TW200808300A - Use of benzo-heteroaryl sulfamide derivatives for the treatment of disease modification/epileptogenesis - Google Patents

Abstract

The present invention is a use for the manufacture of a medicament for treating, preventing, reversing, arresting or inhibiting the occurrence, development and maturation of seizures or seizure-related disorders. More specifically, the present invention is directed to a use of benzo-heteroaryl sulfamide derivatives of formula (I) as described herein for the manufacture of a medicament for treating, preventing, reversing, arresting or inhibiting epileptogenesis and epilepsy.

Description

200808300 九、發明說明： 【發明所屬之技術領域】 本發明係關於苯并-雜芳基磺醯二胺衍生物用於治 療^預防、逆轉、停止或抑制癲癇發作或與癲癇發作相關 的p爭礙之电生、發展及成熟之用途。更確定地說，本發明 係關於苯并’雜芳麟酿二胺衍生物醫療性賴防性地治 療、預防、逆轉、停止或抑舰癲性及_之方法。 【先前技術】 、中樞神經(CNS)或末梢神經系統(pNS)不同種類的傷害 或創傷會產生深遠且長久的神經及精神性症狀與障礙。產 生這些效應的常見機制是在CNS或在pNS的神經及神經 節中誘發癲癇發作活性或類癲癇發作的現象。在CNS或 PNS電子活性中的症狀性或發作性阻礙，癲癇發作或類癲 癇發作的神經機制咸信在多種神經及精神障礙中引起許多 病理現象。 癲癇發作特徵的一個嚴重神經病情是癲癇。癲癇單在 美國疋景》響超過兩百五十萬人的一種常見但有毀滅性的障 礙。癲癇是描述一種病情其中一個人因為慢性、引發的歷 程而有再發生的癲癇發作。癲癇係指一種臨床現象而不是 一個單獨的疾病實體，因為癲癇有許多形式及原因。使用 癲癇的定義作為二或多個無緣無故的癲癇發作，在世界不 同人口中癲躺發生率估狀約（U至〇.5%，癲癇的盛行 率估計每1000人中約5至10人。 在臨床及腦造影術現象的基準上，可以再細分成四種 5 200808300 癲癇發作：大發作癲癇的癲癇發作(子集：全身性局限性 傑克森性)、小發作癲癇的癲癇發作、精神運動性或顯葉性 癲癇發作(子集：有不良或扭轉移動或p且嚼現象的精神運 動、自動有遺忘症、或感覺有幻覺或做夢狀態)及自主神經 系統或間腦性癲癇發作(有潮紅、蒼白、心跳太快、高血壓、 出汗或其他内臟的症狀）。 雖然癲癇是與癲癇發作相關的障礙之其中一種主要的 φ 實例，多種神經及精神上的症狀與障礙根據其原因有癲癎 發作或相關類似癲癇發作的神經現象。簡單地說，痛痛發 作或相關類似癲癇發作的神經現象是經由稱為「猝發 (ictogenesis)」的歷程從神經元或癲癇發作易受影響的神經 兀群之收集過度電子釋放所造成的單一獨立的臨床事件。 據此，猝發的癲癇發作僅是一種疾病之徵狀。但是，癲癇 及其他類似與癲癇發作相關的障礙是動態且通常持續性的 疾病，具有複雜且了解很少的結果之病理轉化特徵之—種 _ 成熟歷程。 Μ 此種變化之發展及成熟是「致癲性」的歷程，正常大 腦較大量收集神經元因而被改變且隨後變成容易被不正 常、自動、突然、復發、過量電子放電影響，也就是 發=°致癲性歷程之成熟導致r致癲性焦點」之發展厂; 正常放電的神經元或容易被癲癇發作影響的神經元之收夢 形成局部的群組或「致癲癇區」散佈再整個外皮組織中本 致癲癇區是生物化學性相互連接，所以不正常的猝三 可以在各區之間級聯。 ^孜黾 200808300 至於致癲癇的歷程，神經系統牽涉的區域變成更易被 癲癇發作影響且其變成更料引發癲癇發作，導致_發 作或與癲癇發作相關的障礙之持續性虛弱症狀。 雖然猝發及致癲性在多種疾病之部份生物化學 常見神經通道中有共同的來源，兩種歷程並不相同◊猝發 是癲癇發作在獨立的時間及空間之引發及傳送，一個快速 且敢終的電子/化學事件其發生時間歷經數秒鐘至數分鐘: 比較地，致癲性是一種漸進的生物化學或神經改組歷 程，其中正常的大腦經由猝發的事件轉化成致癲性集中的 大腦，神經電路變成敏化且與猝發事件相關，使得個體漸 進地受到自動、片段、有限時間的痛痛發作影響，導致痛 癇發作或與癲癇發作相關的障礙之持續性虛弱症狀及持續 性對治療無反應。「致癲性焦點」之成熟是一個缓慢的生 物化學及/或結構的歷程其通常發生歷經數月致數年。 致癲性是一個兩階段的歷程：「第1階段的致癲性」 疋引發第一次癲痛性癲癇發作或類似與癲癇發作相關的障 礙之症狀之前的致癲性歷程，且經常是大腦某些種類的傷 害或創傷之結果，例如中風、疾病(例如感染例如腦膜炎）、 或創傷例如意外擊中頭部或在大腦進行的手術。「第2階 段的致癲性」係指大腦組織已經受到癲癇性癲癇發作或類 似與癲癇發作相關的障礙之癲癇發作相關的現象影響，變 成更容易受到癲癇發作影響而增加頻率及/或嚴重性及/或 變成對治療較無反應之歷程。 雖然涉及致癲性的歷程還未明確地鑑定，部份研究者 7 200808300 咸#涉及經由N-甲基天冬胺酸鹽(NMDA)受體仲介的 神經几之間的刺激性偶合之上調節。其他研究者認為與神 了元間之抑制偶聯的向下調節、受到，胺基_丁酸(GABA) 受體調節有關。許多其他因子可能涉及此歷程，包括腿（氧 化氮)或鐵、鈣或鋅離子之存在、濃度或活性。 雖然癲癇性癲癇發作很少致命，大量的病人需要藥物 f法以避免破壞性及潛在危險性的癲癇發作後果。在許多 • 情形中，用於管理癲癇性癲癇發作或類似與癲癇發作相關 的障礙之症狀需要長期的藥物療法，且在部份情形中，病 人生必須持續使用此處方的藥物。而且，此藥劑只是對 於症狀之管理有效，而且長期使用伴隨著副作用。 —現有多種藥劑用於管理癲癇性癲癇發作，包括較舊的 藥劑例如苯妥英、丙戊酸酯及又癲寧(鐵通道阻滯劑），以 及較新的藥劑例如費巴美(felbamate)、加巴本丁 (gabapentin)、多比瑞美(topiramate)及帝加賓(tiagabine)。此 • 外，例如β-丙胺酸經報告具有抗癲癇發作活性、NMDA抑 制活性及GAB A能刺激活性，但是尚未臨床用於治療癲癇。 用於治療癲癇的接受藥劑是抗抽搐劑，或更適當地稱 為抗癲癇性藥劑(AEDs)，其中「抗癲癇性」一詞係與「抗 癲癇發作」或「抗猝發性」同義。這些藥劑經由阻止單一 猝發性事件之引發而在醫療上抑制癲癇發作。但是這些在 臨床上有供應的AED，s無法預防致癲性之歷程。 在治療癲癇發作或類似與癲癇發作相關的障礙之相關 的症狀時，也就是具有類似癲癇發作的神經現象之疾病或 8 200808300 障礙其明顯與_發作障礙相關，例如雙相性情感障礙之 情緒循環、在神_動控辦礙的病人之神經衝動性行為 或源自大腦傷害之癲癇發作，部份AEDs也具有醫療效 用但疋’現在核准的這些AED，s無法預防性《醫療性防 止引I致舰之發展或持續性_核癲縣點，此點也 在類似與癲癇發作相關的病症證實。200808300 IX. INSTRUCTIONS: [Technical Field] The present invention relates to a benzo-heteroarylsulfonamide derivative for treating, preventing, reversing, stopping or inhibiting seizures or relating to seizures The use of electricity, development and maturity. More specifically, the present invention relates to a method for medically treating, preventing, reversing, stopping, or inhibiting epilepsy of benzo-indene diamine derivatives. [Prior Art] Different types of injuries or traumas of the central nervous system (CNS) or peripheral nervous system (pNS) can produce profound and long-lasting neurological and psychiatric symptoms and disorders. A common mechanism for producing these effects is the induction of seizure activity or seizure-like seizures in the CNS or in the nerves and ganglia of the pNS. Symptomatic or episodes in the electronic activity of the CNS or PNS, the neurological mechanisms of seizures or seizures cause many pathological phenomena in a variety of neurological and psychiatric disorders. A serious neurological condition characterized by seizures is epilepsy. Epilepsy alone has a common but devastating barrier to more than 2.5 million people in the United States. Epilepsy is a seizure that describes a condition in which a person relapses because of a chronic, triggered history. Epilepsy refers to a clinical phenomenon rather than a separate disease entity because epilepsy has many forms and causes. The definition of epilepsy is used as two or more seizures for no reason, and the incidence of seizures in different populations around the world is estimated to be about 5%. The prevalence of epilepsy is estimated to be about 5 to 10 per 1,000 people. On the basis of clinical and cerebral angiography, it can be further subdivided into four types. 200808300 seizures: seizures of epileptic seizures (subset: systemic localized Jackson), seizures of seizures, psychomotors Sexual or lobular seizures (subset: mental movements with poor or torsional movements or p and chewing, automatic amnesia, or feeling hallucinations or dreaming) and autonomic or diencephalic seizures (with Flushing, paleness, rapid heartbeat, high blood pressure, sweating, or other visceral symptoms. Although epilepsy is one of the major φ examples of disorders associated with seizures, multiple neurological and psychiatric symptoms and disorders are based on their causes. A neurological phenomenon with epileptic seizures or related seizures. Simply put, a painful episode or a neurological phenomenon associated with a seizure is called "ictogenesis" The course of a single independent clinical event caused by the excessive electron release from the collection of neuronal or seizure-sensitive neural crests. According to this, seizures are only a symptom of the disease. However, epilepsy and other similar The disorder associated with seizures is a dynamic and often persistent disease with a complex and poorly understood pathological transformation characteristic of the species _ maturity history. 发展 The development and maturity of this change is the epileptic process Larger amounts of neurons collected in the normal brain are thus altered and subsequently become susceptible to abnormal, automatic, sudden, recurrent, and excessive electrical discharges, that is, the development of the epileptic process leading to the development of the epileptic focus. The normal discharge of neurons or neurons that are easily affected by seizures form a local group or "epileptic area". The entire epithelial tissue is biochemically interconnected, so it is abnormal. The third can be cascaded between the districts. ^孜黾200808300 As for the course of epilepsy, the area involved in the nervous system becomes It is susceptible to seizures and it becomes a more persistent symptom of seizures, leading to _ episodes or persistent weakness associated with seizures. Although bursts and epilepsy are common in some biochemical common neural pathways in many diseases The source, the two processes are not the same. Hair is the initiation and transmission of seizures in independent time and space. A fast and daring electronic/chemical event takes place from a few seconds to a few minutes: comparatively, epileptic Sex is a gradual biochemical or neurological reorganization process in which a normal brain is transformed into a brain that is epileptically concentrated through a burst of events, and the neural circuits become sensitized and associated with burst events, causing the individual to progressively be automated, fragmented, and limited. The effects of painful episodes of time lead to persistent signs of weakness or persistentness of painful episodes or disorders associated with seizures that do not respond to treatment. The maturity of the "epileptic focus" is a slow process of biochemistry and/or structure that usually occurs over several months. Epilepticity is a two-stage process: "Phenomena of epilism in stage 1" causes an epileptic process before the first epileptic seizure or symptoms similar to those associated with seizures, and is often the brain The result of certain types of injury or trauma, such as a stroke, a disease (such as an infection such as meningitis), or a trauma such as an accidental hit on the head or surgery in the brain. "Phase 2 epilepsy" refers to a phenomenon in which brain tissue has been affected by epileptic seizures or seizures similar to those associated with seizures, becoming more susceptible to seizures and increasing frequency and/or severity. And / or become less reactive to treatment. Although the process involved in epilepticity has not been clearly identified, some investigators 7 200808300 咸# are involved in the regulation of stimulatory coupling between nerves via N-methyl aspartate (NMDA) receptors. . Other investigators believe that down-regulation of inhibition coupling with divine elements is associated with regulation of amino-butyric acid (GABA) receptors. Many other factors may be involved in this process, including the presence, concentration or activity of the legs (nitrogen oxides) or iron, calcium or zinc ions. Although epileptic seizures are rarely fatal, a large number of patients require medication f to avoid the consequences of destructive and potentially dangerous seizures. In many cases, the symptoms of managing epileptic seizures or similar disorders associated with seizures require long-term drug therapy, and in some cases, the patient must continue to use the drug here. Moreover, this agent is only effective for the management of symptoms, and long-term use is accompanied by side effects. - A variety of agents are available for the management of epileptic seizures, including older agents such as phenytoin, valproate and retinal (iron channel blockers), as well as newer agents such as felbamate, plus Gabapentin, topiramate and tiagabine. In addition, for example, β-alanine has been reported to have anti-seizure activity, NMDA inhibitory activity, and GAB A stimulating activity, but has not been clinically used for the treatment of epilepsy. The agents used for the treatment of epilepsy are anticonvulsants, or more appropriately, anti-epileptic agents (AEDs), wherein the term "anti-epileptic" is synonymous with "anti-seizure" or "anti-caries". These agents medically inhibit seizures by preventing the initiation of a single burst event. However, these clinically available AEDs do not prevent the pathogenesis of epilepsy. In the treatment of seizures or symptoms associated with disorders associated with seizures, ie diseases with neurological phenomena similar to seizures or 8 200808300 disorders, which are clearly associated with _ episodes of disorders, such as the emotional cycle of bipolar disorder, Some of the AEDs have medical effects in the neuro-acoustic behavior of patients who are motivated by the dynasty, or some of the AEDs that are now approved, but they are not preventable. Development or persistence _ nuclear epilepsy point, this point is also confirmed by similar conditions associated with seizures.

