TW200938189A

TW200938189A - [2-(6-flouro-1H-indol-3-ylsulfanyl)benzyl]methyl amine for the treatment of affective disorders

Info

Publication number: TW200938189A
Application number: TW098106811A
Authority: TW
Inventors: Jeffrey Scott Sprouse; Karina Kroejer Soeby; Neil Anderson
Original assignee: Lundbeck & Co As H
Priority date: 2008-03-13
Filing date: 2009-03-03
Publication date: 2009-09-16
Also published as: CL2009000593A1; AR072449A1; WO2009112541A2; WO2009112541A3

Abstract

[2-(6-fluoro-1H-indol-3-ylsulfanyl)benzyl] methyl amine and pharmaceutically acceptable salts thereof is provided for the treatment of CNS disorders.

Description

200938189 六、發明說明：【發明所屬之技術領域】本發明提供CNS疾病的治療性治療。【先前技術】 ' 睡眠為許多情感性精神病（諸如抑鬱症及焦慮）中的活力因素。實際上，睡眠中斷（sleepdisrupti〇n)為抑鬱症的主要症狀，且通常正是睡眠中斷才使罹患抑鬱症之患者尋求幫助。為此，重要的是向患者提供的任何醫學介入改善睡眠障礙，且當然其本身不會加重睡眠問題。當然，對於治療其他情感性精神病亦如此。情感性精神病的標準醫學治療包括具有增加大腦中單胺神經傳遞質金清素及/或去甲腎上腺素含量之作用的化合物。儘管此等藥劑用於治療多種情感性精神病，但其通常稱為「抗抑鬱劑」。最普遍之治療形式包括增加血清素含 Q 量之選擇性血清素再吸收抑制劑（SSRI )，其熟知且市售實例包括依他普余（escitalopram)、氟西汀（flu〇xetine) 及舍曲林（sertraline)。選擇性去甲腎上腺素再吸收抑制劑（NRI)增加去甲腎上腺素之含量，其—實例為瑞波西江 (reboxetine )。其他化合物抑制血清素再吸收及去甲腎上腺素再吸收兩者，且稱為SNRIe此藥劑群組的重要實例包括文拉法辛（venlafaxine)及度洛西汀（dul〇xetine)。最終’稱為三環狀抗抑鬱劑（TCA)之藥劑群組廣泛用於治療抑繫症，且此化合物群組之成員傾向於具有較寬藥理概 200938189 況’其除了對血清素及去甲腎上腺素轉運體的抑制作用之外，對其他大腦受體（諸如，乙醯膽鹼受體、腎上腺素能受體及組織胺受體）亦有作用。 b 不幸的是，睡眠障礙似乎為多數抗抑誉劑的普遍不良影響。詳言之，SSR卜腿及S腿據報導產生關於入睡及睡眠保持的問題且通常亦報導失眠問題隱，21 (增刊 1}，S25_S29, 2〇〇6]。其他資料報導該等化合物產生受抑制之REM睡眠、增加之睡眠潛伏期、低效睡眠、夜間覺醒增加及睡眠斷斷續續 [Hum.Psychopharm.CZin.ExjK，20, 533-559, 2005]。使用具有去甲腎上腺素再吸收抑制作用之化合物引起去甲腎上腺素含量增加，其為情感性精神病治療中治療作用的原因。然而，去甲腎上腺素亦具有周邊作用，例如增加之心率、血管收縮及隨之發生的血壓增加。此等周邊作用導致對於去甲腎上腺素再吸收抑制劑報導之不良作用。文拉法辛及度洛西汀（兩者皆為去曱腎上腺素及血清素再吸收抑制劑）據報導引起血壓增加[Cwrr以〜及以， 522-540, 2005 ; 59, 502_5〇8, 1998]。血壓增加一般且尤其對於已罹患增加之企壓（高血壓）之患者 (例如，老年人）而言成問題。已知上腺素能受體（αι受體）拮抗劑引起周邊血管舒張且隨後由於流阻降低而血壓降低[c//w几以,26, 1701·1713, 2004]。上述發現及觀測結果表明對血清素及/或去甲腎上腺素 200938189 再吸收具有抑制作用且具有αι受體拮抗活性之化合物的鑑別將提供適於治療情感性精神病（諸如，抑鬱症）而不具有或具有減少之不良心血管作用（諸如，增加之血壓）之化合物。作為WO 2〇05/061455公開之國際專利申請案揭示某些 2-(1//-吲哚基硫烷基【sulfanyl】）节基胺衍生物，且尤其 [2-(6-氟-Ι/f-吲哚-3_基硫烷基）苄基]甲基胺為血清素再吸收抑制劑且亦可能為去甲腎上腺素再吸收抑制劑。該等化合物據稱適用於治療情感性精神病，諸如抑繫症。作為WO 2008/037258公開之國際專利申請案揭示 [2-(6-氟-1孖-吲哚_3_基硫烷基）苄基]曱基胺的結晶鹽以及該等鹽的治療應用。【發明内容】本發明者已驚奇地發現[2-(6-氟-1A吲哚_3_基硫烷基） ◎ 苄基]甲基胺為有效的血清素再吸收抑制劑，有效的去甲腎上腺素再吸收抑制劑及有效的αΐΑ受體拮抗劑，且因而適用於治療CNS病症。因此，在一具體實例中，本發明係關於治療方法，該方法包含向有需要之患者投予治療有效量之[2-(6-氟-1"-吲哚_3_基硫烷基）苄基]_甲基胺或其醫藥上可接受之鹽（化合物I)。在一具體實例中，本發明係關於用於治療疾病之[2_(6_ 氟-If吲哚-3-基硫烷基）苄基]甲基胺或其醫藥上可接受之鹽（化合物I) » 200938189 在一具體實例中，本發明係關於^吲哚_3_基硫烷基）苄基]甲基胺或其醫藥上可接受之鹽（化合物n於製造藥劑之用途。【實施方式】本發明係關於[2-(6-氟-1//-吲哚_3_基硫烷基）苄基]_曱200938189 VI. Description of the Invention: [Technical Field to Which the Invention Is Present] The present invention provides therapeutic treatment of CNS diseases. [Prior Art] 'Sleep is a vital factor in many affective mental illnesses such as depression and anxiety. In fact, sleep disruption (sleepdisrupti〇n) is the main symptom of depression, and it is usually the interruption of sleep that causes patients with depression to seek help. To this end, it is important that any medical intervention provided to the patient improves the sleep disorder and, of course, does not itself aggravate sleep problems. Of course, this is also true for the treatment of other emotional psychosis. Standard medical treatments for affective psychosis include compounds that have the effect of increasing the levels of monoamine neurotransmitters and/or norepinephrine in the brain. Although these agents are used to treat a variety of affective psychosis, they are often referred to as "antidepressants." The most common forms of treatment include selective serotonin reuptake inhibitors (SSRIs) that increase the amount of serotonin Q, well known and commercially available examples include escitalopram, fluoxetine, and fluoxetine Qulin (sertraline). The selective norepinephrine reuptake inhibitor (NRI) increases the amount of norepinephrine, an example of which is reboxetine. Other compounds inhibit both serotonin reuptake and norepinephrine reuptake, and are referred to as SNRIe. Important examples of this group of agents include venlafaxine and dulxine. Finally, a group of agents called tricyclic antidepressants (TCA) is widely used to treat depressive disorder, and members of this group of compounds tend to have a broader pharmacological profile of 200938189, except for serotonin and desmethyl In addition to the inhibition of adrenergic transporters, it also has effects on other brain receptors such as acetylcholine receptors, adrenergic receptors and histamine receptors. b Unfortunately, sleep disorders appear to be a general adverse effect of most anti-suppressants. In particular, SSR legs and S legs are reported to have problems with falling asleep and sleep retention and are often reported as insomnia, 21 (Supplement 1}, S25_S29, 2〇〇6). Other information reports on the production of these compounds. Inhibited REM sleep, increased sleep latency, inefficient sleep, increased nighttime arousal, and sleep on and off [Hum. Psychopharm. CZin. ExjK, 20, 533-559, 2005]. Use of compounds with norepinephrine reuptake inhibition Causes an increase in norepinephrine levels, which is the cause of therapeutic effects in the treatment of affective psychosis. However, norepinephrine also has peripheral effects such as increased heart rate, vasoconstriction, and consequent increase in blood pressure. Leads to adverse effects reported for norepinephrine reuptake inhibitors. Venlafaxine and duloxetine (both are norepinephrine and serotonin reuptake inhibitors) have been reported to cause an increase in blood pressure [Cwrr to ~ And, 522-540, 2005; 59, 502_5〇8, 1998]. The increase in blood pressure is general and especially for patients who have suffered an increased stress (hypertension) (for example, It is a problem for the elderly. It is known that the adrenergic receptor (αι receptor) antagonist causes peripheral vasodilation and then lowers blood pressure due to decreased flow resistance [c//w, 26, 1701·1713, 2004] The above findings and observations indicate that the identification of compounds that have an inhibitory effect on serotonin and/or norepinephrine 200938189 reuptake and that have alpha 1 receptor antagonistic activity will provide for the treatment of affective psychosis (eg, depression). A compound that does not have or has a reduced adverse cardiovascular effect, such as increased blood pressure. The international patent application published as WO 2 〇 05/061455 discloses certain 2-(1//-mercaptosulfanyl groups). [sulfanyl]) stilbene amine derivatives, and especially [2-(6-fluoro-Ι/f-吲哚-3_ylsulfanyl)benzyl]methylamine is a serotonin reuptake inhibitor and may also a norepinephrine reuptake inhibitor. These compounds are said to be suitable for the treatment of affective psychosis, such as amelioration. The international patent application published as WO 2008/037258 discloses [2-(6-fluoro-1孖- Crystalline salts of 吲哚_3_ylsulfanyl)benzyl]decylamine and such Therapeutic applications of the present invention have surprisingly found that [2-(6-fluoro-1A吲哚_3_ylsulfanyl) ◎ benzyl]methylamine is an effective serotonin reuptake inhibitor An effective norepinephrine reuptake inhibitor and an effective alpha guanidine receptor antagonist, and thus suitable for treating a CNS disorder. Thus, in one embodiment, the invention relates to a method of treatment, the method comprising The patient is administered a therapeutically effective amount of [2-(6-fluoro-1"-indole-3-ylsulfanyl)benzyl]-methylamine or a pharmaceutically acceptable salt thereof (Compound I). In one embodiment, the invention relates to [2-(6-fluoro-If吲哚-3-ylsulfanyl)benzyl]methylamine for use in the treatment of a disease, or a pharmaceutically acceptable salt thereof (Compound I) » 200938189 In one embodiment, the invention relates to the use of a compound or a pharmaceutically acceptable salt thereof (compound n) for the manufacture of a medicament. [Embodiment] The present invention relates to [2-(6-fluoro-1//-吲哚_3_ylsulfanyl)benzyl]_曱

及其醫藥上可接受之鹽（化合物I)的用途。在一具體實例中’該等醫藥上可接受之鹽為無毒酸之酸加成鹽。該等鹽包括由諸如以下各者之有機酸類製成的鹽：沙巴克酸（sabaconic acid)、2_羥基異丁酸、順丁稀二酸、反丁浠二酸、苄酸、抗壞血酸、丁二酸、草酸、雙亞甲基水揚酸、甲烧續酸、乙烧二績酸、乙酸、丙酸、酒石酸、水楊酸、檸檬酸、葡糖酸、乳酸、蘋果酸、扁桃酸、肉桂酸、檸康酸、天冬胺酸、硬脂酸、掠櫚酸、衣康酸、乙醇酸、對胺基苄酸、麩胺酸、苯磺酸、茶鹼乙酸以及8· 鹵基茶驗’例如8 -溴茶驗。該等鹽亦可由諸如以下各者之無機鹽類製成：鹽酸、氫溴酸、硫酸、胺磺酸、填酸及硝酸。尤其提及由甲烷磺酸、順丁烯二酸、反丁稀二酸、内 200938189 口服劑型（且尤其錠劑或膠囊因此之較佳順應性而為患者及醫師囊而言’活性成份較佳為晶體。在所用之化合物為晶體。消旋酒石酸、（+)-酒石酸、酸、亞磷酸及硝酸製成之鹽 (-)-酒石酸、鹽酸、氫溴酸、硫。特別提及L-(+)-酒石酸氫鹽。 )通常由於易於投予及所青睞。對於錠劑及膠一具體實例中，本發明 ❹And the use of its pharmaceutically acceptable salt (Compound I). In one embodiment, the pharmaceutically acceptable salts are acid addition salts of non-toxic acids. Such salts include salts made from organic acids such as: sabaconic acid, 2-hydroxyisobutyric acid, cis-butanedioic acid, succinic acid, benzylic acid, ascorbic acid, butyl Diacid, oxalic acid, bismethylene salicylic acid, methyl acid, acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, Cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzylic acid, glutamic acid, benzenesulfonic acid, theophylline acetic acid, and 8·halo-based tea Test 'for example, 8-bromo tea test. The salts may also be prepared from inorganic salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, amine sulfonic acid, acid and nitric acid. In particular, it is mentioned that the active ingredient is preferred for the patient and the physician's capsule by methanesulfonic acid, maleic acid, butyric acid, oral 200938189 oral dosage form (and especially for the better compliance of the tablet or capsule) It is a crystal. The compound used is a crystal. Racemic acid, (+)-tartaric acid, acid, phosphorous acid and nitric acid (-)-tartaric acid, hydrochloric acid, hydrobromic acid, sulfur, especially L-( +) - Hydrogen tartrate. ) Usually due to ease of administration and favor. For tablets and gels, a specific example, the present invention

