TWI429429B

TWI429429B - Use of benzo-fused heterocycle sulfamide derivatives for the treatment of mania and bipolar disorder

Info

Publication number: TWI429429B
Application number: TW95147361A
Authority: TW
Inventors: Virginia L Smith-Swintosky; Allen B Reitz
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2005-12-19
Filing date: 2006-12-18
Publication date: 2014-03-11
Also published as: ES2360135T3; PE20071065A1; TW200744581A; UY30039A1; UA95094C2; AR058395A1

Description

苯并稠合之雜環磺醯胺衍生物於治療躁狂及兩極病症之用途Use of benzofused fused sulfonamide derivatives for the treatment of manic and bipolar disorders

相關申請案之交互參照Cross-references to related applications

本申請案主張2005年12月19日所提申之美國臨時申請案60/751,493的利益，其整體係以參照方式併入本案。This application claims the benefit of U.S. Provisional Application Serial No. 60/751,493, filed on Dec. 19, 2005, which is incorporated herein in its entirety by reference.

發明領域Field of invention

本發明係關於苯并稠合之雜環磺醯胺衍生物於治療躁狂及兩極病症之用途。This invention relates to the use of benzofused heterocyclic sulfonamide derivatives for the treatment of manic and bipolar disorders.

發明背景Background of the invention

兩極病症是特徵為情緒不可預測地從躁狂(或輕躁狂)轉變至抑鬱的精神疾病。一些病患僅受躁狂反覆發作之苦，躁狂的單純形式係和精神運動活性增加；交際過於外向；睡眠需求減少；判斷過於衝動及判斷力變差；以及自我膨脹、誇張且有時急躁的情緒相關。在嚴重躁狂時，病患可能會體驗到很難和精神***症區別的妄想與偏執思想。有一半的兩極病症病患呈現伴有煩躁、焦慮與敏感的精神運動焦躁與活化的混合現象。可能極難區分混合型躁狂 和焦躁型抑鬱 。在一些兩極型病患(第II型兩極病症 )中，缺少躁狂的充分要素，不可或缺的週期性抑鬱係間隔著輕微活化與精力增加的時期(輕躁狂)。在循環性疾患 (cyclothymic disorder )中，有無數個輕躁期，通常歷時相當短，並交替著多種不論是在嚴重性或歷時皆不符合重鬱症要素的憂鬱症狀。該等情緒擾動是慢性的且在下診斷前應出現至少2年。A bipolar disorder is a mental illness characterized by an unpredictable shift in mood from mania (or madness) to depression. Some patients suffer only from manic episodes, manic form and psychomotor activity increase; communication is too extroverted; sleep demand is reduced; judgment is too impulsive and judgment is worse; and self-expansion, exaggeration and sometimes impatience The emotions are related. In the case of severe mania, patients may experience delusions and paranoia that are difficult to distinguish from schizophrenia. Half of the patients with bipolar disorder present a mixture of irritability, anxiety and sensitivity in psychomotor anxiety and activation. It may be extremely difficult to distinguish between mixed mania and eschar type depression . In some bipolar patients ( type II bipolar disorder ), the lack of sufficient elements of mania, the indispensable periodic depression is a period of mild activation and increased energy (light mania). Circulation disorders (cyclothymic disorder), there are numerous hypomanic period, typically a relatively short duration, alternating with more depressive symptoms and whether the severity or duration in major depression are not met elements. These emotional disturbances are chronic and should occur for at least 2 years before the next diagnosis.

躁狂發作事件通常需時數天到數周才會顯現，但有可能在數小時之內起始，經常是清晨時刻。未經治療的抑鬱或躁狂發作事件可短如數周或持續長達8至12個月，極少病患會有不間斷的慢性病程。快速循環 (rapid cycling )一詞係用於一年中有四次或更多次抑鬱或躁狂發作事件的病患。此型態發生在15%病患身上，該類病患幾乎都是女性。在一些情況中，快速循環係關連到潛在的甲狀腺功能失調，在其他情況中，快速循環是由醫源性的長期抗抑鬱劑治療所引起。大約有一半病患在工作表現與心理社會運作方面出現持續性困難。Manic episodes usually take days to weeks to appear, but may start within hours, often early morning. Untreated depression or manic episodes can be as short as several weeks or lasting for 8 to 12 months, with very few patients having an uninterrupted chronic course. The term rapid cycling is used in patients with four or more episodes of depression or manic episodes in a year. This type occurs in 15% of patients, almost all of whom are women. In some cases, rapid circulation is associated with potential thyroid dysfunction, and in other cases, rapid cycling is caused by iatrogenic long-term antidepressant treatment. About half of patients have persistent difficulties in performance and psychosocial functioning.

罹患兩極病症的病患通常主訴下列類型的症狀，端視其處於「躁狂」或「高張」期或「抑鬱」或「低落」期的哪一期而定。在躁狂期時，症狀包括但不限於(a)生理與心理活力與精力充沛(b)心情很好、過份樂觀與自信；(c)極度激發、行為激進；(d)睡眠需求減少但不覺疲累；(e)誇大妄想、自以為是；(h)說話快速、思考快速、思考靈活；(i)衝動、判斷力差、注意力渙散；(j)行為鹵莽及在最嚴重情況時(k)妄想及幻覺。在躁狂期，症狀包括但不限於(a)持續悲傷或無法解釋的經常性哭泣；(b)食慾與睡眠型態顯著改變；(c)敏感、發怒、憂慮、焦躁、焦慮；(d)悲觀、漠然；(e)活力喪失、反覆昏睡；(f)罪惡感、無價值感；(g)無法專心、無法做決定；(h)無法從先前興趣取得愉悅感、社交退縮；(i)無法解釋的疼痛及(j)反覆思及死亡或自殺。Patients with bipolar disorder usually complain of the following types of symptoms, depending on which period of the "manic" or "high" or "depressed" or "low" period. During the manic period, symptoms include, but are not limited to, (a) physical and mental energy and energy (b) good mood, excessive optimism and self-confidence; (c) extreme stimulation, behavioral agitation; (d) reduced sleep demand but (e) exaggerating delusions and self-righteousness; (h) speaking fast, thinking fast, thinking flexibly; (i) impulsive, poor judgment, distracting; (j) behavioral recklessness and in the worst case (k ) delusions and hallucinations. During manic periods, symptoms include, but are not limited to, (a) constant sorrow or unexplained recurrent crying; (b) significant changes in appetite and sleep patterns; (c) sensitivity, anger, anxiety, anxiety, anxiety; (d) Pessimistic, indifferent; (e) loss of vitality, fainting; (f) guilt, worthless; (g) unable to concentrate, unable to make decisions; (h) unable to obtain pleasure from the previous interests, social withdrawal; (i) Unexplained pain and (j) rethinking death or suicide.

兩極病症很常見，影響~1%的美國人口。通常在20與30歲之間發病，但許多個體在兒童期後期或***前期就報導有發病前症狀。在男性與女性的盛行程度差不多；在一生當中女性似乎有較多的抑鬱發作事件而男性有較多的躁狂發作事件。Bipolar disorders are common and affect ~1% of the US population. It usually develops between the ages of 20 and 30, but many individuals report pre-onset symptoms in late childhood or pre-puberty. The prevalence of men and women is similar; women seem to have more depressive episodes during their lifetime and men have more manic episodes.

兩極病症的治療係以碳酸鋰為主，儘管丙基戊酸鈉與奧氮呯(olanzapine)針對急性躁狂係同樣有效，正如拉莫三(lamotrigine)針對抑鬱期。急性躁狂對碳酸鋰的反應率為70至80%，有利效果在1至2周後出現。鋰亦具有防止週期性躁狂－以及程度上較少地－防止週期性抑鬱的預防效果。鋰投藥導致的嚴重副作用極罕見，但常有對例如腸胃不適、噁心、腹瀉、多尿、體重增加、皮膚出疹、掉髮及水腫的輕微抱怨。The treatment of bipolar disorder is based on lithium carbonate, although sodium valproate and olanzapine are as effective against acute mania, as Lamo III (lamotrigine) for the depression period. The acute mania response rate to lithium carbonate is 70 to 80%, and the beneficial effect occurs after 1 to 2 weeks. Lithium also has the preventive effect of preventing periodic mania - and to a lesser extent - preventing periodic depression. Severe side effects caused by lithium administration are extremely rare, but there are often minor complaints about gastrointestinal discomfort, nausea, diarrhea, polyuria, weight gain, skin rash, hair loss and edema.

在急性躁狂的治療中，鋰係以每天兩次或每天三次300毫克開始，然後每2至3天給藥增加300毫克，以達到0.8至1.2 meq/L之血液含量。因為鋰的治療效果可能要到治療7至10天後才會出現，所以羅拉西泮(lorazepam)(每4小時1至2毫克)或氯氮平(clozepam)(每4小時0.5至1毫克)的附帶使用可有利於控制焦躁。抗精神病藥物(antipsychotics)係開立給嚴重焦躁且對苯并二氮呯僅有部份反應的病患。In the treatment of acute mania, lithium is started twice daily or 300 mg three times a day, and then 300 mg is administered every 2 to 3 days to achieve a blood content of 0.8 to 1.2 meq/L. Because the therapeutic effect of lithium may not occur until 7 to 10 days after treatment, lorazepam (1 to 2 mg every 4 hours) or clozepam (0.5 to 1 mg every 4 hours) The accompanying use can be beneficial to control the anxiety. Antipsychotics are patients who are severely irritated and have only partial response to benzodiazepines.

丙戊酸(valproic acid)是不耐鋰或對其反應差的病患的替代物。就經歷快速循環(亦即一年超過四次發作事件)或出現混合型或煩躁型躁狂的病患而言，丙戊酸可能比鋰好。顫抖與體重增加是最常見的副作用；肝毒性與胰臟炎為罕見毒性。卡巴氮呯(carbamazepine)和奧卡氮呯(oxcarbazepine)－儘管美國食品醫藥管理局(FDA)尚未正式核准用於兩極病症－在急性躁狂治療上具有臨床功效。初步證據也顯示其他抗癲癇劑，例如(levtiracetam)、唑尼沙胺(zonisamide)與托吡酯(topiramate)可擁有某些治療好處。Valproic acid is a substitute for patients who are not resistant to lithium or who respond poorly. For patients experiencing rapid cycling (ie, more than four episodes a year) or mixed or irritated mania, valproic acid may be better than lithium. Trembling and weight gain are the most common side effects; hepatotoxicity and pancreatitis are rare toxicities. Carbamazepine and oxcarbazepine - although the US Food and Drug Administration (FDA) has not formally approved for bipolar conditions - clinically useful in the treatment of acute mania. Preliminary evidence also suggests that other anti-epileptic agents, such as (levtiracetam), zonisamide and topiramate, may have certain therapeutic benefits.

兩極情感性病症的週期性本質使維持治療有其必要性。依從性經常是問題所在且時常需要關心的家庭成員從旁協助與教育。盡力辨認並改變有可能引發發作事件的心理社會因素係極為重要，就像重視生活規律一樣。抗抑鬱劑物治療對嚴重突發抑鬱的治療而言有時是必要的，但在維持治療期間一般應避免使用抗抑鬱劑物治療，因有陷入躁狂或加快循環頻率的風險。任何情緒穩定劑在經過一段時日後都會被觀察到失效現象。在該種情況下，替代藥劑或療法通常會有幫助。The cyclical nature of bipolar affective disorders makes maintenance therapy necessary. Compliance is often the problem and family members who often need to be concerned are assisted and educated. It is extremely important to try to identify and change the psychosocial factors that may trigger seizures, just as it is to pay attention to the laws of life. Antidepressant treatment is sometimes necessary for the treatment of severe depressive depression, but antidepressant treatment should generally be avoided during maintenance therapy because of the risk of being paralyzed or accelerating the frequency of circulation. Any mood stabilizer will be observed to be ineffective after a period of time. In this case, an alternative agent or therapy will usually help.

對提供針對躁狂及/或針對兩極病症的有效治療仍有需求。較佳地，兩極病症的治療包含抑鬱與躁狂的治療。更佳地，兩極病症的治療係包含該病症特有之抑鬱、躁狂與循環的治療。There is still a need to provide effective treatment for mania and/or for bipolar conditions. Preferably, the treatment of a bipolar disorder involves treatment of depression and mania. More preferably, the treatment of a bipolar disorder comprises treatment of depression, mania and circulation characteristic of the condition.

發明概要Summary of invention

本發明係關於式(I)化合物或其藥學上可接受之鹽於製造用以治療躁狂及兩極病症之醫藥品的用途其中R¹ 與R² 係各別獨立地選自於由氫與低級烷基所構成的群組；R⁴ 係選自於由氫與低級烷基所構成的群組；a為1至2之整數；係選自於由下列所構成的群組：其中b為0至4之整數；且其中c為0至2之整數；各個R⁵ 係獨立地選自於由鹵素、低級烷基與硝基所構成的群組；前提是當為或時，a為1。The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of manic and bipolar disorders Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and lower alkyl; R ⁴ is selected from the group consisting of hydrogen and lower alkyl; a is 1 to 2. Integer Is selected from the group consisting of: Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro; for or When a is 1.

本發明又關於式(II)化合物或其藥學上可接受之鹽於製造用以治療躁狂及兩極病症之醫藥品的用途 The invention further relates to the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of manic and bipolar disorders

本發明又關於本案所述之式(I)或式(II)化合物用於製造用以治療躁狂之醫藥品的用途，其包含與治療有效量之至少一抗精神病藥物的協同療法。本發明又關於本案所述之式(I)或式(II)化合物用於製造用以治療兩極病症之醫藥品的用途，其包含與治療有效量之至少一抗抑鬱劑的協同療法。本發明又關於本案所述之式(I)或式(II)化合物用於製造用以治療兩極病症之醫藥品的用途，其包含與治療有效量之至少一情緒穩定劑的協同療法。The invention further relates to the use of a compound of formula (I) or formula (II) as described herein for the manufacture of a medicament for the treatment of mania comprising synergistic therapy with a therapeutically effective amount of at least one antipsychotic. The invention further relates to the use of a compound of formula (I) or formula (II) as described herein for the manufacture of a medicament for the treatment of a bipolar disorder comprising a synergistic treatment with a therapeutically effective amount of at least one antidepressant. The invention further relates to the use of a compound of formula (I) or formula (II) as described herein for the manufacture of a medicament for the treatment of a bipolar disorder comprising synergistic therapy with a therapeutically effective amount of at least one mood stabilizer.

例示本發明的是上述任一化合物的治療有效量用於製造用以治療躁狂之醫藥品的用途。例示本發明的是上述任一化合物的治療有效量用於製造用以治療兩極病症之醫藥品的用途。Illustrative of the invention is the use of a therapeutically effective amount of any of the above compounds for the manufacture of a medicament for the treatment of mania. Illustrative of the invention is the use of a therapeutically effective amount of any of the above compounds for the manufacture of a medicament for the treatment of a bipolar disorder.

在一具體例，本發明係關於躁狂的治療。在另一具體例，本發明係關於兩極型躁狂的治療。在另一具體例，本發明係關於兩極型抑鬱的治療。在另一具體例，本發明係關於兩極病症的治療。在另一具體例，本發明係關於兩極循環的治療。在另一具體例，本發明係關於和兩極病症有關的抑鬱與躁狂的治療。在又另一具體例，本發明係關於和兩極病症有關的抑鬱、躁狂及循環的治療。在又另一具體例，本發明係關於一種治療兩極病症的方法，其包含使循環穩定。於是，在一具體例，本發明係關於一種穩定兩極循環的方法。In one embodiment, the invention relates to treatment of mania. In another embodiment, the invention is directed to the treatment of bipolar mania. In another embodiment, the invention relates to the treatment of bipolar depression. In another embodiment, the invention relates to the treatment of a bipolar disorder. In another embodiment, the invention relates to the treatment of a bipolar cycle. In another embodiment, the invention relates to the treatment of depression and mania associated with bipolar disorders. In yet another embodiment, the invention relates to the treatment of depression, mania, and circulation associated with bipolar disorders. In yet another embodiment, the invention is directed to a method of treating a bipolar disorder comprising stabilizing the circulation. Thus, in one embodiment, the invention is directed to a method of stabilizing a bipolar cycle.

發明詳細說明Detailed description of the invention

本發明係關於式(I)化合物或其藥學上可接受之鹽於製造治療躁狂及兩極病症之醫藥品的用途 The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of manic and bipolar disorders

其中、a、R¹ 、R² 及R⁴ 係如本案所定義者。更明確地說，本發明化合物係有益於躁狂的治療－無論病因為何。再者，本發明化合物係有益於兩極病症特有、為兩極病症症狀或和兩極病症有關之抑鬱、躁狂及/或循環的治療。among them , a, R ¹ , R ² and R ⁴ are as defined in the present application. More specifically, the compounds of the invention are beneficial for manic treatment - regardless of the cause. Furthermore, the compounds of the invention are useful for the treatment of depression, mania and/or circulation characteristic of a bipolar disorder, a symptom of a bipolar disorder or a bipolar disorder.

本發明又關於本案所述之式(I)或式(II)化合物用於製造用以治療躁狂、兩極型抑鬱、兩極型躁狂、兩極型循環及/或兩極病症之醫藥品的用途，其包含與至少一抗抑鬱劑及/或至少一抗精神病藥劑及/或至少一情緒穩定劑的協同療法。The invention further relates to the use of a compound of formula (I) or formula (II) as described herein for the manufacture of a medicament for the treatment of manic, bipolar depression, bipolar mania, bipolar circulation and/or bipolar disorder, It comprises a synergistic therapy with at least one antidepressant and/or at least one antipsychotic agent and/or at least one mood stabilizing agent.

兩極病症是特徵為情緒不可預測地從躁狂(或輕躁狂)轉變至抑鬱的精神疾病。用於本案時，「兩極病症 」一詞係包括第I型兩極病症〔譬如單一躁狂發作事件型(single manic episode)、最近發作事件輕躁狂型(most recent episode hypomanic)、最近發作事件躁狂型(most recent episode manic)、最近發作事件混合性型(most recent episode mixed)、最近發作事件抑鬱型(most recent episode depressed)與最近發作事件未明定型(most recent episode unspecified)〕、第II型兩極病症、循環性情感疾患及其他未明定之兩極病症(該等用詞係以其訂於Diagnostic and Statistical Manual of Mental Disorders, 4^th Edition,Text Revision,American Psychiatric Association,2000 (DSM－IV－TR)中的診斷準則來定義)。較佳地，兩極病症的特徵為抑鬱期與躁狂(或輕躁狂)期，其中該等時期會循環。較佳地，兩極病症為第I型兩極病症或第II型兩極病症。A bipolar disorder is a mental illness characterized by an unpredictable shift in mood from mania (or madness) to depression. In the case of this case, the term " bipolar disorder " includes Type I bipolar disorder (such as single manic episode, most recent episode hypomanic, recent episodes) Most recent episode manic, most recent episode mixed, most recent episode depressed and most recent episode unspecified, type II bipolar disorders, circulatory disorders and other emotional unknown set of bipolar disorder (such terms in their department is scheduled to Diagnostic and Statistical Manual of Mental disorders, 4 th Edition, Text Revision, American Psychiatric Association, 2000 (DSM-IV-TR) The diagnostic criteria in the definition). Preferably, the bipolar disorder is characterized by a period of depression and mania (or manic), wherein the periods circulate. Preferably, the bipolar disorder is a Type I bipolar disorder or a Type II bipolar disorder.

用於本案時，「躁狂」一詞係包括躁狂或躁狂情緒期－無論潛在病因為何。用於本案時，「兩極型躁狂 」一詞係企圖表示和兩極病症有關、兩極病症特有或為兩極病症症狀的躁狂。於是，本發明之治療兩極型躁狂的方法係關於治療兩極病症之躁狂及/或躁狂期的方法。When used in this case, the term " manic " includes a period of mania or mania - regardless of the underlying cause. In the case of this case, the term " bipolar mania " was intended to mean a mania associated with a bipolar disorder, a bipolar disorder or a symptom of a bipolar disorder. Thus, the method of the present invention for treating bipolar mania is directed to a method of treating manic and/or manic stages of a bipolar disorder.

用於本案時，「兩極型抑鬱 」一詞係企圖表示和兩極病症有關、兩極病症特有或為兩極病症症狀的抑鬱。於是，本發明之治療兩極型抑鬱的方法係關於治療兩極病症之抑鬱及/或抑鬱期的方法。In the present case, the term " polar depression " was intended to mean depression associated with a bipolar disorder, a bipolar disorder or a symptom of a bipolar disorder. Thus, the method of treating bipolar depression of the present invention relates to a method of treating depression and/or depression in a bipolar disorder.

用於本案時，除另有指明外，「循環」或「兩極型循環 」用詞係指兩極病症所特有的情緒交替於抑鬱期與躁狂期之間。於是，本發明包括穩定該循環的方法，其包括但不限於減少循環頻率及/或減少躁狂期及/或抑鬱期的強度。In the case of this case, unless otherwise specified, the term " circular " or " bipolar cycle " means that the mood specific to a bipolar disorder alternates between depression and mania. Thus, the invention includes methods of stabilizing the cycle including, but not limited to, reducing the frequency of circulation and/or reducing the intensity of the manic phase and/or depression.

用於本案時，「情緒穩定劑 」一詞係包括任何控制情緒的藥劑，其包括但不限於鋰、丙戊酸、丙基戊酸鈉、卡巴氮呯、拉莫三、托吡酯及類似物。更明確地說，情緒穩定劑是任何穩定病患情緒、作用如同抗抑鬱劑、抗躁狂藥或兩者並使病患情緒趨向情感正常(euthymia)的藥劑。As used in this case, the term " mood stabilizer " includes any agent that controls mood, including but not limited to lithium, valproic acid, sodium valproate, kappa azide, and lamo , topiramate and the like. More specifically, mood stabilizers are any agents that stabilize the mood of the patient, act like antidepressants, anti-manic drugs, or both, and tend to be emotionally euthymia.

用於本案時，除另有指明外，「抗抑鬱劑 」一詞係指任何治療抑鬱的藥劑。適宜的例子包括但不限於單胺氧化酶抑制劑，例如苯乙(phenelzine)、反苯環丙胺(tranylcypromine)、嗎氯貝胺(moclobemide)及類似物；三環類，例如伊米帕明(imipramine)、阿米替林(amitriptyline)、地昔帕明(desipramine)、去甲替林(nortriptyline)、多塞平(doxepin)、普羅替林(protriptyline)、曲米帕明(trimipramine)、氯米帕明(chlomipramine)、異戊塞平(amoxapine)及類似物；四環類，例如馬普替林(maprotiline)及類似物；非環類，例如諾米芬辛(nomifensine)及類似物；***吡啶類，例如曲唑酮(trazodone)及類似物；血清素再吸收抑制劑，例如氟西汀(fluoxetine)、舍曲林(sertraline)、帕羅西汀(paroxetine)、西酞普蘭(citalopram)、氟伏沙明(fluvoxamine)及類似物；血清素受體拮抗劑，例如奈法唑酮(nefazadone)及類似物；血清素正腎上腺素激性再吸收抑制劑，例如文拉法辛(venlafaxine)、米那普侖(milnacipran)及類似物；正腎上腺素激性與專一血清素激性藥劑，例如米氮呯(mirtazapine)及類似物；正腎上腺素再吸收抑制劑，例如瑞波西汀(reboxetine)及類似物；非典型抗抑鬱劑，例如安非他酮(bupropion)及類似物；天然產物，例如卡法椒(Kava－Kava)、聖約翰草(St.John's Wort)及類似物；膳食補充品，例如s－腺苷甲硫胺酸及類似物；神經肽，例如甲狀腺促素釋素及類似物及類似物；靶向神經肽受體的化合物，例如神經激素受體拮抗劑及類似物；以及荷爾蒙，例如三碘甲狀腺胺酸及類似物。較佳地，抗抑鬱劑係選自於由氟西汀、伊米帕明、安非他酮、文拉法辛與舍曲林所構成的群組。In the case of this case, the term " antidepressant " means any agent for the treatment of depression, unless otherwise specified. Suitable examples include, but are not limited to, monoamine oxidase inhibitors such as phenylethyl (phenelzine), tranylcypromine, moclobemide and the like; tricyclics such as imipramine, amitriptyline, desipramine ), nortriptyline, doxepin, protriptyline, trimipramine, chlomipramine, amoxapine and the like Tetracyclics, such as maprotin and analogs; acyclics such as nomifensine and the like; triazole pyridines such as trazodone and the like; serum Reuptake inhibitors, such as fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, and the like; serotonin receptor antagonism Agents such as nefazadone and analogs; serotonin adrenergic reuptake inhibitors such as venlafaxine, milnacipran and analogs; norepinephrine Sexual and specific serotonin agents, such as mirtazapi Ne) and analogs; norepinephrine reuptake inhibitors, such as reboxetine and the like; atypical antidepressants such as bupropion and the like; natural products such as kava (Kava-Kava), St. John's Wort and the like; dietary supplements such as s-adenosylmethionine and the like; neuropeptides such as thyroid stimulating hormone and the like and the like Compounds that target neuropeptide receptors, such as neurohormone receptor antagonists and analogs; and hormones, such as triiodothyronine and the like. Preferably, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine and sertraline.

用於本案時，「抗精神病藥物 」一詞係企圖包括但並不限於(a)典型或傳統抗精神病藥物，例如啡噻類(譬如氯丙(chlorpromazine)、硫利嗒(thioridazine)、氟啡(fluphenazine)、過啡(perphenazine)、三氟拉(trifluoperazine)、左美丙(levomepromazin))、噻吨類(thioxanthenes)(譬如硫噻吨(thiothixene)、氟哌噻吨(flupentixol))、苯丁酮類(譬如氟哌啶醇(haloperidol))、二苯氧氮呯類(譬如洛沙平(loxapine))、二氫吲哚酮類(譬如嗎啉酮(molindone))、經取代之苯醯胺類(譬如磺必利(sulpride)、胺磺必利(amisulpride))及類似物；及(b)非典型抗精神病藥物，例如二丙基戊酸鈉、帕潘立酮(paliperidone)、氯氮呯(clozapine)、利培酮(risperidone)、奧氮呯、喹硫呯(quetiapine)、佐替呯(zotepine)、齊拉西酮(ziprasidone)、伊潘立酮(iloperidone)、哌羅匹隆(perospirone)、波那舍林(blonanserin)、舍吲哚(sertindole)、ORG－5222(歐嘉隆公司(Organon))及類似物；以及其他，例如索尼哌唑(sonepiprazole)、阿立哌唑(aripiprazole)、奈莫必利(nemonapride)、SR－31742(賽諾菲製藥(Sanofi))、CX－516(Cortex藥廠)、SC－111(Scotia公司)、NE－100(大正製藥(Taisho))及類似物。In this case, the term " antipsychotic drugs " is intended to include, but is not limited to, (a) typical or traditional antipsychotic drugs, such as thiophene Chloropropion (chlorpromazine), thiopurine (thioridazine), fluoromorphine (fluphenazine), morphine (perphenazine) (trifluoperazine), Zuomei C (levomepromazin)), thioxanthenes (such as thiothixene, flupentixol), phenylbutanone (such as haloperidol), benzophenone (such as loxapine), indoline (such as molindone), substituted benzoguanamines (such as sulpride, amisulpride) And analogs; and (b) atypical antipsychotic drugs, such as sodium dipropylvalerate, paliperidone, clozapine, risperidone, olanzapine, quetiapine Quet quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole , ORG-5222 (Organon) and the like; and others, such as sonepiprazole, aripiprazole, nemonapride, SR-31742 (Sanofi) Pharmaceutical (Sanofi), CX-516 (Cortex Pharmaceuticals), SC-111 (Scotia), NE-100 (Taisho) and the like.