對於引起致癲性了解很少的病理機制當然在多種臨床 情況下參與癲癇發作及類似與_發作相_病症之發 展’包括自動發展或多種中樞或末梢神經系統之傷害或 傷之結要。 从目别的癲癇治療是集中在明顯的臨床癲癇發展後經由 投樂AEDs抑制癲癇發作活性。雖然AEDs在抑制瘤痛發 作時具有正面效應，現有的藥劑無法全面地成功預防致痛 性，也就是癲癇及其他類似與癲癇相關的疾病之發展或進 行及惡化。即㈣細5航纽，無紗止神㈣統受 傷或創傷後發展癲癇。而且，如果停止AED 旅、 癇發作通常復發且在不幸的情形下，隨時間惡化：目、 臨床上沒有方法祕治療、預防、逆轉、停止或抑制= 或其他癲癇疾病或許多類似與癲癇相關的障礙之笋及^ 或進行。 & 此外，也相信對應於致癲性的類似神經機制 沒有出現為明顯「癲癇」的臨床上類似於_ = 癇發作相關的障礙之進化及發展，例如在雙相性 〃 /、 神經衝動㈣障礙、強迫症、精神***症、物 9 200808300 及:神及神經障礙中說明的成熟疾病中觀 察的取初發展及持績性惡化。Pathological mechanisms that are less known to cause epilepsy are of course involved in seizures and similar developments in a variety of clinical situations, including the development of autopsy or multiple central or peripheral nervous system injuries or injuries. The treatment of epilepsy from the eye is focused on the inhibition of seizure activity via the AEDs after significant clinical epilepsy development. Although AEDs have a positive effect in inhibiting the onset of neonatal pain, existing agents are not fully successful in preventing pain, which is the development or progression and progression of epilepsy and other similar epilepsy-related diseases. That is, (4) fine 5 navigation, no yarn to stop the god (four) unified injury or post-traumatic development of epilepsy. Moreover, if the AED brigade is stopped, seizures usually recur and in an unfortunate situation worsen over time: there is no method of treatment, prevention, reversal, cessation or inhibition = or other epilepsy or many similar epilepsy-related Shoot the bamboo shoots and ^ or proceed. & In addition, it is believed that the similar neural mechanisms corresponding to epilepticity do not appear to be clinically similar to the evolution and development of _= epileptic seizure-related disorders, such as bipolar 〃 /, nerve impulse (4) disorders , obsessive-compulsive disorder, schizophrenia, substance 9 200808300 and: the initial development and deterioration of performance observed in mature diseases described in divine and neurological disorders.

據匕，雖“、、:現有夕種藥劑用於治療痛痛(也就是經由抑 制猝發癲癇，也就是伴隨著癲癇發作之減)及其他類似斑 癲癇發作相關的障礙，沒有全面性可接受的藥劑用於治療、 預防、逆轉、知止或抑制引起致癲性的歷程，其在許多毁 滅性的神缺精雜礙例如細及驗與赫發作相關的 障礙包括雙相性情感障礙中可能猝發。 目則’沒有已知的方法可抑制致癲性的歷程，在尚未 在臨床上顯現其症狀，但是在孙道的情形下患有該疾病 或有發展該疾病的風險之病人巾祕預防赫或其他類似 與癲癇發作相關轉礙。此外，沒有已知的方法可預防致 癲顯性之發展或逆轉其歷程，據此將在來源或肖受影響或 可參與癲雜作活性的致細區域神經元之㈣，轉化成 沒有顯現不正常、自動、突然、復發或過度電子釋放或不 易受影響或可具有此癲癇發作活性之神經組織。而且，沒 有核准或未核准的藥劑已知具有此抗致癲性質，也就是實 際的抗致癲性藥劑(AEGDs)(見 Schmidt，D. and R〇gawski， Μ·A” EpilepSy Research，2〇〇2, 50; 71-78)。 據此，較宜除了在已經表現這些症狀的病人中抑制癲 癇發作或抽搐或與癲癇發作相關的症狀之外，有很大的需 求去研發安全且有效的藥劑或人^^^及治療方法其可以有 放地/α療、預防、停止、抑制及/或逆轉在與癲癇發作相關 的神經及/或精神障礙中的致癲性。 200808300 【發明内容】 發明概述 本發明係關於式(I)化合物 其中According to sputum, although ",,: the existing medicinal agent for the treatment of pain (that is, by inhibiting epileptic seizures, that is, with the reduction of seizures) and other similar plaque-related disorders, there is no comprehensive acceptable The agent is used to treat, prevent, reverse, stop, or inhibit the pathogenesis that causes epilepsy, which may be manifested in many devastating dysfunctions such as dysfunction and dysfunction associated with Hershes, including bipolar disorder. The goal is that there is no known method to inhibit the epileptic process, but the symptoms have not yet appeared in the clinic, but in the case of Sun Dao, the patient has the disease or has the risk of developing the disease. Other similarities are associated with seizures. In addition, there are no known methods to prevent the development of epileptic or to reverse the course of the episode, which will result in a fine-grained regional nerve that is affected or may be involved in the activity of the epileptic activity. Yuan (4), transformed into nerve tissue that does not show abnormal, automatic, sudden, recurrent or excessive electron release or is not easily affected or may have this seizure activity. Approved or unapproved agents are known to have this anti-epileptic property, ie actual anti-epileptic agents (AEGDs) (see Schmidt, D. and R〇gawski, Μ·A) EpilepSy Research, 2〇〇2 , 50; 71-78). Accordingly, in addition to inhibiting seizures or convulsions or symptoms associated with seizures in patients who have already exhibited these symptoms, there is a great need to develop safe and effective agents or humans and treatments. There may be locus/alpha therapy, prevention, cessation, inhibition, and/or reversal of epilepticity in neurological and/or psychiatric disorders associated with seizures. SUMMARY OF THE INVENTION The present invention relates to compounds of formula (I) wherein

(1) 硝基及氰基； X-Y 是選自包括-S-CH-、-S_C(CH3；K -0-CH-、 -〇-C(CH3)、-N(CH3>ch-及-CH=CH-CH-; A是選自包括-CH2-及-CH(CH3)-; r2是選自包括氫及甲基； R及R4是各獨立地選自包括氫及Ci 4烷基； 口或者是，R3及R4 —起與和其鍵結的氮原子形成5至 7貝飽和、部份不飽和或芳族環結構，視需要含有一至三 個獨立地選自包括0、M s之其他雜原子； ▲或其藥學上可接受的鹽，製造藥劑用於治療、預防、 停止、抑制及/或逆轉致癲性之用途。 在-個具體實施例中，本發明係關於醫療有效量本文 ⑴化合物製造藥劑在與癲癇發作相關的神經及/ 或精神P早礙中用於治療、預防、停止 癲性之崎。 、卩似或轉致 200808300 在另一個具體實施例中，本發明係關於製造藥劑在有 發展癲癇、癲癇發作障礙或類似與癲癇發作相關的障礙的 風險之病人巾用於治療、預防、停止、抑制及/或 癲性之用途。 w欠 ^另一個具體實施例中，本發明係關於製造藥劑在對 其有而要的病人巾用於治療及預防癲癇發作及與癲痛發 作相關的障礙之改良用途。此用it包括將醫療有效量之'本 春文揭示在受實驗者t治療及預防癲癇發作、抽搐或與 發作相關的障礙出現且同時抑制致癲性的任何化合物、。 在本發明之-個具體實施例中，將預防或醫療有效旦 在已經顯現障礙的症狀之病人中用於預防或治療痛痛發里 作、抽搐或與癲癇發作相關的障礙之含有一或多種^ 化合物並摻混藥學上可接受的載劑或賦形冑之醫藥=成 物投藥至對此治療有需要的受實驗者。 在另-個具體實施例中，將預防或醫療有效量用於 _ 防、治療、逆轉、停止及/或抑制致癲性之含有一戋夕 式(I)化合物並摻混藥學上可接受的載魏賦形劑之^ 組成物投藥至軸AEGD 射需要㈣實驗者。勺二 至少-種式(I)化合物及一或多種藥學上可接 二 之醫藥組成物係投藥至有需要該治療的受實賦形別 本發明還關於醫療有效量的至少一種合適的藥劑與 至少=種本文揭示的式⑴化合物製造藥綱於治療預 防、停止、抑制及/或逆轉致癲性之用途。 “ 發明之詳細說 12 200808300 本發明係關於式(i)化合物(1) Nitro and cyano; XY is selected from the group consisting of -S-CH-, -S_C(CH3; K-0-CH-, -〇-C(CH3), -N(CH3>ch- and -CH) =CH-CH-; A is selected from the group consisting of -CH2- and -CH(CH3)-; r2 is selected from the group consisting of hydrogen and methyl; R and R4 are each independently selected from the group consisting of hydrogen and Ci 4 alkyl; Alternatively, R3 and R4 together with the nitrogen atom bonded thereto form a 5 to 7-shell saturated, partially unsaturated or aromatic ring structure, optionally containing one to three independently selected from the group consisting of 0, M s a heteroatom; ▲ or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment, prevention, cessation, inhibition and/or reversal of epileptic properties. In a specific embodiment, the invention relates to a medically effective amount herein (1) A compound-producing agent for treating, preventing, or stopping epilepsy in a neurological and/or mental P-related disorder associated with seizures. 卩 或 转 转 808 200808300 In another embodiment, the present invention relates to Manufacture of a medicament for the treatment, prevention, cessation, inhibition, and/or epilepsy of a patient having a risk of developing epilepsy, seizure disorder, or similar disorder associated with seizures In another specific embodiment, the present invention relates to an improved use of a medicament for the manufacture of a medicament for treating and preventing seizures and disorders associated with epileptic seizures. A medically effective amount of 'this spring' reveals any compound that is treated in the subject and that prevents seizures, convulsions, or episodes associated with seizures while inhibiting epileptogenicity. In a particular embodiment of the invention For the prevention or treatment of painful, convulsions or seizure-related disorders in a patient who has developed symptoms of the disorder and which contains one or more compounds and is pharmaceutically acceptable. Carrier or Formed Medicine = The subject is administered to the subject in need of this treatment. In another specific embodiment, a prophylactic or medically effective amount is used for prevention, treatment, reversal, cessation, and/or Or inhibiting epilepticity of a compound containing a compound of formula (I) and admixing a pharmaceutically acceptable carrier containing a Wei excipient to a shaft AEGD. (4) The experimenter. Scoop 2 at least one species (I) Compound One or more pharmaceutically acceptable pharmaceutical compositions are administered to a subject in need of such treatment. The invention also relates to a medically effective amount of at least one suitable agent and at least = a compound of formula (1) disclosed herein. The invention relates to the use of therapeutic prevention, cessation, inhibition and/or reversal of epilepsy. "Details of the Invention 12 200808300 The present invention relates to a compound of the formula (i)