在一具體實例中，本發明所用之晶體為溶劑合物，亦即溶劑分子形成晶體結構之部分的晶體。溶劑合物可由水形成，在該狀況下溶劑合物通常稱為水合物。或者，溶劑合物可由諸如乙醇、丙酮或乙酸乙醋之其他溶劑形成。溶劑合物的確切量通常視條件而定。舉例而言，水合物將典型地隨溫度增加或隨相對濕度降低而釋放水。在一具體實例中，本發明所用之化合物不為溶劑合物。對於使用結晶活性成份之口服劑型而言，若該等晶體經明確定義則亦為有益的。在本文中，術冑「經明確定曰義_ 尤其意謂化學計量經明確定義，亦即形成鹽之離子之間的比率為小整數之間的比率，諸如1:1、1:2、2:1、1:1:1等。在一具體實例中，本發明所用之化合物為經明確定義之晶體。曰曰一些化合物可具吸濕性’亦即當暴露於濕氣時吸水。一般認為吸濕性為欲存在於醫藥調配物（尤其乾燥調配物，諸如錠劑或膠囊）中之化合物的非所要特性。在一具趙實例中’本發明使用具有低吸濕性之晶艘。 7 200938189 活性成份之溶解度對於劑型選擇而言因為其可能對生物可用性I 、有重要性， ^ , 具有直接影響。對於口服劑型而言，咸信活性成份之較苒笮鈕# $ 服則孓而可用性增加。-肽患者η 囚為其使生物 ", :者（例如’老年患者）可能難以吞咽錠劑，且口服滴劑可能為 ^ 广而资吞咽錠劑的合適替代物。為了限制口服滴劑之體積，需 # ώ ^ 價需要使溶液中之活性成份為高濃度，其又需要化合物具有高溶解度。已發現自2經基異丁酸、鹽酸及氫漠酸製成的酸加成鹽以相對較高之溶解度形成明確定義之1:1鹽°本發明結晶化合物可以-種以上形式存在，'亦即其可以多晶型形式存在。若化合物可以一種以上形式結晶’則存在多晶型形式。本發明意欲涵蓋所有該等多晶型形式（作為純化合物或其混合物）之用途。在一具艎實例中，本發明使用以兩種多晶型形式形及/9形）存在之[2·(6_氟引哚_3_基硫烷基）苄基]甲基胺L-(+)酒石酸氫鹽的晶形。α形及/3形之xrpD分別顯示於圖1及圖2中。如下文之實施例所示，形具有較高熔點及較低溶解度且因此預期為比谷形穩定之形式。在一特定具體實例中，本發明使用α形卩^^氟—丨仏吲哚_3_基硫烷基）节基]甲基胺L-(+)_酒石酸氫鹽。在一特定具體實例中，本發明使用XRPD具有在約9.66、14.53、18.14及30.48(。 2 Θ )之主峰的[2-(6-氟-1H-吲哚-3-基硫烷基）苄基]甲基胺 L-(+)酒石酸氫鹽的晶形。在一特定具體實例中，本發明使用XRPD如圖1中所描繪之[2-(6-氟-1H_吲哚-3-基硫烷基）节基]甲基胺L-( + )-酒石酸氫鹽的晶形。 200938189 睡眠模式在各人之間亦及個體的生命期間廣泛變化。典型地，成人一晚睡眠7-8小時，而一些人需要1〇_12小時且其他人又可能以4-5小時勉強應付。睡眠量及品質應足以使睡眠者感覺得以休息、精力恢復且能適當進行第二天的活動。睡眠品質可主觀定量，亦即所涉及的個體自行評分或根據描述睡眠感受之相關參數對其加以評分。所用臨床評分包括HAS、HRSD及匹茲堡睡眠品質指數（Pittsburgh ❹ Sleep Quality Index)。或者，可藉由量測大腦活動（腦電流描記法（electroencephalography，EEG ))、肌肉活動（肌電描記法（electromyography，EMG ))或觀測生理參數（諸如，眼動）獲得客觀資訊。使用睡眠之客觀定量，已在哺乳動物中且實際上在人類中定義兩種睡眠類型（亦即，REM 及非REM睡眠）。REM (快速眼動）睡眠係由類似於覺醒狀態之快速低壓腦電波（如EEG所量測）及不規則自主活 ❹動（諸如，心率及呼吸）定義。此類型之睡眠與快速水平眼動、無意識肌肉痙攣及作夢有關。另一方面，非REM睡眠係由緩慢高壓腦電波及低且規則之自主活動（諸如，心率及血壓）定義。非REM睡眠為深度無夢型睡眠。認為某些恢復過程在非REM睡眠期間發生，例如生長激素在此類型之睡眠期間釋放。當自睡眠個體獲得EEG時，顯現由5個不同階段組成之睡眠模式：四個非REM階段及一個REM階段。階段j 顯示EEG活動減緩且為困倦至輕度睡眠之過渡階段。階段 200938189 2顯示睡眠紡錘波及K複合波形式顯現。階段3及4特徵為慢波且為深度睡眠。階段5為REM睡眠。階段3及階段4 通常稱為慢波睡眠或SWS。在夜間，個體自覺醒狀態進展至階段1 (睡眠潛伏期）且緩慢經由階段2進展至4 ^個體接著進入REM睡眠環節，隨後再歷經階段1 _4 ^模式在各人之間不同，但典型地在夜間由4-5個循環組成。該等循環在夜間變化’使得多數深度睡眠（階段3與4 )在前半夜發生且多數REM睡眠在後半夜發生《總之’成人平均將經歷 80%之睡眠為非REM睡眠且20%之睡眠為REM睡眠。夜間各個睡眠階段的存在模式稱為睡眠結構。最終由患者對睡眠品質之感受來判斷與治療介入有關之睡眠改善或不良睡眠作用的缺乏。典型地，諸如睡眠潛伏期（入睡之前的時間）、夜間覺醒次數、覺醒時的睡眠潛伏期、早晨得以休息及精力恢復的感覺、失眠、睡眠持續時間、睡眠充分性、清晨覺醒、第二天的表現及過多日間嗜睡之參數對於個體對其睡眠之感受而言為重要的。此等參數中有-些可藉由如上文所述量測EEG或EMG來更客觀地評估。如實施例中所示，本發明所用之化合物以劑量依賴方式增加大鼠之慢波睡眠量、減少REM睡眠量及縮短睡眠潛伏期。預期此等臨床前發現體現為該等化合物所投予之患者的睡眠品質改善。因為表面上預期具有對血清素及去甲腎上腺素吸收之組合抑制作用之化合物將降低睡眠品質，所以此為未預料之結果。 200938189 增加之血壓可能引起頭暈及困倦，但罹患增加之血壓之個體通常不清楚其狀況，因為不存在即刻或嚴重症狀。然而’避免即使略微增加的血壓為重要的，因為長期而言其可能導致諸如心肌梗塞、心臟功能不全、腎功能不全及腦溢血之後果。血壓通常表述為舒張壓及收縮壓β收縮壓為心臟完全收縮時的壓力而舒張壓為心臟完全放鬆時的壓力。血壓典 ❹ 型地在靜止及仰臥時，亦即個體躺下時量測。健康個體平均將具有80-90/130-140 mm Hg舒張/收縮壓。實施例中所示之資料顯示本發明化合物引起犬之血壓降低。預期此臨床前發現在臨床情境中體現為極少或無血壓增加，或者血壓略微降低。此為未預料之結果，因為表面上預期具有去曱腎上腺素再吸收抑制作用之化合物將引起企壓增加。雙極性情感疾患先前稱為躁鬱病（manic_depressive 〇 lUness)且其特徵為躁症與抑鬱症的週期性發作。典型地，躁狂發作以諸如喧硫平（quetiapine )或奥氮平（。心叫⑹）之抗精神病藥物治療，其皆展示或與鐘—起展示5·Ητ2Α枯抗作用。如實施例12及13所示，本發明所用之化合物顯不抗躁狂作用，該作用與抗抑#特性組合表明以下用途：治療雙極性情感疾患，例如治療（輕度）躁狂發作，治療雙極性情感疾患構架中的重繁發作（雙極性抑繫症），使 ==疾患的情緒穩定’維持治療雙極性情感疾患及預防雙極性情感疾患復發。 11 200938189In one embodiment, the crystals used in the present invention are solvates, i.e., crystals in which the solvent molecules form part of the crystal structure. The solvate can be formed from water, in which case the solvate is often referred to as a hydrate. Alternatively, the solvate can be formed from other solvents such as ethanol, acetone or ethyl acetate. The exact amount of solvate will generally depend on the conditions. For example, hydrates will typically release water as temperature increases or as relative humidity decreases. In a specific embodiment, the compound used in the present invention is not a solvate. For oral dosage forms using crystalline active ingredients, it is also beneficial if such crystals are well defined. In this paper, 胄胄经曰曰曰 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ : 1, 1: 1:1, etc. In a specific example, the compound used in the present invention is a well-defined crystal. 曰曰 Some compounds may be hygroscopic, that is, absorb water when exposed to moisture. Hygroscopicity is an undesirable property of a compound to be present in a pharmaceutical formulation, especially a dry formulation, such as a lozenge or capsule. In one example, the invention employs a crystallizer having a low hygroscopicity. 200938189 The solubility of the active ingredient is directly related to the choice of dosage form because it may have a significant impact on bioavailability I. ^ For oral dosage forms, the active ingredient is more useful than the button ## Increased - peptide patients η prisoners for their biological ", : (such as 'elderly patients) may be difficult to swallow tablets, and oral drops may be a suitable substitute for swallowing lozenges. To limit oral drops Volume of agent , need # ώ ^ The price needs to make the active ingredient in the solution a high concentration, which in turn requires the compound to have high solubility. It has been found that the acid addition salt made from 2 mesobutyric acid, hydrochloric acid and hydrogen desert acid is relatively more The high solubility forms a well-defined 1:1 salt. The crystalline compound of the present invention may exist in more than one form, that is, it may exist in a polymorphic form. If the compound may be crystallized in more than one form, a polymorphic form exists. The invention is intended to cover the use of all such polymorphic forms (as pure compounds or mixtures thereof). In one example, the invention uses both polymorphic forms and /9 shapes) [2·( The crystal form of 6-fluoroindolyl _3_ylsulfanyl)benzyl]methylamine L-(+) hydrogen tartrate. The α-form and /3-form xrpD are shown in Fig. 1 and Fig. 2, respectively. As shown in the examples, the shape has a higher melting point and lower solubility and is therefore expected to be more stable than the valley shape. In a specific embodiment, the invention uses alpha-form 氟^^-fluoro-丨仏吲哚_3_ Sulfhydryl)]methylamine L-(+)-hydrotartanic acid hydrogenate In the present invention, XRPD has [2-(6-fluoro-1H-indol-3-ylsulfanyl)benzyl]methylamine having a main peak at about 9.66, 14.53, 18.14 and 30.48 (. 2 Θ). Crystal form of L-(+) hydrogen tartrate. In a particular embodiment, the invention uses XRPD as described in Figure 1 [2-(6-fluoro-1H-indol-3-ylsulfanyl) nodal Crystalline form of methylamine L-(+)-hydroartrate. 200938189 Sleep patterns vary widely between individuals and individuals. Typically, adults sleep 7-8 hours a night, while some need 1〇_12 hours and others may be able to cope with 4-5 hours. The amount and quality of sleep should be sufficient to allow the sleeper to feel rested, energized and properly exercised the next day. The quality of sleep can be subjectively quantified, i.e., the individuals involved are self-rating or scored according to relevant parameters describing sleep sensations. Clinical scores used included HAS, HRSD, and the Pittsburgh Sleep Quality Index. Alternatively, objective information can be obtained by measuring brain activity (electroencephalography (EEG)), muscle activity (electromyography (EMG)), or observing physiological parameters (such as eye movement). Using the objective quantification of sleep, two types of sleep (i.e., REM and non-REM sleep) have been defined in mammals and indeed in humans. REM (rapid eye movement) sleep is defined by fast low-pressure brain waves (as measured by EEG) and irregular autonomous movements (such as heart rate and respiration) similar to the arousal state. This type of sleep is associated with rapid levels of eye movements, unconscious muscle spasms, and dreaming. On the other hand, non-REM sleep is defined by slow high-pressure brain waves and low and regular autonomic activities such as heart rate and blood pressure. Non-REM sleep is a deep dreamless sleep. It is believed that some recovery processes occur during non-REM sleep, such as growth hormone release during this type of sleep. When an EEG is obtained from a sleeping individual, a sleep pattern consisting of five different phases is revealed: four non-REM phases and one REM phase. Stage j shows a slow transition from EEG activity and a transition from drowsiness to mild sleep. Stage 200938189 2 shows the appearance of the sleep spindle wave and the K complex wave. Stages 3 and 4 are characterized by slow waves and deep sleep. Stage 5 is REM sleep. Phase 3 and Phase 4 are commonly referred to as slow wave sleep or SWS. At night, the individual's self-awake state progresses to stage 1 (sleep latency) and slowly progresses through stage 2 to 4^, then enters the REM sleep session, and then goes through the phase 1 _4 ^ mode, which varies from person to person, but typically It consists of 4-5 cycles at night. These cycles change at night' such that most deep sleep (stages 3 and 4) occur in the first half of the night and most REM sleep occurs in the second half of the night. "In general, adults will experience 80% of sleep as non-REM sleep and 20% of sleep. REM sleep. The mode of existence of each sleep stage at night is called the sleep structure. Ultimately, the patient's perception of sleep quality is used to judge the lack of sleep improvement or poor sleep associated with treatment intervention. Typically, such as sleep latency (time before falling asleep), number of nighttime awakenings, sleep latency during awakening, feeling of rest in the morning and restoring energy, insomnia, sleep duration, sleep adequacy, early morning awakening, second day performance And the parameters of excessive daytime sleepiness are important for the individual's perception of their sleep. Some of these parameters can be more objectively evaluated by measuring EEG or EMG as described above. As shown in the examples, the compounds used in the present invention increased the slow wave sleep, reduced REM sleep, and shortened sleep latency in rats in a dose dependent manner. These preclinical findings are expected to be manifested in the improvement of sleep quality in patients administered with such compounds. This is an unexpected result because compounds that are expected to have a combined inhibitory effect on serotonin and norepinephrine absorption will reduce sleep quality. 200938189 Increased blood pressure may cause dizziness and drowsiness, but individuals with increased blood pressure are often unclear because there are no immediate or severe symptoms. However, it is important to avoid even a slight increase in blood pressure, which may cause consequences such as myocardial infarction, cardiac insufficiency, renal insufficiency, and cerebral hemorrhage in the long term. Blood pressure is usually expressed as diastolic blood pressure and systolic blood pressure. The systolic blood pressure is the pressure at which the heart is completely contracted and the diastolic blood pressure is the pressure at which the heart is completely relaxed. The blood pressure pattern is measured at rest and in the supine position, that is, when the individual is lying down. Healthy individuals will have an average diastolic/systolic blood pressure of 80-90/130-140 mm Hg. The data shown in the examples show that the compounds of the invention cause a decrease in blood pressure in dogs. It is expected that this preclinical finding will show little or no increase in blood pressure or a slight decrease in blood pressure in the clinical setting. This is an unexpected result because the compound expected to have a norepinephrine reuptake inhibitory effect on the surface will cause an increase in the pressure. Bipolar emotional disorders, formerly known as manic_depressive 〇 lUness, are characterized by periodic episodes of snoring and depression. Typically, manic episodes are treated with antipsychotic drugs such as quetiapine or olanzapine (heart (6)), all of which exhibit or exhibit a 5 Η Α 2 Α Α effect. As shown in Examples 12 and 13, the compounds used in the present invention are not resistant to manic effects, and the combination of this effect and anti-suppressive properties indicates the following uses: treatment of bipolar emotional disorders, such as treatment (mild) manic episodes, treatment The recurrence of bipolar emotional disorders (bipolar suppression) makes the emotional stability of == disorders maintain the treatment of bipolar emotional disorders and prevent the recurrence of bipolar emotional disorders. 11 200938189

由於對血清素及去甲腎上腺素再吸收的組合作用，化合物Ο)亦可用於治療疼痛，參看TCA在疼痛治療中之用途。在一具體實例中，疼痛為以下疼痛或與以下疼痛有關：鞭打、IBS、慢性疼痛、幻肢痛、神經病性疼痛、糖尿病性神經病變、疱疹後神經痛（PHN)、腕道症候群（cts)、 HIV神經病變、複雜性局部疼痛症候群（cpRs)、三又神經痛（trigeminal neuralgia/trigeminus 咖响^/心 d〇ul〇Ureux)、手術介入後之疼痛（例如，術後鎮痛）、糖尿病性血管病變、毛細血管抗性、與胰島炎有關之糖尿病性症狀、與月經有關之疼痛、與癌症有關之疼痛、牙痛、頭痛、偏頭痛、緊張型頭痛、顳骨下顎關節症候群、肌筋膜疼痛、肌肉損傷、骨路及關節疼痛（骨關節炎）、類風濕性關節炎、與燒傷有關之外傷所引起的浮腫、骨質疏鬆症、骨轉移、痛風、纖維組織炎、胸廓出口症候群 '骨^Due to the combined action of serotonin and norepinephrine reuptake, the compound Ο) can also be used to treat pain, see TCA for pain management. In one embodiment, the pain is painful or associated with: whipping, IBS, chronic pain, phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (PHN), carpal tunnel syndrome (cts) , HIV neuropathy, complex local pain syndrome (cpRs), trigeminal neuralgia (trigeminal neuralgia/trigeminus coffee ring / heart d〇ul〇 Ureux), pain after surgical intervention (eg, postoperative analgesia), diabetes Vascular lesions, capillary resistance, diabetic symptoms associated with isletitis, pain associated with menstruation, pain associated with cancer, toothache, headache, migraine, tension headache, lower jaw joint syndrome, myofascial pain, Muscle damage, bone and joint pain (osteoarthritis), rheumatoid arthritis, edema caused by burn-related trauma, osteoporosis, bone metastasis, gout, fibrositis, thoracic outlet syndrome 'bone ^

痛、心源性胸痛、非心源性胸痛、與脊髓損傷（SCI)有關之疼痛、中風後中樞神經痛、癌性神經病變、AIDS、鐮狀細胞痛或老人痛（geriatric pain) 就以下意義而言一部分抑鬱患者將對以（例如）ssri 治療有反應：SSRI將改良臨床相關抑鬱症量表（諸如， MADRS及HAMD )，但其他托壯（钱& 〇头他症狀（諸如，睡眠障礙及認知損傷）仍存在。在本文中’此等患者稱為部分反應者。由於上述對睡眠品質的作用，預期化合物！適用於治療部分反應者或改述為以化合物〗治療抑鬱患者將減少部分反應者的分率。 12 200938189 由於本發明所用化合物之藥理概況，其適用㈣㈣受益於大腦中血清素及/或去甲腎上腺素含量增加的疾病。本發明化合物尤其適用，因為其不引起患者睡眠品質的進一步降低，且甚至可能引起該睡眠品質的改良，且因為其不引起心血管副作用或僅引起減少之心企管副作用，諸如血壓增加。因n具體實例，本發明係關於治療將受益於大腦中血清素及/或去甲腎上腺素含量增加之疾病的方法，該方法包含向有需要之患者投予治療有效量之化合物 I。在一具體實例中，該治療伴有極少或無不良睡眠作=或患者睡眠品質之改良且/或伴有減少或無心血管副作用（諸如，增加之血壓）。在一具體實例中，本發明提供用於治療以下病症之方法：躁症、輕度躁狂、雙極性情感疾患（維持）、預防雙極性情感疾患復發、使雙極性情感疾患穩定、部分反應者之抑鬱症；抗治療性抑鬱症；重度抑鬱症；情感迴環；全身性醫學病況引起之情感疾患；物質誘發之抑鬱症；復發性抑鬱症；單次發作抑鬱症；兒科抑鬱症；非典型抑鬱症；中風後抑鬱症；耗竭性抑鬱症；季節性情感性精神病 (SAD );與精神***症有關之抑鬱症、***情感性精神病、胃腸痛、IBS、濫用、敵意、易怒、疲勞、焦慮（焦慮性抑鬱症）、路易體病（Lewy Body disease )或多發性硬化症；飛行電梯或小房間恐懼症，與疼痛有關之一般性焦慮症；高血壓風險增加之患者的焦慮；有睡眠問題之患者的焦慮，s忍知損害、阿茲海默氏病（Alzheimer’s disease )、癌 13 200938189 呆；輕度認知損害（MCI );血管型癡呆；白質疏鬆 (leucariosis);小血管疾病；與ADHD有關之強迫及注意力譜系病症、亞斯柏格症候群（Asperger,ssyndr〇me);自閉症；與情感性精神病有關之認知損害、抑鬱症、整體抑營症、重鬱症、焦慮症、-般性焦慮症、恐慌症、強迫症、精神***症、帕金森氏病（parkins〇n，s disease)、癡呆、 AIDS癌呆、ADHD、年齡相關的記憶損害、唐氏症候群 (Down’s syndrome)、癲癇症、外傷性腦損傷、亞斯柏格症候群、色氨酸經化酶基因突變及阿兹海默氏病；與癌呆有關之行為障礙；與癡呆及阿茲海默氏病有關之攻擊性及焦躁；精神***症中之負向症狀；㈣、㈣或碳水化合物成癮，物質濫用；酒精或藥物濫用；進食障礙；肥胖症；厭食症；貪食症；暴食症；衝動控制病症；間歇性爆怒症；偷竊癖；縱火癖；病理性賭博；拔毛髮癖；晝夜節律障礙；原發性失眠、長期失眠、暫時性失眠；睡眠呼吸暫停；睡眠呼吸障礙1通氣症候群；與壓力有關之病症；急性壓力；燒傷；壓力；慢性疲勞症候群；品行障礙；行為障礙；老年行為障礙；與HPA軸活性過高有關之姨島素抗性；熱潮紅、嘔吐、停經前、圍停經期及停經後不悅症；病理性哭泣，弱視，妥瑞氏症候群（T〇urette，s syndr〇me )或疼痛，該方法包含向有需要之患者投予治療有效量之化合物I。詳言之，該患者已經診斷患有上述適應症中之一或多種。在具體實例中，待治療之患者罹患睡眠有關病症。在具體實例中，待治療之患者罹患高血壓或處於罹 200938189 患高血虔之風險中。在一具體實例中，本發明包含判定該患者是否罹患增加之血壓或睡眠有關病症抑或處於罹患增加之血壓或睡目2 有關病症之風險中的起始步驟，且其中僅有未罹患增加之血壓或睡眠有關病症或不處於罹患增加之血壓或睡眠有關病症風險中之患者才接受上述醫學治療。 ❹Pain, cardiogenic chest pain, non-cardiac chest pain, pain associated with spinal cord injury (SCI), post-stroke central nervous system pain, cancerous neuropathy, AIDS, sickle cell pain or geriatric pain For example, some depressed patients will respond to (for example) ssri treatment: SSRI will improve the clinically relevant depression scale (such as MADRS and HAMD), but other support (money & hoe his symptoms (such as sleep disorders) And cognitive impairment) still exists. In this article, 'these patients are called partial responders. Due to the above effects on sleep quality, the expected compound! is suitable for treating partial responders or rephrases to treat patients with depression. The fraction of the responder. 12 200938189 Due to the pharmacological profile of the compounds used in the present invention, it is applicable (IV) (iv) Diseases that benefit from increased levels of serotonin and/or norepinephrine in the brain. The compounds of the invention are particularly useful because they do not cause sleep in patients. The quality is further reduced, and may even cause an improvement in the quality of sleep, and because it does not cause cardiovascular side effects Inducing only side effects, such as an increase in blood pressure. As a specific example, the present invention relates to a method of treating a disease that would benefit from increased levels of serotonin and/or norepinephrine in the brain, including The patient is administered a therapeutically effective amount of Compound I. In one embodiment, the treatment is accompanied by little or no adverse sleep = or improved sleep quality of the patient and/or accompanied by reduced or no cardiovascular side effects (such as increased blood pressure). In one embodiment, the invention provides methods for treating snoring, mild mania, bipolar affective disorders (maintenance), prevention of bipolar affective disorder recurrence, stabilization of bipolar affective disorders, partial response Depression; anti-therapeutic depression; major depression; emotional loop; emotional illness caused by systemic medical conditions; substance-induced depression; recurrent depression; single-onset depression; pediatric depression; atypical Depression; post-stroke depression; depletion depression; seasonal affective psychosis (SAD); associated with schizophrenia Depression, schizoaffective psychosis, gastrointestinal pain, IBS, abuse, hostility, irritability, fatigue, anxiety (anxiety depression), Lewy Body disease or multiple sclerosis; flight elevator or small room fear Symptoms, general anxiety disorder associated with pain; anxiety in patients with increased risk of hypertension; anxiety in patients with sleep problems, s tolerance, Alzheimer's disease, cancer 13 200938189 staying; Cognitive impairment (MCI); vascular dementia; leucariosis; small vessel disease; obsessive-compulsive lineage disorder associated with ADHD, Asperger, ssyndr〇me; autism; Cognitive impairment related to affective psychosis, depression, overall inhibition, severe depression, anxiety, general anxiety disorder, panic disorder, obsessive-compulsive disorder, schizophrenia, Parkins〇n, s disease , dementia, AIDS, cancer, ADHD, age-related memory impairment, Down's syndrome, epilepsy, traumatic brain injury, Asperger syndrome, color ammonia Chemase gene mutation and Alzheimer's disease; behavioral disorders associated with cancer; aggression and irritability associated with dementia and Alzheimer's disease; negative symptoms in schizophrenia; (d), (d) or Carbohydrate addiction, substance abuse; alcohol or drug abuse; eating disorders; obesity; anorexia; bulimia; binge eating disorder; impulsive control disorder; intermittent anger; thief; arson; pathological gambling;昼; circadian rhythm disorder; primary insomnia, long-term insomnia, temporary insomnia; sleep apnea; sleep-disordered breathing 1 ventilation syndrome; stress-related disorders; acute stress; burns; stress; chronic fatigue syndrome; conduct disorder; Obstacle; senile behavioral disorder; valerian resistance associated with hyperactivity of HPA axis; hot flashes, vomiting, premenopausal, peri-menopausal and post-menopausal discomfort; pathological crying, amblyopia, Tourette's syndrome (T 〇urette, s syndr〇me ) or pain, the method comprising administering to a patient in need thereof a therapeutically effective amount of Compound I. In particular, the patient has been diagnosed with one or more of the above indications. In a specific example, the patient to be treated is suffering from a sleep related condition. In a specific example, the patient to be treated is at high risk or at risk of high blood stasis in 200938189. In one embodiment, the invention comprises the initial step of determining whether the patient is suffering from increased blood pressure or sleep related conditions or is at increased risk of blood pressure or sleepy 2 related conditions, and wherein only the increased blood pressure is not affected The above medical treatment is only received by patients who are sleep-related or who are not at risk of increased blood pressure or sleep-related conditions. ❹