更明確地說，非典型抗精神病藥物包括但不限於：2－甲基－4－(4－甲基－1－哌基)－10H－噻吩并[2,3－b]苯并二氮呯，習知為奧氮呯，美國專利第5,229,382號中描述可用於治療精神***症、類精神***性疾患、急性躁狂、輕度焦慮狀態及精神病；建議劑量為5－30毫克/日，較佳為5－10毫克/日(Physician's Desk Reference；Kaplan & Sadock's Comprehensive Textbook of Psychiatry,Seventh Edition,Volume II,Lippincott Williams & Wilkins：Philadelphia,2000)；8－氯基－11－(4－甲基－哌基)－5H－二苯并[b,e][1,4]二氮呯，習知為氯氮呯，揭示於美國專利第3,539,573號，具有治療精神***症的臨床功效，描述於Hanes,et al.,Psychopharmacological Bulletin ,24 ,62(1988))；建議劑量為12.5－600毫克/日，較佳為250－450毫克/日(Physician's Desk Reference；Kaplan & Sadock's Comprehensive Textbook of Psychiatry,Seventh Edition,Volume II,Lippincott Williams & Wilkins：Philadelphia,2000)；3－[2－[4－(6－氟基－1,2－苯并異唑－3－基)N－哌啶基]乙基]－2－甲基－6,7,8,9－四氫－4H－吡啶并－[1,2－a]嘧啶－4－酮，習知為利培酮 ，美國專利第4,804,663號中描述可用於治療精神疾病；建議劑量為0.25－16毫克/日，較佳為1－16毫克/日，更佳為2－8毫克/日(Physician's Desk Reference；Kaplan & Sadock's Comprehensive Textbook of Psychiatry,Seventh Edition,Volume II,Lippincott Williams & Wilkins：Philadelphia,2000)；3－[2－[4－(6－氟基－1,2－苯并異唑－3－基)－1－哌啶基]乙基]－6,7,8,9－四氫－9－羥基－2－甲基－H－吡啶并[1,2－a]嘧啶－4－酮，習知為帕潘立酮 ，亦習知為9－羥基－利培酮，美國專利第5,5158,952號中描述可用於治療精神疾病，預期劑量介於每天0.01毫克/公斤至約2毫克/公斤體重；1－[2－[3－[5－氯基－1－(4－氟基苯基)－1H－吲哚－3－基]－1－哌啶基]乙基]咪唑啶－2－酮，習知為舍吲哚且揭示於美國專利第4,710,500號，美國專利第5,112,838號與美國專利第5,238,945號揭示了舍吲哚用於治療精神***症的用途；起始劑量為4毫克/日，每隔一天增加4毫克至多達24毫克/日，最終建議劑量範圍介於12至20毫克/日(Kaplan & Sadock's Comprehensive Textbook of Psychiatry,Seventh Edition,Volume II,Lippincott Williams & Wilkins：Philadelphia,pp.2467－2468,2000)；5－[2－(4－二苯并[b,f][1,4]噻氮呯－11－基－1－哌基)乙氧基]乙醇，習知為喹硫呯，美國專利第4,879,288號中揭示用於治療精神***症；建議劑量為25－800毫克/日，較佳為150－750毫克/日(Physician's Desk Reference；Kaplan & Sadock's Comprehensive Textbook of Psychiatry,Seventh Edition,Volume II,Lippincott Williams & Wilkins：Philadelphia,2000)；5－[2－[4－(1,2－二苯并異噻唑－3－基)－1－哌基]乙基]－6－氯基－1,3－二氫－2H－吲哚－2－酮，習知為齊拉西酮 ，揭示於美國專利第4,831,031號與美國專利第5,312,925號，其於治療精神***症的利用性係揭示於美國專利第4,831,031號；建議劑量為40－160毫克/日，用於維持治療及防止復發的較佳劑量為一天兩次40至60毫克(Kapian & Sadock's Comprehensive Textbook of Psychiatry,Seventh Edition,Volume II,Lippincott Williams & Wilkins：Philadelphia,pp.2470－2471,2000)；以及雙(2－丙基戊酸)氫鈉，亦習知為雙丙基戊酸鈉(divalproex sodium) ，揭示於美國專利第5212326號，治療躁狂的建議劑量為初始750毫克/日，最大建議劑量為60毫克/公斤/日(Physicians Desk Reference)。More specifically, atypical antipsychotic drugs include, but are not limited to, 2-methyl-4-(4-methyl-1-piperidin -10H-thieno[2,3-b]benzodiazepines, conventionally known as olanzapine, described in U.S. Patent No. 5,229,382, which is useful in the treatment of schizophrenia, schizophrenic disorders, acute mania Mild anxiety and psychosis; recommended dose is 5-30 mg/day, preferably 5-10 mg/day (Physician's Desk Reference; Kaplan &Sadock's Comprehensive Textbook of Psychiatry, Seventh Edition, Volume II, Lippincott Williams & Wilkins :Philadelphia, 2000); 8-Chloro-11-(4-methyl-piperidin -5H-dibenzo[b,e][1,4]diazepine, conventionally known as chloroazepine, is disclosed in U.S. Patent No. 3,539,573, which has the clinical utility of treating schizophrenia, described in Hanes, Et al., Psychopharmacological Bulletin , 24 , 62 (1988)); the recommended dose is 12.5-600 mg/day, preferably 250-450 mg/day (Physician's Desk Reference; Kaplan &Sadock's Comprehensive Textbook of Psychiatry, Seventh Edition, Volume II, Lippincott Williams & Wilkins: Philadelphia, 2000); 3-[2-[4-(6-fluoro-1,2-benziso) Zin-3-yl)N-piperidinyl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one, It is conventionally described as risperidone , which is described in U.S. Patent No. 4,804,663, which is incorporated herein by reference in its entirety for the benefit of the present invention. The recommended dosage is 0.25-16 mg/day, preferably 1-16 mg/day, more preferably 2-8 mg/day ( Physician's Desk Reference; Kaplan &Sadock's Comprehensive Textbook of Psychiatry, Seventh Edition, Volume II, Lippincott Williams & Wilkins: Philadelphia, 2000); 3-[2-[4-(6-fluoro-1,2-benziso) Zyrid-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-H-pyrido[1,2-a]pyrimidine- 4-ketone, conventionally known as paliperidone , is also known as 9-hydroxy-risperidone, and is described in U.S. Patent No. 5,5,158,952, which is incorporated herein by reference in its entirety for the benefit of the present invention. Up to about 2 mg/kg body weight; 1-[2-[3-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl] The use of sulphate for the treatment of schizophrenia is disclosed in U.S. Patent No. 4,710,500, U.S. Patent No. 5,112,838, and U.S. Patent No. 5,238,945. The initial dose is 4 mg/day, increasing every 4 mg up to 24 mg/day, and the final recommended dose range is 12 to 20 mg/day (Kaplan &Sadock's Comprehensive Textbook of Psychiatry, Seventh Edition, Volume II, Lippincott Williams & Wilkins: Philadelphia, pp. 2467-2468, 2000); 5-[2-(4-dibenzo[b,f][1,4]thiazol-11-yl-1-piperidin Ethyloxy]ethanol, conventionally known as quetiapine, is disclosed in U.S. Patent No. 4,879,288 for the treatment of schizophrenia; the recommended dosage is 25-800 mg/day, preferably 150-750 mg/day (Physician's) Desk Reference; Kaplan &Sadock's Comprehensive Textbook of Psychiatry, Seventh Edition, Volume II, Lippincott Williams & Wilkins: Philadelphia, 2000); 5-[2-[4-(1,2-dibenzisothiazol-3-yl) -1-piper Alkyl]-6-chloro-1,3-dihydro-2H-indol-2-one, which is known as ziprasidone , is disclosed in U.S. Patent No. 4,831,031 and U.S. Patent No. 5,312,925. The utilization line for the treatment of schizophrenia is disclosed in U.S. Patent No. 4,831,031; the recommended dose is 40-160 mg/day, and the preferred dose for maintenance therapy and prevention of recurrence is 40 to 60 mg twice a day (Kapian &Sadock's) Comprehensive Textbook of Psychiatry, Seventh Edition, Volume II, Lippincott Williams & Wilkins: Philadelphia, pp.2470-2471,2000); and bis (2-propyl-pentanoic acid) of sodium hydroxide, also known as conventional double sodium valproate (Divalproex sodium) , disclosed in U.S. Patent No. 5,212,326, the recommended dosage for treating mania is 750 mg/day, and the maximum recommended dose is 60 mg/kg/day (Physicians Desk Reference).

本案所使用的「受試者 」一詞指的是動物，較佳為哺乳動物，最佳為人類，其係治療、觀察或實驗之標的物。The term " subject " as used in this context refers to an animal, preferably a mammal, preferably a human, which is the subject of treatment, observation or experimentation.

本案所使用的「治療有效量 」意指在組織系統、動物或人類引起研究者、獸醫、醫師或其他臨床醫師所尋求之生物或醫學反應(包括緩解被治療疾病或疾患的症狀)的活性化合物或藥劑之量。As used herein, " therapeutically effective amount " means an active compound which, in a tissue system, animal or human, elicits a biological or medical response sought by a researcher, veterinarian, physician or other clinician, including alleviating the symptoms of the disease or condition being treated. Or the amount of the agent.

其中本發明係關於協同療法或合併療法(combination therapy)，其包含投予一或多個式(I)或式(II)化合物及一或多個抗精神病藥物及/或抗抑鬱劑，「治療有效量」係指一起服用之藥劑的合併量，俾使合併之效用引起所欲的生物或醫學反應。舉例來說，包含投予式(I)或式(II)化合物及至少一抗抑鬱劑及/或至少一抗精神病藥物之協同療法的治療有效量會是一起或依序服用時有治療上有效之合併效用的式(I)或式(II)化合物之量與抗抑鬱劑及/或抗精神病藥物之量。此外，熟習此藝者可理解在具備治療有效量之協同療法的情況中，如上述例子，式(I)或式(II)化合物之量及/或抗抑鬱劑及/或抗精神病藥物之量個別而言可能治療有效或可能治療無效。Wherein the invention relates to synergistic therapy or combination therapy comprising administering one or more compounds of formula (I) or formula (II) and one or more antipsychotics and/or antidepressants, "treatment "Effective amount" means the combined amount of the agents taken together, such that the combined effect causes the desired biological or medical response. For example, a therapeutically effective amount comprising a synergistic therapy with a compound of formula (I) or formula (II) and at least one antidepressant and/or at least one antipsychotic may be therapeutically effective when administered together or sequentially. The amount of the compound of formula (I) or formula (II) combined with the amount of antidepressant and/or antipsychotic drug. In addition, those skilled in the art will appreciate that in the case of a therapeutically effective amount of synergistic therapy, such as the above examples, the amount of the compound of formula (I) or formula (II) and/or the amount of antidepressant and/or antipsychotic drug Individually it may be effective or may be ineffective.

用於本案時，「協同療法 」與「合併療法 」用詞係指藉由投予一或多個式(I)或式(II)化合物與一或多個(多個)抗抑鬱劑及/或(多個)抗精神病藥物治療對其有需求之受試者，其中(多個)式(I)或式(II)化合物與(多個)抗抑鬱劑及/或(多個)抗精神病藥物係藉由任何適宜方式、同時地、依序地、分別地或以單一醫藥配方投予。當(多個)式(I)或式(II)化合物與(多個)抗抑鬱劑及/或(多個)抗精神病藥物係以分別劑型投予時，各化合物每日所投予的劑量數目可相同或不同。(多個)式(I)或式(II)化合物與(多個)抗抑鬱劑及/或(多個)抗精神病藥物可經由相同或不同投藥途徑投予。適宜的投藥方法例子包括但不限於口服、靜脈內(iv)、肌肉內(im)、皮下(sc)、經皮及經直腸。化合物亦可直接投予至神經系統，其包括但不限於腦內、腦室內、側腦室內、髓鞘內、腦池內、脊髓內及/或經由顱內或椎管內針頭輸送的脊椎旁投藥途徑及/或具備或不具備幫浦裝置的導管。(多個)式(I)或式(II)化合物與(多個)抗抑鬱劑及/或(多個)抗精神病藥物可根據同時或交替攝生法在療程期間以相同或不同次數並行地以分割或單一形式投予。As used in this case, the terms " synergistic therapy " and " combination therapy " refer to the administration of one or more compounds of formula (I) or formula (II) with one or more antidepressant(s) and/or Or a subject in need of antipsychotic treatment, wherein the compound(s) of formula (I) or formula (II) and antidepressant(s) and/or antipsychotic(s) The drug is administered by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation. When the compound(s) of formula (I) or formula (II) and the antidepressant(s) and/or antipsychotic drug(s) are administered in separate dosage forms, the daily dose of each compound is administered. The numbers can be the same or different. The compound(s) of formula (I) or formula (II) and the antidepressant(s) and/or antipsychotic agent(s) can be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, and transrectal. The compounds may also be administered directly to the nervous system including, but not limited to, intraspinal, intraventricular, intraventricular, intramedullary, intracisternal, intraspinal, and/or paravertebral delivery via intracranial or intraspinal needles. Routes of administration and/or catheters with or without a pumping device. The compound(s) of formula (I) or formula (II) and the antidepressant(s) and/or antipsychotic agent(s) may be concurrently present in the same or different times during the course of treatment according to simultaneous or alternating regimen Segmentation or single form of administration.

在一具體例，本發明係關於和兩極病症有關或兩極病症特有或為兩極病症症狀之抑鬱的治療。在另一具體例，本發明係關於和兩極病症有關或兩極病症特有或為兩極病症症狀之躁狂的治療。在又另一具體例，本發明係關於和兩極病症有關或兩極病症特有或為兩極病症症狀之循環(於抑鬱與躁狂或抑鬱期與躁狂期之間)的治療。In one embodiment, the invention relates to the treatment of depression associated with a bipolar disorder or a bipolar disorder or a symptom of a bipolar disorder. In another embodiment, the invention relates to the treatment of mania associated with a bipolar disorder or a bipolar disorder or a symptom of a bipolar disorder. In yet another embodiment, the invention relates to the treatment of a bipolar disorder or a bipolar disorder or a cycle of symptoms of a bipolar disorder (between depression and mania or between depression and mania).

在本發明一具體例中，R¹ 係選自於由氫與甲基所構成的群組。在本發明另一具體例中，R² 係選自於由氫與甲基所構成的群組。在本發明又另一具體例中，R¹ 與R² 各為氫或R¹ 與R² 各為甲基。In a specific embodiment of the invention, R ¹ is selected from the group consisting of hydrogen and methyl. In another embodiment of the invention, R ² is selected from the group consisting of hydrogen and methyl. In still another embodiment of the present invention, each of R ¹ and R ² is hydrogen or R ¹ and R ^{2 are} each a methyl group.

在本發明一具體例中，－(CH₂ )_a －係選自於由－CH₂ －與－CH₂ －CH₂ －所構成的群組。在本發明另一具體例中，－(CH₂ )_a －為－CH₂ －。In a specific embodiment of the invention, -(CH ₂ ) _a - is selected from the group consisting of -CH ₂ - and -CH ₂ -CH ₂ -. In another embodiment of the invention, -(CH ₂ ) _a - is -CH ₂ -.

在本發明一具體例中，R⁴ 係選自於由氫與甲基所構成的群組，較佳地，R⁴ 為氫。In a specific embodiment of the present invention, R ⁴ is selected from the group consisting of hydrogen and methyl, and preferably R ⁴ is hydrogen.

在本發明一具體例中，a為1。In one embodiment of the invention, a is one.

在本發明一具體例中，b為0至2之整數。在本發明另一具體例中，c為0至2之整數。在本發明另一具體例中，b為0至1之整數。在本發明另一具體例中，c為0至1之整數。在本發明又另一具體例中，b與c的總和為0至2之整數，較佳為0至1之整數。在本發明又另一具體例中，b為0至2之整數且c為0。In a specific embodiment of the invention, b is an integer from 0 to 2. In another embodiment of the invention, c is an integer from 0 to 2. In another embodiment of the invention, b is an integer from 0 to 1. In another embodiment of the invention, c is an integer from 0 to 1. In still another embodiment of the present invention, the sum of b and c is an integer of 0 to 2, preferably an integer of 0 to 1. In still another embodiment of the present invention, b is an integer from 0 to 2 and c is zero.

在本發明一具體例中，係選自於由下列所構成的群組：。在本發明另一具體例中，係選自於由下列所構成的群組： In a specific example of the present invention, Is selected from the group consisting of: . In another embodiment of the present invention, Is selected from the group consisting of:

在本發明一具體例中，係選自於由下列所構成的群組：2－(2,3－二氫－苯并[1,4]二基)、2－(苯并[1,3]二唑基)、3－(3,4－二氫－苯并[1,4]二呯基)、2－(6－氯基－2,3－二氫－苯并[1,4]二基)、2－(6－氟基－2,3－二氫－苯并[1,4]二基)、2－(啶基)、2－(5－氟基－2,3－二氫－苯并[1,4]二基)、2－(7－氯基－2,3－二氫－苯并[1,4]二基)、2－(6－氯基－苯并[1,3]二唑基)、2－(7－硝基－2,3－二氫－苯并[1,4]二基)、2－(7－甲基－2,3－二氫－苯并[1,4]二基)、2－(5－氯基－2,3－二氫－苯并[1,4]二基)、2－(6－溴基－2,3－二氫－苯并[1,4]二基)、2－(6,7－二氯基－2,3－二氫－苯并[1,4]二基)、2－(8－氯基－2,3－二氫－苯并[1,4]二基)、2－(2,3－二氫－萘并[2,3－b][1,4]二基)與2－(4－甲基－苯并[1,3]二唑基)。In a specific example of the present invention, Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Base), 2-(benzo[1,3] Zozolyl), 3-(3,4-dihydro-benzo[1,4] Mercapto), 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-fluoro-2,3-dihydro-benzo[1,4] Base), 2-( Pyridyl), 2-(5-fluoro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-chloro-benzo[1,3] Azyl), 2-(7-nitro-2,3-dihydro-benzo[1,4] Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] Base, 2-(5-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] Base, 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] Base, 2-(8-chloro-2,3-dihydro-benzo[1,4] Base, 2-(2,3-dihydro-naphtho[2,3-b][1,4] And 2-(4-methyl-benzo[1,3] Azolyl).

在本發明另一具體例中，係選自於由下列所構成的群組：2－(苯并[1,3]二唑基)、2－(2,3－二氫－苯并[1,4]二基)、2－(6－氯基－2,3－二氫－苯并[1,4]二基)、2－(7－氯基－2,3－二氫－苯并[1,4]二基)、2－(7－甲基－2,3－二氫－苯并[1,4]二基)、2－(6－溴基－2,3－二氫－苯并[1,4]二基)與2－(6,7－二氯基－2,3－二氫－苯并[1,4]二基)。在本發明另一具體例中，係選自於由下列所構成的群組：2－(2,3－二氫－苯并[1,4]二基)、2－(7－甲基－2,3－二氫－苯并[1,4]二基)與2－(6－溴基－2,3－二氫－苯并[1,4]二基)。In another embodiment of the present invention, Is selected from the group consisting of 2-(benzo[1,3] Azyl), 2-(2,3-dihydro-benzo[1,4] Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] And 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] base). In another embodiment of the present invention, Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] And 2-(6-bromo-2,3-dihydro-benzo[1,4] base).

在本發明一具體例中，R⁵ 係選自於由鹵素與低級烷基所構成的群組。在本發明另一具體例中，R⁵ 係選自於氯基、氟基、溴基及甲基。In a specific embodiment of the invention, R ⁵ is selected from the group consisting of halogen and lower alkyl. In another embodiment of the invention, R ⁵ is selected from the group consisting of a chloro group, a fluoro group, a bromo group, and a methyl group.

在本發明一具體例中，式(I)化合物上的立體中心係呈S－構形。在本發明另一具體例中，式(I)化合物上的立體中心係呈R－構形。In a specific embodiment of the invention, the stereocenter of the compound of formula (I) is in the S-configuration. In another embodiment of the invention, the stereocenter of the compound of formula (I) is in the R-configuration.

在本發明一具體例中，式(I)化合物係呈現為鏡像異構富集混合物，其中%鏡像異構富集值(% ee)係大於約75%，較佳大於約90%，更佳大於約95%，最佳大於約98%。In one embodiment of the invention, the compound of formula (I) is present as a mirror image-enriched mixture wherein the % image enrichment value (% ee) is greater than about 75%, preferably greater than about 90%, more preferably Greater than about 95%, optimally greater than about 98%.

本發明的額外具體例係包括該等其中就本案所定義的一或多個變數(即R¹ 、R² 、R³ 、R⁴ 、X－Y與A)挑選的取代基係獨立地被選為任何個別取代基或從本案所定義的完整名單中挑選的取代基的任意子集者。Additional specific examples of the invention include those substituents selected among one or more of the variables defined herein (i.e., R ¹ , R ² , R ³ , R ⁴ , X-Y, and A) are independently selected. Any subset of substituents selected for any individual substituent or from the complete list defined in this case.

本發明的代表性化合物係如下方表1所列者。本發明的額外化合物係如表3所列者。在下方表1與2中，「立體」開頭的欄位係定義連接於打星號鍵的雜環碳原子的立體構形。若未列出命名，化合物係製備為立體構形混合物。若列出"R"或"S"命名，該立體構形係以富含鏡像異構物之起始材料為基礎。Representative compounds of the invention are listed in Table 1 below. Additional compounds of the invention are listed in Table 3. In Tables 1 and 2 below, the field at the beginning of "stereo" defines the stereo configuration of the heterocyclic carbon atom attached to the star-shaped bond. If no nomenclature is listed, the compounds are prepared as a mixture of stereoconfigurations. If the "R" or "S" designation is listed, the stereo configuration is based on a starting material rich in mirror image isomers.

用於本案時，除另有註明外，「鹵素」係指氯、溴、氟與碘。For the purposes of this case, " halogen " means chlorine, bromine, fluorine and iodine unless otherwise stated.

用於本案時，除另有註明外，「烷基」一詞－無論單獨使用或用作取代基的一部分－係包括直鏈與支鏈。舉例來說，烷基包括甲基、乙基、丙基、異丙基、丁基、異丁基、二級丁基、三級丁基、戊基及類似物。除另有註明外，和烷基共同使用的「低級」意指由1－4個碳原子構成的碳鏈組成物。For use in this case, the term " alkyl ", whether used alone or as part of a substituent, is intended to include both straight and branched chains, unless otherwise indicated. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, and the like. Unless otherwise indicated, " lower " used in conjunction with an alkyl group means a carbon chain composition composed of 1-4 carbon atoms.

用於本案時，除另有註明外，「烷氧基 」係表示上述直鏈或支鏈烷基基團的氧醚基。舉例來說，甲氧基、乙氧基、正丙氧基、二級丁氧基、三級丁氧基、正己氧基及類似物。In the case of the present invention, " alkoxy " means an oxygen ether group of the above linear or branched alkyl group unless otherwise stated. For example, methoxy, ethoxy, n-propoxy, di-butoxy, tert-butoxy, n-hexyloxy and the like.

用於本案時，"^＊ "記號係表示立體中心的存在。When used in this case, the " ^* " symbol indicates the presence of a stereocenter.

當一特定基團為「經取代的 」(譬如烷基、芳基等等)時，該基團可具有獨立地選自於取代基名單的一或多個取代基，較佳一至五個取代基，更佳一至三個取代基，最佳一至兩個取代基。When a particular group is " substituted " (e.g., alkyl, aryl, etc.), the group may have one or more substituents, preferably one to five, independently selected from the list of substituents. More preferably one to three substituents, most preferably one to two substituents.

和取代基有關的「獨立地 」一詞意指當可能有不止一個該類取代基時，該類取代基可相同或互異。The term " independently " in relation to a substituent means that when there may be more than one such substituent, the substituents may be the same or different.

按照本揭示內容通篇所採用的標準命名法，係先說明經命名側鏈的末端部分，再繼續說明近連接點的毗鄰官能性。於是，舉例來說，「苯基－烷基－胺基－羰基－烷基 」取代基指的是具下式之基團 In accordance with the standard nomenclature used throughout the disclosure, the end portion of the named side chain is described first, and the adjacent functionality of the near junction is continued. Thus, for example, a " phenyl-alkyl-amino-carbonyl-alkyl " substituent refers to a group of the formula

本說明書－尤其是反應方案與實施例－所使用的縮寫係如下列：DCC＝二環己碳二亞胺DCE＝二氯乙烷DCM＝二氯甲烷DIPEA或DIEA＝二異丙基乙胺DMF＝N,N－二甲基甲醯胺DMSO＝二甲基亞碸EDC＝乙基碳二亞胺Et₃ N或TEA＝三乙胺Et₂ O＝***EA或EtOAc＝乙酸乙酯EtOH＝乙醇IPA＝2－丙醇Hept＝庚烷HOBT＝1－羥基苯并***HPLC＝高壓液相層析LAH＝鋁氫化鋰M或MeOH＝甲醇NMR＝核磁共振Pd－C＝鈀活性碳催化劑RP HPLC＝逆相高壓液相層析RT或rt＝室溫TEA＝三乙胺TFA＝三氟乙酸THF＝四氫呋喃TLC＝薄層層析The abbreviations used in this specification, especially the reaction schemes and examples, are as follows: DCC = dicyclohexylcarbodiimide DCE = dichloroethane DCM = dichloromethane DIPEA or DIEA = diisopropylethylamine DMF =N,N-dimethylformamide DMSO = dimethyl hydrazine EDC = ethyl carbodiimide Et ₃ N or TEA = triethylamine Et ₂ O = diethyl ether EA or EtOAc = ethyl acetate EtOH = ethanol IPA=2-propanol Hept=heptane HOBT=1-hydroxybenzotriazole HPLC=high pressure liquid chromatography LAH=lithium aluminum hydride M or MeOH=methanol NMR=nuclear magnetic resonance Pd-C=palladium activated carbon catalyst RP HPLC = reverse phase high pressure liquid chromatography RT or rt = room temperature TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography

若根據本發明之化合物具有至少一對掌中心，彼等可因此以鏡像異構物存在。若該等化合物擁有二或多個對掌中心，彼等可另以非對映鏡像異構物存在。欲被理解的是所有該類異構物及其混合物係包含在本發明的範疇內。再者，該等化合物的若干晶型可以多晶形存在且於是係意圖包括在本發明的範疇內。此外，若干化合物可和水(即水合物)或一般有機溶劑形成溶劑合物，這樣的溶劑合物亦意圖包含在本發明的範疇內。If the compounds according to the invention have at least one pair of palm centers, they may thus be present as mirror image isomers. If the compounds possess two or more pairs of palm centers, they may additionally exist as diastereomeric mirror isomers. It is to be understood that all such isomers and mixtures thereof are included within the scope of the invention. Furthermore, several crystal forms of such compounds may exist in a polymorphic form and are intended to be included within the scope of the invention. In addition, several compounds may form solvates with water (i.e., hydrates) or general organic solvents, and such solvates are also intended to be encompassed within the scope of the invention.

為供藥物使用，本發明的化合物鹽指的是無毒的「藥學上可接受之鹽 」。然而，其他鹽可有用於製備根據本發明之化合物或其藥學上可接受之鹽。適宜的藥學上可接受之化合物鹽係包括酸式加成鹽，其可，舉例來說，藉由混合化合物溶液和藥學上可接受之酸(例如氫氯酸、硫酸、延胡索酸、馬來酸、琥珀酸、乙酸、苯甲酸、檸檬酸、酒石酸、碳酸或磷酸)的溶液形成。再者，若本發明之化合物帶有酸性部分，則其適宜的藥學上可接受之鹽可包括鹼金屬鹽，譬如，鈉或鉀鹽；鹼土金屬鹽，譬如，鈣或鎂鹽；以及和適宜有機配位體形成的鹽，譬如，四級銨鹽。於是，代表性的藥學上可接受之鹽係包括下列：乙酸鹽、苯磺酸鹽、苯甲酸鹽、碳酸氫鹽、硫酸氫鹽、酒石酸氫鹽、硼酸鹽、溴鹽、乙二胺四乙酸鈣鹽、樟腦磺酸鹽、碳酸鹽、氯鹽、克拉維酸鹽(clavulanate)、檸檬酸鹽、二氫氯酸鹽、乙二胺四乙酸鹽、乙二磺酸鹽、依托鹽(estolate)、乙磺酸鹽、延胡索酸鹽、葡庚糖酸鹽、葡糖酸鹽、麩胺酸鹽、乙醇醯苯砷酸鹽、己基間二酚鹽、海巴胺鹽(hydrabamine)、氫溴酸鹽、氫氯酸鹽、羥基萘甲酸鹽、碘鹽、異硫代羥酸鹽、乳酸鹽、乳糖酸鹽、月桂酸鹽、蘋果酸鹽、馬來酸鹽、扁桃酸鹽、甲磺酸鹽、甲基溴鹽、甲基硝酸鹽、甲基硫酸鹽、黏液酸鹽、萘磺酸鹽、硝酸鹽、N－甲基葡糖銨鹽、油酸鹽、雙羥萘酸(pamoate)(恩波鹽(embonate))、棕櫚酸鹽、泛酸鹽、磷酸鹽/二磷酸鹽、聚半乳糖醛鹽、水楊酸鹽、硬脂酸鹽、硫酸鹽、次乙酸鹽、琥珀酸鹽、丹寧酸鹽、酒石酸鹽、茶氯酸鹽(teoclate)、甲苯磺酸鹽、三乙碘鹽及戊酸鹽。For use in medicine, the compound salt of the present invention refers to a non-toxic " pharmaceutically acceptable salt ". However, other salts may be used in the preparation of the compounds according to the invention or pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salt compounds include acid addition salts which can be, for example, by mixing a solution of the compound with a pharmaceutically acceptable acid (eg, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, A solution of succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid is formed. Further, if the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; A salt formed by an organic ligand, such as a quaternary ammonium salt. Thus, representative pharmaceutically acceptable salts include the following: acetate, besylate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, ethylenediamine Calcium acetate, camphor sulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, ethylenediaminetetraacetate, ethanedisulfonate, eto salt ), ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, ethanol phthalate, hexyldiphenolate, hydrabamine, hydrobromic acid Salt, hydrochloride, hydroxynaphthoate, iodide salt, isothiohydroxy acid salt, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonic acid Salt, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalene sulfonate, nitrate, N-methyl glucoammonium salt, oleate, pamoate ( Embone, palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, times , Succinate, tannate, tartrate, teoclate (teoclate), tosylate, and valerate triethylammonium salt.

可用於製備藥學上可接受之鹽的代表性酸與鹼係包括下列：酸，包括乙酸、2,2－二氯基乙酸、醯化胺基酸、己二酸、藻酸、抗壞血酸、L－天門冬胺酸、苯磺酸、苯甲酸、4－乙醯胺基苯甲酸、(＋)－樟腦酸、樟腦磺酸、(＋)－(1S)－樟腦－10－磺酸、癸酸、己酸、辛酸、肉桂酸、檸檬酸、環己烷基胺基磺酸(cyclamic acid)、十二烷基硫酸、乙－1,2－二磺酸、乙磺酸、2－羥基－乙磺酸、甲酸、延胡索酸、半乳糖二酸、龍膽酸、葡庚糖酸、D－葡糖酸、D－葡糖醛酸、L－麩胺酸、α－氧基－戊二酸、甘醇酸、馬尿酸、氫溴酸、氫氯酸、(＋)－L－乳酸、(±)－DL－乳酸、乳糖酸、馬來酸、(－)－L－蘋果酸、丙二酸、(±)－DL－扁桃酸、甲磺酸、萘－2－磺酸、萘－1,5－二磺酸、1－羥基－2－萘甲酸、菸鹼酸、硝酸、油酸、乳清酸、草酸、棕櫚酸、雙羥萘酸、磷酸、L－焦麩胺酸、水楊酸、4－胺基－水楊酸、癸二酸、硬脂酸、琥珀酸、硫酸、丹寧酸、(＋)－L－酒石酸、硫氰酸、對甲苯磺酸與十一碳烯酸；以及鹼，包括氨、L－精胺酸、苯明(benethamine)、芐星(benzathine)、氫氧化鈣、膽鹼、二甲胺基乙醇(deanol)、二乙醇胺、二乙胺、2－(二乙基胺基)－乙醇、乙醇胺、乙二胺、N－甲基－葡糖胺、海巴胺、1H－咪唑、L－離胺酸、氫氧化鎂、4－(2－羥基乙基)－嗎啉、哌、氫氧化鉀、1－(2－羥基乙基)－吡咯啶、二級胺、氫氧化鈉、三乙醇胺、胺基丁三醇與氫氧化鋅。Representative acids and bases useful in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroacetic acid, deuterated amino acid, adipic acid, alginic acid, ascorbic acid, L- Aspartic acid, benzenesulfonic acid, benzoic acid, 4-ethylguanidinobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, citric acid, Caproic acid, caprylic acid, cinnamic acid, citric acid, cyclocyclyl acid, dodecyl sulfate, ethyl-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonate Acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxy-glutaric acid, glycol Acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, ±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid , oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-joy bran Amine acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid Undecylenic acid; and alkali, including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, two Ethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucosamine, seabamine, 1H-imidazole, L-isoamine, magnesium hydroxide, 4- (2-hydroxyethyl)-morpholine, piperazine , potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, aminobutyric triol and zinc hydroxide.