〇々〇 n、r3 R (I) 或其藥學上可接受的鹽，其中R1、R2、R3、R4、-X-Y_ φ 及Α是根據文中的定義，製造藥劑用於治療及/或預防致 癲性、癲癇及相關的障礙之用途。 式(I)化合物是抗抽搐劑且可以抑制癲癇性癲癇發 作。此外，式(I)化合物經不熟練地發現是強力的抗致癲 性化合物，其可以在容許癲癇發作及相關的現象發生及/ 或散播之神經系統中預防病理變化之開始發展及成熟。式 (I)化合物還可以逆轉從致癲性產生的變化。據此，本發 明之式(I)化合物在本發明的方法中使用時，是真實的抗 _ 致癲性藥劑(AEGDs)且具有任何現在核准的AED藥劑明 顯不同且沒有的性質。 ▲本务明因此係關於製造藥劑用於治療、預防、逆轉、 停止及/或抑制致癲性之用途。在某些具體實施例中，這 二用返包括將預防或醫療有效量的式⑴化合物投藥至對 其有需要之受實驗者。 從事此項技藝者將了解預防或醫療性投藥本文揭示 =何化合物用於治療、·、抑制、逆轉或停止致癲性 ，將進行/収以確妓實驗者是否罹患癲癇或類似與 13 200808300 癲癇發作相關轉礙或認為是树展此麵發作或與痛 癎發作相關的病症之高風險。 ’、、、 在本發明之-個具體實施例中，對治療有需要的受實 驗者或病人可以是已經顯現癲癇症狀的受治療者，也就是 癲癇發作或抽搐，或可以是在投藥之_現類似與痛痛發 作相關的障礙的症狀之受實驗者。 、又〇々〇n, r3 R (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, -X-Y_ φ and oxime are used to treat and/or prevent a medicament according to the definition herein Uses for epilepsy, epilepsy and related disorders. The compound of formula (I) is an anticonvulsant and can inhibit epileptic seizures. Furthermore, the compounds of formula (I) have been unskilled to be potent anti-epileptic compounds which can develop and mature at the onset of preventing pathological changes in the nervous system which allows seizures and associated phenomena to occur and/or spread. The compounds of formula (I) can also reverse the changes resulting from the epilepticity. Accordingly, the compounds of formula (I) of the present invention, when used in the methods of the present invention, are true anti-epileptic agents (AEGDs) and have significantly different and non-existing properties of any currently approved AED agents. ▲This is a use of pharmaceuticals for the treatment, prevention, reversal, cessation and/or inhibition of epilepticity. In certain embodiments, the dual use comprises administering a prophylactically or medically effective amount of a compound of formula (1) to a subject in need thereof. Those skilled in the art will be aware of preventive or medical administration. This article reveals: what compounds are used to treat, inhibit, reverse or stop epilepsy, will be carried out / to determine whether the tester has epilepsy or similar with 13 200808300 epilepsy A seizure-related disorder is considered to be a high risk of developing a disease in this area or a condition associated with a seizure. ',,, in a specific embodiment of the present invention, the subject or patient in need of treatment may be a subject who has developed symptoms of epilepsy, that is, seizures or seizures, or may be in the administration of medicine_ Subjects who are similar to the symptoms of the disorder associated with the onset of pain. ,also

在本發明之另-個具體實施例中，需要用抗致廟性藥 劑(AEG聯療的受倾錢紅可从尚棚現義或 類似與癲麟仙_障礙之受實驗者，也 作或抽搐之前投^ g 再體貫施例中，對治療有需要㈣ ^驗者或病人在投藥時將測試是否有發展癲癇或類㈣ 癲癇發作相_障礙之顺，且娜此 AEGD治療的病人。 勹疋而要月 個频實_巾，本购是關於製造藥劑用於^ 制、停止及/或逆轉致癲性之用途，不論是 引發及/或根本的原因。 個频料财，本㈣難本 ==姆發展_或任何種類的 生傷ί 3傷障礙但是因㈣經系統發 向或务現一或多種這些障礙經證實的生 發展癲癇發作或類似與癲癇發作相關的障^風險:病 200808300 ，、:Γ防、延轉、停止及/或抑制致癲性之用途。 之=口 ί致痛性時，本發明方法可以預先阻止癲癇發作In another embodiment of the present invention, it is necessary to use an anti-miao agent (AEG combined therapy for the money to be red-skinned from the shack or similar to the person with the epilepsy _ obstacle, also for or Before convulsions, in the case of re-integration, there is a need for treatment (4). The tester or patient will test whether there is development of epilepsy or class (4) seizure phase _ disorder, and patients treated with AEGD.勹疋 要 月 月 月 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Difficulty == 姆development _ or any kind of birth injury ί 3 injury disorder but because of (4) through the system to send or to present one or more of these disorders confirmed birth development seizures or similar disorders associated with seizures risk: disease 200808300,,: use of preventing, delaying, stopping, and/or inhibiting epilepticity. The method of the present invention can prevent seizures in advance when the mouth is painful.

舰軌輔齡狀魏），降低在 ^實驗者的_之嚴重性及逆轉在_巾的致癲性之歷 程。 止 此外，經由根據本發财法轉、獅、抑制停止 癲性，其猝發是部份或整個基於類癲癇發作 的作用機歡_㈣驗/或精神轉蚊發展或進 行，可以被治療、預防、抑制、停止及/或逆轉。 在本文中使㈣，「致癲性」—觸指生物化學、遺 傳、組織或其他結構㈣魏性縣或變化，其造成神經 組織，包括中樞神經系統(CNS)容易受到復發、自動的^ 癇發作影響。料，「致舰」_詞在本文中也在更廣義 下用於表示造成在患有細或其他_發轉礙或類似 與癲癇發作相關的障礙的病人中觀察到的臨床進行之變 化及/或齡，包括但不限於：障礙或其症狀之惡化或進 行或「致癲性」之發展，其中該障礙因為神經生物學的變 化而變成更難治療，造成降低藥劑敏性或非癲癇發作傾向 的神經組織之至癲癇性的歷程之募集。 而且，「致癲性」-詞在最廣義下在本文中使用時係 15 200808300 =顯f癲癇障礙的表徵或症狀隨著時間持續性惡化之 象’匕括精神性障礙其猝發顯示與癲癇發作相關。 在本文中使用時，「致癲性之抑制 減緩、停止及/歧概麵性之聽。1射日預防、 、在本文中使用時，「抗致癲性藥劑」及縮寫「AEGD」 當投藥至對其有需要之受實驗者時，可以抑制致 癲性的樂劑。 一 j本文中使用知，「抽搐障礙」及「癲癇發作障礙」 種障礙其中該受實驗者患有抽搐，例如因為癲 =癲癇發作之抽搐。抽搐障礙包括但不限於癲癇及非痛 癇性抽搐，例如因駿餘·或毒素至受實驗者造 抽搐。 「在本文巾使㈣，「類似與赫發作相_障礙」或 癲癇相關的癲癇發作樣神經現象」一詞係指一種神經障 ，或精神障礙其顯現少許或沒有明顯的癲癇發作活性但 疋仍然相健錢或部份魏細發作或相_的神經機 制之結果且其通常發現可以用AEDs治療。 在本文中使用時，「受實驗者」一詞係指動物，較宜 是哺乳動物，最宜是人類，其是治療、觀察或實驗之標的。 ，本文中使用時，「受實驗者」或r病人」_詞也包括受 只1¾者，較且疋人類，其尚未顯現癲癇或類似與癲癇發作 相關的障礙之症狀但是高風險族群。 在本文中使用時，「需要用AEGD治療的受實驗者」 一詞包括有曾經或現在有癲癇、癲癇發作障礙或類似與癲 16 200808300 癎相關的癲癇發作例如神經現象或癲癇發作相關的障礙、 或任何障礙其中病人存在的臨床情形或預後可以從壓制 或抑制致癲性之歷程得到益處以防止延伸、進展、惡化或 增加任何神經或精神障礙治療的抵抗性之任何個體。The ship's post-aged Wei) reduces the severity of the experimenter's _ and reverses the epilepticity of the towel. In addition, through the transfer of funds according to this method of financing, lions, inhibition of epilepsy, the burst is part or all of the seizure-based action of the machine _ (four) test / or mental mosquito development or progress, can be treated, prevent , suppress, stop, and/or reverse. In this paper, (4), "epileptic" - refers to biochemical, genetic, tissue or other structures (4) Weixian County or changes, which cause nervous tissue, including the central nervous system (CNS) to be susceptible to recurrence, automatic epilepsy Attack effects. The term "to the ship" is also used in this context to mean, in a broader sense, the clinical changes that are observed in patients with fine or other dysfunction or similar disorders associated with seizures and/ Or age, including but not limited to: progression of the disorder or its symptoms or progression or "epileptic", which becomes more difficult to treat due to changes in neurobiology, resulting in reduced drug sensitivity or non-seizure tendency The recruitment of neural tissue to the epileptic process. Moreover, the term "epileptic" - the word used in the broadest sense in this article is 15 200808300 = the manifestation of symptoms or symptoms of epilepsy worsening over time - including mental disorders, their manifestations and seizures Related. As used herein, "inhibition of epilepticity is slowed down, stopped, and/or ambiguous. 1 shot prevention, when used herein, "anti-epileptic drug" and abbreviation "AEGD" when administered When it is necessary for the subject to be tested, the epileptic agent can be inhibited. A j used in this article, "convulsive disorder" and "seizure disorder", in which the subject suffers from convulsions, for example, because of epileptic seizures. Convulsion disorders include, but are not limited to, epilepsy and non-painful convulsions, such as convulsions due to Jun Yu· or toxins to the subject. "In this article, (4), the term "epileptic-like neuropathy associated with epilepticus or disorder" or epilepsy refers to a type of neurological disorder, or a mental disorder that exhibits little or no seizure activity but remains The result of a neural mechanism of health or partial sputum or phase and which is usually found to be treatable with AEDs. As used herein, the term "subject" refers to an animal, preferably a mammal, and most preferably a human, which is the subject of treatment, observation or experimentation. As used herein, the term "subjector" or "patient" also includes subjects who are only 13⁄4, and who are more likely to present with epilepsy or symptoms similar to those associated with seizures but are at high risk. As used herein, the term "subjects requiring treatment with AEDG" includes the presence or absence of epilepsy, seizure disorder, or similar disorders associated with epileptic seizures such as neurological or seizures associated with epilepsy, 200808300, Or any disorder in which the clinical condition or prognosis of the patient may benefit from the process of suppressing or inhibiting the epilepticity to prevent any individual from extending, progressing, worsening, or increasing the resistance of any neurological or psychiatric treatment.