在-具體實例中，本發明向由於睡眠或血廢有關之不良作用而不能使用其他藥物（例如抗抑繫劑，諸如獻卜 SNRI、NRI或TCA )之患者提供二線治療。在此具體實例中：待治療之患者先前已接受另一藥物治療（或仍在接受該藥物治療），該藥物治療由於睡眠或血壓有關之不良作用而已停用（或必需停用）。本文所用之化合物的「治療有效量」意謂足以治癒、緩解或。P 77遏止指定疾病及其併發症的臨床表現之量。足以實現此目的之量定義|「治療有效量」。各目的之有效量將視個體之疾病或損傷的嚴重程度以及體重及總艎狀況而定。應理解可使用常規實驗，冑由建構值矩陣且測試該矩陣中之不同點來實現適當劑量的確定，此均在受訓醫師的一般技能範疇内。本文所用之術語「治療」意謂出於抗擊病況（諸如疾病或病症）之目的對患者進行之管理及護理，包含投予本發明之，合物°該術語意欲包括針對患者所罹患之指定病况的全谱系治療’諸如投予活性化合物以緩解症狀或併發症’延遲疾病m病況進程’緩解或減輕症狀及併發 15 200938189 症，及/或治癒或消除疾病、病症或病況以及預防病況，其中預防應理解為出於抗擊疾病、病況或病症之目的對患者進行之管理及護理’且包括投予活性化合物以預防症狀或併發症發作。然而’預防性（pr〇phyiactic/preventive )及治療性（therapeutic/curative )治療為本發明之兩個獨立態樣。待治療之患者較佳為哺乳動物，尤其為人類。在一具體實例中，化合物I係以每天每公斤體重約 0·001至約100 mg之量投予。典型口服劑量在每天每公斤體重約〇〇〇1至約1〇〇 ❹ mg ’較佳每天每公斤體重約〇〇1至約5〇 mg範圍内。確切劑量將視投予頻率及模式、所治療個體之性別、年齡、體重及一般狀況、所治療病況之性質及嚴重程度及待治療之任何伴隨疾病及熟習此項技術者顯而易見的其他因素而定。成人之典型口服劑量在每天〇1_5〇 mg化合物I，諸如每天0.5-30 mg或每天0.5-25 mg範圍内。此劑量可典型地藉由投予 0.1-50 mg，諸如 0.5-30 mg，諸如〇 5、i、2、3 ' 〇 4、5 ' 6、9、10、20或30 mg本發明所用之化合物來實現。典型地，本發明之治療將涉及每日投予本發明化合物。此舉可涉及每天投予一次，或每天投予兩次或甚至更頻繁投予。在—具體實例中，本發明係關於化合物Ϊ於製造用以治療以下病症之藥劑的用途：躁症、輕度躁狂、雙極性情感疾患（維持）、預防雙極性情感疾患復發、使雙極性情感 16 200938189 疾患穩定、部分反應者之抑鬱症；抗治療性抑鬱症；重度抑鬱症；情感迴環；全身性醫學病況引起之情感疾患；物質誘發之抑鬱症；復發性抑鬱症；單次發作抑鬱症；兒科抑鬱症；非典型抑鬱症；中風後抑營症；耗竭性抑鬱症；季節性情感性精神病（SAD);與精神***症有關之抑鬱症、 ***情感性精神病、胃腸痛、IBS、濫用、敵意、易怒、疲勞、焦慮（焦慮性抑鬱症）、路易體病或多發性硬化症；In a specific example, the present invention provides second-line therapy to patients who are unable to use other drugs (e.g., anti-repressive agents such as SNRI, NRI, or TCA) due to adverse effects associated with sleep or blood waste. In this particular example: the patient to be treated has previously received another medication (or is still receiving the medication) that has been discontinued (or must be discontinued) due to sleep or blood pressure-related adverse effects. A "therapeutically effective amount" of a compound as used herein means sufficient to cure, alleviate or otherwise. P 77 suppresses the amount of clinical manifestations of a given disease and its complications. To define the amount of this purpose | "therapeable effective amount". The effective amount for each purpose will depend on the severity of the individual's disease or injury, as well as the weight and overall condition. It will be appreciated that routine experimentation can be used to determine the appropriate dose by constructing a matrix of values and testing different points in the matrix, all within the general skill of the trained physician. The term "treating" as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or condition, including administration of the present invention. The term is intended to include a specified condition for a patient. Full-lineage therapy 'such as administering an active compound to relieve symptoms or complications 'to delay the progression of the disease m' to alleviate or alleviate symptoms and complications, and/or cure or eliminate the disease, condition or condition and prevent disease, including prevention It is to be understood that management and care of a patient for the purpose of combating a disease, condition or disorder' and includes administration of the active compound to prevent the onset of symptoms or complications. However, 'pr〇phyiactic/preventive' and therapeutic/curative treatments are two independent aspects of the invention. The patient to be treated is preferably a mammal, especially a human. In one embodiment, Compound I is administered in an amount from about 0.0001 to about 100 mg per kilogram of body weight per day. A typical oral dose is in the range of from about 1 to about 1 〇〇 mg per kilogram of body weight per day, preferably from about 1 to about 5 mg per kilogram of body weight per day. The exact dose will depend on the frequency and mode of administration, the sex, age, weight and general condition of the individual being treated, the nature and severity of the condition being treated, and any accompanying conditions to be treated and other factors apparent to those skilled in the art. . A typical oral dose for an adult is 〇1_5〇 mg of Compound I per day, such as 0.5-30 mg per day or 0.5-25 mg per day. This dose can be typically administered by administering 0.1-50 mg, such as 0.5-30 mg, such as 〇5, i, 2, 3' 〇4, 5' 6, 9, 10, 20 or 30 mg of the compound used in the present invention. to realise. Typically, the treatment of the invention will involve the daily administration of a compound of the invention. This may involve administering once a day, or twice a day or even more frequently. In a specific embodiment, the invention relates to the use of a compound for the manufacture of a medicament for the treatment of snoring, mild mania, bipolar affective disorder (maintenance), prevention of recurrence of bipolar affective disorders, bipolarity Emotion 16 200938189 Susceptibility to stable disease, partial response; anti-therapeutic depression; major depression; emotional loop; emotional illness caused by systemic medical condition; substance-induced depression; recurrent depression; Pediatric depression; atypical depression; post-stroke depression; depletion depression; seasonal affective psychosis (SAD); depression associated with schizophrenia, schizoaffective psychosis, gastrointestinal pain, IBS, Abuse, hostility, irritability, fatigue, anxiety (anxiety depression), Lewy body disease or multiple sclerosis;

❹ 飛行、電梯或小彡恐懼症；與疼痛_之一般性焦慮症；尚血壓風險增加之患者的焦慮；有睡眠問題之患者的焦慮；認知損害、阿茲海默氏病、癡呆；輕度認知損害（mci 血管型癡呆，白質疏鬆；小血管疾病；與ADHD有關之強迫及注意力譜系病症、亞斯柏格症候群；自閉症；與情感性精神病有關之認知損害、抑鬱症、整體抑鬱症、重鬱症、焦慮症、一般性焦慮症、恐慌症、強迫症、精神***症、 1金森氏病、癡呆、AIDS #呆、ADHD、年齡相關的記憶損害、唐氏症候群、癲癇症、外傷性腦損傷、亞斯柏格症候群、色氨酸羥化酶基因突變及阿茲海默氏病；與癡呆有關之行為障礙；與癡呆及阿茲海默氏病有關之攻擊性及焦躁；精神***症中之負向症狀；酒精、菸鹼或碳水化合物成瘾；物質濫用；酒精或藥物濫用；進食障礙；肥胖症；厭食症，貪食症，暴食症；衝動控制病症；間歇性爆怒症；偷竊癖；縱火癖；病理性賭博；拔毛髮癖；晝夜節律^礙| 原發性失眠、長期失眠、暫時性失眠；睡眠呼吸暫停；睡眠呼吸障礙；低通氣症候群；與壓力有關之病纟；急性壓 17 200938189 力；燒傷；麼力；慢性疲勞症候群；品行障礙；行為障礙. 老年行為障礙；與HPA軸活性過高有關之胰島素抗性；熱潮紅、嘔吐、停經前、圍停經期及停經後不悅症；病理性哭泣；弱視；妥瑞氏症候群或疼痛。在一具體實例中，本發明係關於用於治療以下病症之化合物I :躁症、輕度躁狂、雙極性情感疾患（保養預防雙極性情感疾患復發、使雙極性情感疾患穩定、部分反應者之抑鬱症；抗治療性抑鬱症；重度抑鬱症；情感迴環；全身性醫學病況引起之情感疾患；物質誘發之抑鬱症；復 © 發性抑鬱症；單次發作抑鬱症；兒科抑鬱症；非典型抑鬱症；中風後抑鬱症；耗竭性抑鬱症；季節性情感性精神病 (SAD );與精神***症有關之抑鬱症、***情感性精神病、胃腸痛、IBS、濫用、敵意、易怒、疲勞、焦慮（焦慮性抑鬱症）、路易體病或多發性硬化症；飛行、電梯或小房間恐懼症，與疼痛有關之一般性焦慮症；高血壓風險增加之患者的焦慮；有睡眠問題之患者的焦慮；認知損害、阿茲海默氏病、癡呆；輕度認知損害（MCI );血管型癡呆；白 © 質疏鬆；小血管疾病；與ADHD有關之強迫及注意力譜系病症、亞斯柏格症候群；自閉症；與情感性精神病有關之認知損害、抑鬱症、整體抑鬱症、重鬱症、焦慮症、一般性焦慮症、恐慌症、強迫症、精神***症、帕金森氏病、癡呆、AIDS癡呆、ADHD、年齡相關的記憶損害、唐氏症候群、癲癇症、外傷性腦損傷、亞斯柏格症候群、色氨酸羥化酶基因突變及阿茲海默氏病；與癡呆有關之行為障 18 200938189 礙’與癡呆及阿茲海默氏病有關之攻擊性及焦躁；精神分裂症中之負向症狀；酒精、菸鹼或碳水化合物成癮；物質也用酉精或藥物濫用；進食障礙；肥胖症；厭食症；貪食症；暴食症；衝動控制病症；間歇性爆怒症；偷竊癖；縱火癖，病理性賭博；拔毛髮癖；晝夜節律障礙；原發性失眠長期失眠、暫時性失眠；睡眠呼吸暫停；睡眠呼吸障礙；低通氣症候群；與壓力有關之病症；急性壓力；燒傷，壓力；慢性疲勞症候群；品行障礙；行為障礙；老年行為障礙；與ΗΡΑ軸活性過高有關之胰島素抗性；熱潮紅、嘔吐、停經前、圍停經期及停經後不悅症；病理性哭泣；弱視；妥瑞氏症候群或疼痛。化合物I可單獨投予或與另一治療活性化合物組合投予，其中該兩種化合物可同時或相繼投予。可有利地與化合物I組合之治療活性化合物之實例包括鎮靜劑或催眠劑’諸如苯并二氮呼；抗驚厥藥，諸如拉莫三嗪 ❹ (lamotrigine )、丙戊酸、托0比醋（topiramate )、加巴喷丁（ gabapentin )、痛痙寧（carbamazepjne );情緒穩定劑，諸如裡；多巴胺能藥，諸如多巴胺促效劑及L_D〇pa ;治療 ADHD之藥物，諸如阿托莫西汀（at〇m〇xetine);精神刺激劑’諸如莫達非尼（modafinil)、氣胺酮（ketamine)、派醋甲酉曰（methylphenidate )及***（amphetamine ); 其他抗抑誉劑’諸如如米胺平（mirtazapine )、米安色林 (mianserin )及丁胺苯丙酌（buproprion );激素，諸如 T3、 ***、DHEA及睪固酮；非典型抗精神病藥物，諸如奥氮 19 200938189 平及阿立略唑（aripiprazole );典型抗精神病藥物，諸如氟哌啶醇（haloperidol );治療阿茲海默氏病之藥物，諸如膽驗醋酶抑制劑及美金剛（memantine )、葉酸鹽；S-脉普-甲硫胺酸；免疫調節劑，諸如干擾素；鴻片劑，諸如丁丙諾啡（buprenorphin);血管收縮素II受體1拮抗劑（ATI 拮抗劑）；ACE抑制劑；士他汀（statin );及α腎上腺素月b括抗劑，諸如派峻u秦（praz〇sjn ) 〇本發明化合物可作為純化合物單獨或與醫藥上可接受之載劑或賦形劑組合以單次或多次劑量投予。本發明醫藥、、且成物可根據習知技術（諸如’揭不於Remingt〇n: The❹ flight, elevator or phobia; general anxiety disorder with pain _; anxiety in patients with increased blood pressure; anxiety in patients with sleep problems; cognitive impairment, Alzheimer's disease, dementia; Cognitive impairment (mci vascular dementia, leukoaraiosis; small vessel disease; obsessive-compulsive lineage disorder associated with ADHD, Asperger syndrome; autism; cognitive impairment associated with affective psychosis, depression, overall depression Symptoms, severe depression, anxiety, general anxiety disorder, panic disorder, obsessive-compulsive disorder, schizophrenia, 1 Jinsen's disease, dementia, AIDS #呆, ADHD, age-related memory impairment, Down's syndrome, epilepsy, trauma Brain injury, Asperger syndrome, tryptophan hydroxylase gene mutation and Alzheimer's disease; behavioral disorders associated with dementia; aggression and anxiety related to dementia and Alzheimer's disease; spirit Negative symptoms in schizophrenia; alcohol, nicotine or carbohydrate addiction; substance abuse; alcohol or substance abuse; eating disorders; obesity; anorexia, bulimia, violence Impulsive control disorder; intermittent irritability; thief; arson; pathological gambling; hair removal; circadian rhythm | primary insomnia, long-term insomnia, temporary insomnia; sleep apnea; Hypoventilation syndrome; stress-related sputum; acute stress 17 200938189 force; burn; virulence; chronic fatigue syndrome; conduct disorder; behavioral disorder. senile behavioral disorder; insulin resistance associated with excessive HPA axis activity; Red, vomiting, premenopausal, peri-menopausal and post-menopausal discomfort; pathological crying; amblyopia; Tourette's syndrome or pain. In one embodiment, the invention relates to a compound I for use in the treatment of: Symptoms, mild mania, bipolar emotional disorders (maintenance to prevent recurrence of bipolar affective disorders, stabilization of bipolar emotional disorders, depression in some responders; anti-therapeutic depression; major depression; emotional loopback; systemic medicine Emotional disorders caused by the condition; substance-induced depression; complexive depression; single-onset depression; pediatric depression; Atypical depression; post-stroke depression; depletion depression; seasonal affective psychosis (SAD); depression associated with schizophrenia, schizoaffective psychosis, gastrointestinal pain, IBS, abuse, hostility, irritability, Fatigue, anxiety (anxiety depression), Lewy body disease or multiple sclerosis; flight, elevator or small room phobia, general anxiety disorder associated with pain; anxiety of patients with increased risk of hypertension; sleep problems Patient anxiety; cognitive impairment, Alzheimer's disease, dementia; mild cognitive impairment (MCI); vascular dementia; white protein loose; small vessel disease; obsessive-compulsive and attentional lineage disorders associated with ADHD, Yass Berger syndrome; autism; cognitive impairment associated with affective psychosis, depression, overall depression, major depression, anxiety, general anxiety disorder, panic disorder, obsessive-compulsive disorder, schizophrenia, Parkinson's disease, Dementia, AIDS dementia, ADHD, age-related memory impairment, Down's syndrome, epilepsy, traumatic brain injury, Asperger syndrome, tryptophan hydroxylase Mutations and Alzheimer's disease; behavioral disorders associated with dementia 18 200938189 Afflictions of aggression and irritability associated with dementia and Alzheimer's disease; negative symptoms in schizophrenia; alcohol, nicotine or Carbohydrate addiction; substances also use sputum or drug abuse; eating disorders; obesity; anorexia; bulimia; binge eating disorder; impulsive control disorder; intermittent anger; stealing sputum; arson, pathological gambling; Hair sputum; circadian rhythm disorder; primary insomnia, long-term insomnia, temporary insomnia; sleep apnea; sleep-disordered breathing; hypopnea syndrome; stress-related disorders; acute stress; burns, stress; chronic fatigue syndrome; Behavioral disorders; senile behavioral disorders; insulin resistance associated with hyperactivity of the sacral axis; hot flashes, vomiting, premenopausal, peri-menopausal and post-menopausal discomfort; pathological crying; amblyopia; Tourette's syndrome or pain. Compound I can be administered alone or in combination with another therapeutically active compound, wherein the two compounds can be administered simultaneously or sequentially. Examples of therapeutically active compounds which may be advantageously combined with Compound I include sedatives or hypnotics such as benzodiazepine; anticonvulsants such as lamotrigine, valproic acid, topiramate ), gabapentin, carbamazepjne; mood stabilizers, such as; dopaminergic agents, such as dopamine agonists and L_D〇pa; drugs for the treatment of ADHD, such as atomoxetine (at〇m) 〇xetine); psychostimulants such as modafinil, ketamine, methylphenidate and amphetamine; other anti-counterfeiting agents such as, for example, melamamine Mirtazapine), mianserin and buproprion; hormones such as T3, estrogen, DHEA and testosterone; atypical antipsychotic drugs such as aziridine 19 200938189 and alitrazol ( Aripiprazole ); a typical antipsychotic such as haloperidol; a drug for the treatment of Alzheimer's disease, such as a bilirubin inhibitor and memantine, folate S-pulp-methionine; immunomodulatory agents, such as interferons; hong tablets, such as buprenorphin; angiotensin II receptor 1 antagonists (ATI antagonists); ACE inhibitors; Statin; and alpha adrenergic antibiotics, such as praz〇sjn, the compounds of the invention may be used as a pure compound alone or in combination with a pharmaceutically acceptable carrier or excipient. Single or multiple doses are administered. The medicine and the object of the present invention can be based on conventional techniques (such as 'not revealed by Remingt〇n: The