式(I)化合物可根據反應方案1所概示的方法製備。The compound of formula (I) can be prepared according to the procedure outlined in Reaction Scheme 1.

因此，經適宜取代之式(X)化合物(習知化合物或以習知方法製備的化合物)係於諸如THF、二烷及類似溶劑之有機溶劑中以較佳介於約50℃至約100℃之高溫，更佳以大約迴流溫度與磺醯胺(習知化合物，較佳其中磺醯胺為約2至約5當量的量)反應，以生成對應的式(Ia)化合物。Thus, a suitably substituted compound of the formula (X) (a conventional compound or a compound prepared by a conventional method) is used in, for example, THF, The organic solvent of the alkane and the like is preferably at a temperature of from about 50 ° C to about 100 ° C, more preferably at about reflux temperature with a sulfonamide (preferred compound, preferably wherein the sulfonamide is from about 2 to about 5 equivalents) The amount) reacts to form the corresponding compound of formula (Ia).

或者，經適宜取代之式(X)化合物(習知化合物或以習知方法製備的化合物)係於諸如DMF、DMSO及類似溶劑之有機溶劑中在諸如TEA、DIPEA、吡啶及類似物之鹼的存在下與經適宜取代之式(XI)化合物(習知化合物或以習知方法製備的化合物)反應，以生成對應的式(I)化合物。Alternatively, a suitably substituted compound of the formula (X) (a conventional compound or a compound prepared by a conventional method) is used in an organic solvent such as DMF, DMSO and the like in a base such as TEA, DIPEA, pyridine or the like. The reaction with a suitably substituted compound of the formula (XI) (a conventional compound or a compound prepared by a conventional method) is carried out in the presence of a compound of the formula (I).

式(X)化合物(其中為)可根據反應方案2所概示的方法製備。a compound of formula (X) (wherein for It can be prepared according to the method outlined in Reaction Scheme 2.

因此，經適宜取代之式(XII)化合物(習知化合物或以習知方法製備的化合物，舉例來說，如上文反應方案3所述者)係視情況於諸如乙腈及類似溶劑之有機溶劑中與NH₄ OH(習知化合物)反應，以生成對應的式(XIII)化合物。Thus, a suitably substituted compound of the formula (XII) (a conventional compound or a compound prepared by a conventional method, for example, as described in Reaction Scheme 3 above) is optionally used in an organic solvent such as acetonitrile and the like. Reaction with NH ₄ OH (a conventional compound) to give the corresponding compound of formula (XIII).

式(XIII)化合物係於例如THF、***及類似溶劑之有機溶劑中與經適宜挑選的還原劑(例如LAH及類似物及類似物)反應，以生成對應的式(Xa)化合物。The compound of the formula (XIII) is reacted with a suitably selected reducing agent (for example, LAH and the like and the like) in an organic solvent such as THF, diethyl ether and the like to give the corresponding compound of the formula (Xa).

式(X)化合物(其中係選自)可根據反應方案3所概示的方法製備。a compound of formula (X) (wherein Lined up It can be prepared according to the method outlined in Reaction Scheme 3.

因此，經適宜取代之式(XIV)化合物(習知化合物或以習知方法製備的化合物)係於偶合劑(例如DCC及類似物)的存在下、視情況於諸如乙腈及類似溶劑之有機溶劑中與NH₄ OH反應，以生成對應的式(XV)化合物。Thus, a suitably substituted compound of the formula (XIV) (a conventional compound or a compound prepared by a conventional method) is in the presence of a coupling agent (for example, DCC and the like), optionally in an organic solvent such as acetonitrile and the like. Reacts with NH ₄ OH to form the corresponding compound of formula (XV).

式(XV)化合物係於例如THF、***及類似溶劑之有機溶劑中與經適宜挑選的還原劑(例如LAH及類似物)反應，以生成對應的式(Xb)化合物。The compound of the formula (XV) is reacted with an appropriately selected reducing agent (for example, LAH and the like) in an organic solvent such as THF, diethyl ether and the like to give the corresponding compound of the formula (Xb).

式(X)化合物(其中係選自且其中a為2)可根據反應方案4所概示的方法製備。a compound of formula (X) (wherein Lined up And wherein a is 2) can be prepared according to the method outlined in Reaction Scheme 4.

因此，經適宜取代之式(XVI)化合物－其中J¹ 為適宜的離去基團，例如Br、Cl、I、苯磺醯基、甲磺醯基、三氟甲磺醯基及類似基團，習知化合物或以習知方法製備的化合物(舉例來說，藉由活化對應化合物，其中J¹ 為OH)－係於例如DMSO、DMF、THF及類似溶劑之有機溶劑中與氰化物(例如氰化鉀、氰化鈉及類似物)反應，以生成對應的式(XVII)化合物。Thus, a suitably substituted compound of formula (XVI) wherein J ¹ is a suitable leaving group, such as Br, Cl, I, benzenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl and the like a conventional compound or a compound prepared by a conventional method (for example, by activating a corresponding compound in which J ¹ is OH)-based in an organic solvent such as DMSO, DMF, THF, and the like, and cyanide (for example, Potassium cyanide, sodium cyanide and the like) are reacted to form the corresponding compound of formula (XVII).

式(XVII)化合物係根據習知方法還原，舉例來說，藉由與適宜還原劑(例如LAH、硼烷及類似物)反應，以生成對應的式(Xc)化合物。The compound of formula (XVII) is reduced according to conventional methods, for example, by reaction with a suitable reducing agent such as LAH, borane and the like to give the corresponding compound of formula (Xc).

式(X)化合物(其中係選自且其中a為1)可根據反應方案5所概示的方法製備。a compound of formula (X) (wherein Lined up And wherein a is 1) can be prepared according to the method outlined in Reaction Scheme 5.

因此，經適宜取代之式(XVIII)化合物(習知化合物或以習知方法製備的化合物)係根據習知方法活化，以生成對應的式(XIX)化合物，其中J² 為適宜的離去基團，例如苯磺醯基、Cl、Br、I、甲磺醯基、三氟甲磺醯基及類似基團。Thus, a suitably substituted compound of the formula (XVIII) (a conventional compound or a compound prepared by a conventional method) is activated according to a conventional method to give a corresponding compound of the formula (XIX) wherein J ² is a suitable leaving group. Groups such as phenylsulfonyl, Cl, Br, I, methanesulfonyl, trifluoromethanesulfonyl and the like.

式(XIX)化合物係於例如DMF、DMSO、乙腈及類似溶劑之有機溶劑中以較佳介於50℃至約200℃之高溫，更佳以大約迴流溫度與鄰苯二甲醯亞胺鹽(例如鄰苯二甲醯亞胺鉀、鄰苯二甲醯亞胺鈉及類似物)反應，以生成對應的式(XX)化合物。The compound of the formula (XIX) is in an organic solvent such as DMF, DMSO, acetonitrile or the like, preferably at a high temperature of from 50 ° C to about 200 ° C, more preferably at about reflux temperature with an phthalic acid imide salt (for example) The potassium phthalimide, sodium phthalate and the like are reacted to form the corresponding compound of formula (XX).

式(XX)化合物係於例如乙醇、甲醇及類似溶劑之有機溶劑中以較佳介於約50℃至約100℃之高溫，更佳以大約迴流溫度及類似溫度與N₂ H₄ (習知化合物)反應，以生成對應的式(Xd)化合物。The compound of the formula (XX) is in an organic solvent such as ethanol, methanol and the like, preferably at a temperature of from about 50 ° C to about 100 ° C, more preferably at a reflux temperature and the like, and N ₂ H ₄ (a conventional compound) Reaction to produce the corresponding compound of formula (Xd).

熟習此藝者將理解式(X)化合物(其中係選自、、或)可同樣地根據習知方法或，舉例來說，根據上述反應方案2至5所概示的方法製備，藉由選擇對應的萘并稠合化合物取代苯并稠合起始材料。Those skilled in the art will understand the compound of formula (X) (where Lined up , , or The same can be prepared according to conventional methods or, for example, according to the methods outlined in the above Reaction Schemes 2 to 5, by substituting the corresponding naphthalene fused compound for the benzo-fused starting material.

熟習此藝者將進一步理解若式(X)化合物的單一鏡像異構物(或鏡像異構物混合物，其中係富含一鏡像異構物)係所欲的，則反應方案1至5所說明的以上過程可藉由以單一鏡像異構物(或鏡像異構物混合物，其中係富含一鏡像異構物)取代適當起始材料來應用。It will be further understood by those skilled in the art that if a single mirror image isomer (or a mixture of mirror image isomers, in which a mirror image isomer is enriched) of the compound of formula (X) is desired, then steps 1 through 5 are illustrated. The above process can be applied by replacing a suitable starting material with a single mirror image isomer (or a mixture of mirror image isomers in which a mirror image isomer is enriched).

熟習此藝者將理解若本發明的反應步驟可以各式溶劑或溶劑系統進行，則該反應步驟亦可以適宜溶劑或溶劑系統的混合物進行。Those skilled in the art will appreciate that if the reaction steps of the present invention can be carried out in a variety of solvent or solvent systems, the reaction step can also be carried out as a mixture of suitable solvents or solvent systems.

若製備根據本發明之化合物的方法產生立體異構物混合物，那麼該等異構物可藉由習用技術分離，例如製備型層析。該化合物可製備成外消旋形式，或者個別鏡像異構物可藉由鏡像特異性合成或藉由解析法製備。該化合物可，舉例來說，藉由標準技術解析成其組成鏡像異構物，例如藉由與光學活性酸(例如(－)－二－對甲苯甲醯基－D－酒石酸及/或(＋)－二－對甲苯甲醯基－L－酒石酸)形成鹽而形成非對映鏡像異構對，之後分段結晶並使游離鹼再生。該化合物亦可藉由形成非對映鏡像異構酯或醯胺，之後藉由層析分離並移除對掌性輔助物來解析。或者，該化合物可使用對掌性HPLC管柱解析。If a process for preparing a compound according to the invention produces a mixture of stereoisomers, the isomers can be separated by conventional techniques, such as preparative chromatography. The compound can be prepared in racemic form, or the individual mirror image isomers can be prepared by mirror specific synthesis or by analytical methods. The compound can be resolved, for example, by its standard techniques into its constituent mirror image isomers, for example by reaction with an optically active acid such as (-)-di-p-tolylmethyl-D-tartaric acid and/or (+ )-Di-p-tolylmethyl-L-tartaric acid forms a salt to form a diastereomeric enantiomer pair, followed by crystallization in sections and regeneration of the free base. The compound can also be resolved by formation of diastereomeric enantiomers or guanamine, followed by chromatographic separation and removal of the antagonistic aid. Alternatively, the compound can be resolved using a palm-shaped HPLC column.

在任何製備根據本發明之化合物的方法期間，可能有必要及/或希望保護位於任何受關注分子上的敏感性或反應性基團。這可藉由習用保護基的方式達成，例如該等說明於Protective Groups in Organic Chemistry ,ed.J.F.W.McOmie,Plenum Press,1973；及T.W.Greene & P.G.M.Wuts,Protective Groups in Organic Synthesis ,John Wiley & Sons,1991中者。保護基可在合宜的後續階段以本領域習知方法移除。During any method of preparing a compound according to the invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved by the use of a protecting group, such as those described in Protective Groups in Organic Chemistry , ed. JFW McOmie, Plenum Press, 1973; and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis , John Wiley & Sons, 1991. . The protecting group can be removed at a convenient subsequent stage by methods known in the art.

本發明又包含含有一或多個式(I)化合物和藥學上可接受之載劑的藥學組成物。含有一或多個本案所述之本發明化合物作為活性成份的藥學組成物可根據習用藥學調合技術將化合物或多個化合物和藥學載劑仔細地混合而製備。載劑可依照所欲投藥途徑(譬如口服、非經腸)採用眾多不同形式。於是就液態口服製劑－例如懸浮液、酏劑與溶液－而言，適宜的載劑及添加劑係包括水、二醇類、油類、醇類、加味劑、防腐劑、安定劑、著色劑及類似物；就固態口服製劑－例如粉末、膠囊與錠劑－而言，適宜的載劑及添加劑係包括澱粉、糖類、稀釋劑、粒化劑、潤滑劑、黏合劑、崩解劑及類似物。固態口服製劑亦可包覆著，例如糖類的物質或經腸衣包覆以便調整主要吸收位置。就非經腸投藥而言，載劑通常由無菌水構成且可添加其他成份以增加溶解度或防腐性。注射用懸浮液或溶液亦可利用水性載劑與適當的添加劑來製備。The invention further comprises a pharmaceutical composition comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier. A pharmaceutical composition containing one or more of the compounds of the present invention as described herein as an active ingredient can be prepared by carefully mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical blending techniques. The carrier can take a wide variety of forms depending on the route of administration desired (e.g., oral, parenteral). Thus, in the case of liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, odorants, preservatives, stabilizers, colorants and Analogs; in the case of solid oral preparations - such as powders, capsules and lozenges - suitable carriers and additives include starches, saccharides, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. . The solid oral preparation may also be coated with, for example, a saccharide or an enteric coating to adjust the primary absorption site. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservative. The suspension or solution for injection can also be prepared using aqueous carriers with suitable additives.

為製備本發明之醫藥組成物，作為活性成份的一或多個本發明化合物係根據習用藥學調合技術將化合物或多個化合物和藥學載劑仔細地混合，該載劑可依照投藥所欲(譬如口服或非經腸，例如肌肉內)的製劑形式而採用眾多不同形式。在製備口服劑型內的組成物時，可運用任何常見的藥學媒介物。於是，就液態口服製劑－例如，舉例來說，懸浮液、酏劑與溶液－而言，適宜的載劑及添加劑係包括水、二醇類、油類、醇類、加味劑、防腐劑、著色劑及類似物；就固態口服製劑－例如，舉例來說，粉末、膠囊、膠囊狀錠劑(caplets)、膠囊錠(gelcaps)與錠劑－而言，適宜的載劑及添加劑係包括澱粉、糖類、稀釋劑、粒化劑、潤滑劑、黏合劑、崩解劑及類似物。因其易於投藥，故錠劑與膠囊代表最有利的口服單位劑型，在該情況中，顯然係運用固態藥學載劑。若有需要，錠劑可藉由標準技術外覆糖衣或外覆腸衣。就非經腸劑型而言，載劑通常會包含無菌水，儘管可包括－舉例來說－為了，例如增加溶解度或防腐的其他成份。亦可製備注射用懸浮液，在該情況中，可運用適當的液態載劑、懸浮劑及類似物。本案之藥學組成物於每劑量單位(譬如錠劑、膠囊、粉末、注射、一茶匙及類似物)將含有傳遞如上所述之有效給藥所必需的活性成份量。本案之藥學組成物於每單位劑量單位(譬如錠劑、膠囊、粉末、注射、栓劑、一茶匙及類似劑量單位)將含有約0.1－1000毫克且可給予下列劑量：約0.01－200.0毫克/公斤/日，較佳約0.1至100毫克/公斤/日，更佳約0.5－50毫克/公斤/日，更佳約1.0－25.0毫克/公斤/日或其中任何範圍。然而，劑量可視病患需要、被治療病況的嚴重性及運用的化合物而有所變動。可運用每日投藥或定期後(post－periodic)給藥。For the preparation of the pharmaceutical composition of the present invention, one or more compounds of the present invention as an active ingredient are carefully mixed according to a conventional pharmaceutical blending technique, and the compound or a plurality of compounds and a pharmaceutical carrier are carefully mixed, and the carrier can be administered according to the administration (for example, A variety of different forms are employed in the form of formulations, either orally or parenterally, such as intramuscularly. Any of the usual pharmaceutical vehicles can be employed in preparing the compositions within the oral dosage form. Thus, in the case of liquid oral preparations - for example, suspensions, elixirs and solutions - suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, Coloring agents and the like; in the case of solid oral preparations - for example, powders, capsules, caplets, gelcaps and lozenges - suitable carriers and additives include starch , sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Lozenges and capsules represent the most advantageous oral dosage unit form because of their ease of administration, in which case solid pharmaceutical carriers are obviously employed. If desired, the lozenge can be coated with a sugar coating or an outer casing by standard techniques. For parenteral dosage forms, the carrier will usually comprise sterile water, although it may include, for example, - for example, other ingredients which increase solubility or preservative properties. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspensions and the like may be employed. The pharmaceutical composition of the present invention will contain, per dosage unit (e.g., tablets, capsules, powders, injections, one teaspoon, and the like), the amount of active ingredient necessary to deliver the effective administration as described above. The pharmaceutical composition of the present invention will contain about 0.1-1000 mg per unit dosage unit (such as tablets, capsules, powders, injections, suppositories, one teaspoon, and the like) and may be administered in the following dosages: about 0.01-200.0 mg/kg. / day, preferably about 0.1 to 100 mg / kg / day, more preferably about 0.5 - 50 mg / kg / day, more preferably about 1.0 - 25.0 mg / kg / day or any range therein. However, the dosage may vary depending on the needs of the patient, the severity of the condition being treated, and the compound employed. It can be administered daily or post-periodic.

較佳地，該等組成物係於單位劑型，例如錠劑、藥丸、膠囊、粉末、顆粒、無菌非經腸溶液或懸浮液、計量式氣霧劑或液體噴霧、滴劑、安瓿、自動注射裝置或栓劑：用於口服、非經腸、鼻內、舌下或直腸投藥，或者藉由吸入或吹入投藥。或者，該組成物可呈現適用於每星期一次或每個月一次投藥的形式；舉例來說，活性化合物的非可溶性鹽，例如癸酸鹽，可適用於提供用於肌肉內注射的儲藏式製劑。為製備，例如錠劑之固態組成物，主要活性成份係和藥學載劑，譬如習用成錠成份，例如玉米澱粉、乳糖、蔗糖、山梨糖醇、滑石、硬脂酸、硬脂酸鎂、磷酸二鈣或橡膠及其他藥學稀釋劑，譬如水混合，以形成含有本發明化合物或其藥學上可接受之鹽的均質混合物的固態預調配組成物。當提及該等預調配組成物為均質時，意思是活性成份係均勻地分散在整體組成物內，所以該組成物可輕易被細分成同等有效的劑型，例如錠劑、藥丸與膠囊。此固態預調配組成物隨後被細分成含有0.1至約1000毫克本發明活性成份之上述種類的單位劑型。新穎組成物的錠劑或藥丸可經包覆或以其他方式調合，以提供具有延長作用優點的劑型。舉例來說，錠劑或藥丸可包含內層配藥與外層配藥成份，後者係呈包著前者的外殼形式。該二成份可由腸衣層隔開，該腸衣層係適用於抵抗在胃內崩解並容許內層成份原封不動地通過進入十二指腸或延遲釋放。各式各樣的材料可用於該類腸衣層或外衣，該類材料包括眾多聚合酸與，例如蟲膠、鯨臘醇與纖維素乙酸酯之材料。Preferably, the compositions are in unit dosage form, such as lozenges, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, autoinjections Device or suppository: for oral, parenteral, intranasal, sublingual or rectal administration, or by inhalation or insufflation. Alternatively, the composition may be in a form suitable for administration once a week or once a month; for example, a non-soluble salt of the active compound, such as a citrate, may be suitable for providing a reservoir for intramuscular injection. preparation. For the preparation of, for example, the solid composition of the tablet, the main active ingredient and the pharmaceutical carrier, such as conventional ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, phosphoric acid The dicalcium or rubber and other pharmaceutical diluents, such as water, are combined to form a solid pre-formulated composition comprising a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable salt thereof. When it is mentioned that the pre-formulated compositions are homogeneous, meaning that the active ingredients are uniformly dispersed throughout the composition, the composition can be easily subdivided into equally effective dosage forms such as tablets, pills and capsules. The solid pre-formulated composition is then subdivided into unit dosage forms of the above type containing from 0.1 to about 1000 mg of the active ingredient of the present invention. The lozenges or pills of the novel compositions may be coated or otherwise blended to provide a dosage form with the advantage of prolonged action. For example, a lozenge or pill may comprise an inner layer dispensing and an outer layer dispensing component, the latter being in the form of a shell encased in the former. The two components may be separated by an enteric layer which is adapted to resist disintegration in the stomach and to allow the inner layer components to pass intact into the duodenum or to be delayed in release. A wide variety of materials can be used in such casing layers or garments, including materials such as a wide variety of polymeric acids and, for example, shellac, cetyl alcohol and cellulose acetate.

可併入本發明新穎組成物以供口服或注射投藥的液態形式包括水溶液、經適宜加味的糖漿、水性或油性懸浮液，含食用油(例如棉籽油、芝麻油、椰子油或花生油)的加味乳化液以及酏劑及類似的藥學載體。供水性懸浮液用的適宜分散劑或懸浮劑包括了合成與天然橡膠，例如黃蓍膠、***膠、藻酸鹽、聚葡糖、羧甲基纖維素鈉、甲基纖維素、聚乙烯吡咯啶酮或明膠。Liquid forms which may be incorporated into the novel compositions of the present invention for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, flavored emulsifications containing edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Liquids and elixirs and similar pharmaceutical carriers. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural rubbers such as tragacanth, acacia, alginate, polyglucose, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrole Ketone or gelatin.

說明於本發明之治療抑鬱的方法亦可使用包含任何本案所定義的化合物及藥學上可接受之載劑的藥學組成物來進行。該藥學組成物可含有介於約0.1毫克與1000毫克之間，較佳約50至500毫克的化合物，且可構成任何適用於經選用投藥模式的形式。載劑包括必要及惰性藥學賦形劑，其包括但不限於，黏結劑、懸浮劑、潤滑劑、香料、甜味劑、防腐劑、顏料及外衣。適用於口服投藥的組成物包括固態形式，例如藥丸、錠劑、膠囊狀錠劑、膠囊(各包括即刻釋收、長效釋收與持續釋收配方)、顆粒與粉末，以及液態形式，例如溶液、糖漿、酏劑、乳化液與懸浮液。可用於非經腸投藥的形式係包括無菌溶液、乳化液與懸浮液。The method of treating depression in the present invention can also be carried out using a pharmaceutical composition comprising any of the compounds defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 1000 mg, preferably from about 50 to 500 mg, and may constitute any form suitable for use in the mode of administration. Carriers include the necessary and inert pharmaceutical excipients including, but not limited to, binders, suspending agents, lubricants, perfumes, sweeteners, preservatives, pigments, and outer coatings. Compositions suitable for oral administration include solid forms such as pills, troches, capsules, capsules (each comprising immediate release, long-acting release and sustained release formulations), granules and powders, and liquid forms, for example Solutions, syrups, elixirs, emulsions and suspensions. Forms which can be used for parenteral administration include sterile solutions, emulsions and suspensions.

有利地，本發明之化合物可以每日一劑投予，或每日總劑量可以每日二、三或四次分劑投予。而且，本發明之化合物可經由局部使用適宜的鼻內載體以鼻內形式投予，或者經由具本領域通常知識者所熟知的經皮貼片投予。若以經皮傳遞系統形式投予，則在整個給藥方案當中，投藥劑量理所當然為連續性而非間歇性。Advantageously, the compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in two, three or four divided doses per day. Moreover, the compounds of the invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal patches well known to those of ordinary skill in the art. If administered in the form of a transdermal delivery system, the dosage is of course continuous rather than intermittent throughout the dosage regimen.

比方說，就錠劑或膠囊形式的口服投藥而言，活性藥物成份可和口服無毒的藥學上可接受之惰性載劑－例如乙醇、甘油、水及類似物－合併。再者，所欲或必要時，適宜的黏結劑、潤滑劑、崩解劑及著色劑亦可併入混合物內。適宜的黏結劑包括但不限於澱粉、明膠、天然糖類(例如葡萄糖或β－乳糖)、玉米甜味劑、天然與合成橡膠(例如***膠、黃蓍膠或油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉及類似物。崩解劑包括但不限於澱粉、甲基纖維素、洋菜、膨土、三仙膠及類似物。For example, in the case of oral administration in the form of a lozenge or capsule, the active pharmaceutical ingredient may be combined with an oral non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Further, suitable binders, lubricants, disintegrants, and colorants may also be incorporated into the mixture as desired or desired. Suitable binders include, but are not limited to, starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic rubbers (such as acacia, tragacanth or sodium oleate, sodium stearate, Magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, acacia, bentonite, sansin, and the like.

液態形式包括經適宜加味的懸浮劑或分散劑，例如合成與天然橡膠，舉例來說，黃蓍膠、***膠、甲基纖維素及類似物。就非經腸投藥而言，無菌懸浮液與溶液係為所欲。當靜脈內投藥為所欲時，係運用一般含有適宜防腐劑的等張製劑。Liquid forms include suitably flavored suspending or dispersing agents, such as synthetic and natural rubbers, for example, tragacanth, acacia, methylcellulose, and the like. For parenteral administration, sterile suspensions and solutions are desirable. When the intravenous administration is desired, an isotonic preparation which generally contains a suitable preservative is used.

本發明之化合物可在無論何時需要治療抑鬱時以任何前述組成物根據本領域所建立的給藥方案投予。The compounds of the invention can be administered in any of the foregoing compositions according to established dosage regimens in the art whenever treatment for depression is desired.

產品的每日劑量可在每個成人每天0.01至200毫克/公斤的廣大範圍內做變動。就口服投藥而言，組成物係較佳地提供為含有0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100、150、200、250、500與1000毫克活性成份供依照受治療病患的症狀調整劑量的錠劑形式。藥物的有效量通常以每天約0.01毫克/公斤至約200毫克/公斤體重的劑量位準供應。較佳地，該範圍為每天約0.1至約100.0毫克/公斤體重，更佳地，約0.5毫克/公斤至約50毫克/公斤，更佳地，每天約1.0至約25.0毫克/公斤體重。該化合物可以每天1至4次的方案投予。The daily dose of the product can vary from 0.01 to 200 mg/kg per adult per day. For oral administration, the composition is preferably provided to contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 mg activities. The ingredients are in the form of a lozenge that is dose adjusted according to the symptoms of the patient being treated. An effective amount of the drug is usually supplied at a dosage level of from about 0.01 mg/kg to about 200 mg/kg body weight per day. Preferably, the range is from about 0.1 to about 100.0 mg/kg body weight per day, more preferably from about 0.5 mg/kg to about 50 mg/kg, and more preferably from about 1.0 to about 25.0 mg/kg body weight per day. The compound can be administered in a regimen of 1 to 4 times per day.

投予的最理想劑量可輕易地由熟習此藝者決定且將隨著使用的特定化合物、投藥模式、製劑強度、投藥模式及疾病狀況的進展改變。此外，與受治療的特定病患有關的因素，包括病患年齡、體重、飲食與投藥時間將造成調整劑量的需要。The optimal dosage for administration can be readily determined by those skilled in the art and will vary with the particular compound employed, the mode of administration, the strength of the formulation, the mode of administration, and the condition of the condition. In addition, factors associated with the particular patient being treated, including the patient's age, weight, diet, and timing of administration will result in the need to adjust the dose.

熟習此藝者將理解到使用適宜、習知且普遍被接受的細胞及/或動物模式之活體內及試管內試驗係預測測試化合物治療或預防既定病症的能力。Those skilled in the art will appreciate that in vivo and in vitro assays using suitable, conventional, and generally accepted cellular and/or animal models predict the ability of a test compound to treat or prevent a given condition.

熟習此藝者將進一步理解到人類臨床試驗(包括人類首次試驗(first－in－human)、制定給藥範圍與功效試驗、於健康病患及/或該等罹患既定病症的病患)可根據臨床及醫學領域熟知的方法完成。Those skilled in the art will further understand that human clinical trials (including first-in-human, prescription and efficacy trials, in healthy patients and/or patients with established conditions) can be based on Methods well known in the clinical and medical fields are completed.

列出下列實施例係有助於暸解本發明，而非意圖且不應被解讀為以任何方式限制列於稍後的申請專利範圍當中的本發明。The following examples are presented to aid the understanding of the invention, and are not intended to be construed as limiting the invention in any way.

實施例1Example 1

((3,4－二氫－2H－苯并[b][1,4]二 呯－3－基)甲基)磺醯胺(化合物#3) ((3,4-dihydro-2H-benzo[b][1,4]2 Ind-3-yl)methyl)sulfonamide (Compound #3)

使兒茶酚(5.09克，46.2毫莫耳)與碳酸鉀於乙腈中合併並加熱至迴流達一小時。將2－氯基甲基－3－氯基－1－丙烯(5.78克，46.2毫莫耳)加入，以迴流繼續反應24小時。使該溶液冷卻至室溫並過濾。將濾液蒸乾，殘餘物以水稀釋並以***(3 x)萃取。經合併之有機溶液以MgSO₄ 乾燥並濃縮。層析(2%***溶於己烷)生成無色油狀物的3－亞甲基－3,4－二氫－2H－苯并[b][1,4]二呯。Catechol (5.09 g, 46.2 mmol) was combined with potassium carbonate in acetonitrile and heated to reflux for one hour. 2-Chloromethyl-3-chloro-1-propene (5.78 g, 46.2 mmol) was added and the reaction was continued at reflux for 24 hours. The solution was allowed to cool to room temperature and filtered. The filtrate was evaporated to dryness. The combined organic solution was dried over MgSO ₄ and concentrated to. Chromatography (2% diethyl ether in hexane) afforded 3-methylene-3,4-dihydro-2H-benzo[b][1,4] Hey.

MS(ESI)：163.2(M＋H^＋ )¹ H NMR(300 MHz,CDCl₃ ),δ：6.94(m,4H),5.07(s,2H),4.76(s,4H).MS (ESI): 163.2 (M + H +) 1 H NMR (300 MHz, CDCl 3), δ: 6.94 (m, 4H), 5.07 (s, 2H), 4.76 (s, 4H).