「需要用AEGD治療的受實驗者」一詞也包括沒有 癲癇或/及類似與癲癇發作相關的障礙但是因為中樞 (CNS)或末梢神經系統(PNS)的受傷或創傷而對於癲癇發 鲁 作或_發仙關的障礙有高風險的任何鋪。視為因A 咖或_的受傷或創傷而對於發展此種瘤瘤二= 癇發作相關_贿高驗的麵或病人，是因為對痛痛 或類似與癲癇發作相關的障礙之部份已知的生物化學或 基因傾向，或因為-或多種這癖礙之證實的生物指標或 替代指標被發現。 「需要用AEGD治療的受實驗者」一詞也包括任何 個體其臨床情形或預後可從用AEGD治療而獲益。此包 售括但不限於奴是因為任何碰因子在發展上面定義的 癲癇、癲癇發作障礙或類似與癲癇發作相關的障礙或癲癇 ，關的癲癇發賴如神經現象或細發作㈣的障礙有 高風險的任何固體。預後因子包括但不限於：任何種類對 CNS或PNS的受傷或創傷；CNS的感染，例如腦膜炎、 同心性環軸腦炎、缺氧、中風，也就是腦血管音外 (㈣）；f彡響CNS之自發免疫症，例如狼瘡；生產受傷， 例如圍產期缺氧症；心跳驟停；醫療或診斷性灰管手術過 程’例如頸動脈内膜切除或大駐管造影術；心臟繞道手 17 200808300 術；脊髓創傷；低血壓症；從CNS的栓塞、過高或過低 灌流而傷害CNS ;缺氧症影響CNS ;已知對AEGDs反應 的障礙之已知遺傳傾向；CNS之空間佔據損傷；腦腫瘤， 例如膠質母細胞瘤；在CNS内或周圍的流A或大量出金， 例如大腦内的流血或硬膜下的大量出血；腦水腫；熱痙 攣；高體溫；暴露至毒性或有毒的藥劑；藥物中毒，例如 古柯鹼；癲癇發作障礙或類似癲癇發作相關的障礙之家族 魯史、癲癇狀態史；降低癲癇發作閾值的藥劑之目前治療， 例如;δ反g义鐘、托拉侮或克拉平(ci〇zapine);病人需要用抗 癲劑治療的替代指標或生物指標之證據，例如MRI掃描 顯示海馬硬化症或其他CNS病理，提升神經元降解產物 之血清值❶ 在本文中使用時，除非另外說明，「癲癇」一詞係指 任何障礙其中受實驗者(較宜是成人、小孩或嬰兒)經歷一 或夕-人癲癇發作及/或頦抖。合適的實例包括但不限於癲 Φ 癇（包括但不限於局部相關的癲癇、全身性癲癇、全身及 局。卩癲癇叙作之癲癇荨）、作為一種疾病或病情的併發症 之癲癇發作(例如與腦疾、笨丙酮尿症、青少年Gaucher 氏症、Lundborg氏漸進肌肉陣孿性癲癇、申風、頭部創 傷、壓力、荷爾蒙變化、藥物使用或戒除、酒精使用或戒 除、睡眠剝奪等相關的癲癇發作）等。該詞也係指不管癲 癇發作的種類、癲癇發作的起源、癲癇發作的進行或起因 或原因之臨床障礙。 抗痛癇劑」及細寫「AED」一詞在本文中將鱼「抗 18 200808300 發作活性…，可以治療、抑制或預防痛痛 (treH文I使用時，「治療（treating)」或「治療 病产中、_指在錢善㈣、賊、症狀或 成功標記之行動，包括任何客觀及主觀的 病理或/躲、降低錄或使病人能更容忍傷害、 户弱H，減緩退化或衰退之速率；使退化的終點較不 亚’、，或改進受實驗者的身體或精神福利。 括改ΐ此箱「治療(treatment)」或「治療(t〇t咖)」一詞包 田。、預防、逑轉、停止及/或抑制在本文中定義並使 主觀ίίϊ之病理歷程。錄之絲及改善可根據客觀或 數，包括身體檢查、神經檢查之結果及/或精神 一匈勺：，。據此’「治療(treating)」或「治療 "5匕奴樂本發明之化合物或藥劑，以治療、預防逆 轉、停止及/或抑制致癲性之歷程。在部份實例中用本 物治療將册、_及/或停止與_相關的腦 口丨功此卩早礙或腦部過度興奮之進展。 在本文中使用時，「醫療效應」一詞係指在受實驗者 丄治療、抑制、減少、逆轉及/或欲防致癲性、致瘤性之 效應或症狀、或致癲性之副作用。 、，本文中使用時，「醫療有效量」一詞係指活性化合 物或藥劑的量，其在組織纽、動物或人類中顯現的生ς 或醫學回應是研究員、獸醫、醫生或其健床者所尋求， 19 200808300 其包括被治療的病症或障礙的症狀之減輕。據此，「醫療 有效量」或「醫療有效劑量」一詞在本文中將交互使用 係指足夠量或劑量的一或多種本發明化合物或組成物在 對其有需要的病人中產生上述定義的醫療效應，例如治 療、抑制、減少、逆轉及/或預防致癲性、致癲性之效應 或症狀、或致癲性之副作用。這些不同醫療效應所需的劑 量範圍，將根據受實驗者或病人的特性及所要治療的病情 之確實本質而改變。 其中本發明針對的共同醫療或組合醫療，包括投藥一 或多種式(I)化合物及一或多種「合適的藥劑」，「醫療有 效量」將指一起取用的藥劑組合的量，使得結合的效應能 顯現所要的生物或醫學反應。例如，包括投藥式①化合 物及至少一種合適的藥劑的共同醫療之醫療有效量，將是 式(I)化合物的量與合適的藥劑的量當同時或依序投藥時 具有醫療有效的結合效應。而且，從事此項技藝者將可了 解在醫療有效量的共同醫療之情形中，例如上述，個別的 式(I)化合物的量及/或合適的藥劑的量可能有或沒有醫療 有效。 在本文使用時，「共同醫療」及「組合醫療」一詞係 指經由投藥一或多種式(I)化合物結合一或多種合適的藥 劑在對其有需要的受實驗者中治療，其中式(I)化合物及 合適的藥劑可經由任何合適的方法，同時、依序、分開或 在單獨的藥劑調配物中投藥。當式(I)化合物及合適的藥 劑是在分開的給藥形式投藥時，各種化合物每天投藥的給 20 200808300 藥次數可以相同或不同。式(i)化合物及合適的藥劑可以 經由相同或不同的投藥途徑投藥。合適的投藥方法實例包 括但不限於口服、靜脈内（iv)、肌肉内（im)、皮下(sc)、經 皮及直腸。化合物也可以直接投藥至神經系統，包括但不 限於腦内、心室内、腦室内、腦鞘内、腦池内、脊柱内及 /或脊柱周圍的投藥途徑，經由配備有或無泵裝置的顱内 或脊柱内的針及/或導管輸送。式(1)化合物及合適的藥劑 1以根據同時或交互攝生法，在醫療過程中的相同或不同 -人數下，同時在分開或單獨的形式下投藥。The term "subjects requiring treatment with AEDG" also includes no epilepsy or/and similar seizure-related disorders but is caused by epilepsy due to injury or trauma to the central (CNS) or peripheral nervous system (PNS). The barriers to the immortality have any high-risk shop. It is considered that the face or patient who develops such a tumor due to injury or trauma of A coffee or _ is known to be part of the pain or similar disorder associated with seizures. The biochemical or genetic predisposition, or the biomarker or surrogate indicator confirmed by - or a variety of such obstacles was found. The term "subjects requiring treatment with AEDG" also includes any individual whose clinical condition or prognosis can benefit from treatment with AEDD. This package is sold but not limited to slaves because any factor in the development of the above defined epilepsy, seizure disorder or similar disorders associated with seizures or epilepsy, high seizures such as neurological phenomena or fine attacks (four) Risk of any solid. Prognostic factors include, but are not limited to, any type of injury or trauma to the CNS or PNS; CNS infections such as meningitis, concentric circular encephalitis, hypoxia, stroke, ie cerebral vascular sounds ((4)); Spontaneous immune syndrome of the CNS, such as lupus; production injury, such as perinatal hypoxia; cardiac arrest; medical or diagnostic gray tube surgery procedures such as carotid endarterectomy or large resident angiography; cardiac bypass 17 200808300 surgery; spinal cord trauma; hypotension; CNS from embolization, excessive or under-perfusion of CNS; hypoxia affects CNS; known genetic predisposition to obstacles in response to AEGDs; space occupying damage in CNS Brain tumors, such as glioblastoma; flow A or large amounts of gold in or around the CNS, such as massive bleeding in the brain or bleeding under the dura; cerebral edema; enthusiasm; high body temperature; exposure to toxicity or toxic Drugs; drug poisoning, such as ***e; family history of seizure disorders or similar seizure-related disorders, history of epilepsy; current treatment of agents that lower the threshold of seizures, for example; δ anti-g-bell, torah or clarin (ci〇zapine); patients need to use anti-epileptic treatment of alternative indicators or evidence of biological indicators, such as MRI scan showing hippocampal sclerosis or other CNS pathology, improve neuronal degradation Serum value of product ❶ As used herein, unless otherwise stated, the term "epilepsy" refers to any disorder in which an experimenter (preferably an adult, child or infant) experiences a seizure and/or epilepsy. shake. Suitable examples include, but are not limited to, epilepsy (including but not limited to topical epilepsy, generalized epilepsy, systemic and local epilepsy, epilepsy, epilepsy), seizures as a complication of a disease or condition (eg Associated with brain disease, stupid acetonuria, adolescent Gaucher's disease, Lundborg's progressive muscle follic epilepsy, spleen, head trauma, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, etc. Seizures, etc. The term also refers to a clinical disorder regardless of the type of seizure, the origin of the seizure, the onset of the seizure, or the cause or cause. The term "anti-paemic agent" and the word "AED" are used in this article to treat the fish "anti-18 200808300 seizure activity..., which can treat, inhibit or prevent pain ("treating" or "treating" when using treH In the case of illness, _ refers to actions in Qianshan (4), thieves, symptoms or success markers, including any objective and subjective pathology or / hiding, reducing or making patients more tolerant of injury, weaker H, slowing down or declining Rate; make the end point of degradation less than ', or improve the physical or mental welfare of the subject. Include the word "treatment" or "treatment (t〇t coffee)" in the box. Prevent, circulate, stop, and/or inhibit the pathological process defined and subjective in this article. Recording and improvement can be based on objective or numerical, including physical examination, neurological examination results, and/or mental hurricane: According to this, "treating" or "treating" a compound or agent of the invention to treat, prevent reversal, stop, and/or inhibit epilepticity. In some cases, use this substance. Treatment will be booked, _ and / or stopped related to _ In the context of this article, the term "medical effect" refers to the treatment, inhibition, reduction, reversal, and/or prevention of epilepsy in the subject. The effect or symptom of tumorigenicity, or the side effect of epilepticity. As used herein, the term "medically effective amount" refers to the amount of active compound or agent that is manifested in tissue, animal or human. Oysters or medical responses are sought by researchers, veterinarians, doctors or their bedsetters, 19 200808300 which includes a reduction in the symptoms of a condition or disorder being treated. Accordingly, the term "medical effective amount" or "medical effective dose" is used. Cross-administration herein refers to a sufficient amount or dose of one or more compounds or compositions of the invention to produce a medical effect as defined above, such as treatment, inhibition, reduction, reversal, and/or prevention, in a patient in need thereof. Epileptic, epileptic effects or symptoms, or epileptic side effects. The dose range required for these different medical effects will depend on the characteristics of the subject or patient and the condition to be treated. The invention is directed to a common medical or combination medical treatment, which comprises administering one or more compounds of the formula (I) and one or more "appropriate pharmaceutical agents", and the "medical effective amount" will refer to a combination of agents taken together. An amount such that the combined effect manifests a desired biological or medical response. For example, a medically effective amount comprising a co-medication comprising a compound of formula 1 and at least one suitable agent will be an amount of a compound of formula (I) and a suitable agent The amount of the drug has a medically effective combination effect when administered simultaneously or sequentially. Moreover, those skilled in the art will be able to understand the amount of the individual compound of formula (I) in the case of a medically effective amount of co-medication, such as the above. / or the amount of a suitable pharmaceutical agent may or may not be medically effective. As used herein, the terms "common medical" and "combined medical" refer to the administration of one or more compounds of formula (I) in combination with one or more suitable agents. Treated to a subject in need thereof, wherein the compound of formula (I) and a suitable agent can be simultaneously, sequentially, separated by any suitable method Administered in a separate pharmaceutical formulation. When the compound of formula (I) and a suitable pharmaceutical agent are administered in separate administration forms, the number of times the various compounds are administered per day may be the same or different for 20 200808300. The compound of formula (i) and a suitable pharmaceutical agent can be administered via the same or different routes of administration. Examples of suitable administration methods include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal and rectal. The compound can also be administered directly to the nervous system, including but not limited to intracranial, intraventricular, intraventricular, intrathecal, intracisternal, intraspinal, and/or spinal administration routes, via intracranial devices with or without pumping devices. Or needle and/or catheter delivery within the spine. The compound of formula (1) and the appropriate agent 1 are administered in separate or separate forms according to the same or different - number of persons in the course of medical treatment according to simultaneous or interactive methods.