Science and Practice of Pharmacy，第 19 版，Gennaro 編，Science and Practice of Pharmacy, 19th edition, edited by Gennaro,

Mack Publishing Co.，Easton，PA，1995 中之彼等技術）以醫藥上可接受之載劑或稀釋劑以及任何其他已知佐劑及賦形劑調配。醫藥組成物可經特定調配以便藉由任何合適途徑投予，諸如口服、直腸、經鼻、經肺、局部（包括經頰及舌下）、經皮、腦池内、腹膜内、經***及非經腸（包括皮下、肌肉内、鞘内、靜脈内及皮内）途徑，口服途徑較佳。應瞭解，較佳途徑將視待治療個體的一般狀況及年齡，待治療病況之性質及所選活性成份而定。供口服之醫藥組成物包括固體劑型，諸如膠囊、錠劑、糖衣藥丸、丸劑、***劑、散劑及顆粒劑。若適當，則其可製備成具有包衣。供口服之液體劑型包括溶液、乳液、滴劑、懸浮液、 200938189 糖漿及醜劑。、供非經腸投予之醫藥組成物包括無菌水性及非水性可 2射溶液、分散液、懸浮液或乳液’以及有待於在使用之前於無菌可注射溶液或分散液中復原之無菌粉末。其他合適之投藥形式包括栓劑、喷霧劑、軟膏、精華 (creme)、凝膠、吸入劑、皮膺貼#、植入劑等。便利地，本發明化合物係以含有該等化合物之量為約 ❹ 〇.1 至 50 mg，諸如 0.5 mg、i mg、2 叫、3 叫、4 叫、$ 叫、 6 mg、9 mg、i〇 mg、15 mg或2〇 mg本發明所用化合物之單位劑型投予。對於諸如靜脈内、鞘内、肌肉内及類似投藥方式之非經腸途徑而言，劑量典型地為大約用於口服之劑左右。牛對於非經腸投藥而言，可採用本發明化合物於無菌水 :液、水性丙二醇、水性維生素E、水性環糊精或芝麻油或 ❹ A生油中之溶液。若必要’則該等水溶液應經適當緩衝且首先以足量生理食鹽水或葡萄糖使液體稀釋劑等張。水溶液尤其適於靜脈内、肌肉内、皮下及腹膜内投藥。所採用之無菌水性介質均可藉由熟習此項技術者已知的標準技術容易地獲得。合適醫藥載劑包括惰性固體稀釋劑或填充劑、無菌水溶液及各種有機溶劑。固體載劑之實例為微晶纖維;、殿粉、膠、乳糖、白土、嚴糖、環糊精、滑石粉、明膠、壤脂、黏膠質、***朦、硬脂酸鎂、硬脂酸及織維素的低 21 200938189 油、撖欖油、磷碳烷基醚《液體載劑之實例為糖漿、花生脂、脂肪酸、脂肪酸胺、聚氧化乙烯、環糊竹3 W及水。藉由將本發明化合物與醫藥上可接受之載劑紐人又軌削殂合而形成之醫藥組成物因此容易地以適於所揭示投藥途徑之多種劑型投予0 適於口服之本發明調配物可呈現為各自含有預定量之活性成份的離散單元（諸如膠囊或錠劑），且其可包括a 適賦形劑。此外，可口服使用之調配物可為散劑或顆：劑口、滴劑、水性或非水性液體中之溶液或懸浮液，或水中油或 © 油中水液體乳液形式。若固體載劑係用於口服，則製劑可為粉末或小丸形式之錠劑（tablet)或為片劑（tr〇che)或***劑（i〇zenge) 形式。或者，錠劑、粉末及小丸可置於硬明膠膠囊中。固體載劑之量可變化但一般將為約25 mg至約i g。若使用液體載劑，則製劑可為糖漿、乳液、軟明谬膝Mack Publishing Co., their technology in Easton, PA, 1995) is formulated with a pharmaceutically acceptable carrier or diluent and any other known adjuvants and excipients. The pharmaceutical composition can be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, transpulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, transvaginal, and non- The oral route is preferred via the intestinal (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the preferred route will depend on the general condition and age of the individual to be treated, the nature of the condition being treated and the active ingredient chosen. Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, lozenges, dragees, pills, buccal, powders, and granules. If appropriate, it can be prepared to have a coating. Liquid dosage forms for oral administration include solutions, emulsions, drops, suspensions, 200938189 syrups and ugly agents. The pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous aqueous solutions, dispersions, suspensions or emulsions, and sterile powders to be reconstituted in sterile injectable solutions or dispersions before use. Other suitable forms of administration include suppositories, sprays, ointments, creme, gels, inhalants, skin patches #, implants, and the like. Conveniently, the compounds of the invention are present in an amount of from about ❹.1 to 50 mg, such as 0.5 mg, i mg, 2, 3, 4, 4, 6 mg, 9 mg, i.单位mg, 15 mg or 2 〇mg The unit dosage form of the compound used in the present invention is administered. For parenteral routes such as intravenous, intrathecal, intramuscular, and the like, the dosage is typically about the dose for oral administration. Bovine For parenteral administration, a solution of the compound of the present invention in sterile water: liquid, aqueous propylene glycol, aqueous vitamin E, aqueous cyclodextrin or sesame oil or strontium A crude oil may be employed. If necessary, the aqueous solutions should be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose. Aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed can be readily obtained by standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents. Examples of solid carriers are microcrystalline fibers; temple powder, gum, lactose, white clay, Yan sugar, cyclodextrin, talc, gelatin, loam, viscose, arabin, magnesium stearate, stearic acid and Weaver's low 21 200938189 Oil, eucalyptus oil, and phosphocarbon alkyl ether Examples of liquid carriers are syrup, peanut butter, fatty acids, fatty acid amines, polyethylene oxide, cyclodextrin 3 W and water. The pharmaceutical composition formed by the compounding of the compound of the present invention and a pharmaceutically acceptable carrier is thus easily administered in a plurality of dosage forms suitable for the disclosed route of administration. The compositions may be presented as discrete units (such as capsules or lozenges) each containing a predetermined amount of active ingredient, and may include a suitable excipient. In addition, formulations which can be used orally can be in the form of powders or granules: solutions, suspensions, solutions or suspensions in aqueous or non-aqueous liquids, or oils in water or as aqueous liquid emulsions in oils. If the solid carrier is for oral administration, the preparation may be in the form of a tablet in the form of a powder or pellet or in the form of a tablet or a buccal. Alternatively, the lozenges, powders and pellets can be placed in hard gelatin capsules. The amount of solid carrier can vary but will generally range from about 25 mg to about i g. If a liquid carrier is used, the preparation may be a syrup, an emulsion, or a soft knee

囊或無菌可注射液冑（諸如’纟性或非水性液體懸浮液或溶液）形式。 M 錠劑可藉由將活性成份與慣用佐劑及/或稀釋劑混合，且隨後將混合物在習知製鍵機中壓縮來製備。可使用常用於諸如著色、調味、防腐等目的之佐劑或添加劑。包含本發明化合物之膠囊可藉由將包含該化合物之粉末與（例如）微晶纖維素及硬脂酸鎂混合且將該粉末置於硬明勝膠囊中來製備。視情況而言，該膠囊可藉助於合適顏料著色。典型地，膠囊將包含〇卜i 〇%本發明化合物，諸 22 200938189 如 0.15-0.25%、〇.3·〇 4%、1618%及 3 3 3 5%本發明化合物（以游離鹼計算）。此等濃度可用於便利地以單位劑型傳遞0.5、1、5及10 mg本發明化合物。庄射用溶液可藉由將活性成份及可能之添加劑溶解於 4刀注射用溶劑（較佳為無菌水）中，將溶液調整為所要體積’將溶液滅菌且將其填充於合適安瓶或小瓶中來製備了添加此項技術中習用之任何合適添加劑，諸如張力劑、防腐劑、抗氧化劑等。化合物I之游離鹼可如wo 2005/061455中所揭示製備。本發明所用之鹽可藉由將游離鹼溶解於適當溶劑中，添加相應酸，隨後沈澱來製備。沈澱可藉由添加第二溶劑，及/或蒸發，及/或冷卻來達成。或者，該等化合物可如下文所述合成" 步驟1A sac or sterile injectable solution (such as a 'salt or non-aqueous liquid suspension or solution). The M tablet can be prepared by mixing the active ingredient with conventional adjuvants and/or diluents, and then compressing the mixture in a conventional card making machine. Adjuvants or additives commonly used for purposes such as coloring, seasoning, preservation, and the like can be used. Capsules comprising a compound of the invention can be prepared by mixing a powder comprising the compound with, for example, microcrystalline cellulose and magnesium stearate and placing the powder in a hard capsule. Optionally, the capsule can be colored by means of a suitable pigment. Typically, the capsule will comprise a compound of the invention, such as 0.15-0.25%, 〇.3·〇 4%, 1618%, and 3 3 3 5% of the compound of the invention (calculated as the free base). Such concentrations can be used to conveniently deliver 0.5, 1, 5, and 10 mg of a compound of the invention in unit dosage form. Zhuang injection solution can be prepared by dissolving the active ingredient and possible additives in a 4-knife injection solvent (preferably sterile water) to adjust the solution to the desired volume. The solution is sterilized and filled into suitable ampoules or vials. Any suitable additives conventionally used in the art, such as tonicity agents, preservatives, antioxidants, and the like, are prepared. The free base of Compound I can be prepared as disclosed in WO 2005/061455. The salts used in the present invention can be prepared by dissolving the free base in a suitable solvent, adding the corresponding acid, followed by precipitation. Precipitation can be achieved by the addition of a second solvent, and/or evaporation, and/or cooling. Alternatively, the compounds can be synthesized as described below" Step 1

在步驟1中，將1當量2,2-二硫苄酸與1.5_25當量 Ηβ〇4 (諸如’ 2當量）在甲醇中混合。反應係在回流溫度下進行。步驟2 23 200938189In step 1, 1 equivalent of 2,2-dithiobenzyl acid is mixed with 1.5 to 25 equivalents of Ηβ〇4 (such as ' 2 equivalents) in methanol. The reaction is carried out at reflux temperature. Step 2 23 200938189

在步驟2中，在保護氣氛（諸如，No下將丨當量二节酸醋懸浮於DME中，且冷卻至1(Μ5χ：，其後立即緩― 添加略微過量之於DME中之硫醯氯〇_13當量），同= 保持溫度低於25 C。隨後，添加冷卻至i 〇_〗5〇c之〇ΜΕ中之6-氟引哚（約2當量），仍保持溫度低於25<>c。為了完成反應，將混合物加熱至約5(rc歷時〗_3小時。可藉由將反應混合物以EtOAc稀釋，隨後以NaHC〇3及Naa進行洗滌步驟來回收步驟2之產物。將有機相濃縮且與甲苯共蒸發。視情況在以晶體接種且冷卻後，獲得呈沈澱物形式之步驟2產物。In step 2, the equivalent weight of the two-section vinegar is suspended in the DME under a protective atmosphere (such as No, and cooled to 1 (Μ5χ:, immediately thereafter), adding a slight excess to the thiopurine in the DME. _13 equivalents, same = keep the temperature below 25 C. Subsequently, add 6-fluorine bismuth (about 2 equivalents) cooled to i 〇 _ 〇 5 〇 c, still keep the temperature below 25 <gt;c. In order to complete the reaction, the mixture is heated to about 5 (r duration _3 hours. The product of step 2 can be recovered by diluting the reaction mixture with EtOAc, followed by a washing step with NaHC 3 and Naa. Concentrate and co-evaporate with toluene. As in the case of inoculation with crystals and cooling, the product of step 2 in the form of a precipitate is obtained.

步驟3Step 3

在步驟3中，向溶解於THF中之酯（1當量）中緩慢添加約2.5當量之LiBH4。添加後，將溫度升至約4〇°c。接 24 200938189 著緩慢添加約2 5 ♦ 應完成後（約2•备量甲醇’同時保持溫度低於55°c。反過量LiBH4。收隹、時），添加檸檬酸（約2.5當量）以移除所獲得之Ht、有機相，將其濃縮且與異丙醇共蒸發。將所獲得見合物緩物。 * 至水中以進行沈澱，收集該沈澱In step 3, about 2.5 equivalents of LiBH4 were slowly added to the ester (1 equivalent) dissolved in THF. After the addition, the temperature was raised to about 4 ° C. Connect 24 200938189 Slowly add about 2 5 ♦ After completion (about 2 • Prepare methanol 'while keep the temperature below 55 ° C. Reverse excess LiBH4. Retract, time), add citric acid (about 2.5 equivalents) to shift In addition to the obtained Ht, organic phase, it was concentrated and co-evaporated with isopropanol. The compound obtained will be tempered. * to the water for precipitation, collect the precipitate

步驟£Step £

x=oso2ch3 X= Br H3C、 X=CI NH nh2ch3 ❹x=oso2ch3 X= Br H3C, X=CI NH nh2ch3 ❹

在步驟4中，將丨當量溶解於THF中之苄醇添加至約 1.2當量LiBr及約1.5當量NN-二異丙基乙基胺（dipea) 中。向此混合物中添加約1.4當量溶解於THF中之 S〇2ClCH3’同時保持溫度低於50C。將混合物授掉15-20 小時以完成反應。向獲得之混合物中緩慢添加約40當量 NH2CH3，且使反應在約40-45°C下歷時約5小時完成。在此步驟中，可添加適當酸以產生相應酸加成鹽。特定言之， 25 200938189 添加約1.4當量L-(+)酒石酸將實現[2_(6_氟_17/_吲哚_3_基硫烧基）苄基]甲基胺L-(+)-酒石酸氫鹽之沈澱。本文所引用之所有參考文獻（包括公開案、專利申請案及專利）均以引用的方式全部併入本文中，且其引用程度就如同已個別地及特定地將各個參考文獻以引用的方式併入且其全文陳述於本文中（達到法律所允許的最大程度）一般，無論本文別處所作的任何單獨提供之特定文獻的併入0 除非本文另外說明或明確與上下文相矛盾，否則在描❹ 述本發明之上下文中，術語「一」及「該」及類似指示物的使用應解釋為包括單數及複數兩者。舉例而言，除非另外說月否則短语「化合物」或「本發明之化合物」應理解為係指本發明或特定描述態樣之各種化合物。除非另外說明，不目丨丨士七^日否則本文棱供之所有確切值代表相應近似值（例如’可認為關於特定因子或量測提供的所有確切例示值亦提供相應近似量測’適當時以「約」修飾）。二= 〇 2之彼術:特對定本:::何“或“之描述*欲提」供乂組成」或「女、組成」、「基本上由彼或彼等特定要素」S 體上包含彼或彼等特定要素」的；Μ# 0 =二持(―上下文另:::: = 理解為==:rr為包含特定元素之組成物應彼几素組成之組成物）。 26 200938189 實施例分析方法 ^ NMR 譜係在 500·13 MHz 下在 Bruker Avance DRX500儀器上§己錄。將二甲亞硬（99 )用作溶劑且將四甲基矽烷（TMS)用作内部參考標準。熔點係使用示差掃描熱析法（Differential ScanningIn step 4, benzyl alcohol dissolved in THF is added to about 1.2 equivalents of LiBr and about 1.5 equivalents of NN-diisopropylethylamine (dipea). To this mixture was added about 1.4 equivalents of S〇2ClCH3' dissolved in THF while maintaining the temperature below 50C. The mixture was allowed to stand for 15-20 hours to complete the reaction. About 40 equivalents of NH2CH3 were slowly added to the obtained mixture, and the reaction was completed at about 40-45 ° C for about 5 hours. In this step, a suitable acid can be added to produce the corresponding acid addition salt. In particular, 25 200938189 Adding about 1.4 equivalents of L-(+) tartaric acid will achieve [2_(6_fluoro_17/_吲哚_3_ylthioalkyl)benzyl]methylamine L-(+)- Precipitation of hydrogen tartrate. All references (including publications, patent applications, and patents) cited herein are hereby incorporated by reference in their entirety in their entirety in their entirety in the extent of In its entirety (to the maximum extent permitted by law), generally, the incorporation of any particular document provided separately elsewhere herein is zero unless otherwise stated herein or clearly contradicted by context. In the context of the present invention, the use of the terms "a" and "the" and the like are to be construed to include both singular and plural. For example, unless otherwise stated, the phrase "compound" or "compound of the invention" is understood to mean a compound of the invention or a particular embodiment. Unless otherwise stated, all the exact values of the quotations are representative of the corresponding approximations (eg 'can be considered to provide a corresponding approximation for all the specific exemplified values provided for a particular factor or measurement', "about" modification). 2 = 〇 2 术 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : He or his specific elements"; Μ# 0 = two holds ("contextual:::: = understood as ==: rr is a composition of a composition containing a specific element." 26 200938189 EXAMPLES Analytical Methods ^ NMR spectroscopy was recorded on a Bruker Avance DRX500 instrument at 500·13 MHz. Dimethyl hard (99) was used as a solvent and tetramethylnonane (TMS) was used as an internal reference standard. Melting point is the use of differential scanning thermal analysis (Differential Scanning

