） 4毫克 羧甲基澱粉納Η 4.5毫克 硬脂酸鎂 0. 5毫克 滑石 1產克 總ft 170毫克 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央棣準局員工消费合作社印製 將有效成份（澱粉與纖維索 >通遘45號網目的美·篩綱並 完全混合。將含聚乙烯-吡咯啶麵之溶液與產生的粉末混 合，然後令該混合物通βΐ 4號期目的美國籂綱。產生的顆 粒Κ 50 t；乾嫌之，並通遢18號綱目的美_篩期。將先前通 « 60號孀目的美國篩纗之羧甲基纖維索納、硬賄酸鎂、與 滑石加至該顆粒，混合後，在製錠機上壓埔Μ生產每個璽 170毫克之綻鳎。 讕 g..抱......5.. 製備如下之各含130 «克有效成份的膠囊： 氟色汀，消旋混合物，氯化氫鼸 30奄克 普羅普蘭諾® 100毫克 澱粉 59毫克 -25- 本紙張尺度適用中國國家揉準（CNS ) A4规格（210X297公釐） 、11 線 A7 B7 微结晶纖維素 硬脂酸鎂 繼量 棍合m維素 目之美醒篩鑭 五、發明説明（B) 59毫克 2MJS 250奄克 澱粉興硬脂酸鎂與有效成份、通邊45號期 並Μ 250 «克的量充填入硬明膠膠囊。 鱺BR物 fi 製備如下之各含45毫克有效成份的栓_ = ( + )-杜洛色汀，氯化氫鹽 5毫克 替羅替II諾两 40奄克 飽和脂肪酸甘油酗 000毫克 總量 2,045毫克 令有效成份通«60號綱目之美圃篩嫌並懸浮於先前已从 最低需要加熱融熔之脂肪酸甘油酯中。然後將混合物倒入 名義上2克容積的栓劑鑄横並令之冷卻。 製備如下之每5 «升蕖劑含有70«克有效成份之懸浮液 (請先閲讀背面之注意事項再填寫本頁) 裝· ,ιτ 經濟部中央揉準局員工消費合作社印装 氟色汀•消旋混合物 普羅普蘭諾S 羧甲基纖維素納 糖漿 苯甲酸溶液 香料 色素 氣化氫鹽 10毫克 60毫克 50¾克 1. 25« 升 0. 10毫升 定最 定量 -26^ 本紙張尺度逍用中國國家棣準（CNS ) Α4规格（210X297公釐） 經濟部中央梂準局員工消費合作社印製 Α7 Β7 五、發明説明（24 ) 加纯水至纗量 5毫升 令有效成份通邁45號期目的美國篩綱並輿羧甲基纖維素 納及糖漿混合以形成平滑藥膏。以一份的水稀釋苯甲酸液 、番料輿色素並加入此中•攪拌。加足量水至所需«積。 豳配物 8 可製備如下之_脈内注射調配物： (〇-杜洛色汀•氣化氫鹽 10毫克 普羅替蘭諾21 20毫克 等張《液 1,000毫升 如上述，本發明的好處在其第一類成份有增大5-羥色胺 、正腎上腺素輿多巴胺利用率增強之能力，使得治療下述 不同症害時活性增強。5-羥色胺利用率增加特別重要，且 是本發明較佳面向。甚且，本發明提供比單獮以氟色汀或 杜洛色汀治療時更快的起始作用。下述實驗資料清楚顬示 快速的起始作用Μ及一元胺利用率之增強情形。 較遘以本發明的輔助治療方法Β治的症害包括抑鬱症、 強迫症與肥胖症。另外之對包括以杜洛色汀較佳但亦可為 芬拉法辛及米纳西替蘭的組合更專一性的症害為尿失禁。 最近抑_症的諸多差異對一般大眾而言比Κ前清楚，現 今，其經認定為一極端損害的病症且是影響相當大部份人 的病症之一。自殺為抑《症最極皤的激候•但千百萬計的 人雖未受如此刺烈影響*卻生活在可《輿部份或完全徒然 之中且亦因其苦難面影響家人。氟色汀的引介是治療抑鬱 症之一種突破且現今亦比僅僅十年前更易於診断與治療抑 -27- 本紙張尺度適用中國國家揉準（CNS ) Α4規格（210 X 297公兼） (請先閲讀背面之注意事項再填寫本頁) ,ΤΓ 經濟部中央標準局員工消費合作社印策 A7 B7 五、發明説明（朽） 鬱患者。目前杜洛色汀正在臨床試驗治療抑譬症且亦可能 因此成上市蓁物。 抑響症通常輿其他疾病或症害有闞或因其他症害而生。 例如，其與巴金森氐症、HIV 、眄茲海默症、及同化類固 酵的*用有鼷。抑鬱症亦可能與任何物質的濫用或輿臞部 傷客、心智陣礙或中風引起或姐合而生之行為問賵有醑。 就各種差異性的憂轚症而言皆為本發明輔助治療方法輿姐 合物之較佳目檷。 強迫症有多種程度與微候病人，通常伴》強迫性地表現 非必要、儀式性的行為。超越理性或合理範瞩的招想、命 令、淸洗輿相似性動作為此疾病之外部特撤。受劇烈影響 的病人可能除了做此疾病患者持有之儀式外便無法做任何 其他事。美國與其他B家允許使用氟色汀治療強迫症且經 箱實有效。 肥胖症是美Η人常見的症害。頃發現氟色汀可使K胖病 人減重因而對病人循瓖系統與心臟狀況Μ及一般福祉及活 力有所助益。 通常將尿失禁歸類為壓力或強迫失禁、但須視其根源是 否為控制的括約肌之失能或膀胱肌肉之遢度活動而定。杜 洛色汀可立即控制該二種型態的失禁，因而對諸多為此惬 人與殘害症害所苦的人而言很重要。 本發明可用Μ治療很多其他疾病、病症與症害Κ及下述 者。很多情形下，本文所提的疾病之分類均可見於鼷際疾 病分類，第九版（International Classification of 一 2 8 _ 本紙張又度逋用中國國家梂準（CNS ) A4规格（210X297公釐） (請先聞讀背面之注意事項再填寫本頁) 訂 線 A7 B7 經濟部中央橾準局員工消費合作社印裝 五、發明説明（26) Diseases, 9th Edition 1ICD))或美國心理治療協會 (DSM)出版之心理病症的診斷與統計手冊（Diagnostic and Statistical Manual of Mental Disorders) 0 鑑於 此種情形，為方便讓者起見，下文亦列出ICD或DSM编排 號磡。 抑鬱，ICD 296.2 & 296.3, DSM 296，294.80, 293.81, 293.82, 293.83, 310.10, 318.00, 317.00 僑頭痛 痛、特別是神經痛 食疾、ICD 307. 51 , DSM 307.51 經前症侯群或後黄«期症侯群，DSM 307.90 酒精中毒，ICD 305.0, DSM 305.00 & 303.90 煙草濫用，ICD 305·1, DSH 305.10 & 292.00 恐慌症，ICD 300.01, DSM 300.01 & 300.21 焦嫌，ICD 300.02. DSM 300.00 重大削傷後症侯群，DSM 309.89 記憶喪失，DSM 294.00 老年痴呆，ICD 290 社交恐懼症 * ICD 300.23, DSM 300.23 過動性注意缺乏症，ICD 314.0 «壊狂，ICD 312 衡動性疾患，ICD 312, DSM 312.39 & 312.34 邊緣型人格異常，ICD 301.83, DSM 301.83 慢性疲勞症侯群 -29- 本紙張尺度適用中國國家棣準（CNS ) Α4规格（210X 297公釐） (請先閲讀背面之注意事項再填寫本頁) h 裝.I. Printed by the Ministry of Economic Affairs, Central Bureau of Industry and Commerce, Beigong Consumer Cooperatives (difluoromonocyanomethane) 70.00 Total M 115.75 Mix the active ingredients with ethyl acetate and add this compound to a portion of propellant 22, cool to- 30 t: And transferred to the filling device. Then put the required amount into a non-discriminatory steel container and dilute with K_propellant. Then connect the control valve to this container. -24- This paper scale uses the Chinese National Standard (CNS) A4 specification (210X297 mm) 320562 A7 ___B7 V. Description of invention (22) 钃 配 物 4 