本文使用時，除非另外說明，「合適的藥劑」一詞係 ^何^其具有—或多個下列性質：抗氧化劑活性； isjnT又體括抗劑活性、增大内生性GAGB_作用； 二=如Ca(II)螯合劑；鋅結合能力，例如 啟鉀U人的eNS中有效阻止鈉或娜子通道或開 物質濫用及sa=，包括已知的AEDS或用於治療 蘭姆化二硫、包括但不限於***、四乙秋 二氮箪_、抗精神病劑、抗憂鬱劑、苯並 儿旱、丁螺環酮、納 合適的藥劑#嗎侧。 騰A受體(何如4=結合至NMDA受體而拮抗 位置）及/或紐士 Γ & NMDA受體之甘胺酸鍵結 GABA，‘之 =經膠質的GABA攝取而增大 適的藥^丨」可以是已知可抑糊癇發作活 200808300 性之任何藥劑，即使該化合物是未知可抑制致癲性。此種 藥劑包括但不限於從事此項技藝者已知或在未來發現之 任何有效的AED或抗抽搐劑，例如合適的藥劑包括但不 限於胺甲酿苯箪、克巴蘭（clobazam)、克納薩(clonazapam)、 乙號胺柴浪丁、費巴美(felbamate)、加巴丁(gabapentin)、 拉莫地(lamotiginel)、里維地(levetiracetam)、歐卡巴 (oxcarbazepine)、 ***、苯妥英、普加巴林 (pregabalin)、撲癲酮、瑞地加冰(retigabine)、地拉本 (talampanel)、地加平(tiagabine)、多比瑞(topiramate)、丙 戊酸鹽、維加巴(vigabatrin)、洛尼薩(zonisamdde)、苯並 二吖庚因、巴比土酸鹽、或鎮靜***。 「癲癇」一詞係指一種腦功能的障礙，特徵是週期性 及不可預期的出現癲癇發作（見The Treatment Principles & practice, Third Edition, Elaine Wyllie, M.D. Editor, Lippincott Williams & Wilkins, 2001； Goodman & Gilman’s The^Pharmacological Basis of Therapeutics 9¾ edition，1996)(兩份文獻都併於本文供參考）〇沒有明顯觸 怒發生的癲癇發作分類為癲癇性。癲癇可以是先天的或可 能與人生任何階段的某種損傷、畸形或傷害中樞神經相 關。在超過24小時的間隔發生二或多次的癲癇發作，典 型視為患有癲癇的受實驗者。 ^ 臨床上，在腦部或神經系統的其他地方從收集相互連 接的神經it產生的突然且不正f的電子放電引起瘤痛性 癲癇發作。取決於涉及的癲狀麵，所得的神經細胞活 22 200808300 性可經由多種臨床症狀表現，例如失控的運動移動、病人 知覺程度的變化等。癲癇及癲癇性癲癇發作且徵候群可以 用多種方式分類（見 The Treatment of Epilepsy, Principles & Practice, Third Edition, Elaine Wyllie, M.D. Editor, Lippincott Williams & Wilkins，2001)。但是，在本文中使 用的「癲癇」、「癲癇性癲癇發作」及「癲癇徵候群」一詞 係指包括全部已知形態之癲癇性癲癇發作及徵候群，包括 部份癲癇發作，包括簡單、複雜及部份癲癇發作演化至全 面強直-陣攣性抽搐及全面性癲癇發作，抽搐及非抽搐及 未分類的癲癇性癲癇發作。 「致癲性歷程」之「致癲性」通常包括兩個階段。本 發明方法包括在第一及第二致癲性階段或這些階段之後 預防及/或醫療性投藥任何本文揭示的化合物，在對其有 需要的受實驗者中用以治療、抑制、預防、停止或逆轉癲 癎或其他類似與癲癇相關的障礙之後續發展。 第一個致癲性階段是稱為最初發作或損傷階段。最初 或損傷通常是經由一或多個多重可能因子造成之腦 邛傷告性損傷，包括例如創傷性腦部損傷，包括純擊或穿 ^性碩部創傷或神經外科手術；⑽錢，例如細菌性 恥膜^、病毒性腦炎、細菌性大腦膿腫或神經囊尾幼蟲 Ϊ ^腦血管疾病（例如中風或腦部腫瘤，包括例如惡性神 =膠瘤)」神經手術(例如頭顱切開術)及癲癇連續狀態。 部份貫t巾，最初發作岐$生前發育問題(例如但不 限於出生窒息、出生時的顧内創傷、腦部的代謝干擾或先 23 200808300 天性崎形)之結果或遺傳性決定因素之結果。 。 第二個致癲性階段是稱為「潛伏階段」。第二個致癲 性階段包括神經元改組的歷程，其特徵是再發生的癲癇發 作(例如症狀性癲癇）或顯現在類似與癲癇發作相關的障 礙之症狀。致舰難也可以在實際騎癲誠類似與瘤 癇發作相關的障礙者中觀察到。患有瘤瘤者經歷的瘤痛發 作是本身致癲性，其中其傾向於使後續的癲癇發作之再發 Φ 生更容易或擴展受癲癇發作活性影響的神經組織之範圍 或使癲癇發作障礙更抵抗治療。對於有瘤痛發作障礙的病 人，此歷程之結果是癲癇發作傾向於變成更經常發生且更 嚴重且通常對於傳統勘，s治療更有抵抗性。在類似的 方式下，在類似於癲癇的神經或精神障礙中的相關類癲癇 發作反應會隨著時間變成增加嚴重性或#障礙成熟時抵 抗治療。 第一期的致癲性可以經由上列之外的因子引發，例如 _ 、經由，取具有致癲癇可能性的化合物，例如精神藥劑，例 如二環抗憂#劑、氯氮平及料。本發明方法也是要治療、 預防、彳〒止、抑制及/或逆轉經由傾向於增受 成致癲性的可祕之因刊發的致舰之發展。 本文揭示的式⑴化合物可用於治療癲癇及類似與癲 ==相_障礙。此外，本文揭示的式(1)化合物可用 關2、控制及預防導致惡化、臨床進行或增加癲癇及相 ^癲癎發作障礙的治療之抵抗性或因為神經系統部份 ^的知傷或觸而導致全程引發這轉礙或其症狀的 24 200808300 致癲性歷程。 據此，在一個具體實施例中，本發明是關於使臨床醫 生可以治療癲癇、其他癲癇發作障礙的症狀及/或類似與 癲癇發作相關的障礙之症狀且同時抑制與惡化、進行擴 展或增加引起疾病進行的治療抵抗性有關的致癲行性歷 程之方法。此方法包括將抗致癲性有效量之本文揭示的式 (I)化合物預防或醫療性投藥至對其有需要的病人且同時 Φ 治療及預防癲癇發作或障礙之其他症狀，此外，可以在受 實驗者中停止、抑制及逆轉致癲性之歷程。 在某些具體實施例t，對麵有需要的受實驗者或病 人(較宜是對於用AEGD治療有需要的受實驗者或病人) 可以疋已經顯現癲癇症狀的受實驗者，也就是癲癇發作或 抽搐，或可以是在投藥之前或投藥時顯現_與癲癇發作 相關的障礙軸狀(例如情緒週期化、驗料、上癌行 為等)之文實驗者。因此，在一個方面，本發明提供一個 ⑩ 改良的方法在對其有需㈣受實驗者巾麟治療及預防 癲癇發作及與_發作相_障叙錄。此方法之步驟 包括將醫療有效量本文揭示治療及預防癲癇發作、抽搐或 ，癇务作相關的障礙發生之切)化合物預防或醫療性投 樂至對其有需要的受實驗者。 在某些具體實施例中，對治療有需要的受實驗者或病 宜是對於帛AEGD轉有需要岐實驗者或病人) 11疋尚未顯現癲癇或類似與癲癇發作相關的障礙之受 貝驗者，也就是在癲癇發作或抽搐或類似與癲癇發作相關 25 200808300 的障礙的症狀之前投藥。在此具體實施例中，受實驗者或 病人在投藥時將測試是否有發展癲癇或類似與癲癇發作 相關的障礙之風險，且根據此點將認為是需要用AEGD 治療的病人。在此方面，本發明提供一個方法用於停止、 抑制及/或逆轉致癲性。此方法之步驟包括將預防或醫療 有效量本文揭示在受實驗者中治療、預防、停止、抑制及As used herein, unless otherwise stated, the term "appropriate agent" is used to have - or more of the following properties: antioxidant activity; isjnT also includes anti-agent activity, increases endogenous GAGB_ action; Such as Ca(II) chelating agents; zinc binding ability, such as the effective blocking of sodium or nanochannel or substance abuse and sa=, including known AEDS or for the treatment of lamified disulfide, Including but not limited to methadone, tetraethylene quinolate, antipsychotics, antidepressants, benzophenone, buspirone, sodium suitable agents # side. Teng A receptor (such as 4 = binding to the NMDA receptor to antagonize the location) and / or New Zealand Γ & NMDA receptor glycine linkage GABA, ' = glial GABA uptake to increase the appropriate drug ^丨" may be any agent known to inhibit the onset of episodes of episode 200808300, even if the compound is unknown to inhibit epilepsy. Such agents include, but are not limited to, any effective AED or anti-convulsant known to those skilled in the art or found in the future, for example, suitable agents include, but are not limited to, amine phenyl hydrazine, clabazam, gram Clonazapam, acetaminophen, felbamate, gabapentin, lamotiginel, levetiracetam, oxcarbazepine, phenabapine Proton, phenytoin, pregabalin, epilepsy, retiigabine, talampanel, tiagabine, topiramate, valproate, vega Vigabatrin, zonisamdde, benzodiazepine, barbiturate, or sedative sleeping pills. The term "epilepsy" refers to a disorder of brain function characterized by periodic and unpredictable seizures (see The Treatment Principles & Practice, Third Edition, Elaine Wyllie, MD Editor, Lippincott Williams & Wilkins, 2001; Goodman & Gilman's The^ Pharmacological Basis of Therapeutics 93⁄4 edition, 1996) (both references are incorporated herein by reference). Seizures without significant irritability are classified as epileptic. Epilepsy can be congenital or may be associated with some type of injury, deformity or injury to the central nervous system at any stage of life. Two or more seizures occur at intervals of more than 24 hours, which are generally considered to be subjects with epilepsy. ^ Clinically, sudden and unfamiliar electrical discharges from the collection of interconnected nerves in the brain or elsewhere in the nervous system cause neonatal sore seizures. Depending on the ectopic surface involved, the resulting neuronal activity can be manifested through a variety of clinical symptoms, such as uncontrolled movement of the movement, changes in the level of patient perception, and the like. Epilepsy and epileptic seizures and syndromes can be classified in a number of ways (see The Treatment of Epilepsy, Principles & Practice, Third Edition, Elaine Wyllie, M. D. Editor, Lippincott Williams & Wilkins, 2001). However, the terms "epilepsy", "epileptic seizures" and "epilepsy syndrome" as used herein refer to epileptic seizures and syndromes including all known forms, including partial seizures, including simple, Complex and partial seizures evolved to general tonic-clonic convulsions and generalized seizures, convulsions and non-convulsive and unclassified epileptic seizures. The "epileptic" of the "epileptic course" usually consists of two stages. The method of the invention comprises preventing and/or medically administering any of the compounds disclosed herein at or after the first and second epileptic stages, for treatment, inhibition, prevention, and cessation in a subject in need thereof Or reverse the subsequent development of epilepsy or other similar disorders associated with epilepsy. The first epileptic phase is called the initial episode or injury phase. Initial or injury is usually a cerebral palsy injury caused by one or more multiple possible factors, including, for example, traumatic brain injury, including pure or severe trauma or neurosurgery; (10) money, such as bacteria Sexual vaginal membrane, viral encephalitis, bacterial brain abscess or cerebral larval larvae 脑 cerebral vascular disease (such as stroke or brain tumors, including, for example, malignant god = colloid) "neurological surgery (such as craniotomy) and Continuous status of epilepsy. Partial sputum, the result of a pre-existing developmental problem (such as, but not limited to, birth asphyxia, intrauterine trauma at birth, metabolic interference in the brain, or the first genus of 200808300) or the result of hereditary determinants . . The second epileptic phase is called the "latent phase." The second epileptic phase includes a history of neuronal shuffling characterized by recurrent epileptic seizures (such as symptomatic epilepsy) or symptoms that appear to be similar to those associated with seizures. Shipwrecks can also be observed in actual riders who are similar to those associated with septic attacks. The onset of a sore throat experienced by a neoplasia is itself epileptic, which tends to make subsequent recurrence of seizures easier or extend the range of neural tissue affected by seizure activity or make seizure disorders more Resistance treatment. For patients with a sore onset disorder, the result of this process is that seizures tend to become more frequent and more severe and are generally more resistant to traditional treatments. In a similar manner, a related seizure response in a neurological or psychiatric disorder similar to epilepsy will become resistant to treatment over time as the severity increases or the disorder becomes mature. The first stage of epilepsy can be triggered by factors other than those listed above, such as _, via, taking compounds with the potential for epileptic seizures, such as psychotropic agents, such as bicyclic anti-anxie # agents, clozapine and materials. The method of the present invention is also intended to treat, prevent, arrest, inhibit, and/or reverse the development of a ship that has been published through a tendency to increase the risk of epilepsy. The compounds of formula (1) disclosed herein are useful for the treatment of epilepsy and the like and epilepsy. In addition, the compounds of formula (1) disclosed herein can be used to control, prevent, or prevent the progression of epilepsy and epileptic seizure disorders, or the damage or touch of the nervous system. The 2008 200808300 epileptic course that led to this disruption or its symptoms. Accordingly, in one embodiment, the present invention is directed to enabling a clinician to treat symptoms of epilepsy, other symptoms of seizure disorders, and/or similar disorders associated with seizures while inhibiting and worsening, expanding or increasing A method of treating the epileptic course associated with the resistance of a disease. The method comprises preventing or medically administering an anti-epileptically effective amount of a compound of formula (I) disclosed herein to a patient in need thereof while at the same time treating and preventing other symptoms of seizures or disorders, in addition, The experiment stopped, inhibited and reversed the epileptic process. In some embodiments t, the subject or patient in need (preferably for a subject or patient in need of treatment with AEDD) may be present in a subject who has developed epileptic symptoms, ie, a seizure or Twitching, or may be a textual experiment (eg, emotional cycle, test, cancer behavior, etc.) that appears to be associated with a seizure-related disorder before administration or administration. Thus, in one aspect, the present invention provides a 10 improved method for the need to (4) the subject's treatment and prevention of seizures and _ episodes. The steps of the method comprise administering to the subject in need thereof a therapeutically effective amount of the compound disclosed herein for the treatment and prevention of seizures, seizures, or disorders associated with epilepsy. In some embodiments, the subject or treatment for the need for treatment is for the 帛AEGD to be required for the experiment or the patient. 11 受The tester who has not yet developed epilepsy or similar disorders associated with seizures , that is, before seizures or convulsions or symptoms similar to those associated with seizures 25 200808300. In this particular embodiment, the subject or patient will be tested for the risk of developing epilepsy or similar disorders associated with seizures at the time of administration, and will be considered a patient requiring treatment with AEGD according to this point. In this aspect, the invention provides a method for stopping, inhibiting and/or reversing epilepticity. The steps of the method include exposing the prophylactic or medically effective amount to the treatment, prevention, cessation, inhibition, and