Calorimetry，DSC)量測。設備為校準為5 Vmin下以產生作為初始值之熔點之〇 TA-InStruments DSC_Q1000 e將約2 mg樣本在非緊密封閉之盤中在氤氣流下以5。/min加熱。用於估算乾燥材料之溶劑/水含量的熱重分析（Therm〇 gravimetric analysis，TGA )係使用 TA_instruments TGA-Q500進行。將i_10 mg樣本在敞開盤中在氮氣流下以 10 ° /min 加熱。 X-射線粉末繞射圖係在PANalytical X'Pert PRO X-射 0 線繞射儀上使用CuKa 1輻射量測。使用x，celerat〇r偵測器以反射模式在5-40。的2 0範圍内量測樣本。值係以土〇.丨（。 2 0 )表述。 CHN含量分析（CHN)係在來自Elemental*之Elementar Vario EL儀器上量測。將約4 mg樣本用於實驗。實施例1血清素及去甲腎上腺素轉運抑制將測試化合物與大鼠皮層突觸體製備物的等分試樣預培育10 min/37°C，且接著添加[3H]NE或[3H]5-HT (最終濃度10 nM)。在i〇aM他舒普侖（talsupram)或西献普蘭 27 200938189 (citalopram )存在下測定非特異性吸收且在緩衝液存在下測定總吸收。將等分試樣在37°C下培育15分鐘。培育後，藉由使用Tomtec CellHarvester程式經由在〇 1% pEI中預浸泡30分鐘的Unifilter GF/C過濾來分離突觸體所吸收之 [3H]NE 或[3H]5-HT。將過濾器洗滌且在 wallac MicroBeta 計數器中計數。化合物I為血清素再吸收及去曱腎上腺素再吸收的有效抑制劑’使用涵蓋三個數量級（decade )之化合物濃度測定之IC5〇值分別為0.4 nM及4.4 nM。實施例2 αίΑ受體括抗作用測試化合物I對α1Α受體之親和力且發現其展示具有高親和力（Ki 14 nM )之拮抗概況。在實驗當天’將膜（參見下文針對膜製備的描述）解凍且使用ultra turrax在緩衝液中均質化且稀釋至所要濃度 (5微克/孔-5微克/ 900微升’儲存於冰上直至使用）。藉由混合50 " 1測試化合物、50 // 1 [3H]-哌唑嗪及900 // 1膜來開始實驗’且將混合物在25°C下培育20分鐘。在 10# M WB-4101存在下測定非特異性結合且在緩衝液存在下測定總結合。在培育後’藉由使用Tomtec Cell Harvester· 程式（D4.2..4 ) 96孔經由在〇. 1% PEI中預浸泡30分鐘的Calorimetry, DSC) measurement. The device was calibrated to 5 Vmin to produce the melting point as the initial value. 〇 TA-InStruments DSC_Q1000 e Approximately 2 mg of the sample was placed at 5 in a non-tightly closed disk under a helium flow. /min heating. Therm〇 gravimetric analysis (TGA) used to estimate the solvent/water content of the dried material was performed using TA_instruments TGA-Q500. The i_10 mg sample was heated in an open pan at 10 ° /min under a stream of nitrogen. The X-ray powder diffraction pattern was measured on a PANalytical X'Pert PRO X-ray 0-ray diffractometer using CuKa 1 radiation. Use the x, celerat〇r detector to reflect mode at 5-40. Measure the sample within the 2 0 range. The value is expressed in terms of soil 丨.丨 (. 2 0 ). CHN content analysis (CHN) was measured on an Elementar Vario EL instrument from Elemental*. Approximately 4 mg of the sample was used for the experiment. Example 1 Serotonin and Norepinephrine Transport Inhibition An aliquot of test compound and rat cortical synaptosome preparation was pre-incubated for 10 min/37 °C, followed by the addition of [3H]NE or [3H]5 -HT (final concentration 10 nM). Non-specific absorption was measured in the presence of i〇aM talsupram or citalopram 27 200938189 (citalopram) and total absorption was measured in the presence of buffer. Aliquots were incubated for 15 minutes at 37 °C. After incubation, the [3H]NE or [3H]5-HT absorbed by the synaptosome was isolated by filtration using Unifilter GF/C pre-soaked in 〇 1% pEI for 30 minutes using the Tomtec Cell Harvester program. The filter was washed and counted in a wallac MicroBeta counter. Compound I is a potent inhibitor of serotonin reuptake and norepinephrine reuptake. The IC5 values measured using compound concentrations covering three orders of magnitude are 0.4 nM and 4.4 nM, respectively. Example 2 αίΑ Receptor Inhibition The affinity of Compound I for the α1Α receptor was tested and found to exhibit an antagonistic profile with high affinity (Ki 14 nM ). On the day of the experiment, 'film (see description below for membrane preparation) was thawed and homogenized in buffer using ultra turrax and diluted to the desired concentration (5 μg/well - 5 μg / 900 μl 'stored on ice until use ). The experiment was started by mixing 50 " 1 test compound, 50 // 1 [3H]-prazosin and 900 //1 membrane and the mixture was incubated at 25 ° C for 20 minutes. Non-specific binding was determined in the presence of 10# M WB-4101 and total binding was determined in the presence of buffer. After incubation, by pre-soaking for 30 minutes in a 1% PEI using a Tomtec Cell Harvester program (D4.2..4) 96 wells.

Unifilter GF/B過濾來將經結合配位體與未經結合配位體分離。將過濾器以1 ml冰冷緩衝液洗務3次，在50°C下乾燥且向過濾器中每孔添加35 /Z 1閃爍液體。在Wallac OY 1450 MicroBeta中對結合放射性進行計數。自 γ=ι〇〇/(1 + 2〇〇938i89 1〇(X丨。gIC5。))計算親和力（Ki 1〇nM)，其+ γ表示結合%且 χ表示化合物濃度。使用涵蓋2個數量級之化合物濃度計算 IC5〇值。自 Cheng Prusoff 方程式 Ki==(IC5〇/(1+ ([L]/Kd))計算Ki。在功能檢定中，本發明化合物拮抗腎上腺素誘發之Ca2+ 自胞内儲存物中釋放且功能檢定揭示化合物為&1)為6411]^ 之括抗劑。 0 此等實驗基本上如下文所述進行。將所有細胞在37°C下在5% C〇2中在補充有1〇% BCS、4mML-麵醯胺酸（或在c〇S-7狀況下為2 mM)，及100單位/毫升盤尼西林（penicillin)加1〇〇 μ g/mi鏈黴素（streptomycin )的DMEM培養基中培養。在檢定前24小時，將表現人類α 1A-7受體之CH0細胞接種於以聚D·離胺酸塗覆之384孔黑壁微量滴定盤中。抽吸培養基且將細胞在5% C〇2中在”艽下以檢定緩衝液 0 中之1.5" M Fluo-4進行染料荷載歷時丨小時，該緩衝液係由漢克氏平衡鹽溶液（Hank’s Balanced Salt Solution) ( 138 mM NaC卜 5 mM KC1、1.3 mM CaCl2、0.5 mM MgCl2、0.4 mM MgS〇4、0.3 mM KH2P04、0.3 mM Na2HP04、5.6 mM 葡萄糖）加 20 mM HEPES pH 7.4、0.05% BSA 及 2.5 mM 丙續Unifilter GF/B was filtered to separate the bound ligand from the unbound ligand. The filter was washed 3 times with 1 ml of ice-cold buffer, dried at 50 ° C and 35 / Z 1 scintillation liquid was added to each well of the filter. Binding radioactivity was counted in Wallac OY 1450 MicroBeta. Affinity (Ki 1〇nM) was calculated from γ = ι〇〇 / (1 + 2 〇〇 938i89 1〇(X丨.gIC5.)), where + γ represents % binding and χ represents compound concentration. IC5 〇 values were calculated using compound concentrations covering 2 orders of magnitude. Ki was calculated from the Cheng Prusoff equation Ki==(IC5〇/(1+([L]/Kd)). In a functional assay, the compounds of the invention antagonize the release of adrenergic-induced Ca2+ from intracellular stores and reveal functional assays. The compound is &1) is an antagonist of 6411]. 0 These experiments were basically carried out as described below. All cells were supplemented with 1% BCS, 4 mM L-face valeric acid (or 2 mM in the case of c〇S-7) at 5% C 〇 2 at 37 ° C, and 100 units/ml penicillin (penicillin) was cultured in DMEM medium supplemented with 1 μg/m streptomycin. CH0 cells expressing the human α 1A-7 receptor were seeded in a 384-well black wall microtiter plate coated with poly D· lysine 24 hours before the assay. The medium was aspirated and the cells were subjected to dye loading in 5% C〇2 at a dose of 1.5 " M Fluo-4 in assay buffer 0 for a period of hours, which was performed by Hank's Balanced Salt Solution ( Hank's Balanced Salt Solution) (138 mM NaC 5 mM KC1, 1.3 mM CaCl2, 0.5 mM MgCl2, 0.4 mM MgS〇4, 0.3 mM KH2P04, 0.3 mM Na2HP04, 5.6 mM glucose) plus 20 mM HEPES pH 7.4, 0.05% BSA And 2.5 mM Continuation

舒（probenicid) ( 50微升/孔）構成。棄去過量染料後，將細胞在檢定緩衝液中洗滌且以等於45微升/孔（或對於拮抗劑檢定而言30微升/孔）之最終體積層化》在拮抗劑評價之狀況下’此時以15以1於呈4倍最終濃度的含4% DMSO 29 200938189 之緩衝液（最終DMSO=1%)中的等分試樣形式添加拮抗劑或媒劑’隨後培育20分鐘》在來自M〇leculai· Deviees (Sunnyvale，CA)之螢光測定成像盤讀取器或FLIpR™中以488 nm之激發波長及500至560 nm發射範圍監測基礎螢光。調整雷射激發能量以使得基礎螢光讀數為約8，〇〇〇相對螢光單元（RFU )。接著在室溫下以稀釋於檢定緩衝液中之促效劑（15 β 1)刺激細胞，且以1.5秒間隔經2.5 min時期量測RFU。計算各孔的最大螢光改變。藉由非線性回歸 (希爾方程式（Hill equation ))分析由最大螢光改變導出之濃度反應曲線。對於枯抗測定而言，在將化合物培育2〇分鐘（如上文所述）後，添加固定濃度之標準促效劑血清素。膜製備使細胞生長至95%匯合，以緩衝液（50 mM Tris pH 7.7 ’ 125 mM NaCl)洗滌兩次且藉由以1 〇 mi體積之緩衝液 /160 cm2擦刮來分離。將所分離之細胞離心（7 min，12〇xg) 且將離心粒再懸浮於8 ml緩衝液中且均質化（ultra Torax)。以 BCA™ (Pierce #23223+23224)量測蛋白質濃度。實施例3包含化合物I之膠囊在第一步驟中’將[2-(6-氟-1//-吲哚-3-基硫烷基）苄基] 甲基胺L-(+)酒石酸氫鹽與微晶纖維素混合。在第二步驟中，將硬脂酸鎂混入其中。製備具有四種濃度之膠囊活性成份係以游離鹼表述。 200938189 ---— Ί 活性成份 0.5 mg 1 mg 5 mg 10 mg 酒石酸氫鹽 7.62 g 15.24 76.2 152.4 微晶纖維素 2794.1 g 2776.56 2804.7 2748.3 硬脂酸鎂 28.3 g 28.2 29.1 29.3 膠囊内容物重量 283 mg 282 291 293 各批製備10,000粒膠囊。Constructed with probenicid (50 μl/well). After discarding the excess dye, the cells were washed in assay buffer and stratified at a final volume equal to 45 microliters/well (or 30 microliters/well for the antagonist assay) under the condition of antagonist evaluation. At this time, an antagonist or vehicle was added as an aliquot in 15% of a buffer containing 4% DMSO 29 200938189 (final DMSO = 1%) at a final concentration of 4 times, followed by incubation for 20 minutes. Base fluorescence was monitored in a fluorescence assay imaging disc reader or FLIpRTM from M〇leculai· Deviees (Sunnyvale, CA) with an excitation wavelength of 488 nm and an emission range of 500 to 560 nm. The laser excitation energy is adjusted such that the base fluorescence reading is about 8, relative to the fluorescent unit (RFU). The cells were then stimulated with an agonist (15 β 1) diluted in assay buffer at room temperature and the RFU was measured at 1.5 second intervals over a 2.5 min period. Calculate the maximum fluorescence change for each well. The concentration response curve derived from the maximum fluorescence change was analyzed by nonlinear regression (Hill equation). For the dry resistance assay, a fixed concentration of the standard agonist serotonin was added after incubation of the compound for 2 minutes (as described above). Membrane preparation Cells were grown to 95% confluence, washed twice with buffer (50 mM Tris pH 7.7 '125 mM NaCl) and separated by scuffing with 1 〇 mi volume of buffer / 160 cm2. The isolated cells were centrifuged (7 min, 12 〇 xg) and the pellet was resuspended in 8 ml buffer and homogenized (ultra Torax). The protein concentration was measured by BCATM (Pierce #23223+23224). Example 3 Capsules Containing Compound I 'In the First Step' '[2-(6-Fluoro-1//-indol-3-ylsulfanyl)benzyl]methylamine L-(+) Hydrogen Tartrate The salt is mixed with microcrystalline cellulose. In the second step, magnesium stearate is mixed therein. Preparation of capsule active ingredients having four concentrations is expressed as free base. 200938189 ---- Ί Active ingredient 0.5 mg 1 mg 5 mg 10 mg Hydrogen tartrate 7.62 g 15.24 76.2 152.4 Microcrystalline cellulose 2794.1 g 2776.56 2804.7 2748.3 Magnesium stearate 28.3 g 28.2 29.1 29.3 Capsule content Weight 283 mg 282 291 293 10,000 capsules were prepared in each batch.

實施例4對睡眠結構之影響向大鼠體内植入EEG及EMG電極以分別監測腦電活動及肌肉電活動。將電極與無線電發射機連接以允許自由移動、不受打擾且薇養之動物連續收集活動資料。對EEG及 EMG資料進行目測評分以測定醒覺狀態覺醒、sws及REM 睡眠。向10隻大鼠之組投予媒劑或化合物1(對應於〇 4 mg/kg及4 mg/kg游離鹼）。應用威廉方形交叉設計 (William s square cross over design )以使得各動物各接受一次治療。下表顯示記錄之第二小時内（亦即，注射後丨至2小時）醒覺狀態所用時間的百分比。Example 4 Effect on Sleep Structure EEG and EMG electrodes were implanted into rats to monitor brain electrical activity and muscle electrical activity, respectively. The electrodes are connected to a radio transmitter to allow free movement, undisturbed, and volley animals to continuously collect activity data. EEG and EMG data were visually scored to determine wakefulness, sws, and REM sleep. Vehicle or Compound 1 (corresponding to 〇 4 mg/kg and 4 mg/kg free base) was administered to a group of 10 rats. William s square cross over design was applied to allow each animal to receive treatment once. The table below shows the percentage of time spent in the wake-up state within the second hour of the recording (i.e., 丨 to 2 hours after injection).