Prepare the following tablets containing 80 mg of active ingredient per β_: (+) -Durostatin, gaseous hydrogen M 20 mg (-)-«Butuo 60 mg powder 45 mg cellulose 35 mg polyvinylpyrrolidone (10% aqueous solution) 4 mg carboxymethyl Starch sodium Η 4.5 mg magnesium stearate 0.5 mg talc 1 g total ft 170 mg (please read the precautions on the back before filling this page) Printed by the Ministry of Economic Affairs, Central Bureau of Precinct Employee Consumer Cooperatives will be effective ingredients (starch Mix with Fibre Soybeans> Tongyun No. 45 mesh and completely mix the solution. The solution containing polyethylene-pyrrolidine noodles is mixed with the resulting powder, and then the mixture is passed through the American leptoma of the βl No. 4 mesh. Granules Κ 50 t; dry, and pass the No. 18 program of the US _ sieve period. Add the carboxymethyl fiber Sona, magnesium stearate, and talc added to the US sieve of the No. 60 program. The granules, after mixing, are pressed on the ingot machine to produce 170 mg of each seal賰 g..g .. hug ...... 5 .. Prepare the following capsules each containing 130 «g of active ingredient: flustine, racemic mixture, hydrogen chloride 30 mol Propranol® 100 mg starch 59mg-25- This paper scale is suitable for China National Standard (CNS) A4 specification (210X297mm), 11-line A7 B7 microcrystalline cellulose magnesium stearate, followed by m-dimensional Sumei lanthanum. Description of the invention (B) 59 mg of 2MJS 250 gram starch magnesium stearate and active ingredients, Tongbian No. 45 period and M 250 «g are filled into hard gelatin capsules. The BR BR fi is prepared as follows each containing 45 mg Suppositories of active ingredients _ = (+) -durostatin, hydrogen chloride salt 5 mg tirotino II no 40 gram saturated fatty acid glycerol alcohol 000 mg total amount 2,045 mg makes the active ingredient pass the beauty garden screening of «No. 60 program And suspended in the fatty acid glyceride which has been melted from the minimum heating. The mixture is then poured into a suppository of nominal 2 g volume and allowed to cool. The preparation is as follows. Every 5 «Lenghuan contains 70« g effective Suspension of ingredients (please read the notes on the back before filling in Page), ιτ, Ministry of Economic Affairs, Central Bureau of Standardization, Employee Consumer Cooperative Printed Flustine • Racemic Mixture Propranol S Carboxymethylcellulose Nano Syrup Benzoic Acid Solution Flavor Color Gasified Hydrogen Salt 10mg 60mg 50¾g 1. 25 «l 0. 10ml set the most quantitative -26 ^ The paper size is easy to use China National Standards (CNS) Α4 specifications (210X297 mm) Printed Α7 Β7 by the Ministry of Economic Affairs Employee Consumer Cooperative of the Central Bureau of Economic Development 5. Invention Instructions (24) Add pure water to an amount of 5 ml to make the active ingredient of the US-Taiwan sieves of the No. 45 stage of the US, and mix carboxymethyl cellulose and syrup to form a smooth ointment. Dilute the benzoic acid solution and the pigment with one portion of water and add to it • Stir. Add enough water to the required volume. Bintang Compound 8 can be prepared as follows: Intravenous injection formulations: (〇-durostatin • vaporized hydrogen salt 10 mg protripranol 21 20 mg isotonic "1,000 ml of liquid as mentioned above, the benefits of the present invention are in The first type of ingredients have the ability to increase the utilization of serotonin, norepinephrine and dopamine, which enhances