逆轉致癲性之任何化合物預防或醫療性投藥至對其有需 要的受實驗者。 經由抑制致癲性之歷程，可以在神經系統維持某些形 式的損傷或傷害或有高風險之受實驗者預防癲癇發作障 礙或相關的障礙之發展。據此，本發明提供在對1有需要 之受實驗者巾驗轉、肋、停止、㈣及/或逆轉致 癲性之方法，其包括將預防或醫療有效量含有至少一種式 (I)化合物之組成物投藥致受實驗者。 在本發明之-個具體實施例中，此方法是有利於用在 治療沒有罹患或已知罹患此項技齡6知用目前已知的 抗抽搐劑或抗癲鋪(AED)有效治療的賴之病人。這些 病情包括但不限於類似與_發作相_障㊉在這些情 ㈣財法献合物之蚊定^人 疋否為上叙㈣「需要用抗致癲性藥雜咖)治療的 病人」。 在另-個具體實施例中，本發明提 :==r爾禮作相關的障礙=狀 ,祕、⑺療及/或預防_且同時抑制致癲性之歷 26 200808300 程且因而預防引起疾病歷程之擴展或惡化或非癲癇發作 傾向的神經組織致癲性歷程之募集。 立本發明方法是針對在有發展癲癇或癲癇發作相關的 障礙或類似癲癇發作相關的障礙的風險但是沒有癲癇或 癲癇發作的臨床證明之受實驗者中治療致癲性。有發展癲 癇或類似癲癇發作相關的障礙的風險但是沒有癲癇或其 他癲癇發作障礙或類似癲癇發作相關的障礙之受實驗者 # 可以疋尚未診斷有癲癇或類似癲癇發作相關的障礙但是 比一般大眾發展癩癇或類似癲癇發作相關的障礙有更高 風險的受貝驗者。此「較高風險」可以經由識別受實驗者 中的任何因子、或其家族醫療史、身體檢查或顯示發展瘤 2或類似癲癇發作相關的障礙大於平均風險的測試而測 定。因此，經由任何可行的方法識別病人可能是在「較高 風險」之此測定，可以用於測定病人是否需要用本發明方 法治療。 馨有較高風險的病人包括但不限於其中樞神經系統沒 有遭受損傷或傷害，但是因為其健康情形祕環境而很可 能有此損傷或傷害者。此包括但不限於有暫時缺企發作 (TIA’s)或已知_動脈狹窄關單已知重大動脈粥樣硬 化症的歷史之病人以及將要進行神經手術的病人。此外， 因為戰爭或運動傷害^容^遭受神經傷害的個體可以預 防性地投藥本發明化合物，此將包括戰場上的士兵或激烈 接觸運動例如拳擊之運動員。 可以從經由本發明方法治療而受益的受實驗者可以 27 200808300 使用被接受的篩選方法測試與致癲性、癲癇或其他癲癇發 作障礙或類似與癲癇發作相關的障礙之風險而決定。測試 受實驗者有或可能有發展癲痕、其他癲癇發作障礙或類似 與癲癇發作相關的障礙之風險也包括例如醫學評斷其包 括徹底的歷史、身體檢查、及一系列相關的血液測試。其 也可包括腦電示波檢查(EEG)、電腦斷層掃描(CT)、核磁 共振造影(MRI)或正電子放射斷層掃描(PET)。發展癲癇或 類似與癲癇發作相關的障礙增加風險之測試也可經由遺 傳測試進行，包括基因表現情形或蛋白質譜鑑定技術（見Any compound that reverses epilepticity is prevented or administered medically to the subject in need thereof. By inhibiting the epileptic process, it is possible to maintain certain forms of injury or injury in the nervous system or subjects with high risk to prevent the development of seizure disorders or related disorders. Accordingly, the present invention provides a method for detecting, rib, stopping, (d), and/or reversing epilepsy in a subject in need thereof, comprising administering at least one compound of formula (I) in a prophylactically or therapeutically effective amount. The composition is administered to the subject. In a specific embodiment of the invention, the method is advantageous for treating a treatment that is not known or known to be known to be effective in the treatment of the currently known anticonvulsant or anti-epileptic (AED). The patient. These conditions include, but are not limited to, similar to _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In another embodiment, the present invention provides: == err-related disorders = form, secret, (7) treatment and / or prevention _ and at the same time inhibiting the epileptic history of 26 200808300 and thus preventing disease The recruitment of epileptic processes of neural tissue that is extended or worsened or not seizure-prone. The method of the present invention is directed to the treatment of epilepsy in a subject who has a risk of developing a disorder associated with epilepsy or seizures or a similar seizure-related disorder but without clinical evidence of epilepsy or seizures. Subjects who develop risk of epilepsy or similar seizure-related disorders but who do not have epilepsy or other seizure disorders or disorders associated with seizures may be diagnosed with epilepsy or similar seizure-related disorders but are more general than the general public Obsessive or similar seizure-related disorders have a higher risk of being tested by the beauticians. This "higher risk" can be determined by identifying any factor in the subject, or a family medical history, a physical examination, or a test showing that the developmental tumor 2 or similar seizure-related disorder is greater than the average risk. Therefore, identifying the patient via any feasible method may be a "higher risk" of this assay and can be used to determine if a patient needs treatment with the method of the present invention. Patients with a higher risk of sinus include, but are not limited to, those with no damage or injury to the central nervous system, but are likely to be injured or injured because of their healthful environment. This includes, but is not limited to, patients with a history of transient absence (TIA's) or known atherosclerotic stenosis known as major atherosclerosis and patients undergoing neurosurgery. In addition, individuals who suffer from nerve damage due to war or sports injuries can pre-administer the compounds of the present invention, which will include soldiers on the battlefield or athletes who engage in intense contact sports such as boxing. Subjects who may benefit from treatment by the methods of the invention may determine the risk of causing epilepsy, epilepsy or other disorder of epilepsy or a disorder similar to seizures using an accepted screening method using the accepted screening method. Testing Subjects who have or may have the risk of developing a hereditary, other seizure disorder or similar disorder associated with seizures include, for example, medical judgments including thorough history, physical examination, and a range of related blood tests. It may also include electroencephalography (EEG), computed tomography (CT), nuclear magnetic resonance imaging (MRI) or positron emission tomography (PET). Testing for increased risk of developing epilepsy or similar disorders associated with seizures can also be performed via genetic testing, including genetic performance or protein profiling techniques (see