31 200938189 亦即自注射化31 200938189 Self-injection

下表顯示以分鐘為單位的睡眠潛伏期合物直至第一次鞏固入睡的時間。上表中之資料顯示本發明化合物發揮rem 用；sWS睡眠似乎發仰削作削篁依賴性增加，及覺醒狀態似乎The table below shows the sleep latency in minutes until the first consolidation into sleep. The data in the above table shows that the compound of the present invention acts as a rem; sWS sleep seems to be plucked as a reduction in the dependence of the sputum, and the state of arousal seems to

程度上未受本發明化合物影響。因此，如針對且有NAT 及贿活性之化合物所預期，本發明化合物抑制刪睡眠’然而其在發揮此作用的同時無通常伴隨具;t SERT及 NAT活性之化合物的睡眠中斷作用。此外，睡眠潛伏期發生劑量依賴性降低’亦即在投予本發明化合物後睡眠較快開始。此等資料有力地表明化合物〗可用於治療（例如）情感性精神病而不伴隨具有SERT及/或NAT活性之化合物所經歷之不良睡眠作用。實施例5對血壓的作用〇在經遙測之比格爾犬（Beagle dog )體内以藉由胃管灌食法給予之0.25、0.50及1.0 mg/kg劑量研究本發明化合物的心血管作用。化合物之量係以游離鹼計算。實驗中使用6 條犬’三條雄性及三條雌性。所有給藥組中之組平均動脈收縮血壓（ABP )均降低_ 參見下表。 32 200938189 動脈收縮血壓（自基線之改變（平均A±SD)) 治療 (10-380 分鐘）媒劑 2.38 士4.49 0.25 mg/kg -4.26±5.98* 0.50 mg/kg -9.77±5.39* 1.00 mg/kg 6.30±6.63* *相較於媒劑組ρ<0·05 (兩種性別）。所有藥物處理組中之組平均左室收縮壓均類似地降低-參見下表。對於此參數可見性別效應。左室收縮壓 (自基線之改變（平均值±80)) 治療給藥後第I階段（10-380分鐘）媒劑 1.65±3.96 0.25 mg/kg -3.82±3.42? 0.50 mg/kg -11.^4.05^ 1.00 mg/kg -3.08 土 5.37從相較於媒劑組ρ<0.05 (雄性）。相較於媒劑組ρ<0.05 (雌性）。此等資料顯示本發明化合物與血壓增加無關，血壓增加通常與對去曱腎上腺素再吸收具有抑制作用之化合物有關。因此，本發明化合物適於治療情感性精神病（諸如抑鬱症）而不具有或僅具有降低之心血管副作用，諸如增加之金壓。 33 200938189 實施例6 〇：形L(+)酒石酸氫鹽之製備將[2-(6·氧-1H-。引n朵-3-基硫烧基）-节基]-曱基-胺酒石酸氫鹽（75 g)懸浮於甲醇（225 mL)與四氫呋。南（375 mL )之混合物中且在5(rc下加熱24小時。將混合物冷卻至室溫。將產物濾出且以四氫呋喃（6〇 mL )洗滌，且在5〇 °C下乾燥至恆重。NMR符合結構。To a lesser extent, it is not affected by the compounds of the invention. Thus, the compounds of the present invention inhibit the elimination of sleep as expected for compounds with NAT and bribe activity. However, they do not have the usual concomitant effects; sleep disruption of compounds with t SERT and NAT activity. In addition, a dose-dependent decrease in sleep latency', i.e., a faster onset of sleep after administration of a compound of the invention. Such information strongly suggests that the compound can be used to treat, for example, affective psychosis without the adverse sleep effects experienced by compounds having SERT and/or NAT activity. Effect of Example 5 on blood pressure 心血管 The cardiovascular effects of the compounds of the present invention were investigated in a telephoto Beagle dog at doses of 0.25, 0.50 and 1.0 mg/kg administered by gastric tube. The amount of the compound is calculated as the free base. Six dogs were used in the experiment, three males and three females. The mean arterial systolic blood pressure (ABP) was reduced in all groups in the administration group _ see table below. 32 200938189 Arterial systolic blood pressure (change from baseline (mean A ± SD)) Treatment (10-380 minutes) Vehicle 2.38 ± 4.49 0.25 mg / kg - 4.26 ± 5.98 * 0.50 mg / kg -9.77 ± 5.39 * 1.00 mg / Kg 6.30 ± 6.63* * compared to the vehicle group ρ < 0·05 (both genders). The mean left ventricular systolic pressure was similarly reduced in all groups in the drug treatment group - see the table below. A gender effect can be seen for this parameter. Left ventricular systolic pressure (change from baseline (mean ± 80)) Stage I after treatment (10-380 minutes) Vehicle 1.65 ± 3.96 0.25 mg / kg -3.82 ± 3.42 ~ 0.50 mg / kg -11. ^4.05^ 1.00 mg/kg -3.08 Soil 5.37 is compared to the vehicle group ρ < 0.05 (male). ρ < 0.05 (female) compared to the vehicle group. These data show that the compounds of the invention are not associated with an increase in blood pressure, which is generally associated with compounds that have an inhibitory effect on norepinephrine reuptake. Thus, the compounds of the invention are suitable for the treatment of affective psychosis (such as depression) without or with only reduced cardiovascular side effects, such as increased gold pressure. 33 200938189 Example 6 Preparation of 形: Form L(+) hydrogen tartrate [2-(6.Oxy-1H-.Introduced n-3-ylthioalkyl)-]]]]]-decyl-amine tartaric acid The hydrogen salt (75 g) was suspended in methanol (225 mL) and tetrahydrofuran. The mixture was heated in a mixture of THF (24 mL) for 24 hours at rc. The mixture was cooled to room temperature. The product was filtered and washed with tetrahydrofuran (6 mL) and dried to constant weight at 5 ° C. NMR conforms to the structure.

實施例7 α形L( + )酒石酸氫鹽之製備將[2-(6-氟-1H-吲哚-3·基硫烷基）_苄基;|·曱基_胺酒石酸氫鹽（4 g )在回流下溶解於水中且以活性碳處理。將溶液經矽藻土過濾、結晶且濾出結晶產物。將潮濕產物懸浮於乙醇（1〇〇 mL )中，加熱至5(rc且以少許α形晶體接種。將懸浮液在5(TC下攪拌隔夜。將懸浮液在冰浴7冷卻1小時。將產物濾出且在真空烘箱中在40<t下乾燥。nmr 符合結構。Example 7 Preparation of α-form L(+)-tartrate hydrogen salt [2-(6-Fluoro-1H-indol-3-ylsulfanyl)-benzyl;|·decyl-amine tartrate (4) g) Dissolved in water under reflux and treated with activated carbon. The solution was filtered through celite, crystallized and the crystalline product was filtered. The moist product was suspended in ethanol (1 mL), heated to 5 (rc and inoculated with a small amount of alpha crystals. The suspension was stirred overnight at 5 (TC). The suspension was cooled in an ice bath 7 for 1 hour. The product was filtered off and dried in a vacuum oven at 40 <t.

兀素分析：54.85%C 值：55.〇4%C、6.42%N、4.85%H)Alizarin analysis: 54.85% C value: 55. 〇 4% C, 6.42% N, 4.85% H)

實施例8 α形L(+)酒石酸氫鹽之特性化如實施例6或7中所製備之〇形L( + )酒石酸氫體（XRPD)-參見圖1。α形具有約193t之炫點。露於河相對濕度時吸收<0.1%水且在水中具有約i 5 的溶解度，飽和溶液之pH值為3 7。實施例9召形L(+)酒石酸氫鹽之製備藉由在熱水浴上加溫將[2-(6-氟_ 1H_吲哚·3_ 节基]-甲基-胺（108.5 g)溶解於甲醇（丨7L)中。添: 34 200938189 /酉石酸（56.9 g)，且將混合物在環境溫度下挽拌隔夜。將懸浮液在冰浴上冷卻2小時。將固體藉由過濾收集且以冷甲醇洗滌。將產物在真空中在6〇。〇下乾燥。NMR符合結構。元素分析：54.99%C、6.25%N、4.91%H ( 1:1鹽之理論值： 55.04%C > 6.42%N ' 4.85%H)。實施例10召形L(+)酒石酸氫鹽之特性化如實施例9中所製備之冷形L(+)酒石酸氫鹽為晶體 (XRPD) _參見圖2。石形具有約189。(：之熔點。其在暴露於高相對濕度時吸收約〇.6%水且在水中具有約2〇mg/ml 的溶解度，飽和溶液之pH值為3.7。實施例11抗躁狂作用_小鼠之敏化***反應在所有實驗中，將動物保持於12:12亮·暗循環，在06:00 h時開燈。可無限制地獲取食物及水。在進行實驗前丨天下午將動物帶到實驗室。所有藥物劑量係以每公斤之鹽毫克數列出。在測試結束後的3〇分鐘内收集血樣。 ❹ 重複間歇投予***致使對後績***挑釁之敏化反應形成。已提出此現象模擬雙極性情感疾患的慢性及進行性。動物：體重19-21 g的雄性NMRI小鼠係由Harlan(the Nederlands )供應。將動物以每籠4隻圈養於模克隆籠 (Makrolon cage) ( 20x35 cm)中，模克隆籠具有兩個塑膠棚舍及嵌套材料以達成豐富化。在開始實驗前，動物有5 天時間適應動物設施。叹備.將模克隆籠（20x35 cm)置於裝備有5 X §红 35 200938189 外光源之方塊物中且使用間隔4 cm之光電池記錄動物之行為活動（locomotor activity)。光束在籠底部上方18 cm 穿過巍子。記錄運動計數需要中斷相鄰光束，因此避免小鼠穩態運動所誘發之計數。實驗建立：將動物以硫酸***2.50 mg/kg( 10 ml/kg 皮下）或媒劑預處理連續5天。在丨1+Λ1天停藥期後，向動物注射測試藥物或媒劑注射劑。將氣化鋰溶解於蒸餾水中且在測試前30分鐘以40 mg/kg ( 0.94 mEq/kg )之劑量皮下注射（6 ml/kg)。將測試化合物（[2_(6_氟_1丹_吲哚_3_❹ 基硫烧基）节基]甲基胺！^_(+)_酒石酸氫鹽）溶解於羥丙基-/3 -環糊精中且在測試前6〇分鐘以〇〇8及〇 4 mg/kg之劑量皮下注射。由於測試化合物對齧齒動物5HT2A受體之親和力較低（相對於人類受體），因此將測試化合物之測試劑量與實現完全佔據此受體之Mdl 100907 ([M + )-a-(2,3_二甲氧基苯基•氟苯基乙基）]4-哌啶甲醇])的劑量組合。測試之前3〇分鐘，將動物置於活動箱中進行適應。適應期後，將小鼠以低劑量***挑聚〇 (1.25 mg/kg或生理食鹽水，1〇 ml/kg)注射且量測行為活動歷時60分鐘。根據16隻動物的平均體重對小鼠進行給藥。以***預處理（2·5〇 mg/kg ’皮下’ 5天）引起對急性低劑量***挑襞（i.25 mg/kg ’皮下）的敏化反應 (行為活動増加）（"*p<().謝）。鐘（〇94mE_)及 MDL 1〇_7 (〇.3 mg/kg)顯著降低所誘發之行為活動（* 36 200938189 P>〇·05 )。單獨之測試化合物〇·08 mg/kg及0.4 mg/kg對誘發之行為活動無作用。測試化合物、MDL 1〇〇9〇7及鋰的測試劑量對於基礎活動不具有顯著作用。然而，測試化合物 (〇.〇8 mg/kg 及 0.4 mg/kg)與 MDL 100907 ( 0.3 mg/kg) 之組合致使經生理食鹽水預處理之動物之基礎活動明顯減少（***ρ<〇.〇〇1 )-參見圖 3。實施例12抗躁狂作用·***及氣氮卓 (chlordiazapoxide )所誘發之大鼠之行為活動女非他命與氣氮卓之適當組合誘發之行為活動增加為建議之躁症動物模型。所誘發之行為活動可由鋰逆轉。在所有實驗中，將動物保持於12:12亮-暗循環，在06:00 h時開燈。可無限制地獲取食物及水。在進行實驗前1天下午將動物帶到實驗室。所有藥物劑量係以每公斤之鹽毫克數列出。在測試結束後30分鐘内收集血樣。動物：體重160-175g的雄性威斯達大鼠（wistarrat) ©係由Harlan ( the Netherlands )供應。將動物以每籠4隻圈養於模克隆籠（20x35 cm)中’模克隆籠具有一塑膠棚舍以達成豐畐化。在開始實驗前’大鼠有5天時間適應動物設施。設備：將模克隆籠（ 20x3 5 cm)置於縱向裝備有4個紅外光源之U型框架中且使用光電池記錄動物之行為活動。光束在巍底部上方4 cm穿過籠子。記錄運動計數需要中斷相鄰光束，因此避免大鼠穩態運動所誘發之計數。一薄層標準襯墊材料覆蓋籠底部。 37 200938189 實驗建立：將氯化链溶解於蒸館水中且在測試前2i〇分鐘以0.94 mEg/kg(40 mg/kg)之劑量皮下注射（6 ml/kg)。將測試化合物（參見實施例12 )溶解於1 〇%經丙基-冷-環糊精中且在測試之前60分鐘，以〇.4 mg/kg之劑量單獨或與〇.3 mg/kg MDL 100907組合皮下注射。將硫酸*** (1.2 mg/kg )溶解於0.9% NaCl中且在測試之前35分鐘皮下主射（1 ml/kg )。將氣氮卓（1〇〇 mg/kg )溶解於經丙基-点-環糊精中且在***注射後立即皮下注射（5 ml/kg )。女非他命及氣氮卓注射35分鐘後，將動物個別地〇置於測試箱中且量測活動歷時12〇分鐘。以***（1.2 mg/kg)及氣氮卓（1〇.〇 mg/kg)處理致使行為活動增加顯著大於以媒劑處理之動物 (*P<0.001 )。鋰（0.94 mEq/kg)及 MDL 100907 ( 0.3 mg/kg)顯著逆轉所誘發之行為活動（*ρ<〇〇〇ι)。測試化合物0.4 mg/kg顯示增加行為活動所誘發之活動的傾向但不顯著然而，測試化合物（0.4 mg/kg)與MDL· 100907 (〇.3 mg/kg)之組合致使所誘發之行為活動顯著衰減。链、〇 MDL 1 00907及測試化合物的測試劑量對於基礎活動無作用-參見圖4。 … 實施例13抗焦慮作用在所有實驗中，將動物保持於12:12亮暗循環在⑼ h時開燈。可無限制地獲取食物及水。小鼠彈子掩埋行為（Marble Burying ) 對於每齒動物而言，作為防紫行為之掩埋功能用於減 38 200938189 輕威脅強度或動物為威脅的易受傷害性。研究者已使用多種威脅性物體（諸如帶電刺針及口味令人不悦之食物及液體）研究防絮性掩埋行為。諸如彈子及食物丸粒之良性物體亦引起掩埋行為。小鼠掩埋無害物體可能係因為該等無害物體為新穎的且因此被感知為具威脅性。急性投予抗焦慮及抗抑繫藥物兩者減少此範例中經掩埋的彈子數。將雄BALB/cByJ小鼠（22-28 g)以每籠5隻圈養。 a進行兩個實驗。小鼠接受媒劑或0W5M.25或5mg/kg(皮下）測試化合物（參見實施例12)。注射之後3〇分鐘，將動物個別地置於在I·5吋Aspen襯墊頂部含有2〇個（2列，每列10個）彈子的籠中。 3〇分鐘測試期後，使小鼠回到其居住籠中，且計數可見彈子數（少於以草塾覆蓋者的2/3) i 2〇減去該數目產生經掩埋之彈子數。以所有三種劑量之測試化合物預處理顯著且等效減少 • 經掩埋之彈子數（N=9_u/組）-參見圓5。壓力誘發之體溫過高壓力誘發之體溫過高（SIH)測試係基於以下原理·•與其他哺乳動物一樣，小鼠對壓力具有天然體溫過高反應。在此範例中，壓力源量取直腸溫度。認為此生理學反應反映動物焦慮程度，且藉由以抗焦慮藥（諸如，苯并二氮呼）預處理而衰減。將雄性C57B1/6小鼠（18·21 g)以每籠5隻圈養直至實驗前1天，此時將其帶到測試房間且單獨圈養。經2天 39 200938189 時期自9-12 am進行測試。小鼠接受媒劑、氣氮卓（丨〇 mg/kg) 或0.02、0.08或0.32 mg/kg測試化合物（皮下）。1小時後’以直腸探針量測核心溫度（T1 )且使各動物回到其籠中。10分鐘後’獲得第二讀數（T2)。計算兩個讀數之間的差異（Τ2-Τ1 )作為壓力誘發之體溫過高之量度。第一次與第二次量測之間的核心溫度之增加（亦即，壓力誘發之艎溫過高（SIH))藉由以CDP(pc.Ol)預處理顯著降低’且在以測試化合物處理後以劑量依賴性方式降低-參見圖6。 ❹ 實施例14 -[2-(6-氟-1H-吲哚-3-基硫烷基）苄基]甲基胺的結晶鹽將5g [；2-(6-氟吲哚_3_基硫烧基）节基]甲基胺溶解於100 ml EtOH中，產生Et0H中之〇 175 ¥儲備溶液，自該儲備溶液使用2.0 ml之等分試樣（100 mg鹼）。將5g [2-(6-氟-1/Λ吲哚_3_基硫烷基）苄基]甲基胺溶解於125 mlTHF中，產生THF中之〇 14〇M儲備溶液自該儲備溶液使用2.5 ml之等分試樣（1〇〇 mg鹼）。〇木將給定之等分試樣置於試管中且同時攪拌，添加K00 當量之酸。若酸為液體，則其以純形式添加，否則，在添加之前將其溶解於給定溶劑中。在混合及沈澱後，繼續攪拌隔夜且藉由過濾收集沈澱物。將沈澱物在室溫下乾燥隔夜（不使用真空）。【圖式簡單說明】 40 200938189 圖I : α形L(+)酒石酸氫鹽之又射線粉末繞射圖圖2:则+)酒石酸氫鹽之X射線粉末繞射圓圖3:本發明化合物對小鼠之敏化***反應之作用圖4本發明化合物對***/氣氣卓誘發之活性 :5 ·本發明化合物對小鼠彈子掩埋行為的 6.本發明化合物對壓力誘發之體溫Example 8 Characterization of α-form L(+)-tartrate hydrogen salt X-shaped L(+) tartaric acid (XRPD) prepared as in Example 6 or 7 - see Fig. 1. The alpha shape has a dazzling point of about 193t. When exposed to the relative humidity of the river, it absorbs <0.1% water and has a solubility of about i 5 in water, and the pH of the saturated solution is 37. Example 9 Preparation of L (+) Tartrate Hydrogenate by Heating [2-(6-Fluoro-1H_吲哚·3_]-]-Methyl-Amine (108.5 g) by heating on a hot water bath Dissolved in methanol (丨7L). Add: 34 200938189 / tartaric acid (56.9 g), and mix the mixture overnight at ambient temperature. The suspension was cooled on an ice bath for 2 hours. The product was washed with cold methanol. The product was dried under vacuum at 6 Torr. NMR was obtained. Elemental analysis: 54.99% C, 6.25% N, 4.91% H ( 1:1 salt theoretical value: 55.04% C &gt 6.42% N '4.85% H). Example 10 Characterization of L(+) hydrogen tartrate as in Example 9. Cold form L(+) hydrogen tartrate prepared as in Example 9 is crystal (XRPD) - see figure 2. The stone shape has a melting point of about 189. (:: it absorbs about 6%. 