the activity when treating the following different diseases. The increase in the utilization of serotonin is particularly important, and it is a better aspect of the present invention. Moreover, the present invention provides a faster onset of action than fluoxetine or duloxetine alone. The following experimental data clearly show the rapid onset of action M and the enhancement of monoamine utilization. The diseases treated by the adjuvant treatment method B of the present invention include depression, obsessive-compulsive disorder and obesity. In addition, the combination including duloxetine is preferred but it can also be a combination of fenlafaxine and minazetiran A more specific disease is urinary incontinence. Recently, many differences in the suppression of the disease have been clearer to the general public than before, and today, it is recognized as an extremely damaging disease and is one of the diseases affecting a large number of people . Suicide is the most restrictive The irritated sensation • But millions of people are not affected by such a stab * but live in part or completely in vain and also affect their families because of their suffering. Flustine's introduction is to treat depression It is a breakthrough of the disease and it is now easier to diagnose and treat than just ten years ago. -27- This paper scale is suitable for China National Standardization (CNS) Α4 specification (210 X 297 public) (Please read the precautions on the back first (Fill in this page), ΤΓMinistry of Economic Affairs Central Standards Bureau Employee Consumer Cooperatives printed A7 B7 V. Description of invention (deteriorated) Yu patients. At present, duloxetine is in clinical trials for the treatment of constipation and may also be listed as a detriment. Symptoms are usually caused by other diseases or diseases. For example, it is associated with Parkinson's disease, HIV, Ozheimer's disease, and anabolic ferment. Depression also has May be confused with any substance abuse or injury caused by public health, mental barriers or strokes, or sister-in-law behavior. All kinds of different anxiety disorders are auxiliary treatment methods of the present invention. The better compound of the compound. Obsessive-compulsive disorder This kind of patient is usually accompanied by a compulsory performance of non-essential and ceremonial behavior. Thoughts, orders, and similarity actions that transcend rational or reasonable attention are external special withdrawals for this disease. The affected patients may not be able to do anything other than the ritual held by patients with this disease. The United States and other B families are allowed to use flutidine to treat obsessive-compulsive disorder and it is effective. Obesity is a common disease in American people. It has been found that flusetin can cause K fat patients to lose weight and thus contribute to the patient's circulatory system and heart condition M and general well-being and vitality. Urinary incontinence is usually classified as stress or forced incontinence, but it depends on its root cause Whether it is due to the controlled disability of the sphincter or the excessive activity of the bladder muscles. Duloxetine can immediately control these two types of incontinence, so for many people who suffer from this comfort and disability Very important. In the present invention, M can be used to treat many other diseases, disorders, and diseases K and the following. In many cases, the classification