Schmidt，D· R〇gawski，Μ·Α· Epilepsy Research 50; 71-78 (20〇2)及 Loscher，W，Schmidt D· Epilepsy Research 50; 3-16 (2002)) 〇 這些篩選方法包括例如傳統醫學處理以測試與致癲 性相關的風險因子，包括但不限於例如密閉或穿透性頭部 創傷、神經外科手術、細菌或病毒性CNS感染、三叉神 經痛、腦血管疾病包括但不限於中風或TIA，S歷史、腦腫 瘤、腦水腫、囊尾幼蟲病、卟咁症、代謝性腦病、藥物戒 除包括但不限於鎮靜-催眠性或酒精戒除、不正常圍產期 歷史包括出生缺氧或任何種類的出生傷害、大腦麻痹、學 舀P早礙、過動症、發熱抽搐的歷史、癲癇連續狀態的歷史、 癲癇或任何癲癇發作相關的障礙之家族史、腦或企管之發 炎疾病包括狼瘡、直接或經由胎盤轉移的藥物中毒，包括 但不限於古柯鹼及去曱麻黃鹼毒性、親本的血緣、及用降 低癲癇發作閾值的藥劑治療包括精神性藥劑例如抗憂鬱 28 200808300 劑或抗精神病藥劑。 产谥:：個病人可以從在沒有癲癇或其他癲癇發作 ^或齡，、義發作相_障礙之現象或症狀的病人 中使用的AEGD治射以獲益，可以根據綠「替代標 記y或「生物指標」。此種生物指標包括但不限於組織、 血液或CSF巾的基因麵自質表現情形或存在遺傳性的 標記例如SNP，s。 〜在本文中使用時，「替代標記」及「生物指標」一詞 疋父互使用且係指任何解剖、生化、結構、電子、遺傳或 化學性指標或標記，其可以可#地與現在存在或未來發展 的癲癇或癲癇發作障礙或類似與癲癇發作相關的障礙關 連、在伤貝例中’細部造影技術例如電腦斷層掃描(ct) 核磁共振造影(MRI)或正電子放射斷層掃描(ΡΕΤ)，或其他 神經造影技術可以用於測定受實驗者是否有發展其中一 種上述疾病之風險。 用於本發明方法之合適生物指標之實例包括但不限 於·級由MRI、CT或其他造影技術測試在海馬中的硬化 萎縮或體積損失或存在近中顳硬化(MTS)或類似的相關 解剖病狀；在病人血液、血清或組織中檢查分子物種例如 蛋白質或其他生化指標，例如臨床神經因子(CNTI^之资 增加或神經降解產物之血清值增加；或從病人需要用抗精 神病藥劑治療的替代標記或生物指標之其他證據，例如 EEG建議癲癇發作或類似與癲癇發作相關的障礙、癲痛 相關的類癲癇發作神經現象或癲癇發作相關的障礙。 29 200808300 預期未來將發展出利用不同偵測技術的更多此種生 物指標。癲癇發作障礙、癲癇或類似與癲癎發作相關的障 礙存在或未來可能發展的任何此種標記或指標可二在: 發明方法中使用，供測定是否需要用本發明之^且^及方 法治療。 在本發明之一個具體實施例中，治療係在有上述定義 的癲癇或癲癇相關的類癲癇發作神經現象或類似與癲癇 • 發作相關的障礙之病人，並利用本發明化合物逆轉致癲性 之優點，可以逐漸減少在有上述定義的痛痛或廟瘤相關的 類癲癇發作神經現象或類似與癲癇發作相關的障礙的病 人控制臨床現象所需的維持醫療之劑量或強度。 因此，由於在所述的障礙中用本發明方法治療產生改 善，病人可以停止其維持醫療，包括但不限於本發明化合 物如果其係作為單獨醫療錢。據此，癲癇病人在傳統 AED的特s療巾，帛—或録本發魏合物治療後， φ 可以停止AED並逆轉所述的癲癇障礙。 從事此項技藝者根據臨床現象及症狀包括 EEG’s、突 破性進展癲癇發作或所述的障礙之其他合適的生物指標， 可以瞭解如何快速進行逐漸減量少。 & _本發明係關於本文揭示的式⑴及/或式(π)化合物製 彳在對其有需要的病人中用於洽療、預防、壓抑、停 止及/或抑制致癲性之用途，較宜是在需要用AEGD治療 的病人。 在本發明之一個具體實施例中，式(I)化合物是選自其 30 200808300 R1是選自包括氫、鹵基、羥基、甲氧基、三氟甲基、 硝基及氰基； ' X-Y 是選自包括-S-CH、_S-C(CH3)-、-0-CH、 -〇-C(CH3)-、-N(CH3)-CH-及，CH=CH-CH-; A是選自包括-CHy及_Ch(CH3>_; R2是選自包括氫及甲基； _ R及R是各獨立地選自包括氫及曱基； 。或者是，R3及R4 —起與和其鍵結的氮原子形成5至 7貝飽和、部份不飽和或芳族環結構，視需要含有一至兩 個獨立地選自包括〇、N及S之其他雜原子； 或其藥學上可接受的鹽。 在本發明之另一個具體實施例中，式⑴化合物是選自 其中 R1是選自包括氫及鹵基； _ X_Y 是選自包括各CH-、-S-C(CH3)-、-0-CH、 〇-C(CH3)、-N(CH3)-CH-及.CH=CH-CH-; A是選自包括-CH2-及-CH(Ch3K r2是選自包括氫及甲基； r3及R4是各獨立地選自包括氫及甲基； 及其藥學上可接受的鹽。 在本發明之另一個具體實施例中，式⑴化合物是選自 其中 R疋選自包括氫及鹵基；其中鹵基是鍵結在4·、5- 31 200808300 或7-位置； X-Y 是選自包括-0-CH-、-0-C(CH3)-、-S-CH、 -S-C(CH3)-、-N(CH3)-CH-及-CH=CH-CH-; A是選自包括-CH2-及-CH(CH3)-; R是氮； R3及R4各是氫； 及其藥學上可接受的鹽。 在本發明之另一個具體實施例中，式(I)化合物是選自 其中 R1是氫； X-Y 是選自包括-0-CH-、-〇-C(CH3)-、-S-CH-、 -S-C(CH3)-、-N(CH3)-CH-及-CH=CH-CH-; A是選自包括_CH2-及-CH(CH3)-; R2是氫； R3及R4各是氫； 及其藥學上可接受的鹽。 在本發明之另一個具體實施例中，式(1)化合物是選自 其中 一 R是選自包括氩、鹵基、羥基、甲氧基、三氟甲基、 硝基及氰基；較宜R1是選自包括氫及鹵基，更宜Rl是選 自包括氫及鹵基，其中鹵基是鍵結在4-、5_或7-位置； 是-S-CH-; Α是選自包括-CH2-及-CH(CH3)-; R2是選自包括氫及甲基；較宜R2是氫； 32 200808300 R及R4各是獨立地選自包括氫及鹵基；較宜r3 R4各是氫； 及其藥學上可接受的鹽。 友，本發明之一個具體實施例中，選自包括氯、 ，、氟及溴。在本發明之另一個具體實施例中，r1不是 風且鍵結在4·、5·或7·位置，較宜在5_位置。在本發明 之另-個具體實施例巾，Ri不是氫且鍵結在5、6•或 巧置乂較宜在6_位置。在本發明之另一個具體實施例中， ^疋，自包括氫及鹵基。在本發明之另—個具體實施例 R是選自包括經基及τ氧基。在本發明之另一個且 體實施例中，R1是選自包括氫、鹵基及三氟甲基。在ς 發，之另_^目具體實施例中，Rl是選自包括氫、齒基、 :氟甲基、氰基及絲。在本發明之另—個具體實施例中 R是選自包括氫、函基、三氟甲基及氰基。在本發明之 f 一個具體實施财，選自包括三氟甲基及氰基。 ^發明之另-個具體實施例中，Rl是選自包括氣、心 =其5·氣基、5_·、5_漠基、5_三氟甲基、5_氮 7-亂基。 在本發明之-個具體實施例中，R2是氣。在本發明 之另-個具體實施财，。在本發明之另 -個具體魏财，R2是&，R1氫且R4是氣。 在本發明之一個具體實施例中，R3及R4各是獨立地 ，自3包括yc"絲。在本發社另—個具體實施例 ’R及R -起與和其鍵結的氮原子形成5至7員飽和、 33 .200808300 部份不飽和絲族賴構，視需要含有—至兩侧立地選 自包括〇、N及S之其他雜原子。 本發明之—個频實施财，R3及R4各是獨立地選 自3包括f、9曱基及乙基。本發明之另-個具體實施例中， R及^各是獨立地選自包括氫及甲基。本發日月之另一個 具體實施射，R3及R4各是獨立地選自包括氫及乙基。 本發明之另-個具體實施例中，r3是氫且厌4是乙基。 在本發明之一個具體實施例中，R3及R4-起與和1 、 貝飽和、4伤不飽和或芳族環結 冓，視需要含有-至兩個獨立地選自包括ms之兑 他雜原子。在本發明之另—健體實施射，r3及r4: 3和其麟軌軒軸5至7聽和賴構，視需要 =-至兩侧立地選自包括0、s之其他雜原子。 ^柄明之另-個具體實施财，r、r4—起與和續 個成5至7員芳族環結構，視需要含有-至兩 個獨立地選自包括〇、ν及s之其他雜原子。 ，宜，R3及R4—起與和其鍵結的氮原子形成5至6 ft、部份不飽和或芳族環結構，視需要含有-至兩個 自包括。、…之其他雜原子。更宜，以 其鍵結的氮原子形成6員飽和、部份不飽和 ，視需要含有—至兩個獨立地選自包括 N及S之其他雜原子。 —^乂且，R及R起與和其鍵結的氮原子形彭至7(更 且）員飽和或芳族環結構，視需要含有-至兩個(較 34 .200808300 且-個)獨立地選自包括〇、N&s(較宜 N)之其他雜原子❶ XN，更且 在本發明之另-個频實補巾，r3&r4 子形成5至6員飽和或芳族環結構，視; 要3有-至兩個(較宜一個)獨立地選自包括 宜0或Ν，更宜叫之其他雜原子。 』及3(車乂 較宜，該5至7員飽和、部份不飽和或芳 〇至1個齡喊自包括G、S及Ν之其宜， 該雜原子是獨立地選自包括〇&Ν，更宜該雜原子是& 該視需要含有一至兩個獨立地選自包括〇、”及8之 其他雜原子之5至7貞飽和、雜不鮮或芳麵結構之 合適實例包括但不限於吡咯基、吡咯啶基、吡咯唯基、嗎 福啉基、六氳吡啶基、六氫吡啡基、咪唑基、吡唑基吡 啶基、硫嗎福咁基、吡畊基、三畊基、吖庚因基等。較宜 該視需要含有一至兩個獨立地選自包括〇、贝及s之其他 雜原子之5至7員飽和、部份不飽和或芳族環結構包括但 不限於咪唑基、吡咯啶基、六氫吡啶基及嗎福啉基。 在本發明之一個具體實施例中，A是-CH2-。 在本發明之一個具體實施例中，χ-γ是選自包括 -S-CH-、-0-CEK -〇-c(CH3；K -N(CH3)-CH-及 -CH=CH-CH-。在本發明之另一個具體實施例中，χ_γ是 選自包括-S-CH、-0-CH、-0-C(CH3)-及-CH=CH_CH-。 在本發明之另一個具體實施例中，χ-γ是選自、包括 -S-CH-、-OCH、-〇-c(CH3)-及-Ν(αΗ3ΚΉ-。在本發明 35 200808300 之另一個具體實施例中，χ_γ是選自包括_S CH_、_〇_CH_、 -N(CH3)-CH-及·〇ίκ：Η-αι “在本發明之另-個具體實 施例中，Χ-Υ是選自包括各CH_、_〇_CH_及 ' -CH=CH-CH-。在本發明之另一個具體實施例中，χ·γ是 選自包括-S_CH-及-0-CH-。在本發明之另一個具體實施 例中，X-Y 是選自包括-S-CH-、-S-C(CH3K -0-CH-、 -0-C(CH3)_及-N(CH3)-CH-。 在本發明之一個具體實施例中，。在本 發明之另一個具體實施例中，X-Y是·CH=CH_CH_。在本 發明之另一個具體實施例中，X-Yi_N(CH3)-CH·。在本 發明之另一個具體實施例中，X-Y是選自包括—仏^^及 -o-c(ch3)-。 在一個具體實施例中，本發明是關於選自下面的化合 物：N-(苯并[b]喧嗯-3-基曱基)·續酿二胺；N-[(5-氣苯并[b] 噻嗯冬基）曱基]-磺醯二胺；N-(3-苯并呋喃基曱基磺醯 二胺；N-[(5-氣苯并[b]喧嗯-3-基）甲基]-續醢二胺；N-(l_ 苯并作]鳴嗯-3-基乙基)-石黃醢二胺；Ν·»(1-茶基甲基)-石黃酿二 胺，Ν-[(2-曱基-3-苯并咬喃基）甲基]-續酿二胺；ν_[(5-溴 苯并[b]噻嗯-3-基）曱基]-磺醯二胺；Ν-[(4-溴苯并[b]噻嗯 •3-基）甲基]-石黃酿二胺；N-[(7-氟苯并网嗔嗯各基）甲基]_ 石黃酿二胺；N-[(l-曱基-ΙΗ·^引口朵3-基）曱基]-石黃酿二胺； N-[(4-三氟曱基苯并[b]噻嗯冬基）甲基]-磺醯二胺； 氰基苯并[b]噻嗯-3-基）甲基]-磺醯二胺；N-[(苯并[b]噻嗯 -3-基）甲基]-胺磺醯基吡咯啶；N-[(苯并[b]噻嗯-3-基）甲 36 200808300 基]-ν’-乙基續醯二胺 基]邊胺，·及其藥學上可接受的鹽類 基)甲 Α)ί取代基是齡地·成為任何獨立的械基或從本 文定義的整份名稍擇之取储之任何子集。 在化療中使用的代表性化合物列在下面表1及2。 ______ 1 · ^fV 矣，W: 、儿人 *!/、 化合物Schmidt, D. R〇gawski, Μ·Α· Epilepsy Research 50; 71-78 (20〇2) and Loscher, W, Schmidt D· Epilepsy Research 50; 3-16 (2002)) 〇 These screening methods include, for example, tradition Medical treatment to test risk factors associated with epilepsy, including but not limited to, for example, closed or penetrating head trauma, neurosurgery, bacterial or viral CNS infection, trigeminal neuralgia, cerebrovascular disease including but not limited to stroke Or TIA, S history, brain tumors, cerebral edema, cysticercosis, snoring, metabolic encephalopathy, drug withdrawal including but not limited to sedative-hypnotic or alcohol withdrawal, abnormal perinatal history including birth hypoxia or Any type of birth injury, cerebral palsy, sputum premature dysfunction, history of hyperactivity, history of epilepsy, history of status epilepticus, family history of epilepsy or any disorder associated with seizures, inflammatory diseases of the brain or genitals including lupus Drug poisoning, either directly or via placental transfer, including but not limited to ***e and norephedrine toxicity, blood of the parent, and treatment with a drug that lowers the seizure threshold Including psychiatric agents such as antidepressant or antipsychotic agents 28200808300. Calving: A patient can benefit from the AEGD treatment used in patients without epilepsy or other seizures or other seizures, or the symptoms or symptoms of the seizures, depending on the green "alternative marker y or" Biological indicators". Such biological indicators include, but are not limited to, genetic surface self-quality presentation of tissue, blood or CSF towels or the presence of hereditary markers such as SNPs. ~ In the context of this document, the words "substitute mark" and "biological indicator" are used interchangeably by the father and refer to any anatomical, biochemical, structural, electronic, genetic or chemical indicator or marker that may exist and exist now. Or future development of epilepsy or seizure disorders or similar disorders associated with seizures, in the case of inferior cases, detailed imaging techniques such as computed tomography (CT) magnetic resonance imaging (MRI) or positron emission tomography (ΡΕΤ) , or other neuroimaging techniques can be used to determine whether the subject is at risk of developing one of these diseases. Examples of suitable biological indicators for use in the methods of the invention include, but are not limited to, graded sclerosis or volume loss in the hippocampus by MRI, CT or other contrast techniques or the presence of mesenteric sclerosing (MTS) or similar related anatomical conditions. Examination of molecular species such as proteins or other biochemical indicators in the patient's blood, serum or tissues, such as clinical neurological factors (increased CNTI^ or increased serum values of neurodegradation products; or replacement from patients requiring antipsychotic treatment) Other evidence of markers or biomarkers, such as EEG recommendations for seizures or similar disorders associated with seizures, seizure-related seizures, or seizure-related disorders. 29 200808300 It is expected that different detection techniques will be developed in the future. More such biomarkers. Any such markers or indicators of seizure disorders, epilepsy or similar disorders associated with epileptic seizures that may or may develop in the future may be used in the method of the invention for determining whether the invention is required And method and treatment. In a specific embodiment of the invention, treatment In patients with epilepsy or epilepsy-related seizure-like neurological phenomena as defined above or similar disorders associated with epileptic seizures, and using the compounds of the invention to reverse the advantages of epilepsy, the pain defined above may be gradually reduced or A tumor-related seizure-like neurological phenomenon or a patient similar to a seizure-related disorder controls the dose or intensity of maintenance required to control a clinical phenomenon. Thus, due to the improvement in treatment with the method of the present invention in the disorder, the patient It may be discontinued to maintain medical care, including but not limited to the compound of the present invention if it is used as a separate medical expense. Accordingly, after the treatment of the traditional AED, the φ can be stopped after the treatment of the traditional AED The AED reverses the described epilepsy disorder. Those skilled in the art will be able to understand how to rapidly reduce the amount of gradual reduction based on clinical signs and symptoms including EEG's, breakthrough progression of seizures, or other suitable biological indicators of the disorders described. The present invention relates to the preparation of the compound of formula (1) and/or formula (π) disclosed herein. The use of the method for the treatment, prevention, suppression, cessation and/or inhibition of epilepticity in a patient is preferably in a patient in need of treatment with AEGD. In a particular embodiment of the invention, the compound of formula (I) is Selected from its 30 200808300 R1 is selected from the group consisting of hydrogen, halo, hydroxy, methoxy, trifluoromethyl, nitro and cyano; 'XY is selected from the group consisting of -S-CH, _S-C(CH3)- , -0-CH, -〇-C(CH3)-, -N(CH3)-CH-, and CH=CH-CH-; A is selected from the group consisting of -CHy and _Ch(CH3>_; R2 is selected Included from hydrogen and methyl; _ R and R are each independently selected from the group consisting of hydrogen and sulfhydryl; or R3 and R4 together with the nitrogen atom bonded thereto form a 5 to 7 shell saturation, part of which is not The saturated or aromatic ring structure, if necessary, contains one to two other heteroatoms independently selected from the group consisting of hydrazine, N and S; or a pharmaceutically acceptable salt thereof. In another embodiment of the invention, the compound of formula (1) is selected from the group consisting of wherein R1 is selected from the group consisting of hydrogen and a halogen; _X_Y is selected from the group consisting of each CH-, -SC(CH3)-,-0-CH, 〇-C(CH3), -N(CH3)-CH- and .CH=CH-CH-; A is selected from the group consisting of -CH2- and -CH (Ch3K r2 is selected from the group consisting of hydrogen and methyl; r3 and R4 Individually selected from the group consisting of hydrogen and methyl; and pharmaceutically acceptable salts thereof. In another embodiment of the invention, the compound of formula (1) is selected from the group consisting of wherein R is selected from the group consisting of hydrogen and halo; The halogen group is bonded at 4·, 5- 31 200808300 or 7-position; XY is selected from the group consisting of -0-CH-, -0-C(CH3)-, -S-CH, -SC(CH3)-, -N(CH3)-CH- and -CH=CH-CH-; A is selected from the group consisting of -CH2- and -CH(CH3)-; R is nitrogen; R3 and R4 are each hydrogen; and pharmaceutically acceptable In another embodiment of the invention, the compound of formula (I) is selected from the group consisting of wherein R1 is hydrogen; XY is selected from the group consisting of -0-CH-, -〇-C(CH3)-, -S- CH-, -SC(CH3)-, -N(CH3)-CH-, and -CH=CH-CH-; A is selected from the group consisting of _CH2- and -CH(CH3)-; R2 is hydrogen; R3 and R4 Each is hydrogen; and a pharmaceutically acceptable salt thereof. In another specific embodiment, the compound of formula (1) is selected from the group consisting of argon, halo, hydroxy, methoxy, trifluoromethyl, nitro and cyano; R1 is preferred Preferably, R1 is selected from the group consisting of hydrogen and a halogen group, wherein the halogen group is bonded at the 4-, 5- or 7-position; is -S-CH-; Α is selected from the group consisting of -CH2 And -CH(CH3)-; R2 is selected from the group consisting of hydrogen and methyl; preferably R2 is hydrogen; 32 200808300 R and R4 are each independently selected from the group consisting of hydrogen and halo; preferably r3 R4 is hydrogen; And a pharmaceutically acceptable salt thereof. In one embodiment of the invention, selected from the group consisting of chlorine, fluorine, and bromine. In another embodiment of the invention, r1 is not wind and is bonded at 4 The position of 5, or 7 is preferably at the 5_ position. In another embodiment of the invention, Ri is not hydrogen and the bond is at 5, 6 or preferably placed at the 6_ position. In another embodiment of the invention, 疋, includes hydrogen and a halogen group. Another embodiment of the invention R is selected from the group consisting of a thiol group and a τ oxy group. In the embodiment, R 1 is selected from the group consisting of hydrogen, a halogen group, and a trifluoromethyl group. In a specific embodiment, R1 is selected from the group consisting of hydrogen, a dentate group, a fluoromethyl group, a cyano group, and a silk. In another embodiment of the invention, R is selected from the group consisting of hydrogen, a functional group, a trifluoromethyl group, and a cyano group. In a specific implementation of the invention f, it is selected from the group consisting of trifluoromethyl and cyano. In another embodiment of the invention, R1 is selected from the group consisting of gas, heart = 5' gas group, 5', 5' desert, 5_trifluoromethyl, 5-7 nitrogen-7. In a particular embodiment of the invention, R2 is gas. Another specific implementation of the present invention. In another specific embodiment of the invention, R2 is & R1 hydrogen and R4 is gas. In one embodiment of the invention, R3 and R4 are each independently, and from 3, yc" silk. In another embodiment of the present invention, 'R and R' form a 5 to 7 member saturation with the nitrogen atom bonded thereto, and 33.200808300 partially unsaturated silk family structure, as needed - to both sides The site is selected from other heteroatoms including hydrazine, N and S. In the present invention, R3 and R4 are independently selected from 3 including f, 9 fluorenyl and ethyl. In another embodiment of the invention, R and each are independently selected from the group consisting of hydrogen and methyl. Another specific implementation of the present day, R3 and R4 are each independently selected from the group consisting of hydrogen and ethyl. In another embodiment of the invention, r3 is hydrogen and anaphylide 4 is ethyl. In a specific embodiment of the invention, R3 and R4- and R, 1, saturated, 4-inhibited or aromatic ring, optionally contain - to two independently selected from the group consisting of ms atom. In the other embodiment of the present invention, the exercise is carried out, r3 and r4: 3 and its collateral axis 5 to 7 are heard and compliant, as needed - to the two sides are selected from other heteroatoms including 0, s. ^The other is a specific implementation, r, r4 - and continue to form a 5 to 7 member aromatic ring structure, as needed - to two independently selected from other heteroatoms including 〇, ν and s . Preferably, R3 and R4 together with the nitrogen atom to which they are bonded form a 5 to 6 ft, partially unsaturated or aromatic ring structure, optionally containing - to two self-contained. Other hetero atoms of .... More preferably, the nitrogen atom bonded thereto forms 6 members saturated, partially unsaturated, and optionally contains - to two other heteroatoms independently selected from N and S. —^, and R and R are bonded to the nitrogen atom to which they are bonded to a 7 (and more) saturated or aromatic ring structure, optionally containing - to two (more than 34.200808300 and -) independent It is selected from other heteroatoms XN including hydrazine, N&s (preferably N), and in the other embodiment of the present invention, r3 & r4 forms a 5 to 6 member saturated or aromatic ring structure. , from 3 to - two (more preferably one) independently selected from the group consisting of preferably 0 or Ν, more preferably called other heteroatoms. 』 and 3 (the rut is more suitable, the 5 to 7 members are saturated, partially unsaturated or fragrant to 1 year old, including G, S and sputum, the hetero atom is independently selected from the group consisting of 〇 & Ν, more preferably the hetero atom is & suitably including one to two 5 to 7 Å saturated, heterogeneous or aromatic structures independently selected from the other heteroatoms including hydrazine, "and 8" including But not limited to pyrrolyl, pyrrolidinyl, pyrrolyl, morpholinyl, hexamidine pyridyl, hexahydropyramyl, imidazolyl, pyrazolylpyridyl, thiofenofyl, pyridinyl, tri Ploughing base, azepine base, etc. It is preferred to contain one to two 5 to 7 member saturated, partially unsaturated or aromatic ring structures independently selected from other heteroatoms including anthracene, shellfish and s. Not limited to imidazolyl, pyrrolidinyl, hexahydropyridyl and morpholinyl. In a particular embodiment of the invention, A is -CH2-. In one embodiment of the invention, χ-γ is selected Included from -S-CH-, -0-CEK-〇-c(CH3; K-N(CH3)-CH- and -CH=CH-CH-. In another embodiment of the invention, χ_γ is Selected from Including -S-CH, -0-CH, -0-C(CH3)-, and -CH=CH_CH-. In another embodiment of the invention, χ-γ is selected from, including -S-CH- , -OCH, -〇-c(CH3)-, and -Ν(αΗ3ΚΉ-. In another embodiment of the invention 35 200808300, χγ is selected from the group consisting of _S CH_, _〇_CH_, -N (CH3) -CH- and · 〇ίκ: Η-αι "In another embodiment of the invention, Χ-Υ is selected from the group consisting of CH_, _〇_CH_ and '-CH=CH-CH-. In another embodiment of the invention, χ·γ is selected from the group consisting of -S_CH- and -0-CH-. In another embodiment of the invention, XY is selected from the group consisting of -S-CH-, -SC(CH3K -0-CH-, -0-C(CH3)_ and -N(CH3)-CH-. In a specific embodiment of the invention, in another embodiment of the invention, XY is ·CH=CH_CH_. In another embodiment of the invention, X-Yi_N(CH3)-CH. In another embodiment of the invention, XY is selected from the group consisting of -仏^^ and - Oc(ch3)-. In a specific embodiment, the invention relates to a compound selected from the group consisting of N-(benzo[b]non-3-ylindenyl)-continuous diamine; N -[(5-gasbenzo[b]thenyl)-mercapto]-sulfonyldiamine; N-(3-benzofuranylsulfonyldiamine; N-[(5-gas benzo) [b]喧-3-yl)methyl]-continuation of guanidine diamine; N-(l_benzone] -3--3-ylethyl)- scutane diamine; Ν·»(1-tea Methyl)-diazepine diamine, hydrazine-[(2-mercapto-3-benzomanpinyl)methyl]-continuous brewing diamine; ν_[(5-bromobenzo[b]thion -3-yl) fluorenyl]-sulfonyldiamine; hydrazine-[(4-bromobenzo[b]thion-3-yl)methyl]-diazepine diamine; N-[(7-fluoro Benzene 嗔 各 各 ) ) ) ) 甲基 甲基 甲基 甲基 甲基 甲基 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; (4-Trifluorodecylbenzo[b]thenyl)methyl]-sulfonamide; cyanobenzo[b]thia-3-yl)methyl]-sulfonamide; N -[(benzo[b]thia-3-yl)methyl]-amine sulfonylpyrrolidine; N-[(benzo[b]thia-3-yl)-36 200808300 ki]-v' -ethyl hydrazine diamine]amine, and its pharmaceutically acceptable salt base), hydrazine) ί substituent is the age of the body to become any independent mechanical basis or choose from the whole name defined in this article Any subset of the storage. Representative compounds used in chemotherapy are listed in Tables 1 and 2 below. ______ 1 · ^fV 矣, W: , children *!/, compounds