6% of water when exposed to high relative humidity and has a solubility of about 2 〇 mg/ml in water, and the pH of the saturated solution is 3.7. Example 11 Anti-manic action _ sensitized amphetamine reaction in mice In all experiments, animals were kept on a 12:12 light-dark cycle and turned on at 06:00 h. Unrestricted access to food and water was obtained. Before conducting the experiment Animals were brought to the laboratory in the afternoon. All drug doses were listed in milligrams per kilogram of salt. Blood samples were collected within 3 minutes after the end of the test. 重复 Repeated intermittent administration of amphetamines to induce amphetamine The formation of a reaction has been proposed to mimic the chronic and progressive nature of bipolar affective disorders.Animal: Male NMRI mice weighing 19-21 g were supplied by Harlan (the Nederlands). Animals were housed in 4 cages per cage. In the Makrolon cage (20x35 cm), the cloned cage has two plastic sheds and nesting materials to enrich it. Before the experiment, the animals have 5 days to adapt to the animal facility. The cage (20 x 35 cm) was placed in a box equipped with 5 X § red 35 200938189 external light source and the animal's locomotor activity was recorded using a photocell spaced 4 cm apart. The beam passed through the forceps 18 cm above the bottom of the cage. Recording the exercise count requires interrupting the adjacent beam, thus avoiding the counting induced by steady-state movement of the mouse. Experiment establishment: Animals with amphetamine sulfate 2.50 mg/kg (10 ml/kg subcutaneous Or vehicle pretreatment for 5 consecutive days. After the withdrawal period of 丨1+Λ1 day, the test drug or vehicle injection was injected into the animal. Lithium vapor was dissolved in distilled water and 40 mg/kg 30 minutes before the test ( A dose of 0.94 mEq/kg) was injected subcutaneously (6 ml/kg). The test compound ([2_(6_fluoro_1丹_吲哚_3_❹ thiol))methylamine was tested! ^_(+)_hydrogen tartrate) was dissolved in hydroxypropyl-/3-cyclodextrin and injected subcutaneously at a dose of 〇8 and 〇4 mg/kg 6 minutes before the test. Since the test compound has a low affinity for the rodent 5HT2A receptor (relative to the human receptor), the test dose of the test compound is achieved with Mdl 100907 ([M + )-a-(2,3) which completely occupies this receptor. Dosage combination of _dimethoxyphenyl•fluorophenylethyl)]4-piperidinemethanol]). Three to three minutes before the test, the animals were placed in an activity box for adaptation. After the acclimation period, mice were injected with low doses of amphetamine (1.25 mg/kg or saline, 1 〇 ml/kg) and the behavioral activities were measured for 60 minutes. Mice were dosed according to the average body weight of 16 animals. Pretreatment with amphetamine (2·5〇mg/kg 'subcutaneous' for 5 days) caused sensitization of acute low-dose amphetamine provocation (i.25 mg/kg 'subcutaneous)) ("*p&lt ;().thank). The bell (〇94mE_) and MDL 1〇_7 (〇.3 mg/kg) significantly reduced the induced behavioral activities (* 36 200938189 P>〇·05). The test compounds alone 〇·08 mg/kg and 0.4 mg/kg had no effect on the induced behavioral activities. The amount of test compound, MDL 1〇〇9〇7, and lithium did not have a significant effect on the underlying activity. However, the combination of test compounds (〇.〇8 mg/kg and 0.4 mg/kg) with MDL 100907 (0.3 mg/kg) resulted in a significant reduction in the underlying activity of animals pretreated with physiological saline (***ρ<〇 .〇〇1) - See Figure 3. Example 12 Anti-manicactation, amphetamine, and chlordiazapoxide-induced behavioral activities in rats The combination of behavioral activity induced by a combination of feminine and nitrozapine was suggested as a suggested snoring animal model. The induced behavioral activity can be reversed by lithium. In all experiments, animals were kept on a 12:12 light-dark cycle and turned on at 06:00 h. Unlimited access to food and water. Animals were brought to the laboratory one day before the experiment. All drug doses are listed in milligrams of salt per kilogram. Blood samples were collected within 30 minutes of the end of the test. Animals: Male Wistar rats of 160-175 g body weight are supplied by Harlan (the Netherlands). Animals were housed in a modular colony cage (20 x 35 cm) in cages of 4 cages. The cloned cages had a plastic shed to achieve abundance. Rats were allowed to acclimate to animal facilities for 5 days before starting the experiment. Equipment: The cloned cage (20 x 3 5 cm) was placed in a U-frame equipped with 4 infrared sources in the longitudinal direction and the behavior of the animals was recorded using a photocell. The beam passes through the cage 4 cm above the bottom of the crucible. Recording the motion count requires interrupting the adjacent beam, thus avoiding the count induced by steady state motion in the rat. A thin layer of standard gasket material covers the bottom of the cage. 37 200938189 Experimental establishment: The chlorinated chain was dissolved in steaming water and injected subcutaneously (6 ml/kg) at a dose of 0.94 mEg/kg (40 mg/kg) 2 μ〇 min before the test. The test compound (see Example 12) was dissolved in 1% propyl-cold-cyclodextrin and administered at a dose of 〇.4 mg/kg alone or with 〇.3 mg/kg MDL 60 minutes before the test. 100907 combined subcutaneous injection. Amphetamine sulfate (1.2 mg/kg) was dissolved in 0.9% NaCl and subcutaneously injected (1 ml/kg) 35 minutes before the test. Gas nitrogen (1 〇〇 mg/kg) was dissolved in propyl-dot-cyclodextrin and injected subcutaneously (5 ml/kg) immediately after the injection of bupropion. After 35 minutes of injection of the female and the nitroxazole, the animals were individually placed in a test box and the measurement activity lasted 12 minutes. Treatment with amphetamine (1.2 mg/kg) and nitroxazole (1 〇.〇 mg/kg) resulted in a significantly greater increase in behavioral activity than vehicle-treated animals (*P<0.001). Lithium (0.94 mEq/kg) and MDL 100907 (0.3 mg/kg) significantly reversed the induced behavioral activity (*ρ<〇〇〇ι). Test compound 0.4 mg/kg showed a tendency to increase activity induced by behavioral activity but was not significant. However, the combination of test compound (0.4 mg/kg) and MDL·100907 (〇.3 mg/kg) resulted in significant behavioral activity induced. attenuation. The test dose of the chain, 〇 MDL 1 00907 and test compound has no effect on the underlying activity - see Figure 4. Example 13 Anxiolytic Effect In all experiments, animals were kept on at 12:12 light and dark cycle at (9) h. Unlimited access to food and water. Mouse Burying For each toothed animal, the burying function as an anti-purple behavior is used to reduce the vulnerability of light threats or animals to threats. Researchers have used a variety of threatening objects, such as charged needles and unpleasant foods and liquids, to study flocculation burial behavior. Benign objects such as marbles and food pellets also cause burial. The burying of harmless objects by mice may be because these innocuous objects are novel and therefore perceived as threatening. Both acute anti-anxiety and anti-repressive drugs reduce the number of buried marbles in this example. Male BALB/cByJ mice (22-28 g) were housed in 5 cages per cage. a Conduct two experiments. Mice received vehicle or 0W5M.25 or 5 mg/kg (subcutaneous) test compounds (see Example 12). Three minutes after the injection, the animals were individually placed in a cage containing 2 ( (2 columns, 10 per column) of marbles on top of the I·5吋Aspen pad. After the 3 minute test period, the mice were returned to their home cage and the number of visible marbles (less than 2/3 of the grass covered) i 2 〇 minus the number produced the number of buried marbles. Pretreatment with all three doses of test compound was significantly and equivalently reduced • Number of bombs buried (N=9_u/group) - see circle 5. Stress-induced hyperthermia The pressure-induced hyperthermia (SIH) test is based on the following principles: • Like other mammals, mice have a natural hyperthermia response to stress. In this example, the pressure source measures the rectal temperature. This physiological response is believed to reflect the degree of anxiety in the animal and is attenuated by pretreatment with an anxiolytic agent such as benzodiazepine. Male C57B1/6 mice (18·21 g) were housed in 5 cages per cage until 1 day before the experiment, at which time they were brought to the test room and housed separately. Tested from 9-12 am over 2 days 39 200938189. Mice received vehicle, nitroxazole (丨〇 mg/kg) or 0.02, 0.08 or 0.32 mg/kg test compound (subcutaneous). One hour later, the core temperature (T1) was measured with a rectal probe and the animals were returned to their cages. After 10 minutes, a second reading (T2) was obtained. Calculate the difference between the two readings (Τ2-Τ1) as a measure of pressure-induced hyperthermia. The increase in core temperature between the first and second measurements (ie, pressure-induced hyperthermia (SIH)) is significantly reduced by pretreatment with CDP (pc.Ol) and is used to test compounds Reduced in a dose-dependent manner after treatment - see Figure 6.实施 Example 14 - Crystalline salt of [2-(6-fluoro-1H-indol-3-ylsulfanyl)benzyl]methylamine 5 g [; 2-(6-fluoroindole_3_yl) The thiol group) methylamine was dissolved in 100 ml of EtOH to give a 〇 175 </ RTI> stock solution in Et0H from which a 2.0 ml aliquot (100 mg base) was used. Dissolve 5 g of [2-(6-fluoro-1/indol-3-ylsulfanyl)benzyl]methylamine in 125 ml of THF to give a 〇14〇M stock solution in THF from the stock solution. An aliquot of 2.5 ml (1 mg base). The eucalyptus is placed in a test tube with a given aliquot and stirred while adding K00 equivalents of acid. If the acid is a liquid, it is added in pure form, otherwise it is dissolved in a given solvent before being added. After mixing and precipitation, stirring was continued overnight and the precipitate was collected by filtration. The precipitate was dried overnight at room temperature (no vacuum was used). [Simple description of the diagram] 40 200938189 Figure I: Refraction of the ray powder of α-form L (+) hydrogen tartrateFig. 2: X) X-ray powder diffraction circle of hydrogen tartrateFig. 3: Compound of the invention Effect of sensitizing amphetamine reaction in mice Figure 4 Activity of the compounds of the invention on amphetamine/gas-induced activity: 5 · The compound of the invention is immersed in mouse bombs 6. The compound of the invention is subjected to pressure-induced body temperature