of the diseases mentioned in this article can be found in the Interanal Disease Classification, the ninth edition (International Classification of I 2 8 _ This paper again uses the Chinese National Standards (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling out this page) Line A7 B7 Printed by the Central Consumers ’Bureau of the Ministry of Economic Affairs Employee Consumer Cooperative V. Invention Instructions (26) Diseases, 9th Edition 1ICD)) or American Psychotherapy Association (DSM ) Published Diagnostic and Statistical Manual of Mental Disorders 0 In view of this situation, for the sake of convenience, ICD or DSM numbers are also listed below. Depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81, 293.82, 293.83, 310.10, 318.00, 317.00 Overseas Chinese headache pain, especially neuralgia food disorders, ICD 307.51, DSM 307.51 Premenstrual syndrome or post yellow «Phase syndrome, DSM 307.90 Alcoholism, ICD 305.0, DSM 305.00 & 303.90 Tobacco abuse, ICD 305.1, DSH 305.10 & 292.00 Panic disorder, ICD 300.01, DSM 300.01 & 300.21 Ignorance, ICD 300.02. DSM 300.00 Post-traumatic syndrome, DSM 309.89 Memory loss, DSM 294.00 Alzheimer's disease, ICD 290 Social phobia * ICD 300.23, DSM 300.23 Hyperactive attention deficit disorder, ICD 314.0 «Crazy, ICD 312 Balance disease, ICD 312, DSM 312.39 & 312.34 Marginal personality abnormalities, ICD 301.83, DSM 301.83 Chronic Fatigue Hou Group -29- This paper scale is applicable to China National Standards (CNS) Α4 specifications (210X 297 mm) (please read the back (Notes to fill out this page) h installed.

、1T Α7 Β7 經濟部中央梂準局員工消费合作社印裝 五、發明説明（四） 早洩，DSM 302. 75 ***困雞，DSH 302. 72 神經性厭食症，ICD 307.1, DSM 307.10 睡眠失調症，ICD 307 . 4 自閉症 無語症 拔鬚髮狂 吾人已將本發明之代表姐合物對有知覺的實驗動物做遇 試驗而测試的驚人结果顯示本發明的優黏。試驗如下。 將重 270 - 300 公克的 Spr ag ue-Da w 1 ey 大白 R (Har I a η 或 Charles River品糸），經水合氯醛/戊巴比妥麻醉（170 輿36毫克/公斤i . p.，溶於30%丙二酵、14%乙醇）Μ外 科手術移植微透析探針（Perry and Fuller, Effect of fluoxetine on serotonin and d o p a η i n e concentration in rat hypothalamus after administration of fluoxetine plus L-5-hydroxytryptophan, Life Sc i ., 50, 1683-90 (1992))。吾人使用 David Kopf 立 β 固定儀 * Μ同等的嘴-1.5毫米、邊-1.3毫米及背- 9.0毫米將探針 軍邊植人下視丘（Paxinos與Watson, 1986) 。48小時恢復 期後，將老鼠置於有上升液«旋轉***之大型塑膠碗中 (CHA/120糸铳，供自由移動的動物用、Bioanalytical Systems, Vest Lafayette, IN) 。 Ml.0 微升 / 分的速度 將濾過的人選鼷脊《液（CSF)浸潤邊探針（150 bM NaCl, 3.0 ·Μ KC1， 1.7 ·Μ CaCU輿 0.9 MgCU) 。Μ 一 20微 -30- 本紙張尺度逍用中國國家梯準（CNS ) A4规格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) h 裝. 訂 線 320562 A7 B7 五、發明説明（昶） 升的遇管透析液將_出線定於tenport HPLC控制閥上。每 個30分鐘取樣期後，將酒管中收集之透析液注射至分析管 柱中（Spherisorb 3 « 0DS2, 2X150奄米，Keystone Scientific) ° 經濟部中央揉率局員工消費合作社印裝 MPerry與Fuller所述方法（1993)测定一元胺。Μ言之 ，分析收集於20微升埋管的透析液之5-ΗΤ、ΝΕ與DA。以一 可解析ME、DA輿5-ΗΤ的移動相將該20微升的透近液注射至 管柱中：75 _酸鉀、0.5 ·Μ乙烯二胺四乙酸、1.4 »Μ庚烷磺酸納與8 %甲酵、pH 4.9。胺管柱用的移動相Μ 流動的可調節幫浦、初流速0.2毫升/分、在5分鐘時增 加至0.3奄升/分然後慢慢回復到26分鐘時為0.2毫升/ 分、總的流動時間為3 0分鐮。設定流的《程Κ便在25分鐘 時段内溶*出5-ΗΤ。將胺管柱的爾化學偵测器（EC&G， 400 型）定在電位 400 uV、霤敏度 0.2 nA/V。MHevlett-Packard(惠替）HP1000色析糸铳收集並分析資料·其可測 量波峰高度與計算樣本濃度。施藥前最少拥量90分鐘的基 準量。藥物的去雛子水製備並Μ下述结果之«量施 用（體積0.25- 0. 3毫升）。 吾人以與50微微莫耳檷準液的波峰高度比較Κ計算微透 析液之细胞外胺的量。將胞藥直前4種樣本的平均值做為 每一實驗之基準量並將資料轉換成基準量的百分比。用配 對t-测Μ比較施藥直前時間點之基準值的平均與之後每一 時間點的值。 吾人已將資料做遇調鏊Μ使趨勢更明顯。 31 - 本紙張尺度逍用中國國家揉準（CNS ) A4规格（210X297公釐） ---------— 裝—I (請先閲讀背面之注意事項再填寫本頁) .tr 線 經濟部中夬標準局員工消費合作社印製 A7 B7五、發明説明（29 ) 在此測試中、姐合治療包括消旋混合物氱化氫盞輿 4-(2-羥基-3-瑁己基胺基丙氧基）吲哚，順丁烯二酸的氟 色汀。Μ如上方法準備老鼠並於實驗開始100分鐘後皮下 施用吲哚（3¾克/公斤）。實驗開始210分鏡後Μ 10«克 /公斤腹腔内施用氟色汀*加上3毫克/公斤之第二薄的 吲11朵。本文所報導的每一資料點代表單一的動物。 經施用蚓哚後，透析液中所拥得的5-ΗΤ最下降至基準繚 的50% •而於210分鐘時約基準嫌的80%。