將3－亞甲基－3,4－二氫－2H－苯并[b][1,4]二呯(5.00克，30.8毫莫耳)溶於無水THF(100毫升)中。於0℃將硼烷－THF(1.0 M溶於THF，10.3毫升)加入。該反應於RT攪拌5小時。將胺基磺酸(6.97克，61.6毫莫耳)加入。將反應加熱至迴流過夜。使該反應冷卻至室溫並加入氫氧化鈉水溶液(3.0 M，100毫升)。該溶液以乙酸乙酯(3 x 100毫升)萃取。經合併之有機溶液以MgSO₄ 乾燥。該溶液於真空中濃縮並以層析純化(2%至8%甲醇溶於二氯甲烷)，生成無色油狀物的((3,4－二氫－2H－苯并[b][1,4]二呯－3－基)甲基)胺。3-Methylene-3,4-dihydro-2H-benzo[b][1,4] 呯 (5.00 g, 30.8 mmol) was dissolved in dry THF (100 mL). Borane-THF (1.0 M in THF, 10.3 mL) was added at 0 °C. The reaction was stirred at RT for 5 hours. Aminosulfonic acid (6.97 g, 61.6 mmol) was added. The reaction was heated to reflux overnight. The reaction was cooled to room temperature and aqueous sodium hydroxide (3.0 M, 100 mL) was then evaporated. The solution was extracted with ethyl acetate (3 x 100 mL). Dried over MgSO ₄ the organic solutions combined. The solution was concentrated in vacuo and purified by chromatography (2% to EtOAc EtOAc) 4] two Ind-3-yl)methyl)amine.

MS(ESI)：180.1(M＋H^＋ )¹ H NMR(300 MHz,DMSO),δ：6.92(m,4H),4.21(m,2H),4.07(m,2H),3.33(廣幅,2H),3.16(d,J ＝4 Hz,1H),2.72(d,J ＝4 Hz,1H),2.30(m,1H)。MS (ESI): 180.1 (M+H ⁺ ) ^: NMR (m.m.) , 3.16 (d, J = 4 Hz, 1H), 2.72 (d, J = 4 Hz, 1H), 2.30 (m, 1H).

使((3,4－二氫－2H－苯并[b][1,4]二呯－3－基)甲基)胺(2.90克，16.2毫莫耳)與磺醯胺(3.11克，32.4毫莫耳)於無水二烷(60毫升)中合併且加熱至迴流過夜。將氯仿加入並以過濾將沈澱物移除。濾液於真空中濃縮並以層析純化(2%至8%丙酮溶於二氯甲烷)，生成米白色固體的標題化合物。Let ((3,4-dihydro-2H-benzo[b][1,4] two Indole-3-yl)methyl)amine (2.90 g, 16.2 mmol) and sulfonamide (3.11 g, 32.4 mmol) in anhydrous The alkane (60 mL) was combined and heated to reflux overnight. Chloroform was added and the precipitate was removed by filtration. The filtrate was concentrated in vacuo and purified EtOAcqqqqqq

258.8(M＋H^＋ )1H NMR(300 MHz,DMSO),δ：6.92(m,4H),6.71(廣幅,1H),6.59(廣幅,2H),4.19(m,2H),4.04(m,2H),3.00(m,2H),2.39(m,1H)。258.8(M+H ⁺ )1H NMR (300 MHz, DMSO), δ: 6.92 (m, 4H), 6.71 (b, 1H), 6.59 (b, 2H), 4.19 (m, 2H), 4.04 (m, 2H), 3.00 (m, 2H), 2.39 (m, 1H).

實施例2Example 2

N－(2,3－二氫－苯并[1,4]二 －2－基甲基)－磺醯胺(化合物#1) N-(2,3-dihydro-benzo[1,4] -2-ylmethyl)-sulfonamide (Compound #1)

使外消旋2,3－二氫－1,4－苯并二－2－基甲胺(4.4克，26毫莫耳)與磺醯胺(5.1克，53毫莫耳)於1,4二烷(100毫升)中合併並迴流2小時。使該反應冷卻至室溫且將少量固體濾出丟棄。濾液於真空中蒸乾且殘餘物係使用快速管柱層析純化(DCM：甲醇－10：1)，生成白色固體。使該固體於DCM再結晶，以生成白色固體的標題化合物。Racemic 2,3-dihydro-1,4-benzoic acid 2-methylmethylamine (4.4 g, 26 mmol) and sulfonamide (5.1 g, 53 mmol) at 1,4 The alkane (100 mL) was combined and refluxed for 2 h. The reaction was allowed to cool to room temperature and a small portion of solid was filtered and evaporated. The filtrate was evaporated to dryness <RTI ID=0.0> The solid was recrystallized from DCM to give the title compound as a white solid.

mp：97.5－98.5℃元素分析：分析計算：C,44.25；H,4.95；N,11.47；S,13.13分析發現：C,44.28；H,4.66；N,11.21；S,13.15 H¹ NMR(DMSO d6)δ 6.85(m,4H),6.68(bd s,3H,NH),4.28(m,2H),3.97(dd,J＝6.9,11.4 Hz,1H),3.20(m,1H),3.10(m,1H).Mp: 97.5-98.5 ° C Elemental analysis: Analytical calculation: C, 44.25; H, 4.95; N, 11.47; S, 13.13 Analysis found: C, 44.28; H, 4.66; N, 11.21; S, 13.15 H ¹ NMR (DMSO D6) δ 6.85 (m, 4H), 6.68 (bd s, 3H, NH), 4.28 (m, 2H), 3.97 (dd, J = 6.9, 11.4 Hz, 1H), 3.20 (m, 1H), 3.10 ( m, 1H).

實施例3Example 3

(苯并[1,3]二 唑－2－基甲基)磺醯胺(化合物#2) (Benzo[1,3] II Zin-2-ylmethyl)sulfonamide (Compound #2)

使兒茶酚(10.26克，93.2毫莫耳)、甲氧化鈉(25重量%溶於甲醇，40.3克，186毫莫耳)及二氯乙酸甲酯(13.3克，93.2毫莫耳)於無水甲醇(100毫升)中合併。將該溶液加熱至迴流過夜。使該反應冷卻至室溫，添加濃鹽酸酸化，然後於真空中使體積減至約50毫升。將水加入並以***(3 x 100毫升)萃取混合物。經合併之有機溶液以MgSO₄ 乾燥、濃縮至棕色固體並以層析(2%乙酸乙酯溶於己烷)生成無色油狀物的苯并[1,3]二唑－2－羧酸甲酯。Catechol (10.26 g, 93.2 mmol), sodium methoxide (25 wt% in methanol, 40.3 g, 186 mmol) and methyl dichloroacetate (13.3 g, 93.2 mmol) in anhydrous Combined in methanol (100 ml). The solution was heated to reflux overnight. The reaction was allowed to cool to room temperature, acidified with concentrated hydrochloric acid and then reduced to a volume of about 50 mL in vacuo. Water was added and the mixture was extracted with diethyl ether (3 x 100 mL). The combined organic solution was dried of MgSO _4, and concentrated to a brown solid and is chromatographed (2% ethyl acetate in hexanes) as a colorless oil generates Benzo [1,3] Methyl azole-2-carboxylate.

MS(ESI)：195.10(M＋H^＋ ).¹ H NMR(300 MHz,CDCl₃ ),δ：6.89(廣幅,4H),6.29(s,1H),4.34(q,J ＝7Hz,2H),1.33(t,J ＝7Hz,3H)。MS (ESI): 195.10 (M+H ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ), δ: 6.89 (b, 4H), 6.29 (s, 1H), 4.34 (q, J = 7 Hz, 2H), 1.33 (t, J = 7 Hz, 3H).

對苯并[1,3]二唑－2－羧酸甲酯(7.21克，40.0毫莫耳)添加氫氧化銨(29%溶於水，10毫升)以及使混合物均質的足量乙腈(~5毫升)。該溶液於室溫下攪拌兩小時，然後將蒸餾水加入。苯并[1,3]二唑－2－羧酸醯胺係沈澱為白色固體並以過濾收集，不經進一步純化即使用。P-benzo[1,3] Methyl oxazol-2-carboxylate (7.21 g, 40.0 mmol) was added with ammonium hydroxide (29% in water, 10 mL) and acetonitrile (~5 mL). The solution was stirred at room temperature for two hours and then distilled water was added. Benzo[1,3] The oxazolidine-2-carboxylic acid amide was precipitated as a white solid which was collected by filtration and used without further purification.

MS(ESI)：160.00(M＋H^＋ )¹ H NMR(300 MHz,DMSO),6：7.99(s,廣幅,1H),7.72(s,廣幅,1H),6.94(m,2H)6.86(m,2H),6.30(s,1H)。MS (ESI): 160.00 (M+H ⁺ ) ¹ H NMR (300 MHz, DMSO), 6: 7.79 (s, wide, 1H), 7.72 (s, wide, 1H), 6.94 (m, 2H) 6.86 ( m, 2H), 6.30 (s, 1H).

將苯并[1,3]二唑－2－羧酸醯胺(5.44克，32.9毫莫耳)溶於四氫呋喃(THF，100毫升)。將鋁氫化鋰(LAH，1M溶於THF，39.5毫升，39.5毫莫耳)於室溫慢慢加至該溶液中。反應於室溫下攪拌24小時。將蒸餾水加入以破壞多餘的LAH。將氫氧化鈉水溶液(3.0 M，100毫升)加入並以乙酸乙酯(3 x 100毫升)萃取該溶液。經合併之有機溶液以水沖洗並以MgSO₄ 乾燥。將該溶劑蒸乾以生成無色油狀物的C－苯并[1,3]二唑－2－基－甲胺。Benzo[1,3] The oxazol-2-carboxylic acid decylamine (5.44 g, 32.9 mmol) was dissolved in tetrahydrofuran (THF, 100 mL). Lithium aluminum hydride (LAH, 1 M in THF, 39.5 mL, 39.5 mmol) was slowly added to the solution at room temperature. The reaction was stirred at room temperature for 24 hours. Distilled water was added to destroy excess LAH. Aqueous sodium hydroxide (3.0 M, 100 mL) was added and the solution was extracted ethyl acetate (3×100 mL). Rinsed with water, and the combined organic solution was dried of MgSO _4. The solvent was evaporated to dryness to give C-benzo[1,3] Zin-2-yl-methylamine.

MS(ESI)：152.1(M＋H^＋ )¹ H NMR(300 MHz,CDCl₃ ),δ：6.87(m,4H),6.09(t,J ＝4 Hz,1H),3.13(d,J ＝4Hz,2H)MS (ESI): 152.1 (M+H ⁺ ) ¹ H NMR (300 MHz, CDCl ₃ ), δ: 6.87 (m, 4H), 6.09 (t, J = 4 Hz, 1H), 3.13 (d, J = 4 Hz, 2H)

使C－苯并[1,3]二唑－2－基－甲胺(2.94克，19.4毫莫耳)與磺醯胺(3.74克，38.9毫莫耳)於無水二烷(50毫升)中合併且將該溶液加熱至迴流過夜。將反應濃縮並將殘餘物層析(2%－10%丙酮溶於二氯甲烷)，生成白色固體的標題化合物。C-benzo[1,3] Zin-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfonamide (3.74 g, 38.9 mmol) in anhydrous The alkane (50 mL) was combined and the solution was heated to reflux overnight. The reaction was concentrated and the residue was crystallised eluted elute

MS(ESI)：230.0(M＋H^＋ )¹ H NMR(300 MHz,CDCl₃ ),δ：6.87(m,4H),6.25(t,J ＝4 Hz,1H),4.79(廣幅,1H),4.62(廣幅,1H),3.64(d,J ＝4 Hz,2H)。MS (ESI): 230.0 (M + H +) 1 H NMR (300 MHz, CDCl 3), δ: 6.87 (m, 4H), 6.25 (t, J = 4 Hz, 1H), 4.79 ( broad web, 1H), 4.62 (wide format, 1H), 3.64 (d, J = 4 Hz, 2H).

實施例4Example 4

(2S)－(－)－N－(2,3 二氫－苯并[1,4]二 －2－基甲基)－磺醯胺(化合物#4) (2S)-(-)-N-(2,3 dihydro-benzo[1,4] -2-ylmethyl)-sulfonamide (Compound #4)

使兒茶酚(13.2克，0.12莫耳)與碳酸鉀(16.6克，0.12莫耳)於DMF(250毫升)中攪拌並添加(2R)－甲苯磺酸縮水甘油酯(22.8克，0.10莫耳)，該反應於60℃下攪拌24小時。使該反應冷卻至室溫，以冰水(1升)稀釋並用***(4次)萃取。經合併之有機溶液以10%碳酸鉀沖洗3次，用水沖洗一次，用食鹽水沖洗一次並於真空中濃縮，生成白色固體，其以快速管柱層析純化(DCM：甲醇－50：1)，生成了固體的((2S)－2,3－二氫－苯并[1,4]二－2－基)－甲醇。Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glysuccinate (22.8 g, 0.10 mol) The reaction was stirred at 60 ° C for 24 hours. The reaction was cooled to rt, diluted with EtOAc (EtOAc) The combined organic solution was washed 3 times with 10% potassium carbonate, washed once with water, washed once with brine and concentrated in vacuo to give a white solid, which was purified by flash column chromatography (DCM:MeOH - 50:1) , which produced a solid ((2S)-2,3-dihydro-benzo[1,4] -2-yl)-methanol.

將該固體(13.3克，68毫莫耳)溶於冷卻至0℃之吡啶(85毫升)中，將對甲苯磺醯氯(13.0克，68毫莫耳)加入，使反應混合物於室溫下攪拌20小時。以***(1升)與1N HCl(1.2升)稀釋該反應。將有機層分離並用1N HCl(500毫升)沖洗2次，用水沖洗4次(150毫升)，用食鹽水沖洗一次，乾燥(MgSO₄ )並於真空中蒸乾，生成白色固體，其以快速管柱層析純化(Hept：EA－2：1)，生成了白色固體的甲苯－4－磺酸(2S)－2,3－二氫－苯并[1,4]二－2－基甲酯。The solid (13.3 g, 68 mmol) was dissolved in pyridine (85 mL) cooled to 0 ° C, then p-toluenesulfonium chloride (13.0 g, 68 mM) was added and the mixture was allowed to react at room temperature Stir for 20 hours. The reaction was diluted with diethyl ether (1 L) and 1N HCl (1.2 L). The organic layer was separated and the (500 mL) washed twice with 1N HCl, washed with water 4 times (150 mL), washed once with brine, dried (MgS04 ₄₎ and evaporated to dryness in vacuo to give a white solid which is flash tube Column chromatography purification (Hept: EA-2:1) gave a white solid toluene-4-sulfonic acid (2S)-2,3-dihydro-benzo[1,4] -2-yl methyl ester.

使該白色固體與鄰苯二甲醯亞胺鉀(14.4克，78毫莫耳)於DMF(250毫升)中合併並加熱至迴流達1小時，冷卻至室溫，並倒進劇烈攪動的水(1.5升)中攪拌30分鐘。將白色固體濾出，將該固體以水、2% NaOH再用水沖洗數次，使其自然風乾，以生成白色粉狀固體的(2S)－2－(2,3－二氫－苯并[1,4]二－2－基甲基)－異吲哚－1,3－二酮。The white solid was combined with potassium phthalimide (14.4 g, 78 mmol) in DMF (250 mL) and heated to reflux for 1 hour, cooled to room temperature and poured into vigorously stirred water. Stir in (1.5 liters) for 30 minutes. The white solid was filtered off, and the solid was washed with water, 2% NaOH and then with water, and then allowed to air dry to give a white powdery solid (2S)-2-(2,3-dihydro-benzo[ 1,4] two -2-ylmethyl)-isoindole-1,3-dione.

使該粉狀白色固體與肼(2.75克，86毫莫耳)於EtOH(225毫升)中合併並以迴流加熱2小時，冷卻至室溫，添加1N HCl至pH 1.0並攪拌15分鐘。將白色固體濾出並以新鮮EtOH沖洗(將固體丟棄)，使濾液於真空中濃縮成固體，使該固體分配於***與稀NaOH水溶液之間。將***溶液乾燥(Na₂ SO₄ )並於真空中濃縮，以生成淡黃色油狀物。該油狀物以快速管柱層析純化(DCM：MeOH－10：1)，生成一油狀物。溶於2－丙醇(250毫升)的一部分油狀物(4.82克，29毫莫耳)以1N HCl(30毫升)處理並在汽浴上加熱直到均質為止，然後使其冷卻至室溫。3小時後，用冰使混合物冷卻2小時。將白色片狀固體((2S)－C－(2,3－二氫－苯并[1,4]二－2－基)－甲胺的對應HCl鹽)過濾取出，然後以2－丙醇再次再結晶，生成白色固體。The pulverulent white solid was combined with EtOAc (EtOAc: EtOAc (EtOAc). The white solid was filtered and washed with EtOAc (EtOAc). The ether solution was dried (Na ₂ SO ₄₎ and concentrated in vacuo to yield a pale yellow oil. The oil was purified by flash column chromatography (DCM: MeOH-10:1) A portion of the oil (4.82 g, 29 mmol) dissolved in 2-propanol (250 mL) was taken in 1N HCl (30 mL) After 3 hours, the mixture was cooled with ice for 2 hours. White flake solid ((2S)-C-(2,3-dihydro-benzo[1,4]) The corresponding HCl salt of 2-yl)-methylamine was removed by filtration and then recrystallized from 2-propanol to give a white solid.

[α]_D ＝－69.6(c＝1.06,EtOH)[α] _D =-69.6 (c=1.06, EtOH)

使該白色固體分配於DCM與稀NaOH之間，將DCM乾燥(NaSO₄ )並於真空中濃縮，以生成油狀物的(2S)－C－(2,3－二氫－苯并[1,4]二－2－基)－甲胺。The white solid was partitioned between DCM and dilute NaOH, the DCM was dried (NaSO ₄₎ and concentrated in vacuo to yield an oil of (2S) -C- (2,3- dihydro - benzo [1 , 4] two 2-yl)-methylamine.

[α]_D ＝－57.8(c＝1.40_, CHCl₃ )[α] _D = -57.8 (c = 1.40 _, CHCl ₃ )

使該油狀物(2.1克，12.7毫莫耳)與磺醯胺(2.44克，25.4毫莫耳)於二烷(75毫升)中迴流2小時，粗產物以快速管柱層析純化(DCM：MeOH 10：1)，生成白色固體，其以DCM再結晶，生成白色結晶固體的標題化合物。The oil (2.1 g, 12.7 mmol) and sulfonamide (2.44 g, 25.4 mmol) were The title compound was obtained as a white crystals crystals crystals.

mp 102－103℃[α]_D ＝－45.1°(c＝1.05,M)；¹ H NMR(DMSOd6)δ 6.86(m,4H),6.81(bd s,3H,NH),4.3(m,2H),3.97(dd,J＝6.9,11.4 Hz,1H),3.20(dd,J＝5.5,13.7 Hz,1H),3.10(dd,J＝6.9,13.7Hz.1H)元素分析：分析計算：C,44.25；H,4.95；N,11.47；S,13.13分析發現：C,44.20；H,4.69；N,11.40；S,13.22。Mp 102-103 ° C [α] _D = -45.1 ° (c = 1.05, M); ¹ H NMR (DMSOd6) δ 6.86 (m, 4H), 6.81 (bd s, 3H, NH), 4.3 (m, 2H) ), 3.97 (dd, J=6.9, 11.4 Hz, 1H), 3.20 (dd, J=5.5, 13.7 Hz, 1H), 3.10 (dd, J=6.9, 13.7 Hz.1H) Elemental analysis: analytical calculation: C , 44.25; H, 4.95; N, 11.47; S, 13.13 analysis found: C, 44.20; H, 4.69; N, 11.40; S, 13.22.

實施例5Example 5

N－(2,3－二氫－苯并[1,4]二 －2－基甲基)－N',N’二甲基磺醯胺(化合物#6) N-(2,3-dihydro-benzo[1,4] -2-ylmethyl)-N',N'dimethylsulfonamide (Compound #6)

使外消旋2,3－二氫－1,4－苯并二－2－基甲胺(8.25克，5.0毫莫耳)與三乙胺(1.52克，15毫莫耳)於DMF(10毫升)中合併，且在添加二甲基胺磺醯氯(1.44克，10毫莫耳)的同時於冰浴中冷卻。使反應混合物於持續冷卻下攪拌3小時。使該反應混合物分配於乙酸乙酯與水之間，乙酸乙酯溶液以食鹽水沖洗，乾燥(MgSO₄ )並於真空中濃縮以生成一油狀物。該油狀物係使用快速管柱層析純化(乙酸乙酯：庚烷－1：1)，生成白色固體，該固體經過再結晶(乙酸乙酯/己烷)，生成了白色棉絮狀固體的標題化合物。Racemic 2,3-dihydro-1,4-benzoic acid 2-Methylmethylamine (8.25 g, 5.0 mmol) combined with triethylamine (1.52 g, 15 mmol) in DMF (10 mL) with dimethylamine sulfonium chloride (1.44 g) , 10 millimoles) while cooling in an ice bath. The reaction mixture was stirred for 3 hours under continuous cooling. The reaction mixture was partitioned between ethyl acetate and water, the ethyl acetate solution to brine, dried (MgSO ₄₎ and concentrated to yield an oil in vacuo. The oil was purified by flash column chromatography (ethyl acetate: heptane - 1:1) to afford a white solid. Title compound.

mp 76－78℃ MS 273(MH^＋ )元素分析：分析計算：C,48.52；H,5.92；N,10.29；S,11.78分析發現：C,48.63；H,5.62；N,10.20；S,11.90¹ H NMR(CDCl₃ )δ 6.87(m,4H),4.59(bd m,1H,NH),4.35(m,1H),4.27(dd,J＝2.3,11.4 Hz,1H),4.04(dd,J＝7.0,11.4,1H),3.36(m,2H),2.82(s,6H).Mp 76-78 ° C MS 273 (MH ⁺ ) Elemental analysis: C, 48.52; H, 5.92; N, 10.29; S, 11.78 Analysis found: C, 48.63; H, 5.62; N, 10.20; S, 11.90 ¹ H NMR (CDCl ₃ ) δ 6.87 (m, 4H), 4.59 (bd m, 1H, NH), 4.35 (m, 1H), 4.27 (dd, J = 2.3, 11.4 Hz, 1H), 4.04 (dd, J=7.0, 11.4, 1H), 3.36 (m, 2H), 2.82 (s, 6H).

實施例6Example 6

N－(2,3－二氫－苯并[1,4]二 －2－基甲基)－N－甲基磺醯胺(化合物#7) N-(2,3-dihydro-benzo[1,4] -2-ylmethyl)-N-methylsulfonamide (Compound #7)

將外消旋2,3－二氫－1,4－苯并二－2－基甲胺(825毫克，5毫莫耳)溶於甲酸乙酯(15毫升)中，迴流30分鐘並於真空中濃縮，生成油狀物的N－(2,3－二氫－苯并[1,4]二－2－基甲基)－甲醯胺。Racemic 2,3-dihydro-1,4-benzoic 2-Methylmethylamine (825 mg, 5 mmol) was dissolved in ethyl acetate (15 mL). Benzo[1,4] -2-ylmethyl)-carbenamide.

於0℃以溶於THF的1M LAH(9.0毫升，9.0毫莫耳)處理溶於***(25毫升)的油狀物，並於室溫下攪拌5小時。使該反應於冰浴中冷卻並以水(0.50毫升)淬熄，接著以3 N NaOH(0.50毫升)與水(0.50毫升)淬熄。然後使該混合物於室溫下攪拌1小時。將固體濾出，濾液於真空中濃縮，生成一殘餘物，使其分配於1N HCl與***之間。水相以1N NaOH鹼化並以***萃取。將有機相乾燥(MgSO₄ )並於真空中濃縮，以生成油狀物的(2,3－二氫－苯并[1,4]二－2－基甲基)－甲胺。The oil was dissolved in diethyl ether (25 mL) EtOAc (EtOAc) The reaction was quenched in an ice-bath and quenched with water (0.50 mL). The mixture was then stirred at room temperature for 1 hour. The solid was filtered, and the residue was crystallisjjjjjjjj The aqueous phase was basified with 1N NaOH and extracted with diethyl ether. The organic phase was dried (MgSO ₄₎ and concentrated in vacuo to yield an oil (2,3-dihydro - benzo [1,4] -2-ylmethyl)-methylamine.

MS 180(MH^＋ )¹ H NMR(CDCl₃ )δ 6.85(m,4H),4.30(m,2H),4.02(dd,J＝7.9,11.6 Hz,1H),2.85(m,2H),2.50(s,3H)MS 180 (MH ⁺ ) ¹ H NMR (CDCl ₃ ) δ 6.85 (m, 4H), 4.30 (m, 2H), 4.02 (dd, J = 7.9, 11.6 Hz, 1H), 2.85 (m, 2H), 2.50 (s, 3H)

使該油狀物(380毫克，2.1毫莫耳)與磺醯胺(820毫克，8.5毫莫耳)於二烷(15毫升)中合併，迴流1.5小時並於真空中濃縮，以生成粗製殘餘物。該殘餘物係藉快速管柱層析純化(乙酸乙酯/庚烷1：1)且所得固體以乙酸乙酯/己烷再結晶，以生成白色固體的標題化合物。The oil (380 mg, 2.1 mmol) and sulfonamide (820 mg, 8.5 mmol) in two The combined was taken up in EtOAc (15 mL). The residue was purified by flash column chromatography eluting elut elut elut elut elut

mp 97－98℃ MS 257(M^－1 )元素分析：分析計算：C,46.50；H,5.46；N,10.85；S,12.41分析發現：C,46.48；H,5.65；N,10.90；S,12.07¹ H NMR(CDCl₃ )δ 6.86(m,4H),4.52(bs,2H),4.46(m,1H),4.29(dd,J＝2.3,11.5 Hz,1H),4.05(dd,J＝6.5,11.5 Hz,1H),3.51(dd,J＝6.7,14.9 Hz,1H),3.40(dd,J＝5.9,14.9 Hz,1H),2.99(s,3H).Mp 97-98 ° C MS 257 (M ^-1 ) Elemental analysis: C, 46.50; H, 5.46; N, 10.85; S, 12.41 Analysis found: C, 46.48; H, 5.65; N, 10.90; 12.07 ¹ H NMR (CDCl ₃ ) δ 6.86 (m, 4H), 4.52 (bs, 2H), 4.46 (m, 1H), 4.29 (dd, J = 2.3, 11.5 Hz, 1H), 4.05 (dd, J = 6.5, 11.5 Hz, 1H), 3.51 (dd, J = 6.7, 14.9 Hz, 1H), 3.40 (dd, J = 5.9, 14.9 Hz, 1H), 2.99 (s, 3H).

實施例7Example 7

(2S)－(－)－N－(6－氯基－2,3－二氫－苯并[1,4]二 －2－基甲基)－磺醯胺(化合物#8) (2S)-(-)-N-(6-Chloro-2,3-dihydro-benzo[1,4] -2-ylmethyl)-sulfonamide (Compound #8)

照著上面實施例4概示的流程，4－氯基兒茶酚係反應生成(2S)－C－(7－氯基－2,3－二氫－苯并[1,4]二－2－基)－甲胺與(2S)－C－(6－氯基－2,3－二氫－苯并[1,4]二－2－基)－甲胺的混合物(由RP HPLC得知6－氯基：7－氯基異構物約呈3：1比例)。According to the procedure outlined in Example 4 above, 4-chloro catechol reacts to form (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4] -2-yl)-methylamine and (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4] A mixture of 2-yl)-methylamine (6-chloro group: 7-chloro isomer is about 3:1 ratio by RP HPLC).

將該混合物溶於2－丙醇(100毫升)中並添加溶於***的1N HCl直到達到pH＝1.0。將沈澱的氫氯酸鹽濾出(2.65克)並以甲醇/IPA再結晶，生成白色晶體。使該白色晶體分配於DCM與稀NaOH之間。DCM被乾燥並於真空中濃縮，以生成油狀物的經純化(2S)－C－(6－氯基－2,3－二氫－苯并[1,4]二－2－基)－甲胺。The mixture was dissolved in 2-propanol (100 mL) and 1N HCl in diethyl ether was added until pH = 1.0 was obtained. The precipitated hydrochloride was filtered off (2.65 g) and recrystallized from methanol/IPA to yield white crystals. The white crystals were partitioned between DCM and dilute NaOH. The DCM was dried and concentrated in vacuo to give a purified (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4] 2-yl)-methylamine.

[α]_D ＝－67.8(c＝1.51,CHCl₃ )[α] _D = -67.8 (c = 1.51, CHCl ₃ )

使該油狀物(7.75毫莫耳)與磺醯胺(1.50克，15.5毫莫耳)於二烷(50毫升)中合併並迴流2.0小時，冷卻至室溫並於真空中濃縮，以生成一固體。該產物係使用DCM/甲醇20：1經由快速管柱層析純化，以生成如同白色固體的標題化合物。The oil (7.75 mmol) and sulfonamide (1.50 g, 15.5 mmol) were The combined organics were combined with EtOAc (EtOAc)EtOAc. The product was purified by flash column chromatography eluting with EtOAc EtOAc

MS 277(M^－1 )[α]_D ＝－59.9°(c＝1.11,M)¹ H NMR(CDCl₃ )δ 6.90(d,J＝2.2 Hz,1H),6.81(m,2H),4.76(m,1H),4.55(s,2H),4.40(m,1H),4.29(dd,J＝2.4,11.5 Hz,1H),4.05(dd,J＝7.1,11.5 Hz,1H),3.45(m,2H)元素分析：分析計算：C,38.78；H,3.98；N,10.05分析發現：C,38.80；H,3.67；N,9.99.MS 277(M ^-1 )[α] _D = -59.9° (c = 1.11, M) ¹ H NMR (CDCl ₃ ) δ 6.90 (d, J = 2.2 Hz, 1H), 6.81 (m, 2H), 4.76 (m, 1H), 4.55 (s, 2H), 4.40 (m, 1H), 4.29 (dd, J = 2.4, 11.5 Hz, 1H), 4.05 (dd, J = 7.1, 11.5 Hz, 1H), 3.45 ( m, 2H) Elemental analysis: analytical calculation: C, 38.78; H, 3.98; N, 10.05 analysis found: C, 38.80; H, 3.67; N, 9.99.