高的作用過 Μ巧的作用【主要元件符號說明】 (無）High role over good function [Main component symbol description] (none)

Claims

200938189 七、申請專利範圍：種醫藥組成物’其係用於治療患者之躁症、輕度躁狂、雙極性情感疾患（維持）、預防雙極性情感疾患復發、使雙極性情感疾患穩定、部分反應者之抑繫症；抗治療性抑營症；重度抑费症；情感迴環；全身性醫學病況引起之情感疾患；物質誘發之抑鬱症；復發性抑鬱症；單次發作抑鬱症；兒科抑鬱症；非典型抑鬱症；中風後抑鬱症；耗竭性抑鬱症；季節性情感性精神病（SAD);與精神***症有關之㈣症、***情感性精神病、胃腸痛、IBS、溢用、0 敵意、易怒、疲勞、焦慮（焦慮性抑鬱症）、路易體病（Lewy Body disease)或多發性硬化症；飛行、電梯或小房間恐懼症；與疼痛有關之一般性焦慮症；高血壓風險增加之患者的焦慮；有睡眠問題之患者的焦慮；認知損害、阿茲海默氏病（Alzheimer’s disease )、癡呆；輕度認知損害（MCI ); 血b型癡呆’白質疏鬆；小金管疾病；與ADHD有關之強迫及注意力譜系病症、亞斯柏格症候群（Asperger，s syndrome);自閉症；與情感性精神病有關之認知損害、抑〇鬱症、整體抑鬱症、重鬱症、焦慮症、一般性焦慮症、恐慌症、強迫症、精神***症、帕金森氏病（Parkins〇n,s disease )、癡呆、AIDS癡呆、ADHD、年齡相關的記憶損害、唐氏症候群（Down’s syndrome )、癲痛症、外傷性腦才貝傷、亞斯柏格症候群（Asperger’s syndrome )、色氣酸經化酶基因突變及阿茲海默氏病；與癡呆有關之行為障礙；與癡呆及阿茲海默氏病有關之攻擊性及焦躁；精神***症 42 200938189 中之負向症狀，酒精、於驗或碳水化合物成癩；物質溢用；酒精或藥物濫用；進食障礙；肥胖症；厭食症；貪食症；暴食症；衝動控制病症；間歇性爆怒症；偷竊癖；縱火癖；病理性賭博；拔毛髮癖；晝夜節律障礙；原發性失眠、長期失眠、暫時性失眠；睡眠呼吸暫停；睡眠呼吸障礙；低通氣症候群；與壓力有關之病症；急性壓力；燒傷；壓力；慢性疲勞症候群；品行障礙；行為障礙；老年行為障礙；與ΗΡΑ軸活性過高有關之胰島素抗性；熱潮紅、嘔吐、停、’、!·刚圍停經期及停經後不悅症；病理性哭泣；弱視；妥柘氏症候群（Tourette’s syndrome )或疼痛，其包含治療有效量之[2-(6-氟-if吲哚_3_基_基硫烷基【sulfanyi】）苄基] 曱基胺或其醫藥上可接受之鹽（化合物I)。 2.如申凊專利範圍第1項之醫藥組成物，其中該疼痛為以下疼痛或與以下疼痛有關：鞭打、IBS、慢性疼痛、幻肢痛、神經病性疼痛、糖尿病性神經病變、疱疹後神經痛 ❹ （PHN)、腕道症候群（CTS)、mv神經病變、複雜性局部疼痛症候群（CPRS )、三又神經痛（trigeminal neuralgia/trigeminus neuralgia/tic douloureux)、手術介入後之疼痛（例如，術後鎮痛）、糖尿病性血管病變、毛細企管抗性、與胰島炎有關之糖尿病性症狀、與月經有關之疼痛、與癌症有關之疼痛、牙痛、頭痛、偏頭痛、緊張型頭痛、顯骨下顎關節症候群、肌筋膜疼痛、肌肉損傷、骨骼及關節疼痛（骨關節炎）、類風濕性關節炎、與燒傷有關之外傷所引起的浮腫、骨質疏鬆症、骨轉移、痛風、纖 43 200938189 維組織炎、胸廓出口症候群、骨盆痛、心源性胸痛、非心源性胸痛、與脊髓損傷（SCI )有關之疼痛、中風後中框神經痛、癌性神經病變、AIDS、錄狀細胞痛或老人痛（geriatric pain) 〇 3 ·如申請專利範圍第1及2項中任一項之醫藥組成物，其中該患者已接受或正接受抗抑鬱劑藥物治療，該藥物治療因睡眠或血壓相關之不良事件而已停止或必需停止。 4. 如申請專利範圍第1或2項中任一項的醫藥組成物，其中該患者罹患增加之血壓或睡眠相關病症或處於罹患該 © 等病症之風險中。 5. 如申請專利範圍第4項之醫藥組成物，其中該化合物 I為晶艘。 6. 如申請專利範圍第5項之醫藥組成物，其中該化合物 I為[2-(6-氟吲哚_3_基硫烷基）苄基]甲基胺l(+)酒石酸氫鹽8 7. 如申請專利範圍第6項之醫藥組成物，其中該酒石酸鹽具有約 9.66、14.53、18.14 及 30.48 (。2 0 )之 XRPD 峰。〇 8. 如申請專利範圍第7項之醫藥組成物，其中該酒石酸鹽具有如圖1描繪之XRPD。 9. 種[2-(6·氟-1H-吲哚-3-基硫烷基）苄基]曱基胺或其 =藥上可接受之壅（化合物I)之用途，其係用於製造用以療〜 ^下病症之藥物：躁症、輕度躁狂、雙極性情感疾患（維持）、預防雙極性情感疾患復發、使雙極性情感疾患穩定、部分反應者之抑鬱症；抗治療性抑鬱症；重 44 200938189 度抑鬱症；情感迴環；全身性醫學病況引起之情感疾患；物質誘發之抑鬱症；復發性抑鬱症；單次發作抑鬱症，·兒科抑鬱症；非典型抑鬱症；中風後抑鬱症；耗竭性抑鬱症；季節性情感性精神病（SAD與精神***症有關之抑鬱症、 ***情感性精神病、胃腸痛、IBS、濫用、敵意、易怒、疲勞、焦慮（焦慮性抑鬱症）、路易體病或多發性硬化症；飛打、電梯或小房間恐懼症；與疼痛有關之一般性焦慮症；高血壓風險增加之患者的焦慮丨有睡眠問題之患者的焦慮，認知損害、阿茲海默氏病、癡呆；輕度認知損害（mci ); 血管型癡呆；白質疏鬆；小血管疾病；與ADHD有關之強迫及注意力譜系病症、亞斯柏格症候群；自閉症；與情感性精神病有關之認知損害、抑鬱症、整體抑鬱症、重鬱症、焦慮症、一般性焦慮症、恐慌症、強迫症、精神***症、 =金森氏病、癡呆、AIDS㈣、ADHD、年齡相關的記憶損害、唐氏症候群、癲癎症、外傷性腦損傷、亞斯柏格症〇候群、色氨酸羥化酶基因突變及阿兹海默氏病；與癡呆有關之行為障礙；與癡呆及阿茲海默氏病有關之攻擊性及焦躁；精神***症中之負向症狀；酒精、於驗或碳水化合物成瘾；物質溢用；酒精或藥物溢用；進食障礙；肥胖症；厭食症；貪食症；暴食症；衝動控制病症；間歇性爆怒症；偷竊癖；縱火癖·，病理性賭博；拔毛髮癖；畫夜節律障礙；原發性失眠、長期失眠、暫時性失眠；睡眠呼吸暫停；睡眠呼吸障礙；低通氣症候群；與壓力有關之病症；急性壓力；燒傷；壓力；慢性疲勞症候群；品行障礙；行為障礙； 45 200938189 老年行為障礙；與HPA軸活性過高有關之胰島素抗性，·熱潮紅"區吐、停經前、圍停經期及停經後不悅症；病理性哭泣；弱視；妥瑞氏症候群或疼痛。 10.如申請專利範圍第9項之用途，其中該疼痛為以下疼痛或與以下疼痛有關：鞭打、IBS、慢性疼痛、幻肢痛、神經病性疼痛、糖尿病性神經病變、疱疹後神經痛（PHN )、腕道症候群（CTS )、HIV神經病變、複雜性局部疼痛症候群（S) 一叉神經痛（trigeminal neuralgia/trigeminus neuralgia/tic doul〇ureux)、手術介入後之疼痛（例如，術〇後鎮痛）、糖尿病性血管病變、毛細血管抗性、與胰島炎有關之糖尿病性症狀、與月經有關之疼痛、與癌症有關之疼痛、牙痛、頭痛、偏頭痛、緊張型頭痛、顳骨下顎關節症候群、肌筋膜疼痛、肌肉損傷、骨骼及關節疼痛（骨關節炎）、類風濕性關節炎、與燒傷有關之外傷所引起的浮腫、骨質疏鬆症、骨轉移、痛風、纖維組織炎、胸廓出口症候群、骨盆痛、心源性胸痛、非心源性胸痛、與脊髓損傷（SCI)有關之疼痛、中風後中柩神經痛、癌性神經病變、〇 AIDS、鐮狀細胞痛或老人痛。 11. 如申請專利範圍第9至1〇項中任一項之用途，其中該患者已接受或正接受抗抑鬱劑藥物治療，該藥物治療因睡眠或血壓相關之不良事件而已停止或必需停止。 12. 如申請專利範圍第9至1〇項中任一項的用途，其中該患者罹患增加之血壓或睡眠相關病症或處於罹患該等病症之風險中。 46 200938189 13. 如申請專利範圍第9項之用途，其中該化合物工為晶體。 14. 如申請專利範圍第13項之用途其中該化合物^為 [2-(6-氟-111_«弓卜朵_3_基硫院基）节基]甲基胺l_⑴-酒石酸氮鹽。 15. 如申請專利範圍第14項之用途，其令酒石酸鹽具有約 9.66、14.53、18.14 及 3〇 48 (。2 ㈠之 XRpD 峰。200938189 VII. Patent application scope: A kind of pharmaceutical composition' is used to treat patients with snoring, mild mania, bipolar emotional disorders (maintenance), prevention of bipolar emotional disorders, and stabilization of bipolar emotional disorders. Responder's suppression; anti-therapeutic inhibition; severe inducing disorder; emotional loopback; emotional illness caused by systemic medical conditions; substance-induced depression; recurrent depression; single-onset depression; pediatric depression Atypical depression; post-stroke depression; depletion depression; seasonal affective psychosis (SAD); schizophrenia-related (4), schizoaffective psychosis, gastrointestinal pain, IBS, overflow, 0 , irritability, fatigue, anxiety (anxiety depression), Lewy Body disease or multiple sclerosis; flight, elevator or small room phobia; general anxiety disorder associated with pain; increased risk of hypertension Anxiety of patients; anxiety of patients with sleep problems; cognitive impairment, Alzheimer's disease, dementia; mild cognitive impairment (MCI); blood b-type dementia' leukoaraiosis; small golden tube disease; obsessive-compulsive lineage disorder associated with ADHD, Asperger's syndrome; autism; cognition associated with affective psychosis Damage, depression, overall depression, severe depression, anxiety, general anxiety, panic disorder, obsessive-compulsive disorder, schizophrenia, Parkins〇n, s disease, dementia, AIDS dementia, ADHD Age-related memory impairment, Down's syndrome, epilepsy, traumatic brain injury, Asperger's syndrome, serotonin gene mutation and Alzheimer's Disease; behavioral disorders associated with dementia; aggression and irritability associated with dementia and Alzheimer's disease; negative symptoms in schizophrenia 42 200938189, alcohol, test or carbohydrate sputum; Alcohol or substance abuse; eating disorders; obesity; anorexia; bulimia; binge eating disorder; impulsive control disorder; intermittent anger; stealing sputum; arson; pathological gambling Hair licking; circadian rhythm disorder; primary insomnia, long-term insomnia, temporary insomnia; sleep apnea; sleep-disordered breathing; hypopnea syndrome; stress-related disorders; acute stress; burns; stress; chronic fatigue syndrome; Conduct disorder; behavioral disorder; senile behavioral disorder; insulin resistance associated with excessive activity of the sacral axis; hot flashes, vomiting, cessation, ',!· just after menopause and post-menopausal discomfort; pathological crying; amblyopia; Tourette's syndrome or pain, comprising a therapeutically effective amount of [2-(6-fluoro-if吲哚_3_yl-ylsulfanyl)benzyl] decylamine or a pharmaceutical thereof An acceptable salt (Compound I). 2. The pharmaceutical composition of claim 1, wherein the pain is related to or associated with pain: whipping, IBS, chronic pain, phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic nerve Pain (PHN), carpal tunnel syndrome (CTS), mv neuropathy, complex local pain syndrome (CPRS), trigeminal neuralgia/trigeminus neuralgia/tic douloureux, pain after surgical intervention (eg, surgery) Post-analgesia), diabetic angiopathy, capillary resistance, diabetic symptoms associated with isletitis, pain associated with menstruation, pain associated with cancer, toothache, headache, migraine, tension headache, sub-abdominal ankle Syndrome, myofascial pain, muscle damage, bone and joint pain (osteoarthritis), rheumatoid arthritis, edema caused by burn-related trauma, osteoporosis, bone metastasis, gout, fiber 43 200938189 Inflammation, thoracic outlet syndrome, pelvic pain, cardiogenic chest pain, non-cardiac chest pain, and spinal cord injury (SCI) Guan Yu Pain, post-stroke middle-frame neuralgia, cancerous neuropathy, AIDS, sputum cell pain, or geriatric pain 〇3 · If the pharmaceutical composition of any of the scopes 1 and 2 of the patent application, The patient has received or is receiving an antidepressant medication that has stopped or has to be stopped due to a sleep or blood pressure related adverse event. 4. The pharmaceutical composition of any one of claims 1 or 2, wherein the patient is at increased risk of or at risk of developing a blood pressure or sleep related condition. 5. The pharmaceutical composition of claim 4, wherein the compound I is a crystal boat. 6. The pharmaceutical composition according to claim 5, wherein the compound I is [2-(6-fluoroindole-3-ylsulfanyl)benzyl]methylamine 1 (+) hydrogen tartrate 8 7. The pharmaceutical composition of claim 6, wherein the tartrate salt has an XRPD peak of about 9.66, 14.53, 18.14, and 30.48 (.20). 8. The pharmaceutical composition of claim 7, wherein the tartrate salt has an XRPD as depicted in FIG. 9. The use of [2-(6.fluoro-1H-indol-3-ylsulfanyl)benzyl]decylamine or its pharmaceutically acceptable hydrazine (Compound I) for the manufacture of Drugs used to treat ~ underlying conditions: snoring, mild mania, bipolar emotional disorders (maintenance), prevention of recurrence of bipolar affective disorders, stabilization of bipolar emotional disorders, depression of some responders; anti-therapeutic Depression; weight 44 200938189 degree depression; emotional loop; emotional illness caused by systemic medical conditions; substance-induced depression; recurrent depression; single-onset depression, pediatric depression; atypical depression; stroke Post-depression; depletion depression; seasonal affective psychosis (SAD and schizophrenia-related depression, schizoaffective psychosis, gastrointestinal pain, IBS, abuse, hostility, irritability, fatigue, anxiety (anxiety depression) ), Lewy body disease or multiple sclerosis; flying, elevator or small room phobia; general anxiety disorder associated with pain; anxiety of patients with increased risk of hypertension, anxiety of patients with sleep problems, cognition Harm, Alzheimer's disease, dementia; mild cognitive impairment (mci); vascular dementia; leukoaraiosis; small vessel disease; obsessive-compulsive lineage disorder associated with ADHD, Asperger syndrome; autism Cognitive impairment associated with affective psychosis, depression, overall depression, major depression, anxiety, general anxiety disorder, panic disorder, obsessive-compulsive disorder, schizophrenia, = kissenosis, dementia, AIDS (IV), ADHD, age Related memory impairment, Down's syndrome, epilepsy, traumatic brain injury, Asperger's syndrome, tryptophan hydroxylase gene mutation and Alzheimer's disease; behavioral disorders associated with dementia; Aggressiveness and irritability associated with dementia and Alzheimer's disease; negative symptoms in schizophrenia; alcohol, test or carbohydrate addiction; substance spillover; alcohol or drug overdose; eating disorders; Anorexia; bulimia; binge eating disorder; impulsive control disorder; intermittent anger; stealing sputum; arson ,, pathological gambling; hair licking; drawing night rhythm disorder; primary insomnia, long Insomnia, temporary insomnia; sleep apnea; sleep-disordered breathing; hypopnea syndrome; stress-related conditions; acute stress; burns; stress; chronic fatigue syndrome; conduct disorder; behavioral disorder; 45 200938189 senile behavior disorder; Insulin resistance related to hyperactivity, · hot flashes " vomiting, premenopausal, peri-menopausal and post-menopausal discomfort; pathological crying; amblyopia; Tourette's syndrome or pain. Use of 9 items, where the pain is related to or associated with pain: whipping, IBS, chronic pain, phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (PHN), carpal tunnel syndrome (CTS) ), HIV neuropathy, complex local pain syndrome (S) trigeminal neuralgia (trigeminal neuralgia/tic doul〇ureux), pain after surgical intervention (eg, postoperative analgesia), diabetic vascular disease, Capillary resistance, diabetic symptoms associated with isletitis, pain associated with menstruation, and cancer Related pain, toothache, headache, migraine, tension headache, humeral joint syndrome, myofascial pain, muscle damage, bone and joint pain (osteoarthritis), rheumatoid arthritis, burn-related trauma Caused by edema, osteoporosis, bone metastasis, gout, fibrous tissue inflammation, thoracic outlet syndrome, pelvic pain, cardiogenic chest pain, non-cardiac chest pain, pain associated with spinal cord injury (SCI), and middle phrenic nerve after stroke Pain, cancerous neuropathy, sputum AIDS, sickle cell pain or pain in the elderly. 11. The use of any one of claims 9 to 1 wherein the patient has received or is receiving an antidepressant medication that has ceased or has to be stopped due to a sleep or blood pressure related adverse event. 12. The use of any one of claims 9 to 1 wherein the patient is at increased risk of or at risk of developing a blood pressure or sleep related condition. 46 200938189 13. For the purposes of application No. 9 of the patent application, wherein the compound is a crystal. 14. The use of the scope of claim 13 wherein the compound is [2-(6-fluoro-111_«bamboo_3_ylsulfanyl))]methylamine l_(1)-tartaric acid nitrogen salt. 15. For the purposes of application No. 14, the tartrate salt has an XRpD peak of about 9.66, 14.53, 18.14 and 3〇 48 (2).

❹ 16. 如申請專利範圍第15項之用途，其中該酒石酸鹽具有如圖1描繪之XRPD。 17.—種[2-(6-氟-1H-吲哚-3-基硫烷基）苄基]甲基胺及其醫藥上可接受之鹽（化合物Z )，其係用於治療患者之以下病症：躁症、輕度躁狂、雙極性情感疾患（維持）、預防雙極性情感疾患復發、使雙極性情感疾患穩定、部分反應者之抑鬱症；抗治療性抑鬱症；重度抑鬱症；情感迴環；全身性醫學病況引起之情感疾患；物質誘發之抑鬱症；復發性抑鬱症；單次發作抑鬱症；兒科抑鬱症；非典型抑繫症，中風後抑鬱症；耗竭性抑鬱症；季節性情感性精神病 (SAD )’與精神***症有關之抑繫症、***情感性精神病、胃腸痛、IBS、濫用、敵意、易怒、疲勞、焦慮（焦慮性抑繫症）、路易體病或多發性硬化症；飛行、電梯或小房間恐懼症；與疼痛有關之一般性焦慮症；高血壓風險增加之患者的焦慮；有睡眠問題之患者的焦慮；認知損害、阿茲海默氏病、癡呆；輕度認知損害（MCI);血管型癡呆；白質疏鬆；小金管疾病；與ADHD有關之強迫及注意力譜系 47 200938189 病症、亞斯柏格症候群；自閉症；與情感性精神病有關之遇知損害、抑鬱症、整鱧抑费症、重繁症、焦慮症、一般性焦慮症 '恐慌症、強迫症、精神***症、帕金森氏病、癡呆、aIDS癡呆、AmiD、年齡相關的記憶損害、唐氏症候群、癲癇症、外傷性腦損傷、亞斯柏格症候群、色氨酸經化酶基因突變及阿线默氏病；㈣呆㈣之行為障礙；與癡呆及阿兹海默氏病有關之攻擊性及焦躁；精神分裂症中之負向症狀；酒精、於驗或碳水化合物成癌；物質 ’廬用’酒精或藥物濫用；進食障礙；肥胖症；厭食症·貪❹ 食症；暴食症；衝動控制病症；間歇性縱火癖；病理性赌博；拔毛髮癖；畫夜節律障礙H生失眠、長期失眠、暫時性失眠；睡眠啤吸暫停；睡眠呼吸障礙；低通氣症候群；與壓力有關之病症；急性壓力；燒傷，壓力，慢性疲勞症候群；品行障礙；行為障礙；老年行為障礙；與HPA轴活性過高有關之胰島素抗性m 喂吐、停經前、圍停經期及停經後不悦症；病理性哭泣；弱視；妥瑞氏症候群或疼痛。〇 18.如申請專利範圍第17項之化合物，其中該疼痛為以下疼痛或與以下疼痛有關：鞭打、IBS、慢性疼痛、幻肢痛、神經病性疼痛、糖尿病性神經病變、㈣後神經痛（phn)、腕道症候群（CTS)、HIV神經病變、複雜性局部疼痛症候群（CPRS)、三叉神經痛（trigeminal neuralgia/trigeminus neUralgia/tic doul〇ureux)、手術介入後之疼痛（例如，術後鎮痛）、糖尿病性血管病變、毛細血管抗性、與胰島炎 48 200938189 有關之糖尿病性症狀、輿月嫉古^ • 興力級有關之疼痛、與癌症有關之疼痛、牙痛、頭痛、偏頭痛、緊張型頭痛、顳骨下顆關節 $候群、肌筋膜疼痛、肌肉損傷、骨絡及關料痛（骨關郎炎）、類風濕性關節炎、與燒傷有關之外傷所引起的泮腫、骨質疏鬆症、骨轉移、痛風、纖維組織炎、症候群、骨盆痛、心源性胸痛、非心源性胸痛、與脊越損傷（SCI)有關之疼痛、中風後中樞神經痛、癌性神經病變、 aids、鐮狀細胞痛或老人痛。 19. 如申請專利範圍第17至18項中任—項之化合物，其中該患者已接受或正接受抗抑鬱劑藥物治療，該藥物治療因睡眠或血壓相關之不良事件而已停止或必需停止。 20. 如申請專利範圍第17至18項中任一項的化合物，其中該患者罹患增加之血壓或睡眠相關病症或處於罹患該等病症之風險中。 21. 如申請專利範圍第17項之化合物，其中該化合物為〇 [2-(6-氟-1H-吲哚基硫烷基）苄基]甲基胺^(+)_酒石酸氣鹽。 22. 如申請專利範圍第21項之化合物，該化合物具有約 9.66、14.53、18.14 及 30.48 (。20 )之 XRPD 峰。 23. 如申請專利範圍第22項之化合物，該化合物具有如圖1描繪之XRPD。八❹ 16. The use of claim 15 wherein the tartrate salt has an XRPD as depicted in Figure 1. 17. A [2-(6-fluoro-1H-indol-3-ylsulfanyl)benzyl]methylamine and a pharmaceutically acceptable salt thereof (Compound Z) for use in treating a patient The following conditions: snoring, mild mania, bipolar affective disorder (maintenance), prevention of recurrence of bipolar emotional disorders, stabilization of bipolar emotional disorders, depression in some responders; anti-therapeutic depression; major depression; Emotional ring; emotional illness caused by systemic medical conditions; substance-induced depression; recurrent depression; single-onset depression; pediatric depression; atypical suppression, post-stroke depression; exhaustive depression; Sexual psychosis (SAD)'s schizophrenia-related suppression, schizoaffective psychosis, gastrointestinal pain, IBS, abuse, hostility, irritability, fatigue, anxiety (anxiety depression), Lewy body disease or Multiple sclerosis; flight, elevator or small room phobia; general anxiety disorder associated with pain; anxiety in patients with increased risk of hypertension; anxiety in patients with sleep problems; cognitive impairment, Alzheimer's disease, Idiot Mild cognitive impairment (MCI); vascular dementia; leukoaraiosis; small golden tube disease; obsessive-compulsive and attentional lineage associated with ADHD 47 200938189 Disorder, Asperger syndrome; autism; Known damage, depression, stagnation, severe complications, anxiety, general anxiety disorder, panic disorder, obsessive-compulsive disorder, schizophrenia, Parkinson's disease, dementia, aIDS dementia, AmiD, age-related memory Damage, Down's syndrome, epilepsy, traumatic brain injury, Asperger syndrome, tryptophanase gene mutation and A. morgue; (4) Behavioral disorder of staying (4); and dementia and Alzheimer's Aggressiveness and anxiety related to illness; negative symptoms in schizophrenia; alcohol, test or carbohydrate into cancer; substance 'use' alcohol or drug abuse; eating disorders; obesity; anorexia greed Bulimia nervosa; impulsive control disorder; intermittent arson; pathological gambling; hair licking; drawing night rhythm disorder H insomnia, long-term insomnia, temporary insomnia; sleep beer suspension pause; Respiratory disorders; hypopnea syndrome; stress-related conditions; acute stress; burns, stress, chronic fatigue syndrome; conduct disorder; behavioral disorders; senile behavioral disorders; insulin resistance associated with excessive HPA axis activity m vomiting, menopause Before, during menstruation and after menopause, disappointment; pathological crying; amblyopia; Tourette's syndrome or pain. 〇18. The compound of claim 17 wherein the pain is pain or associated with pain: whipping, IBS, chronic pain, phantom limb pain, neuropathic pain, diabetic neuropathy, (4) posterior neuralgia ( Phn), carpal tunnel syndrome (CTS), HIV neuropathy, complex local pain syndrome (CPRS), trigeminal neuralgia/trigeminus neUralgia/tic doul〇ureux, pain after surgical intervention (eg, postoperative analgesia) ), diabetic angiopathy, capillary resistance, diabetic symptoms associated with isletitis 48 200938189, 舆月嫉古^ • pain associated with the level of power, cancer-related pain, toothache, headache, migraine, nervousness Type headache, lower extremity joints, muscle fascia pain, muscle damage, bone collaterals and closure pain (bone stagnation), rheumatoid arthritis, edema caused by burn-related trauma, bone Osteoporosis, bone metastases, gout, fibrotic tissue, syndrome, pelvic pain, cardiogenic chest pain, non-cardiac chest pain, and spinal injury (SCI) Related pain, central nervous system pain after stroke, cancerous neuropathy, aids, sickle cell pain or pain in the elderly. 19. A compound according to any one of claims 17 to 18, wherein the patient has received or is receiving an antidepressant medication which has ceased or has to be stopped due to a sleep or blood pressure related adverse event. 20. The compound of any one of claims 17 to 18, wherein the patient is at increased risk of or at risk of developing a blood pressure or sleep related disorder. 21. The compound of claim 17, wherein the compound is [2-(6-fluoro-1H-indenylsulfanyl)benzyl]methylamine^(+)-tartaric acid gas salt. 22. The compound of claim 21, which has an XRPD peak of about 9.66, 14.53, 18.14, and 30.48 (.20). 23. The compound of claim 22, which has the XRPD as depicted in Figure 1. Eight

:次式如頁 49: The following formula is as shown in page 49