施用氟色汀後 刺烈缮加且於240分鐮後測得約基準埭的410%、270分鐮 時約基準線之450%、3 00分鐮時約46 0%、而於33 0分鐘時 約基準線的390%。 施用蚓哚後，ΝΕ的量增加至約基準線的180 %、並於 210分鐮時，下降至近基準線。施用氟色汀後，於240分 鏟時增至約基準埭的500%，並於27 0、300輿33 0分鐘時分 刖地滅至基準嫌的340%、280%輿200%。 同樣地，DA的量於120分鐘時增至約基準嫌的210%、並 於210分鐘時下降至近基準級。施用氟色汀後，DA的量於 240分鐘時壜至約基準線的1430%、270分鐘時約基準線 的840%、300分鐘時約530%、而330分鏟時約330%。 &Μ.2. 在此測試中，施用蕖物為（ + )_杜洛色汀、氯化氫鹽*施 用量為4毫克/公斤輿（-)-品多Κ ·施用置為5毫克/公 斤。本澜試的進行方式同測試1開始實驗120分鐘後首先 -32- 本紙張尺度適用中國國家揉準（CNS ) Α4规格（210X297公釐） (請先閲讀背面之注$項再填寫本頁) •裝. 訂 線 A7 B7 五、發明説明（30 ) 施用（-)-品多a、然後於210分鐘時為杜洛色汀與第二劑 量的（-)-品多霣、施用量為5毫克/公斤。下示结果為貢 驗開始後不同時間之三種一元胺對基準線的百分比。每一 資料點代表三隻或三隻以上的動物之平均。 (請先閱讀背面之注意事項再填寫本頁) r 裝· 訂 ELJML 5^ΗΤ HA. 120分鐘 8096 9096 90% 150 90 100 90 180 110 120 70 210 100 110 100 240 240 350 230 270 340 230 170 300 360 210 140 330 — 230 150 360 330 170 150 經濟部中央梂準局員工消費合作社印袈 ΆΜΑ. 本澜試進行方式如測試1者，於120分鐘時施用4-(2-羥基-3-環己基胺基丙烷氧基）吲哚、順丁烯二酸»、3 * 克/公斤，並於270分鐘時施用（+ )-杜洛色汀、氣化鼉》 、4邂克/公斤，與第二繭的吲哚、3奄克/公斤。结果 如上述之澜試2所報告者。5-ΗΤ的结果為3隻動物的平均 ，而其他结果為4隻動物的平均。 線· -33- 本紙張X度適用中國國家樣準（CNS ) ( 210X297公釐） 320562 A7 B7 五、發明説明（Μ ) 時間 5-HT Mu \LL 120分嫌 90¾ 10096 10% 150 130 160 150 180 130 140 130 210 80 140 110 240 90 130 100 270 80 150 110 300 650 580 410 330 670 390 280 360 590 450 240 390 490 320 210 420 440 290 200 (請先閲讀背面之注意事項再填寫本頁) 裝·、 1T Α7 Β7 Printed by the Consumers Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economy V. Description of Invention (4) Premature ejaculation, DSM 302. 75 Erectile sleepy chicken, DSH 302. 72 Anorexia nervosa, ICD 307.1, DSM 307.10 Sleep disorders, ICD 307. 4 Autism Aphasia is a mad person. I have tested the representative sister compound of the present invention on conscious experimental animals. The amazing results of the test show that the present invention has excellent adhesion. The test is as follows. An Spr ag ue-Da w 1 ey Dabai R (Har I a η or Charles River product) weighing 270-300 g was anesthetized with chloral hydrate / pentobarbital (170 mg 36 mg / kg i.p. , Soluble in 30% malonylase, 14% ethanol) Μ surgical dialysis probe (Perry and Fuller, Effect of fluoxetine on serotonin and dopa η ine concentration in rat hypothalamus after administration of fluoxetine plus L-5-hydroxytryptophan, Life Sc i., 50, 1683-90 (1992)). We use David Kopf to set up β fixation device * Μ equal mouth-1.5 mm, side-1.3 mm and back-9.0 mm to probe the military side to implant the lower visual hill (Paxinos and Watson, 1986). After a 48-hour recovery period, the rats were placed in a large plastic bowl with a rising fluid «rotating system (CHA / 120 鳸 鳳 for free-moving animals, Bioanalytical Systems, Vest Lafayette, IN). Ml.0 microliters / min. The filtered candidate mandibular ridge "CSF" infiltration edge probe (150 bM NaCl, 3.0 · Μ KC1, 1.7 · Μ CaCU and 0.9 MgCU). Ｍ 一 20 微 -30- The size of this paper is easy to use China National Standard (CNS) A4 specification (210X297mm) (please read the precautions on the back before filling in this page) h Pack. Thread 320562 A7 B7 5. Invention Description (Chang) The dialysis solution in the tube is set to the tenport HPLC control valve. After each 30-minute sampling period, the dialysate collected from the wine tube is injected into the analytical column (Spherisorb 3 «0DS2, 2X150 m, Keystone Scientific) ° MPerry and Fuller are printed on the staff consumption cooperative of the Central Rubbing Bureau of the Ministry of Economic Affairs The method (1993) measures monoamines. In other words, the 5-HT, NE, and DA of the dialysate collected in 20 microliter buried tubes were analyzed. Inject a 20 μl of permeable