將以上製備之(2S)－C－(6－氯基－2,3－二氫－苯并[1,4]二－2－基)－甲胺的結晶氫氯酸鹽的濾液回收(6－氯基：7－氯基異構物約1：1)並於真空中濃縮，以生成一固體，使其分配於DCM(200毫升)與稀NaOH(0.5 M，50毫升)之間。DCM溶液以食鹽水沖洗一次，乾燥(Na₂ SO4)並於真空中濃縮，生成一油狀物，其藉由逆相HPLC(具0.16% TFA之10－50% ACN於具0.20% TFA的水)純化，以生成(2S)－C－(7－氯基－2,3－二氫－苯并[1,4]二－2－基)－甲胺殘餘物。(2S)-C-(6-Chloro-2,3-dihydro-benzo[1,4] The filtrate of the crystalline hydrochloride salt of 2-yl)-methylamine was recovered (6-chloro group: 7-chloro isomer about 1:1) and concentrated in vacuo to give a solid which was partitioned. Between DCM (200 mL) and dilute NaOH (0.5 M, 50 mL). DCM was rinsed with brine once, dried (Na ₂ SO4) and concentrated in vacuo to produce an oil, which by reverse phase HPLC (with 0.16% TFA in the 10-50% ACN with 0.20% TFA water Purification to produce (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4] 2-yl)-methylamine residue.

使該殘餘物與磺醯胺(0.90克，9.4毫莫耳)於二烷(25毫升)中合併並迴流2.5小時，冷卻至室溫並於真空中濃縮，生成一油狀物。該油狀物係使用DCM/甲醇－10：1以快速管柱層析純化，生成白色固體的(2S)－(－)－N－(7－氯基－2,3－二氫－苯并[1,4]二－2－基甲基)－磺醯胺。The residue was combined with sulfonamide (0.90 g, 9.4 mmol) The mixture was combined with EtOAc (EtOAc)EtOAc. The oil was purified by flash column chromatography using DCM/MeOH-10:1 to yield (2S)-(-)-N-(7-chloro-2,3-dihydro-benzo) as a white solid. [1,4] two -2-ylmethyl)-sulfonamide.

MS 277(M^－1 )¹ H NMR(CDCl₃ /CD₃ OD)δ 6.88(d,J＝0.7 Hz,1H),6.81(m,2H),4.37(m,1H),4.30(dd,J＝2.3,11.6 Hz,1H),4.04(dd,J＝7.0,11.6 Hz,1H),3.38(m,2H).MS 277(M ^-1 ) ¹ H NMR (CDCl ₃ /CD ₃ OD) δ 6.88 (d, J = 0.7 Hz, 1H), 6.81 (m, 2H), 4.37 (m, 1H), 4.30 (dd, J =2.3, 11.6 Hz, 1H), 4.04 (dd, J=7.0, 11.6 Hz, 1H), 3.38 (m, 2H).

實施例8Example 8

唍－2－基甲基磺醯胺(化合物#10) Indole-2-ylmethylsulfonamide (Compound #10)

使唍－2－羧酸(4.5克，25毫莫耳)與HOBT(3.86克，25毫莫耳)於DCM(40毫升)與DMF(10毫升)中合併。Make Indole-2-carboxylic acid (4.5 g, 25 mmol) was combined with HOBT (3.86 g, 25 mmol) in DCM (40 mL) and DMF (10 mL).

於室溫將二甲基胺丙基乙基碳二亞胺(EDC，4.84克，25毫莫耳)加入，使反應混合物攪拌30分鐘。將氫氧化銨(2.26毫升，33.4毫莫耳)加入，使反應混合物攪拌16小時。該反應混合物以DCM(50毫升)與水(50毫升)稀釋且用1N HCl將混合物pH調整至約pH＝3.0。Dimethylaminopropylethylcarbodiimide (EDC, 4.84 g, 25 mmol) was added at rt and the reaction mixture was stirred 30 min. Ammonium hydroxide (2.26 mL, 33.4 mmol) was added and the mixture was stirred 16 hr. The reaction mixture was diluted with DCM (50 mL) and water (50 mL) and the mixture was adjusted to pH about 3.0 with 1N HCl.

將DCM分開，水相以DCM萃取兩次。將合併之DCM相乾燥(Na₂ SO₄ )並於真空中濃縮，生成一油狀物，其以快速管柱層析純化(乙酸乙酯)，生成一油狀物。The DCM was separated and the aqueous phase was extracted twice with DCM. The combined DCM phase was dried (Na ₂ SO ₄₎ and concentrated in vacuo to produce an oil, which was purified by flash column chromatography (ethyl acetate) to generate an oil.

使溶於THF(90毫升)的油狀物(5.35克，30毫莫耳)於添加溶於THF(36毫升，36毫莫耳)之1M LAH的同時攪拌，使反應混合物於室溫再攪拌20小時。該反應以水淬熄，攪拌2小時，將該溶液輕輕倒出、乾燥(Na₂ SO₄ )並於真空中濃縮，以生成油狀胺的C－唍－2－基－甲胺。An oil (5.35 g, 30 mmol) dissolved in THF (90 mL) was stirred with EtOAc (EtOAc &lt 20 hours. The reaction was quenched with water, stirred for 2 hours, the solution decanted, dried (Na ₂ SO ₄₎ and concentrated in vacuo to yield an oil-amine C- Ind-2-yl-methylamine.

使油狀胺(1.63克，10毫莫耳)與磺醯胺(1.92克，20毫莫耳)於二烷(50毫升)中合併並迴流2小時。使該溶液冷卻並於真空中濃縮，生成一油狀物，其藉快速管柱層析純化(DCM：甲醇。10：1)，生成白色固體。該固體以乙酸乙酯/己烷再結晶，生成白色固體的唍㊣－2－基甲基磺醯胺。An oily amine (1.63 g, 10 mmol) with sulfonamide (1.92 g, 20 mmol) in two The mixture was combined and refluxed for 2 hours in hexanes (50 mL). The solution was cooled and concentrated in vacuo to give crystals crystals eluted eluting The solid was recrystallized from ethyl acetate / hexane to give a white solid. Indole-2-ylmethylsulfonamide.

mp 100－101℃ MS 241(M^－1 )元素分析：分析計算：C,49.57；H,5.82；N,11.56；S,13.23分析發現：C,49.57；H,5.80；N,11.75；S,13.33.Mp 100-101 ° C MS 241 (M ^-1 ) Elemental analysis: C, 49.57; H, 5.82; N, 11.56; S, 13.23 Analysis found: C, 49.57; H, 5.80; N, 11.75; 13.33.

實施例9Example 9

2－(2,3－二氫－苯并[1,4]二 －2－基)－乙基磺醯胺(化合物#16) 2-(2,3-dihydro-benzo[1,4]di -2-yl)-ethylsulfonamide (compound #16)

將氰化鉀(2.05克，31.5毫莫耳)加至溶於DMSO(90毫升)的2－溴基甲基－(2,3 二氫苯并[1,4]二)(6.87克，30毫莫耳)中並於周遭溫度攪拌20小時。反應混合物稍後以水(250毫升)稀釋並以***萃取兩次。該***以水沖洗一次，然後以食鹽水沖洗兩次，乾燥(Na₂ SO₄ )並於真空中濃縮，以生成白色固體的2－氰基甲基－(2,3 二氫苯并[1,4]二)。Potassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl-(2,3 dihydrobenzo[1,4] in DMSO (90 mL) (6.87 g, 30 mmol) and stirred at ambient temperature for 20 hours. The reaction mixture was later diluted with water (250 mL) and extracted twice with diethyl ether. The ether rinse with water, then washed twice with salt water, dried (Na ₂ SO ₄₎ and concentrated in vacuo to yield a white solid of methyl 2-cyano - (2,3-dihydrobenzo [1 , 4] two ).

¹ H NMR(CDCl₃ )δ 6.89(m,4H),4.50(m,1H),4.31(dd,J＝2.3,11.5 Hz,1H),4.08(dd,J＝6.2,11.6 Hz,1H),2.78(d,J＝6.1,Hz,2H) ¹ H NMR (CDCl ₃ ) δ 6.89 (m, 4H), 4.50 (m, 1H), 4.31 (dd, J = 2.3, 11.5 Hz, 1H), 4.08 (dd, J = 6.2, 11.6 Hz, 1H), 2.78 (d, J = 6.1, Hz, 2H)

將2－氰基甲基－(2,3 二氫苯并[1,4]二)溶於THF(50毫升)中並將溶於THF(80毫升，80毫莫耳)的1M BH₃ 加入，使反應混合物迴流5小時，然後於周遭溫度攪拌16小時。以冰浴冷卻，同時將2N HCl加入直到達到pH＝1.0。然後使反應混合物於室溫攪拌1小時並於真空中濃縮，以生成油狀物。使該油狀物分配於3N NaOH與***之間，***溶液以食鹽水沖洗，乾燥(Na₂ SO₄ )並於真空中濃縮，以生成粗製2－(2,3 二氫苯并[1,4]二－2－基)乙胺。2-cyanomethyl-(2,3 dihydrobenzo[1,4] ) Was dissolved in THF (50 ml) and was dissolved in of THF (80 mL, 80 mmol) was added a 1M BH _3, the reaction mixture was refluxed for 5 hours, then stirred at ambient temperature for 16 hours. It was cooled in an ice bath while 2N HCl was added until pH = 1.0 was reached. The reaction mixture was then stirred at room temperature for 1 h and concentrated in vacuo to give an oil. The oil was partitioned between 3N NaOH and diethyl ether, the ether solution to brine, dried (Na ₂ SO ₄₎ and concentrated in vacuo to yield crude 2- (2,3 dihydrobenzo [1, 4] two -2-yl)ethylamine.

MS(M＋H)^＋ 180.MS (M+H) ⁺ 180.

使溶於二烷(100毫升)之粗製2－(2,3 二氫苯并[1,4]二－2－基)乙胺與磺醯胺(3.0克，31毫莫耳)合併並加熱至迴流達2小時。使該溶液冷卻並於真空中濃縮，生成橙色固體，其以管柱層析純化(DCM：MeOH－10：1)，生成白色固體。該固體以DCM再結晶，生成了固體的標題化合物。Dissolve in two Alkane (100 ml) of crude 2-(2,3 dihydrobenzo[1,4] 2-yl)ethylamine was combined with sulfonamide (3.0 g, 31 mmol) and heated to reflux for 2 hours. The solution was cooled and concentrated in vacuo to give a crystallite crystallite. The solid was recrystallized from DCM to give the title compound.

MS(M^－1 )257 MP 101－103℃(corr)¹ H NMR(CDCl₃ )：δ 6.86(m,4H),4.70(m,1H),4.52(s,2H),4.30(m,2H),3.94(dd,J＝7.4,11.3 Hz,1H),3.43(dd,J＝6.4,12.9 Hz,2H),1.94(dd,J＝6.5,12.9,2H).元素分析：測量：C,46.48；H,5.60；N,10.81；S,12.41計算：C,46.50；H,5.46；N,10.85；S,12.41MS (M ^-1 ) 257 MP 101-103 ° C (corr) ¹ H NMR (CDCl ₃ ): δ 6.86 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 4.30 (m, 2H) ), 3.94 (dd, J = 7.4, 11.3 Hz, 1H), 3.43 (dd, J = 6.4, 12.9 Hz, 2H), 1.94 (dd, J = 6.5, 12.9, 2H). Elemental analysis: Measurement: C, 46.48; H, 5.60; N, 10.81; S, 12.41 Calculation: C, 46.50; H, 5.46; N, 10.85; S, 12.41

實施例10Example 10

(2S)－(－)－N－(6,7 二氯基－2,3－二氫－苯并[1,4]二 －2－基甲基)－磺醯胺(化合物#29) (2S)-(-)-N-(6,7-dichloro-2,3-dihydro-benzo[1,4] -2-ylmethyl)-sulfonamide (Compound #29)

使4,5 二氯基兒茶酚(8.6克，48毫莫耳)與碳酸鉀(6.64克，48毫莫耳)於DMF(200毫升)中攪拌。將(2R)－甲苯磺酸縮水甘油酯(9.12克，40毫莫耳)加入並使反應混合物於60℃攪拌24小時。使反應混合物冷卻至室溫，然後以冰水(600毫升)稀釋並以***萃取(4次)。經合併之有機溶液以10%碳酸鉀沖洗3次，以食鹽水沖洗兩次，乾燥(MgSO₄ )並於真空中濃縮，以生成(2S)－2－(6,7－二氯基－2,3－二氫－苯并[1,4]二)甲醇黏稠油狀物。4,5-Dichlorocatechol (8.6 g, 48 mmol) was stirred with potassium carbonate (6.64 g, 48 mmol) in DMF (200 mL). (2R)-glycidyl sulfonate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 ° C for 24 hours. The reaction mixture was cooled to rt then diluted with EtOAc (EtOAc) The combined organic solution was flushed 3 times with 10% potassium carbonate, washed twice in saline, dried (MgSO ₄₎ and concentrated in vacuo to yield (2S) -2- (6,7- dichloro-2 ,3-dihydro-benzo[1,4] ) Methanol viscous oil.

將(2S)－2－(6,7 二氯基－2,3－二氫－苯并[1,4]二)甲醇油狀物(6.4克，27毫莫耳)溶於冷卻至0℃的吡啶(50毫升)中。然後，將對甲苯磺醯氯(5.2克，27毫莫耳)加入，使反應混合物於室溫下攪拌20小時。以***與1N HCl(750毫升)稀釋反應混合物，將有機層分離並用1N HCl(250毫升)沖洗2次，用水(150毫升)沖洗一次，用食鹽水沖洗兩次，乾燥(MgSO₄ )並於真空中濃縮，以生成甲苯－4－磺酸(2S)－6,7－二氯基－2,3－二氫－苯并[1,4]二－2－基甲酯淡黃色固體。(2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4] A methanolic oil (6.4 g, 27 mmol) was dissolved in pyridine (50 mL) cooled to 0. Then, p-toluenesulfonium chloride (5.2 g, 27 mmol) was added, and the reaction mixture was stirred at room temperature for 20 hr. Diluted with diethyl ether and 1N HCl (750 ml) and the reaction mixture, the separated organic layer (250 ml), washed twice with 1N HCl, washed with water (150 ml), washed once, washed twice with brine, dried (MgSO ₄₎ and in Concentrate in vacuo to form toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4] -2-ylmethyl ester pale yellow solid.

¹ H NMR(CDCl₃ )：δ 7.79(d,J＝8.3 Hz,2H),7.36(d,J＝8.0 Hz,2H),6.94(s,1H),6.83(s,1H),4.37(m,1H),4.2(m,3H),4.03(dd,J＝6.3,11.7 Hz,1H),2,47(s,3H). ¹ H NMR (CDCl ₃ ): δ 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 6.83 (s, 1H), 4.37 (m) , 1H), 4.2 (m, 3H), 4.03 (dd, J = 6.3, 11.7 Hz, 1H), 2, 47 (s, 3H).

使甲苯－4－磺酸(2S)－6,7－二氯基－2,3－二氫－苯并[1,4]二－2－基甲酯(8.0克，20.5毫莫耳)與鄰苯二甲醯亞胺鉀(6.1克，33毫莫耳)於DMF(75毫升)中合併並加熱至迴流達1小時，冷卻至室溫，並倒進劇烈攪動的水(0.5升)中，然後攪拌30分鐘。將白色固體濾出，將該固體以水、2% NaOH再用水沖洗數次，然後使其自然風乾，以生成白色粉狀固體的(2S)－2－(6,7－二氯基－2,3－二氫－苯并[1,4]二－2－基甲基)－異吲哚－1,3－二酮(6.0克，80%)。Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4] 2-methylmethyl ester (8.0 g, 20.5 mmol) and potassium phthalimide (6.1 g, 33 mmol) were combined in DMF (75 mL) and heated to reflux for 1 hour, cooled At room temperature, pour into vigorously stirred water (0.5 L) and stir for 30 minutes. The white solid was filtered off, and the solid was washed with water, 2% NaOH and then with water, and then allowed to air dry to give (2S)-2-(6,7-dichloro-2) as a white powdery solid. ,3-dihydro-benzo[1,4] -2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%).

使該粉狀白色固體與肼(1.06克，33毫莫耳)於EtOH(80毫升)中合併並以迴流加熱2小時，然後冷卻至室溫。加入1N HCl將反應混合物的pH調整成pH 1.0，然後讓反應混合物攪拌15分鐘。將白色固體濾出並以新鮮EtOH沖洗(將固體丟棄)，使濾液於真空中濃縮成固體，使該固體分配於***與稀NaOH水溶液之間。將***溶液乾燥(Na₂ SO₄ )並於真空中濃縮，以生成(2S)－2－胺基甲基－(6,7－二氯基－2,3－二氫－苯并[1,4]二)黏稠油狀物。The powdery white solid was combined with EtOAc (EtOAc m. The pH of the reaction mixture was adjusted to pH 1.0 by the addition of 1N HCl, and then the mixture was stirred for 15 min. The white solid was filtered and washed with EtOAc (EtOAc). The ether solution was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give (2S)-2-aminomethyl-(6,7-dichloro-2,3-dihydro-benzo[1, 4] two ) Viscous oil.

¹ H NMR(CDCl₃ )：δ 6.98(s,1H),6.96(s,1H),4.25(dd,J＝2.0,11.2 Hz,1H),4.15(m,1H),4.0(m,1H),2.97(d,J＝5.5 Hz,2H) ¹ H NMR (CDCl ₃ ): δ 6.98 (s, 1H), 6.96 (s, 1H), 4.25 (dd, J = 2.0, 11.2 Hz, 1H), 4.15 (m, 1H), 4.0 (m, 1H) , 2.97 (d, J = 5.5 Hz, 2H)

一部分油狀物(3.8克，16毫莫耳)與磺醯胺(3.1克，32.4毫莫耳)係於二烷(100毫升)中迴流2小時且粗產物以快速管柱層析純化(DCM：MeOH 20：1)，生成白色固體的標題化合物，其以乙酸乙酯/己烷再結晶，生成如同白色結晶固體的標題化合物。A portion of the oil (3.8 g, 16 mmol) and sulfonamide (3.1 g, 32.4 mmol) are attached to This was refluxed for 2 hours in EtOAc (EtOAc (EtOAc)MeOHMeOHMeOH The title compound of the solid.

MS[M－H]^－ 311.0 mp 119－121℃[α]_D ＝－53.4°(c＝1.17,M)¹ H NMR(DMSOd6)：δ 7.22(s,1H),7.20(s,1H),6.91(bd s,1H),6.68(bd s,2H),4.35(m,2H),4.05(dd,J＝6.5,11.5 Hz,1H),3.15(m,2H)元素分析：元素分析：測量：C,34.52；H,3.22；N,8.95；Cl,22.64；S,10.24計算：C,34.64；H,2.68；N,8.87；Cl,22.94；S,10.35。MS[M-H] ^- 311.0 mp 119-121 ° C [α] _D = -53.4 (c = 1.17, M) ¹ H NMR (DMSOd6): δ 7.22 (s, 1H), 7.20 (s, 1H), 6.91 (bd s, 1H), 6.68 (bd s, 2H), 4.35 (m, 2H), 4.05 (dd, J = 6.5, 11.5 Hz, 1H), 3.15 (m, 2H) Elemental Analysis: Elemental Analysis: Measurement : C, 34.52; H, 3.22; N, 8.95; Cl, 22.64; S, 10.24 Calculated: C, 34.64; H, 2.68; N, 8.87; Cl, 22.94; S, 10.35.

實施例11Example 11

(2S)－(－)－N－(7－胺基－2,3－二氫－苯并[1,4]二 －2－基甲基)－磺醯胺(化合物#36) (2S)-(-)-N-(7-Amino-2,3-dihydro-benzo[1,4] -2-ylmethyl)-sulfonamide (compound #36)

(2S)－(－)－N－(2,3－二氫－7－硝基－苯并[1,4]二－2－基甲基)－磺醯胺(1.2克，4.15毫莫耳)係根據實施例4概示的過程從4－硝基兒茶酚製備。然後使該(2S)－(－)－N－(2,3－二氫－7－硝基－苯并[1,4]二－2－基甲基)－磺醯胺與10% Pd/C於甲醇(120毫升)中合併並於氫氣氛(39 psi)中、室溫下搖晃3小時。將固體過濾並以溶於DCM之10% M沖洗，濾液於真空中濃縮以生成粗產物。將粗產物溶於0.2 N HCl(25毫升)、冷凍並冷凍乾燥，以生成白色片狀固體、為對應氫氯酸鹽的標題化合物。(2S)-(-)-N-(2,3-dihydro-7-nitro-benzo[1,4] 2-Methylmethyl)-sulfonamide (1.2 g, 4.15 mmol) was prepared from 4-nitrocatechol according to the procedure outlined in Example 4. Then the (2S)-(-)-N-(2,3-dihydro-7-nitro-benzo[1,4] The -2-ylmethyl)-sulphonamide was combined with 10% Pd/C in methanol (120 mL) and shaken in a hydrogen atmosphere (39 psi) at room temperature for 3 hours. The solid was filtered and washed with 10% EtOAc EtOAc. The crude product was dissolved in EtOAc (EtOAc) (EtOAc)

MS(M＋H)^＋ 260¹ H NMR(DMSO d6)：δ 10.2(bd s,3H),6.86(m,1H),6.85(s,1H),6.74(dd,J＝2.5,8.4 Hz,1H),4.22(m,2H),3.88(dd,J＝6.7,11.4 Hz,1H),3.04(m,2H) ^{MS (M + H) + 260} 1 H NMR (DMSO d6): δ 10.2 (bd s, 3H), 6.86 (m, 1H), 6.85 (s, 1H), 6.74 (dd, J = 2.5,8.4 Hz, 1H) , 4.22 (m, 2H), 3.88 (dd, J = 6.7, 11.4 Hz, 1H), 3.04 (m, 2H)

實施例12Example 12

(2S)－(－)－N－(7－甲基－2,3－二氫－苯并[1,4]二 －2－基甲基)－磺醯胺(化合物#19) (2S)-(-)-N-(7-methyl-2,3-dihydro-benzo[1,4] -2-ylmethyl)-sulfonamide (Compound #19)

標題化合物係根據上文實施例4所述流程以4－甲基兒茶酚開始製備，生成白色固體，其以乙酸乙酯/己烷再結晶，生成如白色固體的標題化合物。The title compound was prepared as a white solid.

MS[M－H]^－ 257¹ H NMR(CDCl₃ )：δ 6.76(m,1H),6.66(m,2H),4.80(m,1H),4.57(bd s,1H),4.40(m,1H),4.28(m,1H),4.03(dd,J＝6.9,11.4 Hz,1H),3.45(m,2H),2.25(s,3H).元素分析計算：C,46.50；H,5.46；N,10.85；S,12.41發現：C,46.65；H,5.60；N,10.84；S,12.61。MS[M-H] ^- 257 ¹ H NMR (CDCl ₃ ): δ 6.76 (m, 1H), 6.66 (m, 2H), 4.80 (m, 1H), 4.57 (bd s, 1H), 4.40 (m, 1H), 4.28 (m, 1H), 4.03 (dd, J = 6.9, 11.4 Hz, 1H), 3.45 (m, 2H), 2.25 (s, 3H). Elemental analysis: C, 46.50; H, 5.46; N, 10.85; S, 12.41 found: C, 46.65; H, 5.60; N, 10.84; S, 12.61.

實施例13Example 13 大鼠之支配－順從關係(DSR)活體內試驗Rat dominance-compliance (DSR) in vivo test

DSR試驗分成兩種模式：躁狂之支配行為減少模式(RDBM)與抑鬱之順從行為減少模式(RSBM)。RDBM－其中支配型動物以測試化合物處理－係預測測試化合物治療躁狂的能力。RSBM－其中順從型動物以測試化合物處理－係預測測試化合物治療抑鬱的能力。The DSR trial is divided into two modes: the Manic Dominant Behavioral Reduction Model (RDBM) and the Depressive Obedience Reduction Model (RSBM). RDBM - in which the dominant animal is treated with a test compound - predicts the ability of the test compound to treat mania. RSBM - in which compliant animals are treated with test compounds - predicts the ability of test compounds to treat depression.

購自Charles River Laboratories Wilmington,MA的雄性SD大鼠(Sprague Dawley rats，140至160克)係用於本試驗。大鼠的運送係間隔兩周接收。每批運送的大鼠歷經五天隔離、一周適應期及一周挑選過程，接著對選出的多對大鼠進行五周的藥物或載體處理。Male SD rats (Sprague Dawley rats, 140 to 160 g) purchased from Charles River Laboratories Wilmington, MA were used in this experiment. Rat delivery was received two weeks apart. Each batch of rats was subjected to five days of isolation, one week of acclimation, and one week of selection, followed by five weeks of drug or vehicle treatment of the selected pairs of rats.

每籠養四隻大鼠。在星期一至星期四的測試後，食物的取用被限制在每天一小時。在星期五的測試後，大鼠可自由取用食物直到星期天再度被禁食為止。大鼠可在任何時候飲水。使用禁食期對體重增加幾乎沒影響，研究結束時大鼠的平均體重約為300克。在實驗結束後，大鼠被斷頭犧牲，收集軀幹血及腦以供試管內實驗與藥物濃度量測。Four rats were housed per cage. After the test from Monday to Thursday, food intake was limited to one hour per day. After the Friday test, the rats were given free access to food until they were fasted again on Sunday. Rats can drink water at any time. The use of the fasting period had little effect on weight gain, and the average body weight of the rats at the end of the study was approximately 300 grams. At the end of the experiment, the rats were sacrificed by decapitation, and the trunk blood and brain were collected for in-vitro experiments and drug concentration measurements.

基本測試裝置係由以大小僅容許一次一隻大鼠通過的隧道連接的兩個隔室組成。在隧道中點的地板上是甜牛奶的容器。將此基本裝置複製，以便能同時用錄影追踪全部四對大鼠。攝影機可區分以不同顏色標記的大鼠。於是，為了錄影追踪而將大鼠頭部上色，一籠為紅色而另一籠為黃色。一次只有一隻動物可自在地接近飼料箱，但兩隻動物都可在每天五分鐘區段內喝牛奶。在每天五分鐘區段內，以錄影追踪軟體記錄每隻大鼠在飼料箱區域花費的時間並存成文字檔。The basic test device consists of two compartments connected by a tunnel that is only allowed to pass one rat at a time. On the floor at the midpoint of the tunnel is a container of sweet milk. This basic device was copied so that all four pairs of rats could be tracked simultaneously with video. The camera can distinguish between rats marked in different colors. Thus, the head of the rat was colored for video tracking, one cage was red and the other cage was yellow. Only one animal can access the feed bin at a time, but both animals can drink milk in a five-minute section every day. In the five-minute session per day, the video tracking software was used to record the time spent by each rat in the feed bin area and stored as a text file.

將大鼠隨機分成多對開始測試。將一對中的各個成員放置在測試裝置的相對隔室內。記錄每隻動物在飼料箱區域花費的時間。在測試的第一周(五天)期間內，讓動物熟悉新環境。若三個標準都有達到，則將支配性分派給測試的第二周期間內得最高分的動物。首先，兩動物的平均日飲用量得分之間必須有顯著差異(雙側t－測試，P<0.05)。第二，支配性動物得分必須比順從性動物得分多至少25%。最後，在配對周不能出現「逆轉」(在分離場合時，推定的順從性大鼠得分超過其支配性搭檔)。理想地，在適應環境期間亦有最少逆轉。約有百分之二十五到三十三的初始動物對達到該等標準且只有該等對繼續用於研究當中。Rats were randomly divided into pairs to start the test. Each member of the pair is placed in the opposite compartment of the test device. Record the time each animal spent in the feed bin area. Animals are familiar with the new environment during the first week (five days) of the test. If all three criteria are met, the dominance is assigned to the animal with the highest score in the second week of the test. First, there must be a significant difference between the average daily drinking scores of the two animals (two-sided t-test, P < 0.05). Second, dominating animals must score at least 25% more than compliant animals. Finally, there is no "reversal" in the pairing week (in the case of separation, the putative compliance rat scores more than its dominant partner). Ideally, there is also minimal reversal during adaptation to the environment. Approximately 25 to 33 percent of the initial animal pairs meet these criteria and only those pairs continue to be used in the study.

支配性大鼠與順從性大鼠在飼料箱所花費時間的顯著差異係使用GraphPad Prism軟體(GraphPad Software,Inc.San Diego,CA)藉由ANOVA及後續的雙側t－測試(P<0.05)決定。使用多對配對動物的正規化支配性位準值來進行處理組的比較。支配性位準是測量配對受試者之間的社會關係的數值。支配性位準(DL)＝FTD－FTS，其中FTD是支配性大鼠的飼料箱時間而FTS是順從性大鼠的飼料箱時間。正規化係根據下式實施：支配性位準(第n周，以%表示)＝(支配性位準(第n周))/(支配性位準(第2周)Significant differences in time spent between dominating rats and compliant rats in the feed bin were performed using GraphPad Prism software (GraphPad Software, Inc. San Diego, CA) by ANOVA and subsequent two-sided t-test (P < 0.05). Decide. The comparison of the treatment groups was performed using the normalized dominance level values of the pairs of matched animals. The dominance level is a measure of the social relationship between paired subjects. Dominant level (DL) = FTD-FTS, where FTD is the feed bin time of the dominant rat and FTS is the feed bin time of the compliant rat. The normalization system is implemented according to the following formula: Dominance level (nth week, expressed in %) = (dominant level (nth week)) / (dominant level (week 2)

對照組(支配性動物與順從性動物均以載體處理的成對大鼠)與處理組(順從性大鼠以藥物處理而支配性大鼠以載體處理)之間支配性位準差異的統計顯著意義係以ANOVA、接續t－測試決定。50%反應的活性起始時間值(AOT－50)及對藥物的最小與最大反應係使用非線性迴歸分析(GraphPad Software,Inc.,San Diego,CA)以支配性位準值的減少為基礎計算。正規化DL值係用於此計算，其中處理周的DL值係根據上述公式正規化為該對第二周(預處理)數值的百分比。在該等背景值中，反應最小值(DL)決定了藥物的正向活性，其對應於功效，因為假使對藥物的反應呈正向，DL值總是減少的。在對藥物呈負向反應(症狀惡化)的情況中，DL值會增加。假使藥物不具有該類活性，則反應最大值不超過100%。任何明顯高於對照值(約100%)的最大DL值指出藥物的負向活性。Statistically significant differences in dominance levels between the control group (paired rats treated with vehicle in both dominant and compliant animals) and the treatment group (constrained rats treated with drug-treated and vehicle-treated rats) The meaning is determined by ANOVA and subsequent t-test. The 50% response activity onset value (AOT-50) and the minimum and maximum response to the drug were based on a reduction in the dominance level using nonlinear regression analysis (GraphPad Software, Inc., San Diego, CA). Calculation. The normalized DL value is used for this calculation, where the DL value of the processing week is normalized to the percentage of the second week (pre-processed) value of the pair according to the above formula. Among these background values, the reaction minimum (DL) determines the positive activity of the drug, which corresponds to efficacy, because if the reaction to the drug is positive, the DL value is always reduced. In the case of a negative reaction to the drug (symptoms worsening), the DL value increases. If the drug does not have this type of activity, the maximum value of the reaction does not exceed 100%. Any maximum DL value that is significantly higher than the control value (about 100%) indicates the negative activity of the drug.