solution into the column with a mobile phase that can resolve ME, DA and 5-HT: 75_ potassium acid, 0.5 · M ethylenediaminetetraacetic acid, 1.4 »M heptanesulfonic acid Sodium and 8% formazan, pH 4.9. Mobile phase M for amine columns. Adjustable pump for flow, initial flow rate 0.2 ml / min, increase to 0.3 μl / min at 5 minutes, then slowly return to 0.2 ml / min at 26 minutes, total flow The time is 30 minutes. The set flow "Cheng K" will dissolve out 5-HT in a 25-minute period. The chemical detector (EC & G, Model 400) of the amine column was set at a potential of 400 uV and a slip sensitivity of 0.2 nA / V. MHevlett-Packard HP1000 color analysis kit collects and analyzes data. It can measure the peak height and calculate the sample concentration. The baseline amount should be at least 90 minutes before application. The de-seedling water of the drug was prepared and applied in the amount of the following results (volume 0.25-0.3 ml). We calculated the amount of extracellular amine in the microdialysate by comparing K with the peak height of 50 picomolar standard solution. The average value of the top four samples of cytopharmaceuticals was used as the reference amount for each experiment and the data was converted into a percentage of the reference amount. The matching t-test M was used to compare the average of the reference value at the time point immediately before the application with the value at each time point thereafter. We have made the data available to make the trend more obvious. 31-The size of this paper is in accordance with China National Standard (CNS) A4 (210X297mm) ---------— Pack—I (please read the precautions on the back before filling this page) .tr line A7 B7 printed by the Employee Consumer Cooperative of the Ministry of Economic Affairs, China Bureau of Standards V. Description of the invention (29) In this test, the sister treatment included the racemic mixture of hydrogenated hydrogen and 4- (2-hydroxy-3-xylhexylamino) Propoxy) indole, flustine of maleic acid. Μ Prepare mice as above and indole (3¾ g / kg) subcutaneously 100 minutes after the start of the experiment. At 210 minutes after the start of the experiment, M 10 «g / kg intraperitoneal administration of flustatin * plus 3 mg / kg of the second thinnest indole. Each data point reported in this article represents a single animal. After the administration of lumbenole, the 5-HT held in the dialysate fell to 50% of the baseline weight, and at 210 minutes it was approximately 80% of the baseline. After flustine was applied, it was stabbed and measured after 240 minutes of sickle, about 410% of the benchmark dai, 270 minutes of sickle was about 450% of the baseline, 300 minutes of sickle was about 46 0%, and at 33 minutes It was about 390% of the baseline. After the application of lumbenole, the amount of NE increased to approximately 180% of the baseline and fell to near baseline at 210 minutes of sickle. After flustine was applied, it increased to approximately 500% of the benchmark shovel at 240 minutes, and was steadily extinguished to 340% and 280% of the benchmark at 270, 300, and 33 minutes. Similarly, the amount of DA increased to approximately 210% of the baseline at 120 minutes and decreased to near baseline at 210 minutes. After fluethin application, the amount of DA was reduced to approximately 1430% of the baseline at 240 minutes, approximately 840% of the baseline at 270 minutes, approximately 530% at 300 minutes, and approximately 330% at 330 minutes. & Μ.2. In this test, the application of the prosthesis is (+) _ durostine, hydrogen chloride * the application amount is 4 mg / kg and (-)-pinduo K. The application is set at 5 mg / kg . The method of this test is the same as that of Test 1. 