化合物#8係根據下方更詳細說明的程序於大鼠RDBM中評估。Compound #8 was evaluated in rat RDBM according to the procedure described in more detail below.

多組支配性大鼠以化合物#8(p.o.QD)處理；以0.05毫克/公斤(n＝4)、以0.5毫克/公斤(n＝6)、以2.5毫克/公斤(n＝6)、以5.0毫克/公斤(n＝6)及以50.0毫克/公斤(n＝3)。支配性大鼠的載體對照組以0.5%甲基纖維素處理(n＝3)，支配性大鼠的第二對照組以30毫克/公斤的丙基戊酸鈉(i.p.QD)處理(n＝6，各為n＝3的2個研究)。Multiple groups of dominating rats were treated with Compound #8 (poQD); 0.05 mg/kg (n=4), 0.5 mg/kg (n=6), and 2.5 mg/kg (n=6). 5.0 mg/kg (n=6) and 50.0 mg/kg (n=3). The vehicle control group of the dominating rats was treated with 0.5% methylcellulose (n=3), and the second control group of the dominating rats was treated with 30 mg/kg sodium propylvalerate (ipQD) (n= 6, 2 studies each of n=3).

所有處理於測試前約1小時投予。在第二個測試周(挑選周)之後，所有處理係於星期六開始。化合物#8係以口服投予(p.o)。All treatments were administered approximately 1 hour prior to testing. After the second test week (choice week), all processing starts on Saturday. Compound #8 was administered orally (p.o).

當支配性動物以0.05毫克/公斤、0.5毫克/公斤與50.0毫克/公斤的化合物#8處理時，支配性大鼠與順從性大鼠之間的差異在處理第一周後喪失，以2.5毫克/公斤與5.0毫克/公斤給藥則在處理第二周後喪失。同樣地，當支配性動物以丙基戊酸鈉處理時，支配性大鼠與順從性大鼠之間的差異亦於處理第一周後喪失。在此研究中，觀察到以化合物#8或丙基戊酸鈉處理的支配性大鼠的寬容度增加了。於是經處理的支配性大鼠容許其順從性搭檔增加其花在飼料箱上的時間。When the dominant animal was treated with 0.05 mg/kg, 0.5 mg/kg, and 50.0 mg/kg of Compound #8, the difference between the dominating rat and the compliant rat was lost after the first week of treatment, to 2.5 mg. Administration of /kg and 5.0 mg/kg was lost after the second week of treatment. Similarly, when the dominant animal was treated with sodium valproate, the difference between the dominating rat and the compliant rat was also lost after the first week of treatment. In this study, it was observed that the tolerance of the dominating rats treated with Compound #8 or sodium valproate was increased. The treated dominant rat then allowed its compliance partner to increase its time spent on the feed bin.

為比較不同藥物及給藥效果，將資料正規化至初始對照周的數值。化合物#8的最強效果在0.5毫克/公斤劑量觀察到，載體與經化合物處理的大鼠之間支配性位準(DL)值的顯著差異在第二周開始並持續至歷時5周的處理。化合物#8的較高給藥量(2.5毫克/公斤、5.0毫克/公斤與50.0毫克/公斤)顯示較微弱的反應，其和給藥0.5毫克/公斤所觀察到的反應並無顯著差異。To compare the effects of different drugs and administration, the data was normalized to the value of the initial control week. The strongest effect of Compound #8 was observed at a dose of 0.5 mg/kg, and a significant difference in dominance level (DL) values between the vehicle and the compound treated rats started at the second week and continued until 5 weeks of treatment. The higher doses of Compound #8 (2.5 mg/kg, 5.0 mg/kg and 50.0 mg/kg) showed a weaker response, which was not significantly different from the observed response of 0.5 mg/kg.

對照之下，經丙基戊酸鈉處理的動物(30毫克/公斤)一致地顯示出在處理第二周後支配性位準減少且該效果在接下來數周仍增加。氯化鋰的效果(100毫克/公斤)僅在處理第三周後和對照組有顯著不同。In contrast, animals treated with sodium valproate (30 mg/kg) consistently showed a decrease in dominating levels after the second week of treatment and the effect increased over the next few weeks. The effect of lithium chloride (100 mg/kg) was significantly different from the control group only after the third week of treatment.

為估計活性起始時間(AOT)，將支配性與順從性動物對的飼料箱時間的每日平均值繪成圖並使用雙側t－測試計算該兩組之間的顯著差異。統計顯著性一致喪失的首日係發生在以0.05毫克/公斤化合物#8處理後的第3天；0.5毫克/公斤的第4天、2.5毫克/公斤的第10天、5.0毫克/公斤的第11天及50.0毫克/公斤的第3天。To estimate the activity onset time (AOT), the daily mean of the dominance and the feedbox time of the compliant animal pair was plotted and a significant difference between the two groups was calculated using a two-sided t-test. The first day of statistically significant loss of coincidence occurred on day 3 after treatment with 0.05 mg/kg of compound #8; on day 4 of 0.5 mg/kg, on day 10 of 2.5 mg/kg, on the first day of 5.0 mg/kg Day 3 and 50.0 mg/kg on day 3.

為比較不同處理之間的活性起始時間(AOT)，活性起始時間係以非線性迴歸配合來估計。以非線性迴歸模式配合各個藥物與給藥的正規化每日DL值。0.05毫克/公斤與0.5毫克/公斤之化合物#8的AOT₅₀ 明顯短於鋰的AOT₅₀ 。To compare the activity initiation time (AOT) between different treatments, the activity initiation time was estimated using a non-linear regression fit. The normalized daily DL values for each drug and administration were matched in a non-linear regression model. The AOT _{50 of} 0.05 mg/kg and 0.5 mg/kg of compound #8 was significantly shorter than the AOT _{50 of} lithium.

化合物#8在RDBM中的效用為劑量依存性，計算之ED₅₀ 為0.03±0.004毫克/公斤[CI＝0.01－0.04]且E_max 為116.4±2.3%[CI＝109.2－123.6]。Compound # 8 in the RDBM utility of dose dependency was calculated ED ₅₀ of 0.03 ± 0.004 mg / kg [CI = 0.01-0.04] and E _max of 116.4 ± 2.3% [CI = 109.2-123.6 ].

在本試驗中，化合物#8減少了支配行為，顯示該化合物具有抗躁狂劑的活性。In this test, Compound #8 reduced the dominating behavior, indicating that the compound has anti-manic activity.

實施例14Example 14 大鼠之支配－順從關係(DSR)活體內試驗Rat dominance-compliance (DSR) in vivo test

購自Charles River Laboratories Wilmington,MA的雄性SD大鼠(140至160克)係用於本試驗。大鼠的運送係間隔兩周接收。每批運送的大鼠歷經五天隔離、一周適應期及一周挑選過程，接著對選出的多對大鼠進行五周的藥物或載體處理。Male SD rats (140 to 160 grams) purchased from Charles River Laboratories Wilmington, MA were used in this assay. Rat delivery was received two weeks apart. Each batch of rats was subjected to five days of isolation, one week of acclimation, and one week of selection, followed by five weeks of drug or vehicle treatment of the selected pairs of rats.

基本測試裝置係由以大小僅容許一次一隻大鼠通過的隧道連接的兩個隔室組成。在隧道中點的地板上是甜牛奶的容器。將此基本裝置複製，以便能同時用錄影追踪全部四對大鼠。攝影機可區分以不同顏色標記的大鼠。於是，為了錄影追踪而將大鼠頭部上色，一籠為紅色而另一籠為黃色。一次只有一隻動物可自在地接近飼料箱，但兩隻動物都可在每天五分鐘期間內喝牛奶。在每天五分鐘期間內，以錄影追踪軟體記錄每隻大鼠在飼料箱區域花費的時間並存成文字檔。The basic test device consists of two compartments connected by a tunnel that is only allowed to pass one rat at a time. On the floor at the midpoint of the tunnel is a container of sweet milk. This basic device was copied so that all four pairs of rats could be tracked simultaneously with video. The camera can distinguish between rats marked in different colors. Thus, the head of the rat was colored for video tracking, one cage was red and the other cage was yellow. Only one animal can access the feed bin at a time, but both animals can drink milk for five minutes a day. During the five minute period of each day, the video tracking software was used to record the time spent by each rat in the feed bin area and stored as a text file.

實驗後將末端血液樣本(0.5－1.0毫升)收集到添加肝素的管子內。將血液樣本離心以移除細胞，然後將200微升血漿上清液轉至乾淨的小玻璃瓶中、置於乾冰上，在分析之前先儲存在－80℃的冷凍庫裡。將含有內標準的兩百微升乙腈加至100微升血漿或腦組織，以使蛋白質及/或組織殘渣沈澱。將樣本離心並將上清液移出以藉由液相層析－三重四極質譜儀(LC－MS－MS)分析。校正標準係藉由將適當體積的庫存溶液直接添加至空白血漿或腦組織均質物裡並與收集樣本同樣處理來製備。校正標準係製備0.01至10微升以供定量。LC－ESI－MS/MS(負向模式)分析係利用多重反應監測模式(MRM)進行，以偵測測試化合物的特徵性離子。After the experiment, the terminal blood sample (0.5-1.0 ml) was collected into a tube to which heparin was added. The blood samples were centrifuged to remove the cells, and then 200 microliters of the plasma supernatant was transferred to a clean vial, placed on dry ice, and stored in a freezer at -80 °C prior to analysis. Two hundred microliters of acetonitrile containing internal standards were added to 100 microliters of plasma or brain tissue to precipitate protein and/or tissue debris. The sample was centrifuged and the supernatant was removed for analysis by liquid chromatography-triple quadrupole mass spectrometer (LC-MS-MS). Calibration standards were prepared by adding an appropriate volume of stock solution directly to blank plasma or brain tissue homogenate and treating it in the same manner as the collected sample. Calibration standards were prepared from 0.01 to 10 microliters for quantification. LC-ESI-MS/MS (negative mode) analysis was performed using multiple reaction monitoring mode (MRM) to detect characteristic ions of test compounds.

對照組(支配性動物與順從性動物均以載體處理的成對大鼠)與處理組(順從性大鼠以藥物處理而支配性大鼠以載體處理)之間的支配性位準差異的統計顯著性係以ANOVA、接續t－測試決定。50%反應的活性起始時間值(AOT－50)及對藥物的最小與最大反應係使用非線性迴歸分析(GraphPad Software,Inc.,San Diego,CA)以支配性位準值的減少為基礎計算。正規化DL值係用於此計算，其中處理周的DL值係根據上述公式正規化為該對第二周(預處理)數值的百分比。在該等背景值中，反應最小值(DL)決定了藥物的正向活性，其對應於功效，因為假使對藥物的反應呈正向，DL值總是減少的。在對藥物呈負向反應(症狀惡化)的情況中，DL值會增加。假使藥物不具有該類活性，則反應最大值不超過100%。任何明顯高於對照值(約100%)的最大DL值指出藥物的負向活性。Statistics of dominance level differences between the control group (paired rats treated with vehicle in both dominant animals and compliant animals) and the treatment group (constrained rats treated with drugs and the dominant rats were treated with vehicle) Significance was determined by ANOVA followed by t-test. The 50% response activity onset value (AOT-50) and the minimum and maximum response to the drug were based on a reduction in the dominance level using nonlinear regression analysis (GraphPad Software, Inc., San Diego, CA). Calculation. The normalized DL value is used for this calculation, where the DL value of the processing week is normalized to the percentage of the second week (pre-processed) value of the pair according to the above formula. Among these background values, the reaction minimum (DL) determines the positive activity of the drug, which corresponds to efficacy, because if the reaction to the drug is positive, the DL value is always reduced. In the case of a negative reaction to the drug (symptoms worsening), the DL value increases. If the drug does not have this type of activity, the maximum value of the reaction does not exceed 100%. Any maximum DL value that is significantly higher than the control value (about 100%) indicates the negative activity of the drug.

化合物#8係於大鼠之抑鬱之順從行為減少模式(RSBM)中評估(Malatynska,E.,Rapp,R.,Harrawood,D.,and Tunnicliff,G.,Neuroscience and Biobehavioral Review ,82(2005)SOB－SIS；Malatynska,E.,and Knapp,R.J.,Neuroscience and Biobehavioral Review ,29(2005)715－737)。Compound #8 was assessed in the Reducing Behavior Reduction Model (RSBM) of Rat Depression (Malatynska, E., Rapp, R., Harrawood, D., and Tunnicliff, G., Neuroscience and Biobehavioral Review , 82 (2005) SOB-SIS; Malatynska, E., and Knapp, RJ, Neuroscience and Biobehavioral Review , 29 (2005) 715-737).

更明確地說，化合物#8係以2.5毫克/公斤(n＝8)、12毫克/公斤(n＝12)、60毫克/公斤(n＝12)與120毫克/公斤(n＝7)一天一次p.o.(口服)投予順從性大鼠共五周，同時支配性搭檔給予載體(0.5%甲基纖維素水溶液)。作為對照組，另外多組大鼠以10.0毫克/公斤氟西汀i.p.處理(n＝10)及30.0毫克/公斤文拉法辛i.p.處理(n＝6)。所有處理於測試前約1小時投予。觀察到化合物#8以給藥量依存性方式減少順從行為。More specifically, Compound #8 is 2.5 mg/kg (n=8), 12 mg/kg (n=12), 60 mg/kg (n=12) and 120 mg/kg (n=7) a day. One-time po (oral) administration of compliant rats for five weeks, while the dominant partner was given a vehicle (0.5% aqueous solution of methylcellulose). As a control group, additional groups of rats were treated with 10.0 mg/kg fluoxetine i.p. (n=10) and 30.0 mg/kg venlafaxine i.p. (n=6). All treatments were administered approximately 1 hour prior to testing. Compound #8 was observed to reduce compliance in a dose-dependent manner.

當順從性動物以化合物#8處理時，支配性大鼠與順從性大鼠之間的顯著差異在處理第一周後喪失。這在所有使用的給藥量都適用，顯示活性的起始與給藥量無關。對照之下，當順從性動物以氟西汀處理時，支配性大鼠與順從性大鼠之間的顯著差異在處理第三周後喪失。(此資料分析方法不考慮發生在對照組的行為波動)。為比較不同藥物及給藥效果，將資料正規化至初始對照周的數值。Significant differences between dominating rats and compliant rats were lost after the first week of treatment when the compliant animals were treated with Compound #8. This is true for all doses used, indicating that the onset of activity is independent of the amount administered. In contrast, when the compliant animals were treated with fluoxetine, significant differences between dominating rats and compliant rats were lost after the third week of treatment. (This data analysis method does not consider behavioral fluctuations that occur in the control group). To compare the effects of different drugs and administration, the data was normalized to the value of the initial control week.

以2.5毫克/公斤化合物#8給藥處理的順從性大鼠組的支配性位準(DL)值與對照組並無明顯不同。然而，以12.0毫克/公斤化合物#8處理的群組在處理第二周、第四周與第五周之後顯示明顯異於以載體處理之對照組的DL值。同樣地，以60毫克/公斤化合物#8處理的群組顯示相對於載體呈明顯差異的DL值，其係從第一周開始並持續至歷時5周的處理。於化合物#8的最高給藥量(120毫克/公斤)，DL值在第一周後明顯異於對照組，然而，此顯著性在處理第二周後消失。The level of dominance (DL) of the compliant rat group treated with 2.5 mg/kg of Compound #8 was not significantly different from the control group. However, the group treated with 12.0 mg/kg Compound #8 showed significantly different DL values from the vehicle-treated control group after the second, fourth, and fifth weeks of treatment. Similarly, the group treated with 60 mg/kg Compound #8 showed a significantly different DL value relative to the vehicle, starting from the first week and continuing until 5 weeks of treatment. At the highest dose of Compound #8 (120 mg/kg), the DL value was significantly different from the control group after the first week, however, this significance disappeared after the second week of treatment.

以氟西汀(10毫克/公斤)處理的動物在處理第一周期間內一致性地顯現出增多的順從性。相較於以氟西汀(10毫克/公斤)處理的動物，以化合物#8處理的群組並無顯現此效應。就化合物#8之60.0毫克/公斤給藥而言，與氟西汀處理之群組的DL值差異在第一周後有p<0.001且在處理第二周後有p<0.05的統計顯著性。以氟西汀與化合物#8處理之對的正規化DL位準在後續處理周期間並無顯著差異。Animals treated with fluoxetine (10 mg/kg) consistently showed increased compliance during the first week of treatment. This effect was not observed in the group treated with Compound #8 compared to animals treated with fluoxetine (10 mg/kg). For the 60.0 mg/kg administration of Compound #8, the difference in DL values from the group treated with fluoxetine had p < 0.001 after the first week and a statistical significance of p < 0.05 after the second week of treatment. . The normalized DL level of the pair treated with fluoxetine and compound #8 did not differ significantly between subsequent treatment cycles.

為估計活性起始時間，將支配性與順從性動物對的飼料箱時間的每日平均值繪成圖並使用雙側t－測試計算該兩組之間的顯著差異。統計顯著性一致喪失的首日係發生在以12.0毫克/公斤化合物#8處理後的第6天及60毫克/公斤處理後的第4天。以2.5毫克/公斤與120.0毫克/公斤之化合物#8處理的支配性大鼠與順從性大鼠飼料箱時間之間的顯著性並無前後一致的喪失。To estimate the activity onset time, the daily mean of the dominance and the feed bin time of the compliant animal pair was plotted and a significant difference between the two groups was calculated using a two-sided t-test. The first day of statistically significant loss of coincidence occurred on day 6 after treatment with 12.0 mg/kg of compound #8 and on day 4 after treatment with 60 mg/kg. There was no consistent loss of significance between the dominating rats treated with 2.5 mg/kg and 120.0 mg/kg Compound #8 and the compliant rat feed bin time.

為比較不同處理之間的活性起始時間，活性起始時間係以非線性迴歸配合來估計。以非線性迴歸模式配合各個藥物與給藥的正規化每日DL值。50%效果的活性起始時間(AOT₅₀ )及化合物#8於2.5毫克/公斤、12毫克/公斤與60毫克/公斤的Emax分別為2.1；5.3與1.6天且給藥量之間並無顯著的不同。本分析得到的最大效果就2.5毫克/公斤、12毫克/公斤與60毫克/公斤給藥而言係分別為52.4±32.7%(SEM)、87.9±42.6%(SEM)與116.9±29.5%(SEM)且在該等給藥之間亦無明顯不同。To compare the activity onset time between treatments, the activity onset was estimated using a non-linear regression fit. The normalized daily DL values for each drug and administration were matched in a non-linear regression model. The 50% effect of the active start time (AOT ₅₀ ) and the compound #8 at 2.5 mg / kg, 12 mg / kg and 60 mg / kg Emax were 2.1; 5.3 and 1.6 days and the dose was not significant s difference. The maximum effect obtained in this analysis was 52.4 ± 32.7% (SEM), 87.9 ± 42.6% (SEM) and 116.9 ± 29.5% (SEM) for 2.5 mg/kg, 12 mg/kg and 60 mg/kg, respectively. And there is no significant difference between these administrations.

總言之，化合物#8在RSBM試驗中的效用為劑量依存性，計算之ED₅₀ 為6.6±0.8毫克/公斤[CI＝3.0－10.2]且E_max 為131.4±4.7%[CI＝111.3－151.5]。In summary, the effect of Compound #8 in the RSBM trial was dose-dependent, with an calculated ED ₅₀ of 6.6 ± 0.8 mg/kg [CI = 3.0-10.2] and an E _max of 131.4 ± 4.7% [CI = 111.3-151.5 ].

在本試驗中，化合物#8減少了順從行為，顯示該化合物具有抗抑鬱劑的活性。In this test, Compound #8 reduced compliance, indicating that the compound has antidepressant activity.

實施例15－17 激發與兩極型循環Example 15-17 Excitation and Bipolar Cycle

當前文獻中的討論暗示激發背後的機制可能和兩極病症中循環的機制類似且/或可能和情緒穩定有關。於是，下文更詳細說明的杏仁核激發與海馬迴激發試驗可預測測試化合物治療和兩極病症有關、兩極病症特有或為兩極病症症狀之循環的能力。(Ghaemi,S.N.,Boiman,E.E.,and Goodwin,F.K.,Soc.of Bio.Psychiatry,(1999),vol.45,pp137－144；Stoll,A.L,and Severus,W.E.,Harvard Rev.Psychiatry,July/August(1996),Vol.4,No.2,pp 77－89)The discussion in the current literature suggests that the mechanism behind the trigger may be similar to the mechanism of circulation in a bipolar disorder and/or may be related to emotional stability. Thus, the amygdala challenge and hippocampal gyrogenicity test, described in more detail below, can predict the ability of a test compound to be treated in connection with a bipolar disorder, a bipolar disorder, or a cycle of symptoms of a bipolar disorder. (Ghaemi, SN, Boiman, EE, and Goodwin, FK, Soc. of Bio. Psychiatry, (1999), vol. 45, pp 137-144; Stoll, AL, and Severus, WE, Harvard Rev. Psychiatry, July/August (1996), Vol. 4, No. 2, pp 77-89)

實施例15Example 15 杏仁核激發試驗(阻止激發)Amygdala challenge test (to prevent excitation)

簡言之，試驗程序係如下列。體重在250－300克之間的雄性成年SD大鼠係自Charles River,Wilmington,MA獲得。所有動物以12：12晝夜周期飼養並允許自由取用食物(Prolab RMH 3000)及水，除了從居住籠移出進行實驗程序時外。動物係以符合詳述於國家研究委員會出版品「照料及使用實驗動物指導手冊(Guide for the Care and Use of Laboratory Animals)」中建議的方式照料於控溫、無殺蟲劑的設備內。激發刺激係於9 AM－2 PM例行地進行，以避免任何生理節奏變數。In short, the test procedure is as follows. Male adult SD rats weighing between 250-300 grams were obtained from Charles River, Wilmington, MA. All animals were housed on a 12:12 day and night cycle and allowed free access to food (Prolab RMH 3000) and water, except when removed from the living cage for the experimental procedure. Animals are cared for in temperature-controlled, pesticide-free equipment in a manner consistent with the recommendations in the National Research Council publication "Guide for the Care and Use of Laboratory Animals." Stimulation stimulation was routinely performed at 9 AM-2 PM to avoid any circadian variables.

將化合物#8在少量0.5%甲基纖維素中搗碎，以超音波振盪10分鐘，並加0.5%甲基纖維素至最終體積。化合物#8係以0.04毫升/10克體重之體積全身性(i.p.)投予且所有測試係於i.p.投予0.5小時後的預定尖峰效應時間實施。Compound #8 was chopped in a small amount of 0.5% methylcellulose, sonicated for 10 minutes, and 0.5% methylcellulose was added to the final volume. Compound #8 was administered systemically (i.p.) in a volume of 0.04 ml/10 g body weight and all tests were performed at a predetermined spike time of 0.5 h after i.p. administration.

化合物#8阻止杏仁核經激發之發作表現的能力係如下列決定。以K他命(ketamine)(120毫克/公斤，i.p.)與鹽酸甲苯噻(xylazine)(12毫克/公斤，i.p.)的混合物將大鼠麻醉。在無菌條件下，將兩極電極(Plastic One,Roanoke,VA)以立體定位植入杏仁核右側底核(AP－2.2,ML－4.7,DV－8.7；Paxinos and Watson)。前側－後側與側向測量係自前囪，而腹側－背側測量係自頭蓋骨表面。無菌頭蓋骨螺絲(3－4)係植入作為中性參考電極。電極係使用牙科用水泥與丙烯酸酯固定。傷口稍後使用無菌18/8米歇爾縫合夾(Roboz,Gaithersburg,MD)關閉。在返回乾淨籠子以供一周的術後恢復之前將新黴素抗生素軟膏塗覆至傷口並將單劑青黴素(60,000 IU,im,AgriLabs)投予每隻大鼠。The ability of Compound #8 to prevent the amygdala from being triggered by seizures is determined as follows. Take Ketamine (120 mg/kg, ip) with toluene hydrochloride Rats were anesthetized with a mixture of (xylazine) (12 mg/kg, ip). A bipolar electrode (Plastic One, Roanoke, VA) was stereotactically implanted into the right nucleus of the amygdala under sterile conditions (AP-2.2, ML-4.7, DV-8.7; Paxinos and Watson). The anterior-posterior and lateral measurements are from the bregma, while the ventral-dorsal measurements are from the cranial surface. A sterile cranial screw (3-4) is implanted as a neutral reference electrode. The electrode system is fixed with acrylate using dental cement. The wound was later closed using a sterile 18/8 Michelle suture clip (Roboz, Gaithersburg, MD). A neomycin antibiotic ointment was applied to the wound before returning to a clean cage for one week of postoperative recovery and a single dose of penicillin (60,000 IU, im, AgriLabs) was administered to each rat.

稍後根據下列流程進行杏仁核激發。在短暫地適應記錄室(<5分鐘)之後，獲得基線EEG記錄(MP 100,Biopac Systems Inc.,Goleta,CA)。隨後將大鼠隨機分配以接受載體(0.5%甲基纖維素)或化合物#8(75毫克/公斤，i.p.)(每組大鼠n＝10)。在實驗當天，在杏仁核刺激(200 μA歷時2秒)的30分鐘前投予單劑化合物#8或0.5%甲基纖維素。記錄每個處理組中大鼠的行為發作評分與AD持續時間。行為發作評分係使用拉辛等級(Racine scale)決定；亦即0＝無反應；第1階段＝梳毛/活動量大；第2階段＝節律性點頭/顫抖；第3階段＝單側前肢陣攣；第4階段＝站立並陣攣；及第5階段＝持續站立傾倒且全身性僵直陣攣型發作(Racine,1972)。在連串刺激後以數位記錄放電後(AD)活性至多達180秒並測量原始AD持續時間。當展示連續五個第4階段或第5階段全身性發作時，大鼠被認為是完全激發。每日的刺激係於全部三組中持續至多連續13天，直到載體處理組的大鼠被完全激發為止(亦即連續五個第4階段或第5階段發作)。此時，所有大鼠被容許一周的無刺激/無用藥期；在那之後，該等大鼠在無藥物之下再次挑戰獲取期(亦即第1－13天)期間內所運用的相同刺激。以化合物#8處理的大鼠之後每天被刺激一次，直到它們達到完全激發狀態為止。The amygdala challenge was performed later according to the following procedure. Baseline EEG recordings (MP 100, Biopac Systems Inc., Goleta, CA) were obtained after brief adaptation to the recording chamber (<5 minutes). Rats were then randomly assigned to receive vehicle (0.5% methylcellulose) or Compound #8 (75 mg/kg, i.p.) (n=10 per group of rats). On the day of the experiment, a single dose of Compound #8 or 0.5% methylcellulose was administered 30 minutes before amygdala stimulation (200 μA for 2 seconds). The behavioral seizure score and AD duration of the rats in each treatment group were recorded. The behavioral seizure score is determined using the Racine scale; that is, 0 = no response; the first stage = combing / activity is large; the second stage = rhythmic nod / trembling; the third stage = unilateral forelimb clonic Stage 4 = standing and clumping; and stage 5 = standing up and dumping and systemic stiffening clonic episodes (Racine, 1972). The post-discharge (AD) activity was recorded digitally up to 180 seconds after a series of stimuli and the original AD duration was measured. Rats were considered to be fully challenged when five consecutive Stage 4 or Stage 5 systemic episodes were shown. Daily stimulation was continued for up to 13 consecutive days in all three groups until the rats in the vehicle treated group were fully challenged (ie, five consecutive Phase 4 or Phase 5 episodes). At this point, all rats were allowed a one-week non-stimulation/laboratory period; after that, the rats were challenged for the same stimulus during the acquisition period (ie, days 1-13) without the drug. . Rats treated with Compound #8 were stimulated once a day until they reached a fully challenged state.

以載體與化合物#8處理之組的放電後(AD)持續時間在整個激發獲取期過程中展現出漸進式的增加。處理組之間並無觀察到統計差異。The post-discharge (AD) duration of the group treated with vehicle and compound #8 exhibited a progressive increase throughout the excitation acquisition period. No statistical differences were observed between treatment groups.

化合物#8阻止了獲取完全的全身性激發發作。此結論係基於在無用藥/無刺激期結束時的發作評分仍維持明顯低於載體處理組大鼠的發作評分之發現(化合物#8＝1.4±0.40對載體＝4.6±0.24)。此外，當在無藥物之下刺激時，化合物#8處理組大鼠的發作評分係以在經載體處理大鼠中觀察到的相似速率增加－支持化合物#8將激發的獲取延後數天的結論。Compound #8 prevented the acquisition of a complete systemic challenge. This finding is based on the finding that the seizure score at the end of the no-drug/non-stimulation period remained significantly lower than the seizure score of the vehicle-treated rats (Compound #8=1.4±0.40 vs. vehicle=4.6±0.24). Furthermore, when stimulated without drug, the seizure score of the rats in the compound #8 treatment group was increased by a similar rate observed in the vehicle-treated rats - support compound #8 delayed the acquisition of the challenge for several days. in conclusion.