120 minutes after the start of the test -32- This paper size is applicable to the Chinese National Standard (CNS) Α4 specification (210X297 mm) (please read the $ item on the back and fill in this page) • Packing. A7 B7. 5. Description of the invention (30) Application of (-)-pindol a, then at 210 minutes for duloxetine and the second dose of (-)-pindollen, the amount of application is 5. Mg / kg. The results shown below are the percentages of the three monoamines to the baseline at different times after the start of the test. Each data point represents the average of three or more animals. (Please read the precautions on the back before filling in this page) r Pack and order ELJML 5 ^ ΗΤ HA. 120 minutes 8096 9096 90% 150 90 100 90 180 110 120 70 210 100 110 100 240 240 350 230 270 340 230 170 300 360 210 140 330 — 230 150 360 330 170 150 Employee Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs of the People's Republic of China. This test is conducted in the same way as Test 1, using 4- (2-hydroxy-3-cyclohexyl) at 120 minutes Aminopropaneoxy) indole, maleic acid », 3 * g / kg, and (+)-durostatin, gasification 鈥, 4 邂 克 / kg, and the first at 270 minutes Two cocoons of indole, 3 ng / kg. The results were as reported in the above Lanshi test 2. The result of 5-HT is the average of 3 animals, while the other results are the average of 4 animals. Thread · -33- The X degree of this paper is applicable to the Chinese National Standard (CNS) (210X297mm) 320562 A7 B7 V. Description of the invention (Μ) Time 5-HT Mu \ LL 120 points 90¾ 10096 10% 150 130 160 150 180 130 140 130 210 80 140 110 240 90 130 100 270 80 150 110 300 650 580 410 330 670 390 280 360 590 450 240 390 490 320 210 420 440 290 200 (please read the precautions on the back before filling out this page) ·

，1T 經濟部中央樣準局員工消費合作社印製 本紙張尺度適用中國國家梂準（CNS ) A4规格（210X297公釐）, 1T Printed by the Employee Consumer Cooperative of the Central Prototype Bureau of the Ministry of Economic Affairs. The paper size is applicable to China National Standards (CNS) A4 (210X297mm)

Claims (1)

8 8 8 8 ABCD8 8 8 8 ABCD 330562 第331丨0090號專利由請案 中文申請專利範圍修正本（85年11月) 六、申請專利範圍丨 t ^ 公告本 1. 一種治療源自或因5 -羥色胺、正聚上腺素與多巴胺利用 率降低引起之疾病之S藥姐合物，其包括第一種成份， 其涤選自1至80毫克/天之氟洛色汀（flU0xetine)、1至 30毫克/天之杜洛色汀（duloxetine)、10至150毫克/天 之芬拉法辛（venlafaxine)及1〇至1〇〇毫克/天之米納西 普MUilnacipran)，及第二種成份，其係選自1至6〇毫 克/天之品多露（Pindolol)、2至80毫克/天之偏布托兹 (penbutolol)、10至240毫克/天之普羅普蘭諾裔 (propranolol)、1至 100 毫克 / 天-之 X、他多 (tertatolol)、與1至50毫克/天之一種具下式之化合物 0H I ·· I Ar-O-CHjCHCHjNHZ 其中Ar係 (請先閲讀背面之注意事項再填寫本頁)330562 No. 331 丨 0090 Patent application for amendment of the scope of the Chinese patent application (November 1985) VI. Patent scope 丨 t ^ Bulletin 1. A treatment originated from or due to serotonin, polyadrenaline and S-drug compound for diseases caused by reduced dopamine utilization rate, which includes the first ingredient selected from 1 to 80 mg / day of fluoxetine (flU0xetine) and 1 to 30 mg / day of duloxine Duloxetine, venlafaxine from 10 to 150 mg / day and MUilnacipran from 10 to 100 mg / day, and the second ingredient, which is selected from 1 to 6 Pindolol (mg / day), penbutolol (2 to 80 mg / day), propranolol (10 to 240 mg / day), 1 to 100 mg / day (X) , Tertatolol, and 1 to 50 mg / day of a compound of the formula 0H I ·· I Ar-O-CHjCHCHjNHZ where Ar is (please read the precautions on the back before filling this page) 經濟部中央標準局舅工消费合作社印装 R 2為氮； Z為（C4_Ce環烷基），可視需要KCi-C<t烷基或苯基 取代； X 為-H ; 或其翳藥上可接受的鹽。 本紙速财H8家料（CNS ) ( 210^：2#公赛) 320562 含8: D8六、申請專利範圍 經濟部中央標準局肩工消費合作社印製 含 包 病 疾 該 中 其 物 合 . ， 姐 群 ， 之 侯 項 症 1 期 第 ，體 ， ， 圍痛黃 群 症 ，， 範纆後 侯 乏常群 , 利神或 症 ，缺 ，異侯 症， 專 、是 群，， 後，’症意 患格症 ’食症 及 請 ，別 侯毒用， 傷失呆懼注，疾人勞 難厭調，， 申 > 痛特，症中濫症’創喪痴恐性狂性型疲，困性失症症 據鬱頭、疾前精草慌慮大憶年交動壞動緣性洩起羥眠閉語 根抑偏痛食經酒煙恐焦重記老社過破衝遏慢早勃神睡自1 (請先閱讀背面之注意Ϋ項再填寫本页) 本紙涑又度適用中國國家梂準（CNS ) A4規格（210^2為公灰） A8R2 is printed by the Uncle Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. R is nitrogen; Z is (C4_Ce cycloalkyl), KCi-C < t alkyl or phenyl can be substituted if necessary; X is -H; Accept the salt. This paper Sucai H8 materials (CNS) (210 ^: 2 # competition) 320562 Including 8: D8 Six, apply for a patent scope The Central Standards Bureau of the Ministry of Economic Affairs Shoulder Consumer Cooperative printed the packaged diseases and diseases. Sister group, the first phase of the first item, body, perinatal pain, yellow group disease, Fan Houhou Hou Changchang group, divine or syndrome, deficiency, eccentric syndrome, special, is group, after, Intentional illness 'eating disorder and please, don't use it for poisoning, loss of fear and fear, hard work and discomfort ,, Shen > Painful, moderate illness' trauma, dementia, madness, fatigue, Distressed acuity syndrome, according to depression, pre-existing fine grass and worry, recalling the year, the interaction, the dysfunction, the marginal discharge of hydroxysleep, the closed root, the migraine, the diet, the alcohol, the alcohol, the fear, the focus, and the old society. Shenshuizi 1 (Please read the note Ϋ on the back before filling in this page) This paper is again applicable to China National Standards (CNS) A4 specifications (210 ^ 2 is public gray) A8 六、申請專利範圍 320562 拔_髮狂。 3·根據申·請專利範圍第1項之姐合物，其包括杜洛色汀。 4 '根據申請專利範圍第1項之姐合物，其包括氣色汀。 5 根據申請專利範圍第1項之姐合物，其中該第二類成份 係選自品多茲及4-(2 -羥基-3-環己基胺基丙氧基）吲哚 0 6. 根據申請專利範圍第1至5項中任何一項之姐合物*其用 Μ製造可增強第一類成份增加腦中5_羥色胺、正腎上腺 素與多巴胺利用率的作用之辑物。 7. 根撺申請專利範圍第1至5項中任何一項之组合物，其用 Μ製造可治療因減弱的5_羥色胺、正腎上腺素或多巴胺 的利用率所引起或與其有關的病害之藥物。 (請先Μ讀背面之注意事項再填寫本VK ) 、1Τ 4 ! 經濟部中央輮準局w：工消費合作社印装 本紙張尺度逍用中國國家梂準（CNS ) Α4規格（210父_29多公瘦）Sixth, the scope of patent application 320562 is drawn _ crazy. 3. The sister compound according to item 1 of the patent application, which includes dulostatin. 4 'According to the sister compound of item 1 of the scope of the patent application, it includes gastin. 5 The sister compound according to item 1 of the patent application scope, wherein the second type of component is selected from Pindoz and 4- (2-hydroxy-3-cyclohexylaminopropoxy) indole 0 6. According to the application The sister compound of any one of the items 1 to 5 of the patent scope * It is made of M and can enhance the effect of the first class of ingredients to increase the utilization of serotonin, norepinephrine and dopamine in the brain. 7. The composition according to any one of the items 1 to 5 of the patent application scope, which is made of M and can be used for the treatment of diseases caused by or related to the reduced utilization of serotonin, norepinephrine or dopamine. . (Please read the precautions on the back before filling in this VK), 1Τ 4! Central Bureau of Economic Affairs of the Ministry of Economic Affairs w: Printed copies of industrial and consumer cooperatives. The paper size can be used in China National Standards (CNS) Α4 specifications (210 father_29 Duo Gong thin)