本研究結果證實化合物#8擁有在局部癲癇之杏仁核激發大鼠模式中緩和激發進展的能力。該等結果與化合物#8擁有緩和疾病效果的結論一致。此結論係基於在無用藥/無刺激期結束時化合物#8處理組大鼠的發作評分仍維持明顯低於載體處理組大鼠的發作評分之發現。再者，一旦刺激流程在無藥物下重新開始，發作評分則以和載體處理組相似的速率進展。The results of this study demonstrate that Compound #8 possesses the ability to moderate progression in the amygdala-induced rat model of partial epilepsy. These results are consistent with the conclusion that Compound #8 has the effect of mitigating disease. This conclusion is based on the finding that the seizure score of the compound in the compound #8 treatment group remained significantly lower than that in the vehicle-treated group at the end of the drug-free/non-stimulation period. Furthermore, once the stimulation procedure was restarted without drug, the seizure score progressed at a rate similar to that of the vehicle treated group.

在無刺激/無用藥周的一周後化合物處理組的發作評分－而非放電後持續時間－明顯低於載體處理組的發現暗示化合物#8係阻止獲取次發性全身性發作，而不是局部性發作。The seizure score of the compound-treated group after one week without the stimulus/useless week - not the duration after the discharge - was significantly lower than the findings of the vehicle-treated group suggesting that Compound #8 prevented the acquisition of secondary systemic seizures rather than locality. attack.

實施例16Example 16 海馬迴激發模式(激發狀態中斷)Hippocampus back excitation mode (excitation state interruption)

經激發之發作提供局部性發作的實驗模式，使科學家可研究可能促成局部點之發作散播與全身化的複雜腦部網絡。The stimulated episode provides an experimental pattern of localized seizures that allows scientists to study complex brain networks that may contribute to the spread of localized episodes and systemicization.

在此快速海馬迴激發模式中，以手術將兩極電極植入雄性成年SD大鼠(300－400克)，置於海馬迴中。大鼠以重複電刺激激發(50 Hz，每次1毫秒，持續10秒，雙相性200μA脈衝，每隔一天進行每30分鐘一次共6小時，總共60次刺激)，造成第5階段雙側運動性發作。一周後，大鼠接受在以測試化合物處理前每30分鐘傳送的2－3次超臨界刺激，以確保行為發作階段與放電後持續時間的穩定性。最終刺激的十五分鐘後，以i.p.(腹腔內)投予單劑載體或測試化合物。15分鐘後，然後每30分鐘刺激每隻大鼠，共3至4小時。在每次刺激後，記錄個別發作評分與放電後持續時間。計算各參數的組平均±SEM。每劑量八隻大鼠及四個劑量的最小值係用於建立ED₅₀ 值。功效係測量為化合物緩和全身性發作的發作評分(散播嚴重度)與放電後持續時間(ADD；興奮度)的能力。In this rapid hippocampus re-excitation mode, the bipolar electrodes were surgically implanted into male adult SD rats (300-400 g) and placed in the hippocampus. Rats were challenged with repeated electrical stimulation (50 Hz, 1 millisecond each time for 10 seconds, biphasic 200 μA pulse, every other day for every 6 minutes for 6 hours, for a total of 60 stimulations), resulting in stage 5 bilateral motion Sexual attack. One week later, the rats received 2-3 supercritical stimuli delivered every 30 minutes prior to treatment with the test compound to ensure stability of the behavioral onset phase and post-discharge duration. Fifteen minutes after the final stimulation, a single dose of vehicle or test compound was administered as ip (intraperitoneal). After 15 minutes, each rat was then stimulated every 30 minutes for a total of 3 to 4 hours. After each stimulation, individual seizure scores and duration after discharge were recorded. The group mean ± SEM of each parameter was calculated. Minimum of eight rats per dose and four doses of ₅₀ lines for establishing the value of ED. Efficacy was measured as the ability of the compound to alleviate the onset score (spread severity) and post-discharge duration (ADD; excitability) of systemic seizures.

使用此方法，一使發作評分從5減至3但對ADD無任何效應的化合物暗示該化合物於治療次發性全身性發作的實用性。相反地，一使發作評分從5減至小於1且亦減少了ADD的化合物暗示該化合物於治療局部性發作的實用性。於是，根據當前文獻所呈現的理論(Ghaemi,S.N.,Boiman,E.E.,and Goodwin,F.K.,Soc.of Bio.Psychiatry ,(1999),vol.45,pp137－144；Stoll,A.L.,and Severus,W.E.,Harvard Rev.Psychiatry ,July/August(1996),Vol.4,No.2,pp 77－89)，發作評分及/或ADD的減少亦可預測測試化合物治療和兩極病症有關之循環的能力。Using this method, a compound that reduces the seizure score from 5 to 3 but has no effect on ADD suggests the utility of the compound in the treatment of secondary systemic seizures. Conversely, a compound that reduces the seizure score from 5 to less than 1 and also reduces ADD suggests the utility of the compound in treating localized seizures. Thus, according to the theory presented in the current literature (Ghaemi, SN, Boiman, EE, and Goodwin, FK, Soc. of Bio . Psychiatry , (1999), vol. 45, pp 137-144; Stoll, AL, and Severus, WE , Harvard Rev. Psychiatry , July/August (1996), Vol. 4, No. 2, pp 77-89), a reduction in seizure scores and/or ADD can also predict the ability of a test compound to treat a cycle associated with a bipolar disorder.

化合物#8(配於0.5%甲基纖維素水溶液)在此模式中展現了抗痙攣活性且ED₅₀ ＝68.5±1.3毫克/公斤(對應於45分鐘時發作評分減少及165分鐘時的尖峰活性)。8隻大鼠中有4隻的發作評分明顯地從5減至1(p＝0.0003)。對於ADD無統計上顯著的效應(p＝0.07)。乙琥胺(Ethosuximide)於此模式中無效；反之，苯妥英(phenytoin)、卡巴氮呯與丙戊酸顯著地抑制了發作活性，但係以毒性相關劑量。Compound # 8 (with a 0.5% methylcellulose aqueous solution) In this mode exhibit anticonvulsant activity and the ED ₅₀ = 68.5 ± 1.3 mg / kg (corresponding to reduce seizure score at 45 min, and peak activity at 165 min) . The seizure score of 4 out of 8 rats was significantly reduced from 5 to 1 (p=0.0003). There was no statistically significant effect on ADD (p=0.07). Ethosuximide is ineffective in this mode; conversely, phenytoin, carbamazepine, and valproic acid significantly inhibit seizure activity, but with toxicity-related doses.

在本模式中，8隻大鼠中有6隻在以化合物#8處理後顯示泛發性發作活性明顯降低(得分<3)，如第5圖所示。在丙戊酸(於>300毫克/公斤之有毒劑量)與卡巴氮呯(於>26毫克/公斤之有毒劑量)觀察到類似的防護作用。In this model, 6 out of 8 rats showed a significant reduction in generalized seizure activity (score < 3) after treatment with Compound #8, as shown in Figure 5. A similar protective effect was observed with valproic acid (at a toxic dose of >300 mg/kg) and kappa azide (a toxic dose of >26 mg/kg).

本試驗的比較結果列於下方表4。The comparison results of this test are listed in Table 4 below.

實施例17Example 17 拉莫三 抗性杏仁核激發大鼠模式(激發狀態中斷) Lamo III Resistant amygdala stimulates rat mode (excitation state disruption)

化合物#8係於拉莫三(LTG)－抗性杏仁核激發大鼠模式(NINDS)中評估。杏仁核激發比海馬迴激發輕微，所以許多AED對杏仁核被激發的發作有效，但對海馬迴被激發的發作無效。舉例來說，拉莫三可顯著地降低杏仁核被激發的發作評分與ADD(ED₅₀ ＝25毫克/公斤，i.p.，CI＝4－50毫克/公斤；評分~2；ADD減少62%)，但不能對海馬迴被激發的發作提供防護作用。Compound #8 is tied to Lamo III (LTG)-resistant amygdala challenged rat model (NINDS) assessment. Amygdala challenge is milder than hippocampus, so many AEDs are effective for the onset of amygdala, but not for the onset of hippocampus. For example, Lamo III Can significantly reduce the amygdala stimulated seizure score and ADD (ED ₅₀ =25 mg / kg, ip, CI = 4-50 mg / kg; score ~ 2; ADD reduced 62%), but can not be stimulated hippocampus The attack provides protection.

在LTG－抗性杏仁核激發模式中，大鼠在激發獲取期期間被給予LTG(5毫克/公斤，i.p.，q.d.)。已顯示此劑量對激發本身不具效應，但會導致發展出對LTG抗痙攣效應有抗性的完全激發大鼠。一旦經激發(150 μA的超臨界刺激，雙相性60 Hz電流脈衝1秒；~2周)，待一周後大鼠以高劑量LTG(45毫克/公斤，i.p.)再次挑戰，以確保抗性。在3－4日的洗出期後，大鼠接受在以化合物#8(或載體)處理前每30分鐘傳送的2－3次超臨界刺激，以確保行為發作階段與放電後持續時間的穩定性。最終刺激的十五分鐘後，以i.p.投予單劑載體或測試化合物。15分鐘後，然後每30分鐘刺激每隻大鼠，共3至4小時。在每次刺激後，記錄個別發作評分與放電後持續時間。計算各參數的組平均±SEM。In the LTG-resistant amygdala challenge mode, rats were given LTG (5 mg/kg, i.p., q.d.) during the challenge acquisition phase. This dose has been shown to have no effect on the challenge itself, but results in the development of fully challenged rats that are resistant to the LTG anti-spasmodic effect. Once challenged (150 μA supercritical stimulation, biphasic 60 Hz current pulse for 1 second; ~2 weeks), rats were challenged again with high dose LTG (45 mg/kg, i.p.) after one week to ensure resistance. After the washout period of 3-4 days, the rats received 2-3 supercritical stimuli every 30 minutes before treatment with Compound #8 (or vehicle) to ensure stability during the behavioral phase and duration after discharge. Sex. Fifteen minutes after the final stimulation, a single dose of vehicle or test compound was administered as i.p. After 15 minutes, each rat was then stimulated every 30 minutes for a total of 3 to 4 hours. After each stimulation, individual seizure scores and duration after discharge were recorded. The group mean ± SEM of each parameter was calculated.

化合物#8(75毫克/公斤，i.p.，n＝9)明顯地減少發作評分與放電後持續時間。九隻大鼠中有八隻受到防護，使得發作評分從5降到0.8且放電後持續時間減少了86%(從73秒降至10秒)。九隻大鼠中有四隻在此劑量出現運動失調與鎮靜作用。Compound #8 (75 mg/kg, i.p., n=9) significantly reduced seizure scores and duration after discharge. Eight of the nine rats were protected, reducing the seizure score from 5 to 0.8 and the duration after discharge by 86% (from 73 seconds to 10 seconds). Four of the nine rats developed ataxia and sedation at this dose.

實施例18Example 18 尾部懸吊測試(急性)Tail suspension test (acute)

在評估化合物抗抑鬱劑活性的尾部懸吊測試(TST)中，使用夾子或透明膠帶將小鼠尾巴懸吊至金屬或塑膠桿。測試通常十分短暫，5－7分鐘，以人工或以自動化裝置記錄小鼠靜止不動的時間量。在本測試中，具有抗抑鬱劑活性的藥劑可減少小鼠靜止不動的持續時間。In the tail suspension test (TST) for assessing compound antidepressant activity, the mouse tail was suspended from a metal or plastic rod using a clip or scotch tape. The test is usually very brief, 5-7 minutes, and the amount of time the mouse is stationary is recorded manually or by automated means. In this test, an agent with antidepressant activity reduces the duration of immobility in the mouse.

尾部懸吊試驗的基本裝置包括一黃色塑膠隔室(91 x 45 x 10公分)，其分成25、20、20與25公分寬並以0.75公分厚黃色塑膠牆隔開的四個活動場所。小鼠尾巴係使用附在置於測試室頂端穿過其深度方向一半的塑膠桿的橡膠夾子(7公分長)懸吊。各實驗區段以錄影記錄並以電腦軟體("Depression Scan" Clever Sys Inc.)即時分析四隻動物。電腦對靜止不動的判斷係使用經羅拉西泮給藥的動物校正，而電腦對活動的判斷係使用經高劑量地昔帕明處理的動物校正。對照組(經載體處理的動物)及以化合物#8處理的動物係於該等校正設定下分析。設定係分別就暗色小鼠(CH3/HeJ與C57BI/6J品系)與白色小鼠(Balb/cJ與A/J品系)調整。黃色背景係用於暗色小鼠且藍色背景係用於記錄白色小鼠的活動。The basic device for the tail suspension test consisted of a yellow plastic compartment (91 x 45 x 10 cm) divided into four active spaces separated by 25, 20, 20 and 25 cm wide and separated by a 0.75 cm thick yellow plastic wall. The mouse tail was suspended using a rubber clip (7 cm long) attached to a plastic rod placed at the top of the test chamber through its depth direction. Each experimental section was recorded by video and analyzed immediately by computer software ("Depression Scan" Clever Sys Inc.) for four animals. The computer's judgment of standing still was corrected using animals administered with lorazepam, and the computer's judgment of activity was corrected using animals treated with high doses of desipramine. Controls (carrier-treated animals) and animals treated with Compound #8 were analyzed under these calibration settings. The settings were adjusted for dark mice (CH3/HeJ and C57BI/6J strains) and white mice (Balb/cJ and A/J strains). The yellow background was used for dark mice and the blue background was used to record the activity of white mice.

測試化合物減少靜止不動持續時間或增加活動的能力係使用上述TST程序測量。在TST中以臨床上有效的抗抑鬱劑及/或可能具有抗抑鬱劑特性的新穎化合物進行急性處理減少了靜止不動持續時間且同時增加活動性。The ability of a test compound to reduce static immobility duration or increase activity is measured using the TST procedure described above. Acute treatment with a clinically effective antidepressant and/or a novel compound that may have antidepressant properties in TST reduces the duration of restlessness while increasing mobility.

資料使用GraphPad Prism軟體(GraphPad Software,Inc.San Diego,CA)分析。為比較TST中各種藥物不同給藥量對靜止不動的效應，使用單因子變異數分析(ANOVA)，接著使用唐氏多重比較測試(Dunnett's multiple comparsion test)。使用非線性迴歸分析以單相指數衰退算式作曲線配合計算DMI、VLX、DLX與化合物#8的ED₅₀ 與E_max 值。ED₅₀ 與E_max 值係使用雙因子ANOVA與班氏事後檢定(Bonferroni post－hoc test)比對。Data were analyzed using GraphPad Prism software (GraphPad Software, Inc. San Diego, CA). To compare the effects of different doses of various drugs in TST on immobility, single factor analysis of variance (ANOVA) was used followed by Dunnett's multiple comparation test. The ED ₅₀ and E _max values of DMI, VLX, DLX and Compound #8 were calculated using a non-linear regression analysis using a single-phase exponential decay equation as a curve fit. ED ₅₀ and E _max values based two factor ANOVA with post test Bancroft (Bonferroni post-hoc test) comparison.

評估CH₃ /HeJ小鼠中不同抗抑鬱劑與化合物#8的劑量依存性。將化合物#8懸浮於0.5%甲基纖維素。正向對照組包括度洛西汀(duloxetine/DLX)、文拉法辛(VLX)與地昔帕明(DMI)(該等溶於0.5%甲基纖維素)以及羅拉西泮(LOR)(其以超音波振盪懸浮於溶於水之0.5%甲基纖維素中)。所有藥物與載體係以10毫升/公斤之體積經口(p.o.)餵食投予。Evaluation CH ₃ / HeJ mice of different antidepressants and Compound # 8 in a dose dependency. Compound #8 was suspended in 0.5% methylcellulose. The positive control group included duloxetine (DLX), venlafaxine (VLX) and desipramine (DMI) (these were dissolved in 0.5% methylcellulose) and lorazepam (LOR) ( It is suspended by ultrasonic vibration in 0.5% methylcellulose dissolved in water). All drugs and carriers were administered orally (po) in a volume of 10 ml/kg.

訂購5周大的小鼠，在實驗開始時小鼠體重為20±5克。動物以四隻一組飼養在塑膠籠內，周遭溫度21℃至23℃、自動化12/12小時晝/夜周期且無限制地取用水與市購的齧齒動物食物。Mice aged 5 weeks were ordered and the mice weighed 20 ± 5 grams at the start of the experiment. Animals were housed in plastic cages in groups of four, ambient temperature 21 ° C to 23 ° C, automated 12/12 hour day/night cycle and unlimited access to water and commercially available rodent food.

此組分成八個實驗，測試不同劑量的化合物#8、正向對照組(DMI,VLX,DLX)及5毫克/公斤負向對照組(LOR)的效應。每個實驗包括每組4隻動物的七個處理組。每個實驗使用總共28隻動物。每兩個連續實驗(1 & 2、3 & 4、5 & 6與7 & 8)是彼此的完全複製實驗。這造成研究結束時每個處理組共有八隻動物。在各實驗中一個有四隻動物的處理組為載體處理組。除了載體處理組以外，DMI(6毫克/公斤、12毫克/公斤、30毫克/公斤、60毫克/公斤與120毫克/公斤)與LOR(5毫克/公斤)的效應係以實驗1與2測試。實驗3與4係測試化合物#8(6毫克/公斤、12毫克/公斤、30毫克/公斤、60毫克/公斤、120毫克/公斤與240毫克/公斤)的效應。實驗5與6係測試DLX(6毫克/公斤、12毫克/公斤、30毫克/公斤、60毫克/公斤、120毫克/公斤)與LOR(5毫克/公斤)的效應。實驗7與8係測試VLX(6毫克/公斤、12毫克/公斤、30毫克/公斤、60毫克/公斤、120毫克/公斤)與LOR(5毫克/公斤)的效應。在研究過程中，在化合物#8 12毫克/公斤處理組的一隻小鼠因遺漏給藥而死亡，所以此組在研究結束時包括七隻動物。This component was tested in eight experiments to test the effects of different doses of Compound #8, positive control (DMI, VLX, DLX) and 5 mg/kg negative control (LOR). Each experiment included seven treatment groups of 4 animals per group. A total of 28 animals were used for each experiment. Every two consecutive experiments (1 & 2, 3 & 4, 5 & 6 and 7 & 8) are complete replication experiments with each other. This resulted in a total of eight animals per treatment group at the end of the study. A treatment group with four animals in each experiment was the vehicle treatment group. In addition to the vehicle treatment group, the effects of DMI (6 mg/kg, 12 mg/kg, 30 mg/kg, 60 mg/kg and 120 mg/kg) and LOR (5 mg/kg) were tested in experiments 1 and 2 . Experiments 3 and 4 tested the effects of Compound #8 (6 mg/kg, 12 mg/kg, 30 mg/kg, 60 mg/kg, 120 mg/kg and 240 mg/kg). Experiments 5 and 6 tested the effects of DLX (6 mg/kg, 12 mg/kg, 30 mg/kg, 60 mg/kg, 120 mg/kg) and LOR (5 mg/kg). Experiments 7 and 8 tested the effects of VLX (6 mg/kg, 12 mg/kg, 30 mg/kg, 60 mg/kg, 120 mg/kg) and LOR (5 mg/kg). During the course of the study, one mouse in the compound #8 12 mg/kg treatment group died due to omission, so this group included seven animals at the end of the study.

在CH3/HeJ小鼠的7－分鐘測試區段期間，化合物#8及所有測試抗抑鬱藥減少了靜止不動時間並增加了活動時間。化合物#8效應在12毫克/公斤、60毫克/公斤與120毫克/公斤有統計上的顯著性。顯著性係和以載體處理的平行對照組比較而決定。Compound #8 and all tested antidepressants reduced resting time and increased activity time during the 7-minute test session of CH3/HeJ mice. Compound #8 effect was statistically significant at 12 mg/kg, 60 mg/kg, and 120 mg/kg. The significance line was determined by comparison with the vehicle-treated parallel control group.

DMI效應在12、30、60與120毫克/公斤有統計上的顯著性。VLX效應在6、12、30、60與120毫克/公斤有統計上的顯著性。DLX效應在60與120毫克/公斤有統計上的顯著性。The DMI effect was statistically significant at 12, 30, 60 and 120 mg/kg. The VLX effect was statistically significant at 6, 12, 30, 60 and 120 mg/kg. The DLX effect was statistically significant at 60 and 120 mg/kg.

ED₅₀ 與E_max 值係以非線性迴歸分析由該等結果計算。ED₅₀ 與E_max 值係列於下方表5。就各處理靜止不動與活動計算的ED₅₀ 值並無統計顯著性。化合物#8的ED₅₀ 值明顯低於DLX的ED₅₀ 值，但與DMI與VLX的ED₅₀ 值並無不同。就靜止不動與活動計算的E_max 值於化合物#8並無明顯差異，但所有測試抗抑鬱劑皆有明顯差異。化合物#8的靜止不動E_max 值亦明顯低於抗抑鬱藥的值。The ED ₅₀ and E _max values were calculated from these results by nonlinear regression analysis. The ED ₅₀ and E _max values are summarized in Table 5 below. There was no statistical significance for the ED ₅₀ values calculated for each treatment stationary and activity. Compound 8 # ED ₅₀ values significantly lower than the value of ED DLX _50, but with the value of ED DMI and VLX ₅₀ is not different. There was no significant difference in E _max values calculated for stationary and activity in Compound #8, but all tested antidepressants were significantly different. The resting E _max value of Compound #8 was also significantly lower than the value of the antidepressant.

總言之，本實施例說明的研究顯示化合物#8具有類抗抑鬱劑活性，其係以尾部懸吊測量測試。在我們的研究條件下，化合物#8的ED₅₀ 經計算為3.6±2.9毫克/公斤且E_max 經計算為22.2±6.1%。In summary, the studies illustrated in this example show that Compound #8 has anti-depressant activity as a tail suspension measurement test. In our study conditions, Compound # ED 8 to ₅₀ was calculated to be 3.6 ± 2.9 mg / kg and the E _max calculated as 22.2 ± 6.1%.

實施例19Example 19 強迫游泳測試(急性)Forced swimming test (acute)

強迫游泳測試(FST)是篩選化合物之可能抗抑鬱特性的常用程序。此測試亦習知為行為絕望測試。置於充滿水的普通水槽內的齧齒動物呈現各式各樣的脫逃或靜止不動行為。不同種類的抗抑鬱藥顯著地增加脫逃行為及/或減少靜止不動的潛伏期或持續時間。由於該等效應是臨床上有活性的抗抑鬱劑所特有的，所以顯示該類效應而臨床活性不明的化合物被解讀成具有治療人類情緒病症的潛力。The Forced Swimming Test (FST) is a common procedure for screening for possible antidepressant properties of a compound. This test is also known as a behavioral despair test. Rodents placed in ordinary water-filled sinks exhibit a variety of escape or stationary behavior. Different types of antidepressants significantly increase escape behavior and/or reduce the latency or duration of restlessness. Since these effects are characteristic of clinically active antidepressants, compounds exhibiting such effects with unknown clinical activity are interpreted as having the potential to treat human mood disorders.

將化合物#8與麥普替林(maprotyline)溶於10%聚乙二醇硬脂酸酯(Solutol)。將文拉法辛與地昔帕明溶於水。所有藥物及其載體以5毫升/公斤之體積經口餵食(p.o.)投予。Compound #8 and maprotyline were dissolved in 10% polyethylene glycol stearate (Solutol). Venlafaxine and desipramine are dissolved in water. All drugs and their carriers were administered orally (p.o.) in a volume of 5 ml/kg.

使用購自Charles River Laboratories Wilmington,MA的雄性SD大鼠(140至160克)。在投至實驗程序之前讓動物經歷五天隔離期。Male SD rats (140 to 160 grams) purchased from Charles River Laboratories Wilmington, MA were used. Animals were subjected to a five-day isolation period prior to the experimental procedure.

動物以四隻一組飼養在塑膠籠內，周遭溫度21℃至23℃、自動化12/12小時晝/夜周期且無限制地取用水與市購的齧齒動物食物。除例行更換墊料外，在預測試游泳區段前不搬動動物。Animals were housed in plastic cages in groups of four, ambient temperature 21 ° C to 23 ° C, automated 12/12 hour day/night cycle and unlimited access to water and commercially available rodent food. Except for routine replacement of litter, animals are not moved before the pre-test swimming section.

研究分成六個實驗，測試不同劑量之化合物#8、三個正向對照組(地昔帕明、麥普替林、文拉法辛)與一個負向對照組(羅拉西泮)的效應。每個實驗包括每組4隻動物的七個處理組。每個實驗使用總共28隻動物。兩個連續實驗(1與2、3與4及5與6)是彼此的完全複製實驗。這造成研究結束時每個處理組共有八隻動物。各實驗中有一個四隻動物的處理組為載體處理組。除了載體處理組以外，地昔帕明(3毫克/公斤、6毫克/公斤、12毫克/公斤、30毫克/公斤與60毫克/公斤)及羅拉西泮(1毫克/公斤)的效應係於實驗1與2測試。實驗3與4係測試化合物#8(3毫克/公斤、6毫克/公斤、12毫克/公斤、30毫克/公斤、60毫克/公斤與120毫克/公斤)的效應。實驗5與6係測試文拉法辛與麥普替林(12毫克/公斤、30毫克/公斤與60毫克/公斤)的效應。在研究過程中，在地昔帕明12毫克/公斤處理組的一隻小鼠因遺漏給藥而死亡，所以此組在研究結束時包括七隻動物。The study was divided into six experiments to test the effects of different doses of Compound #8, three positive control groups (desipramine, metoprine, venlafaxine) and one negative control group (Lolacitin). Each experiment included seven treatment groups of 4 animals per group. A total of 28 animals were used for each experiment. Two consecutive experiments (1 and 2, 3 and 4 and 5 and 6) were complete replication experiments with each other. This resulted in a total of eight animals per treatment group at the end of the study. A treatment group of four animals in each experiment was a vehicle treatment group. In addition to the vehicle treatment group, the effects of desipramine (3 mg/kg, 6 mg/kg, 12 mg/kg, 30 mg/kg and 60 mg/kg) and lorazepam (1 mg/kg) were Experiments 1 and 2 were tested. Experiments 3 and 4 tested the effects of Compound #8 (3 mg/kg, 6 mg/kg, 12 mg/kg, 30 mg/kg, 60 mg/kg and 120 mg/kg). Experiments 5 and 6 tested the effects of venlafaxine and maprotiline (12 mg/kg, 30 mg/kg and 60 mg/kg). During the study, one mouse in the desipramine 12 mg/kg treatment group died as a result of omission, so this group included seven animals at the end of the study.

基本裝置包括裝水30公分深、溫度為25±1℃的圓柱體(46公分高x~20公分直徑)。使用FST的自動化版本進行實驗。用於自動填充及清空水的管路連接四個圓柱體。圓柱體係放置於25公分寬的分隔室內，以視覺上隔開動物。各個5分鐘實驗區段以錄影記錄並以電腦軟體(Clever Systems,Inc.)一次即時分析四隻動物。以該軟體記錄靜止不動、游泳、攀爬與脫逃的時間。四種活動係定義如下。靜止不動：動物靜止不動地漂浮或僅做為保持其頭部在水面上所必需的動作；攀爬：動物抓著圍繞圓柱體的牆壁激烈地垂直移動；游泳：動物以超過為保持其頭部在水面上所必需的程度在圓柱體內來回水平移動；及脫逃：所有激烈主動動作的總和。The basic unit consists of a cylinder (46 cm high x 20 cm diameter) with a water depth of 30 cm and a temperature of 25 ± 1 °C. Experiment with the automated version of FST. The tubing used to automatically fill and empty the water connects the four cylinders. The cylindrical system was placed in a 25 cm wide compartment to visually separate the animals. Each 5-minute experimental section was recorded by video and analyzed in real time by computer software (Clever Systems, Inc.) for four animals. Use this software to record the time of standing still, swimming, climbing and escape. The four activity lines are defined as follows. Static: The animal floats still or acts only as necessary to keep its head on the water; climbing: the animal is moving vertically and vertically against the wall of the cylinder; swimming: the animal keeps its head with more than The degree necessary on the water surface moves horizontally back and forth in the cylinder; and escape: the sum of all intense active actions.

測試化合物減少靜止不動的持續時間或頻率或改變游泳、攀爬與脫逃時間的能力係使用上述FST程序測量。當在預測試區段與測試區段之間投予時，臨床上有效的抗抑鬱劑及/或具有潛在抗抑鬱特性的新穎化合物在FST中減少了靜止不動的持續時間或頻率。所說明的此研究結果分析係集中在5分鐘測試區段期間內的靜止不動時間。The ability of a test compound to reduce the duration or frequency of immobility or to change the time of swimming, climbing and escape is measured using the FST procedure described above. When administered between the pre-test segment and the test segment, clinically effective antidepressants and/or novel compounds with potential antidepressant properties reduce the duration or frequency of immobility in the FST. The results of this study described are focused on the stationary time during the 5-minute test session.

每個實驗中有兩個游泳區段。首先，進行15分鐘的預測試游泳區段。接下來的48小時後是歷時5分鐘的測試區段。待游泳區段完成後，立刻把每隻動物放進鋪有柔軟墊料籠子裡的加熱燈下大約15分鐘，以避免體溫過低。There are two swimming sections in each experiment. First, a 15-minute pre-test swim section was performed. The next 48 hours is a test session that lasts 5 minutes. Immediately after the swimming section is completed, place each animal under a heat lamp in a soft padded cage for approximately 15 minutes to avoid hypothermia.

在完成預測試游泳區段之後、稍後24小時後及稍後在5分鐘測試區段不久前，以載體或測試化合物預先處理動物；亦即在發生在3個連續日的兩段游泳區段之間給予每隻動物三次注射。測試區段前的時間就地昔帕明、麥普替林、文拉法辛、羅拉西泮而言為1小時或就化合物#8而言為4小時；最大電擊發作(MES)測試中的最大效應時間。The animal is pretreated with the vehicle or test compound shortly after completion of the pretest swimming section, 24 hours later and later in the 5 minute test section; that is, in two swimming sections occurring on 3 consecutive days Three injections were given to each animal. The time before the test section was 1 hour in the case of in situ simvamin, meptintin, venlafaxine, and lorazepam or 4 hours in the case of compound #8; in the maximum shock attack (MES) test Maximum effect time.

資料使用GraphPad Prism軟體(GraphPad Software,Inc.San Diego,CA)分析。為比較FST中各種藥物不同給藥量對靜止不動的效應，使用單因子ANOVA，接著使用唐氏多重比較測試。使用非線性迴歸分析以單相指數衰退算式作曲線配合計算地昔帕明與化合物#8的ED₅₀ 與E_max 值。使用雙側t－測試以統計比對ED₅₀ 與E_max 值。Data were analyzed using GraphPad Prism software (GraphPad Software, Inc. San Diego, CA). To compare the effect of different doses of various drugs in the FST on immobility, single factor ANOVA was used followed by Down's multiple comparison test. The ED ₅₀ and E _max values of desipramine and Compound #8 were calculated using a non-linear regression analysis using a single-phase exponential decay formula as a curve fit. Using two-sided statistical t- test ₅₀ and the ratio of E _max value of ED.

所有測試抗抑鬱藥減少了5分鐘測試區段期間的靜止不動時間。地昔帕明效應在6毫克/公斤、12毫克/公斤、30毫克/公斤與60毫克/公斤有統計上的顯著性。地昔帕明經計算之ED₅₀ 為2.0±0.1毫克/公斤(CI＝1.3－3.3毫克/公斤)且其E_max 為50.0±8.4秒(CI＝31.8－57.7)。相較於經載體處理的對照組，化合物#8的處理效果在12毫克/公斤、60毫克/公斤與120毫克/公斤有統計上的顯著性。個別大鼠之間的極大變異性致使30毫克/公斤劑量之化合物#8的效應和對照組無明顯不同。因此，30毫克/公斤劑量的靜止不動現象資料不使用在ED₅₀ 計算。化合物#8經計算之ED₅₀ 為5.6±0.6毫克/公斤(CI＝2.2－15.6毫克/公斤)且其E_max 為67.0±11.6秒(CI＝30.3－103.8)。化合物#8的ED₅₀ 值明顯異於地昔帕明的ED₅₀ 值，p<0.001(雙側t－測試)。地昔帕明與化合物#8的E_max 值則無統計上的顯著差異。文拉法辛與麥普替林(正向對照組)係以12毫克/公斤、30毫克/公斤與60毫克/公斤三種劑量測試。就文拉法辛與麥普替林兩者而言，以30毫克/公斤與60毫克/公斤劑量處理之動物的靜止不動現象明顯異於經載體處理的對照組。然而，資料點不足，故無法算出該二藥物的ED₅₀ 。羅拉西泮(負向對照組)係以1毫克/公斤測試且對測試區段期間的大鼠靜止不動時間並無顯示明顯效應。結果指出化合物#8在FST中具有類抗抑鬱劑活性。All tested antidepressants reduced the resting time during the 5 minute test session. The desipramine effect was statistically significant at 6 mg/kg, 12 mg/kg, 30 mg/kg, and 60 mg/kg. The ED ₅₀ calculated by desipramine was 2.0 ± 0.1 mg / kg (CI = 1.3 - 3.3 mg / kg) and its E _max was 50.0 ± 8.4 seconds (CI = 31.8-57.7). The treatment effect of Compound #8 was statistically significant at 12 mg/kg, 60 mg/kg, and 120 mg/kg as compared to the vehicle-treated control group. The great variability between individual rats resulted in a no significant difference between the effect of Compound #8 at 30 mg/kg dose and the control group. Therefore, the static immobility data for the 30 mg/kg dose is not used in the ED ₅₀ calculation. The calculated ED ₅₀ for Compound #8 was 5.6 ± 0.6 mg/kg (CI = 2.2-15.6 mg/kg) and its E _max was 67.0 ± 11.6 seconds (CI = 30.3 - 103.8). ED ₅₀ value of the compound 8 # ED ₅₀ values significantly different from desipramine, p <0.001 (two-sided t- test). There was no statistically significant difference in the _Emax values of desipramine and Compound #8. Venlafaxine and metoprolin (forward control) were tested at three doses of 12 mg/kg, 30 mg/kg and 60 mg/kg. For both venlafaxine and maprotiline, the immobility of animals treated at doses of 30 mg/kg and 60 mg/kg was significantly different from the vehicle-treated control group. However, the data points are insufficient, so the ED _{50 of} the two drugs cannot be calculated. Lorazepam (negative control) was tested at 1 mg/kg and showed no significant effect on the resting time of the rat during the test period. The results indicate that Compound #8 has an anti-depressant activity in the FST.

實施例20 慢性溫和壓力模式(慢性)Example 20 Chronic mild stress mode (chronic)

在慢性溫和壓力(CMS)模式中，長時間遭受各式溫和壓力源的大鼠顯現出－在其他行為、生物化學與生理學損傷當中－其對獎勵刺激的反應性大為降低。此缺失通常以1%蔗糖溶液消耗減少來監測，但亦可以其他測試查看，例如位置偏好制約性或自我顱內電擊。由於對獎勵的次發性敏感度似乎反映了快感缺乏(不能感受愉悅)－其為重鬱症的核心症狀，所以CMS程序可作為抗抑鬱作用機制研究中的適宜研究工具。In chronic mild stress (CMS) mode, rats exposed to a variety of mild stressors for a long time - in other behavioral, biochemical, and physiological lesions - are significantly less responsive to reward stimuli. This deficiency is usually monitored as a 1% reduction in sucrose solution consumption, but can also be viewed in other tests, such as position preference constraints or self-intracranial shocks. Since the secondary sensitivity to rewards seems to reflect a lack of pleasure (not feeling pleasure) - it is a core symptom of severe depression, the CMS program can be used as a suitable research tool in the study of antidepressant mechanisms.

雄性溫斯特(Wistar)大鼠在實驗開始兩個月前帶至實驗室。除下文說明外，動物係單獨飼養，可自由取用食物與水並維持於12小時晝/夜及固定的溫度(22±2℃)與濕度(50±5%)條件。Male Wistar rats were brought to the laboratory two months before the start of the experiment. Except as described below, the animals were housed separately and were free to access food and water and maintained at 12 hours day/night and fixed temperature (22 ± 2 ° C) and humidity (50 ± 5%).

首先訓練動物消耗1%蔗糖溶液；訓練包括八次1小時的基線測試，其中蔗糖係出現在居住籠中，接著14小時禁食物禁水；蔗糖攝取係藉由在測試結束時秤已預先秤重的含蔗糖溶液瓶子的重量來測量。之後，蔗糖的消耗係於整個實驗中以每周為區間在類似條件下監測。The animals were first trained to consume 1% sucrose solution; the training consisted of eight 1-hour baseline tests in which the sucrose system appeared in the living cage, followed by a 14-hour ban on food; the sucrose intake was pre-weighed by the end of the test. The weight of the sucrose-containing solution bottle is measured. Thereafter, the consumption of sucrose was monitored throughout the experiment in a weekly interval under similar conditions.

以其於最終測試基線中的蔗糖攝取為基礎，將動物分成兩個相稱組。對一組動物施加連續7周的慢性溫和壓力程序。每周的壓力方案包括：兩段禁食或禁水期、兩段45度籠子傾斜時期、兩段間歇照明(每隔2小時開燈或關燈)時期、兩段髒污籠子時期(加250毫升水至鋸木屑墊料)、一段成對飼養時期、兩段低強度頻閃照明(每分鐘閃150次)時期及三段無壓力時期。所有壓力源歷時10－14小時且係個別連續地日夜施加。對照組動物關在分別空間內且不接觸遭受壓力動物。在每次蔗糖測試前，對照組動物被禁食禁水14小時，但除此之外在居住籠內可自由地取用食物與水。Animals were divided into two proportional groups based on their sucrose uptake in the final test baseline. A chronic mild stress program for 7 weeks was applied to a group of animals. The weekly stress program includes: two fast or water-free periods, two 45-degree cage tilt periods, two intermittent illuminations (turning lights on or off every 2 hours), and two dirty cage periods (plus 250) ML water to sawdust litter), a pair of feeding period, two low-intensity stroboscopic lighting (150 flashes per minute) and three periods of no stress. All pressure sources were applied for 10-14 hours and were applied individually and continuously day and night. Control animals were housed in separate spaces and were not exposed to stressed animals. Before each sucrose test, the control animals were fasted and banned for 14 hours, but otherwise free access to food and water was obtained in the living cage.

以其在最初2周壓力後的蔗糖攝取為基礎，遭受壓力動物與對照組動物各又分成相稱的亞組(n＝8)，接下來的五周，該等動物接受一天一次腹腔內投予載體(0.5%甲基纖維素，1毫升/公斤)、化合物#8(12毫克/公斤、30毫克/公斤或60毫克/公斤)、作為參考處理的伊米帕明(10克/公斤)或文拉法辛(10毫克/公斤)。藥物大約在10.00投予，每周的蔗糖測試係於最後一次藥物注射24小時後進行。五周之後，停止所有處理，24小時後，收集所有動物的血液及/或腦部樣本並送至進一步的生物化學分析。壓力在整個處理期期間皆持續。Based on the sucrose intake after the first 2 weeks of stress, the stressed and control animals were subdivided into commensurate subgroups (n=8), and the animals received intraperitoneal administration once a day for the next five weeks. Carrier (0.5% methylcellulose, 1 ml/kg), Compound #8 (12 mg/kg, 30 mg/kg or 60 mg/kg), imipramine (10 g/kg) as a reference or Venlafaxine (10 mg/kg). The drug is administered at approximately 10.00 and the weekly sucrose test is performed 24 hours after the last drug injection. After five weeks, all treatments were stopped and after 24 hours, blood and/or brain samples of all animals were collected and sent to further biochemical analysis. Stress persists throughout the treatment period.

動物係個別從其居住空間移至另一空間以供犧牲。然後以半隨機順序將其斷頭。犧牲之後立刻將全腦移出、急速冷凍於乾冰/正庚烷並儲存在－70℃、塑膠小瓶內。將欲取血漿的驅幹血收集到含有EDTA(大約1.6毫克/毫升血液)的EDTA管中。該EDTA血直接以1500 xg於4℃離心10分鐘。將血漿吸出並儲存在微量管內及－70℃。此外，準備2批取自空白動物的20毫升血漿以產生供生物分析用的化合物標準曲線。Animals are individually moved from their living space to another space for sacrifice. Then break it in a semi-random order. Immediately after sacrifice, the whole brain was removed, rapidly frozen in dry ice/n-heptane and stored in a -70 ° C, plastic vial. The dried blood to be taken from the plasma was collected into an EDTA tube containing EDTA (about 1.6 mg/ml blood). The EDTA blood was centrifuged directly at 1500 xg for 10 minutes at 4 °C. Plasma was aspirated and stored in microtubes at -70 °C. In addition, 2 batches of 20 ml of plasma taken from blank animals were prepared to generate a standard curve for the compound for bioassay.

本研究獲得的所有結果係以三個受試者間因素(壓力/對照組、藥物處理與相繼的蔗糖測試)藉由變異數多重分析來分析。費雪LSD測試係用於平均值的事後比對。All results obtained in this study were analyzed by three-subject factors (pressure/control, drug treatment, and successive sucrose tests) by variability analysis. The Fisher LSD test is used for post hoc comparison of the mean.

慢性溫和壓力造成1%蔗糖溶液消耗量逐漸減少。在最終基線測試中，所有動物飲用大約11克蔗糖溶液。在最初2周壓力後，對照組的攝取量維持在類似位準，但遭受壓力動物的攝取量下降至大約6克，產生顯著的群組效應[F(1,84)＝87.204；p<0.001]。以載體處理的對照組和遭受壓力動物之間的該類差異在其餘實驗仍維持於類似位準。Chronic mild stress causes a gradual decrease in the consumption of 1% sucrose solution. In the final baseline test, all animals drank approximately 11 grams of sucrose solution. After the first 2 weeks of stress, the intake of the control group was maintained at a similar level, but the intake of stressed animals decreased to approximately 6 grams, resulting in a significant group effect [F (1, 84) = 87.204; p < 0.001 ]. This type of difference between the vehicle-treated control group and the stressed animal remained at a similar level in the remaining experiments.

和載體投藥相比，伊米帕明 於對照組動物無活性[處理效應：F(1,84)＝1.578；NS]且於遭受壓力動物造成顯著的處理效應：F(1,84)＝22.651；p<0.001與處理x周數交互作用：F(5,84)＝2.717；p＝0.025]。同樣地，文拉法辛 於對照組動物無活性[處理效應：F(1,84)＝0.208；NS]且於遭受壓力動物造成顯著的處理效應：F(1,84)＝35,724；p<0.001與處理x周數交互作用：F(5,84)＝3.219；p＝0.010]。Compared with vehicle administration, imipramine was inactive in the control animals [treatment effect: F(1,84)=1.578; NS] and caused significant treatment effects in stressed animals: F(1,84)=22.651 ;p<0.001 interacts with the number of weeks of treatment: F(5,84)=2.717; p=0.025]. Similarly, venlafaxine was inactive in the control animals [treatment effect: F(1,84)=0.208; NS] and caused significant treatment effects in stressed animals: F(1,84)=35,724; p< 0.001 interacts with the number of weeks of treatment: F (5, 84) = 3.219; p = 0.010].

和第0周評分相比，遭受壓力動物對蔗糖攝取的增加在以伊米帕明(p<0.05)與文拉法辛(p<0.01)處理四周後達到統計顯著性，而且此效應之後仍繼續維持。一隻遭受壓力動物(第480號)對文拉法辛處理沒反應，但統計分析並無排除該動物。Compared with the 0th week score, the increase in sucrose uptake in stressed animals reached statistical significance after four weeks of treatment with imipramine (p<0.05) and venlafaxine (p<0.01), and this effect remained after Continue to maintain. A stressed animal (No. 480) did not respond to venlafaxine treatment, but the statistical analysis did not exclude the animal.

和載體投藥相比，化合物#8於對照組動物[F(3,168)＝1.198；NS]及遭受壓力動物[F(3,168)＝1.676；NS]並無造成顯著的處理效應，指出該化合物在CMS抑鬱模式中無活性。Compared with the vehicle administration, Compound #8 did not cause significant treatment effects in the control animals [F(3,168)=1.198; NS] and the stressed animals [F(3,168)=1.676; NS], indicating that the compound was in CMS. Inactive in depression mode.

實施例21Example 21 居留者/入侵者試驗(亦習知為慢性社會壓力試驗)Resident/intruder trial (also known as chronic social stress test)

行為性居留者/入侵者試驗係用來篩選化合物的類抗抑鬱劑活性。化合物#8係於本試驗中測試，試驗係根據Rygula,R.,Abumaria,N.,Fiugge,G.,Fuchs,E.,Ruther,E.,Havemann－Reinecke,U.,Behavioral Brain Research, 162(2005),pp127－134中所描述的程序進行。The Behavioral Resident/Intruder Test is used to screen for antidepressant activity of the compound. Compound #8 was tested in this test according to Rygula, R., Abumaria, N., Fiugge, G., Fuchs, E., Ruther, E., Havemann-Reinecke, U., Behavioral Brain Research, 162 (2005), the procedure described in pp 127-134.

下方表5、6與7列出下列化合物測量參數的平均值與標準誤差值，p.o.(口服)投予的載體、對照化合物10毫克/公斤伊米帕明與10毫克/公斤文拉法辛、60毫克/公斤化合物#8與120毫克/公斤化合物#8。Tables 5, 6 and 7 below list the mean and standard error values for the following compound measurement parameters, po (oral) administered vehicle, control compound 10 mg/kg imipramine and 10 mg/kg venlafaxine, 60 mg/kg compound #8 with 120 mg/kg compound #8.

化合物#8在居留者/入侵者試驗中有活性，顯示化合物#8被預期具有抗抑鬱劑活性。Compound #8 was active in the Resident/Invaders test, indicating that Compound #8 is expected to have antidepressant activity.

實施例22Example 22

作為口服組成物的特定具體例，如實施例7中製備的100毫克化合物#8係以充分切細的乳糖調配，以提供填充O型尺寸硬膠囊錠的580至590毫克總量。As a specific specific example of the oral composition, 100 mg of Compound #8 prepared as in Example 7 was formulated with fully finely divided lactose to provide a total amount of 580 to 590 mg of the O-sized hard capsule.

雖然先前說明書係教示本發明原理並且為了例示提供實施例，但將被暸解到的是本發明之實行係涵蓋所有落於下列申請專利範圍及其等效範圍的範疇之內的常見變化、改編及/或修飾。While the description of the present invention is intended to be illustrative of the embodiments of the invention and the embodiments of the invention / or modification.

Claims

一種式(I)化合物或其藥學上可接受之鹽於製造用以治療躁狂之醫藥品的用途，其中R¹ 與R² 係各別獨立地選自於由氫與C_1-4 烷基所構成的群組；R⁴ 係選自於由氫與C_1-4 烷基所構成的群組；a為1至2之整數；係：其中b為0至4之整數；各個R⁵ 係獨立地選自於由鹵素與C_1-4 烷基所構成的群組。A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating mania, Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and a C _1-4 alkyl group; and R ⁴ is selected from the group consisting of hydrogen and a C _1-4 alkyl group; a is an integer from 1 to 2; system: Wherein b is an integer from 0 to 4; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl.

如申請專利範圍第1項之用途，其中R¹ 與R² 係各別獨立地選自於由氫與C_1-4 烷基所構成的群組；R⁴ 係選自於由氫與C_1-4 烷基所構成的群組；a為1至2之整數；係：其中b為0至2之整數；各個R⁵ 係獨立地選自於由鹵素與C_1-4 烷基所構成的群組。The use of claim 1, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and a C _1-4 alkyl group; and R ⁴ is selected from the group consisting of hydrogen and C _{1 a} group consisting of _-4 alkyl groups; a is an integer from 1 to 2; system: Wherein b is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl.

如申請專利範圍第1項之用途，其中R¹ 與R² 係各別獨立地選自於由氫與C_1-4 烷基所構成的群組；R⁴ 係選自於由氫與甲基所構成的群組；a為1至2之整數；係選自於由下列所構成的群組：2-(2,3-二氫-苯并[1,4]二基)、2-(6-氯基-2,3-二氫-苯并[1,4]二基)、2-(6-氟基-2,3-二氫-苯并[1,4]二基)、2-(5-氟基-2,3-二氫-苯并[1,4]二基)、2-(7-氯基-2,3-二氫-苯并[1,4]二基)、2-(7-甲基-2,3-二氫-苯并[1,4]二基)、2-(5-氯基-2,3-二氫-苯并[1,4]二基)、2-(6-溴基-2,3-二氫-苯并[1,4]二基)、2-(6,7-二氯基-2,3-二氫-苯并[1,4]二基)與2-(8-氯基-2,3-二氫-苯并[1,4]二基)。The use of claim 1, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; and R ⁴ is selected from hydrogen and methyl. a group formed; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-fluoro-2,3-dihydro-benzo[1,4] Base, 2-(5-fluoro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] Base, 2-(5-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] Base, 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] And 2-(8-chloro-2,3-dihydro-benzo[1,4] base).

如申請專利範圍第1項之用途，其中R¹ 與R² 係各別獨立地選自於由氫與甲基所構成的群組；R⁴ 係選自於由氫與甲基所構成的群組；a為1至2之整數；係選自於由下列所構成的群組：2-(2,3-二氫-苯并[1,4]二基)、2-(6-氯基-2,3-二氫-苯并[1,4]二基)、2-(7-氯基-2,3-二氫-苯并[1,4]二基)、2-(7-1甲基-2,3-二氫-苯并[1,4]二基)、2-(6-溴基-2,3-二氫-苯并[1,4]二基)與2-(6,7-二氯基-2,3-二氫-苯并[1,4]二基)。The use of claim 1, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and methyl; and R ⁴ is selected from the group consisting of hydrogen and methyl. Group; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-1-methyl-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] And 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] base).

如申請專利範圍第1項之用途，其中該式(I)化合物係選自於由(2S)-(-)-N-(6-氯基-2,3-二氫-苯并[1,4]二-2-基甲基)-磺醯胺所構成的群組；及其藥學上可接受之鹽。The use of the formula (1), wherein the compound of the formula (I) is selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1, 4] two a group consisting of -2-ylmethyl)-sulfonamide; and a pharmaceutically acceptable salt thereof.

一種(2S)-(-)-N-(6-氯基-2,3-二氫-苯并[1,4]二-2-基甲基)-磺醯胺或其藥學上可接受之鹽於製造用以治療躁狂之醫藥品的用途。(2S)-(-)-N-(6-Chloro-2,3-dihydro-benzo[1,4] Use of -2-ylmethyl)-sulfonamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating mania.

一種式(I)化合物或其藥學上可接受之鹽於製造用以治療兩極病症之醫藥品的用途，其中 R¹ 與R² 係各別獨立地選自於由氫與C_1-4 烷基所構成的群組；R⁴ 係選自於由氫與C_1-4 烷基所構成的群組；a為1至2之整數；係：其中b為0至4之整數；各個R⁵ 係獨立地選自於由鹵素與C_1-4 烷基所構成的群組。A use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a bipolar disorder, Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and a C _1-4 alkyl group; and R ⁴ is selected from the group consisting of hydrogen and a C _1-4 alkyl group; a is an integer from 1 to 2; system: Wherein b is an integer from 0 to 4; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl.

如申請專利範圍第7項之用途，其中R¹ 與R² 係各別獨立地選自於由氫與C_1-4 烷基所構成的群組；R⁴ 係選自於由氫與C_1-4 烷基所構成的群組；a為1至2之整數；係：其中b為0至2之整數；各個R⁵ 係獨立地選自於由鹵素與C_1-4 烷基。The use of claim 7, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and a C _1-4 alkyl group; and R ⁴ is selected from the group consisting of hydrogen and C _{1 a} group consisting of _-4 alkyl groups; a is an integer from 1 to 2; system: Wherein b is an integer from 0 to 2; each R ⁵ is independently selected from halo and C _1-4 alkyl.

如申請專利範圍第7項之用途，其中R¹ 與R² 係各別獨立地選自於由氫與C_1-4 烷基所構成的群組；R⁴ 係選自於由氫與甲基所構成的群組；a為1至2之整數；係選自於由下列所構成的群組：2-(2,3-二氫-苯并[1,4]二基)、2-(6-氯基-2,3-二氫-苯并[1,4]二基)、2-(6-氟基-2,3-二氫-苯并[1,4]二基)、2-(5-氟基-2,3-二氫-苯并[1,4]二基)、2-(7-氯基-2,3-二氫-苯并[1,4]二基)、2-(7-甲基-2,3-二氫-苯并[1,4]二基)、2-(5-氯基-2,3-二氫-苯并[1,4]二基)、2-(6-溴基-2,3-二氫-苯并[1,4]二基)、2-(6,7-二氯基-2,3-二氫-苯并[1,4]二基)與2-(8-氯基-2,3-二氫-苯并[1,4]二基)。The use of claim 7, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; and R ⁴ is selected from hydrogen and methyl. a group formed; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-fluoro-2,3-dihydro-benzo[1,4] Base, 2-(5-fluoro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] Base, 2-(5-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] Base, 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] And 2-(8-chloro-2,3-dihydro-benzo[1,4] base).

如申請專利範圍第9項之用途，其中R¹ 與R² 係各別獨立地選自於由氫與甲基所構成的群組；R⁴ 係選自於由氫與甲基所構成的群組；a為1至2之整數；係選自於由下列所構成的群組：2-(2,3-二氫-苯并[1,4]二基)、2-(6-氯基-2,3-二氫-苯并[1,4]二基)、 2-(7-氯基-2,3-二氫-苯并[1,4]二基)、2-(7-1甲基-2,3-二氫-苯并[1,4]二基)、2-(6-溴基-2,3-二氫-苯并[1,4]二基)與2-(6,7-二氯基-2,3-二氫-苯并[1,4]二基)。The use of claim 9, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and methyl; and R ⁴ is selected from the group consisting of hydrogen and methyl. Group; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-1-methyl-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] And 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] base).

如申請專利範圍第7項之用途，其中該式(I)化合物係選自於由(2S)-(-)-N-(6-氯基-2,3-二氫-苯并[1,4]二-2-基甲基)-磺醯胺所構成的群組；及其藥學上可接受之鹽。The use of the seventh aspect of the invention, wherein the compound of the formula (I) is selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1, 4] two a group consisting of -2-ylmethyl)-sulfonamide; and a pharmaceutically acceptable salt thereof.

如申請專利範圍第7項之用途，其中治療兩極病症係包含治療兩極病症的抑鬱及躁狂。 For example, the use of the scope of claim 7 wherein the treatment of bipolar disorder comprises depression and mania for treating a bipolar disorder.

如申請專利範圍第7項之用途，其中治療兩極病症係包含治療兩極病症的抑鬱、躁狂及循環。 The use of claim 7 wherein the therapeutic bipolar disorder comprises depression, mania, and circulation for treating a bipolar disorder.

一種(2S)-(-)-N-(6-氯基-2,3-二氫-苯并[1,4]二-2-基甲基)-磺醯胺或其藥學上可接受之鹽於製造用以治療兩極病症之醫藥品的用途。(2S)-(-)-N-(6-Chloro-2,3-dihydro-benzo[1,4] Use of -2-ylmethyl)-sulfonamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a bipolar disorder.

如申請專利範圍第14項之用途，其中治療兩極病症係包含治療兩極病症的抑鬱及躁狂。 For example, the use of the scope of claim 14 wherein the treatment of bipolar disorder comprises depression and mania for treating a bipolar disorder.

如申請專利範圍第14項之用途，其中治療兩極病症係包含治療兩極病症的抑鬱、躁狂及循環。 The use of claim 14 wherein the therapeutic bipolar disorder comprises depression, mania, and circulation for treating a bipolar disorder.

一種式(I)化合物或其藥學上可接受之鹽於製造用以治療兩極型抑鬱之醫藥品的用途，其中R¹ 與R² 係各別獨立地選自於由氫與C_1-4 烷基所構成的群組；R⁴ 係選自於由氫與C_1-4 烷基所構成的群組；a為1至2之整數；係：其中b為0至4之整數；各個R⁵ 係獨立地選自於由鹵素與C_1-4 烷基所構成的群組。A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of bipolar depression, Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and a C _1-4 alkyl group; and R ⁴ is selected from the group consisting of hydrogen and a C _1-4 alkyl group; a is an integer from 1 to 2; system: Wherein b is an integer from 0 to 4; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl.

如申請專利範圍第17項之用途，其中R¹ 與R² 係各別獨立地選自於由氫與C_1-4 烷基所構成的群組；R⁴ 係選自於由氫與C_1-4 烷基所構成的群組；a為1至2之整數；係：其中b為0至2之整數；各個R⁵ 係獨立地選自於由鹵素與C_1-4 烷基所構成的群組。The use of claim 17, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; and R ⁴ is selected from hydrogen and C _{1 a} group consisting of _-4 alkyl groups; a is an integer from 1 to 2; system: Wherein b is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl.

如申請專利範圍第17項之用途，其中R¹ 與R² 係各別獨立地選自於由氫與C_1-4 烷基所構成的群組；R⁴ 係選自於由氫與甲基所構成的群組；a為1至2之整數；係選自於由下列所構成的群組：2-(2,3-二氫-苯并[1,4]二基)、2-(6-氯基-2,3-二氫-苯并[1,4]二基)、2-(6-氟基-2,3-二氫-苯并[1,4]二基)、2-(5-氟基-2,3-二氫-苯并[1,4]二基)、2-(7-氯基-2,3-二氫-苯并[1,4]二基)、2-(7-甲基-2,3-二氫-苯并[1,4]二基)、2-(5-氯基-2,3-二氫-苯并[1,4]二基)、2-(6-溴基-2,3-二氫-苯并[1,4]二基)、2-(6,7-二氯基-2,3-二氫-苯并[1,4]二基)、2-(8-氯基-2,3-二氫-苯并[1,4]二基)、2-(2,3-二氫-萘并[2,3-b][1,4]二基)與2-(4-甲基-苯并[1,3]二唑基)。The use of claim 17, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; and R ⁴ is selected from hydrogen and methyl. a group formed; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-fluoro-2,3-dihydro-benzo[1,4] Base, 2-(5-fluoro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] Base, 2-(5-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] Base, 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] Base, 2-(8-chloro-2,3-dihydro-benzo[1,4] Base, 2-(2,3-dihydro-naphtho[2,3-b][1,4] And 2-(4-methyl-benzo[1,3] Azolyl).

如申請專利範圍第19項之用途，其中R¹ 與R² 係各別獨立地選自於由氫與甲基所構成的群組；R⁴ 係選自於由氫與甲基所構成的群組；a為1至2之整數；係選自於由下列所構成的群組：2-(2,3-二氫-苯并[1,4]二基)、2-(6-氯基-2,3-二氫-苯并[1,4]二基)、2-(7-氯基-2,3-二氫-苯并[1,4]二基)、2-(7-1甲基-2,3-二氫-苯并[1,4]二基)、2-(6-溴基-2,3-二氫-苯并[1,4]二基)與2-(6,7-二氯基-2,3-二氫-苯并[1,4]二基)。The use of claim 19, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and methyl; and R ⁴ is selected from the group consisting of hydrogen and methyl. Group; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-1-methyl-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] And 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] base).

如申請專利範圍第17項之用途，其中該式(I)化合物係選自於由(2S)-(-)-N-(6-氯基-2,3-二氫-苯并[1,4]二-2-基甲基)-磺醯胺所構成的群組；及其藥學上可接受之鹽。The use according to claim 17, wherein the compound of the formula (I) is selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1, 4] two a group consisting of -2-ylmethyl)-sulfonamide; and a pharmaceutically acceptable salt thereof.

一種(2S)-(-)-N-(6-氯基-2,3-二氫-苯并[1,4]二-2-基甲基)-磺醯胺或其藥學上可接受之鹽於製造用以治療兩極型抑鬱之醫藥品的用途。(2S)-(-)-N-(6-Chloro-2,3-dihydro-benzo[1,4] Use of -2-ylmethyl)-sulphonamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of bipolar depression.