ΝΗ Ο 立-ί體㈣例，包括彼等其中選擇用於本 文疋義的一或夕個變數(也就是^、^尺3 Μ χυ 夕〇 N—R3ΝΗ 立 立 - 体 (4), including the one or eve variables selected by them for the meaning of this article (ie ^, ^尺3 Μ 〇 〇 〇 N-R3

編5虎 R1 -Χ_Υ- A R3 ——~~—-R4 1 Η -S-CH- -ch2- H H 3 5-C1 -S-CH- -ch2- H 6 Η -O-CH- -ch2- H — H 7 Η -n(ch3)-ch_ -ch2- H H 8 5-F -S-CH- -ch2- H H 9 Η -S-CH- -ch2- H H 10 Η -CH=CH-CH- -CH(CH3)- H H 13 Η -0-C(CH3) -ch2- H H 15 5-Br 各CH- -ch2. H H 17 4-Br -S-CH- -ch2- H H 37 200808300编5虎R1 -Χ_Υ- A R3 ——~~--R4 1 Η -S-CH- -ch2- HH 3 5-C1 -S-CH- -ch2- H 6 Η -O-CH- -ch2- H — H 7 Η -n(ch3)-ch_ -ch2- HH 8 5-F -S-CH- -ch2- HH 9 Η -S-CH- -ch2- HH 10 Η -CH=CH-CH- - CH(CH3)-HH 13 Η -0-C(CH3) -ch2- HH 15 5-Br Each CH- -ch2. HH 17 4-Br -S-CH- -ch2- HH 37 200808300

一部份使用，包括直鏈及支鏈。例如，烷基包括曱基、乙 基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、 戊基等，除非另外說明，「Cw烷基」係指碳鏈含1-4個碳 原子。 當一個特定基是「經取代」（例如烧基、苯基、芳基、 雑烷基、雜芳基)，該基可有一或多個取代基，較宜從一至 五個取代基，更宜從一至三個取代基，最宜從一至兩個取 代基，獨立地選自取代基之名單。 關於取代基，「獨立地」一詞係指當可能有一個以上 38 200808300 的此基時，此取代基彼此可相同或不同。 為了k供更精礦的描述，本文提供的部份定量表示沒 有授與「約」一詞。不論是否明確使用「約」一詞，本文 提供的每一個量係指實際給予的值，且其也係指此給予值 在根據從事此項技藝下的合理大約值，包括此給予值在實 驗及/或測量情形下的誤差。 在本文使用時，除非另外說明，「釋離基」一詞係指 • 帶電或不帶電的原子或基團，其在取代或替代反應中離 開。合適的貫例包括但不限於Br、Cl、I、甲磺酿酯基、甲 苯磺醯酯基等。 ~ ' 除非另外說明，R1取代基鍵結的位置將沿著核心結構 在順時鐘方向從標示為K 2的H位置開始並根據下面 從其接續計數而決定：Part of the use, including straight and branched. For example, alkyl includes fluorenyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, pentyl, and the like, unless otherwise stated, "Cw alkyl" refers to The carbon chain contains from 1 to 4 carbon atoms. When a particular group is "substituted" (eg, alkyl, phenyl, aryl, decyl, heteroaryl), the group may have one or more substituents, preferably from one to five substituents, more preferably From one to three substituents, most preferably from one to two substituents, are independently selected from the list of substituents. With respect to substituents, the term "independently" means that when there is more than one such base of 38 200808300, the substituents may be the same or different from each other. In order to provide a description of the concentrate, some of the quantitative representations provided herein do not give the word "about". Whether or not the term "about" is used explicitly, each quantity provided herein refers to the value actually given, and it also means that the value given is based on a reasonable approximate value of the skill, including the value given in the experiment and / or the error in the measurement situation. As used herein, unless otherwise stated, the term "release group" means a charged or uncharged atom or group that is removed in a substitution or substitution reaction. Suitable examples include, but are not limited to, Br, Cl, I, methanesulfonyl ester, toluenesulfonate, and the like. ~ ' Unless otherwise stated, the position of the R1 substituent bond will be determined along the core structure from the H position labeled K 2 in the clockwise direction and determined from the subsequent counts from it:

當Χ-γ取代基是-ch=：ch-ch-，則Χ-Υ基將計數為夏 2、3且隨後如同前述沿著核心結構接續計數。 、 在整份說明書使用的標準命名中，指明側鏈的末端部 說明，隨後是朝向連接點之相鄰官能基。據此，例如 「苯基-Cw烷基胺基羰基Ci_6烷基」取代基係指下式基’ 39 200808300When the Χ-γ substituent is -ch=:ch-ch-, the Χ-fluorenyl group will be counted as summer 2, 3 and then counted successively along the core structure as previously described. In the standard nomenclature used throughout the specification, the end portion of the side chain is indicated, followed by the adjacent functional groups towards the point of attachment. Accordingly, for example, the "phenyl-Cw alkylaminocarbonyl Ci_6 alkyl" substituent refers to the formula: 39 200808300

下列是在本說明書特別是在圖示及實 寫·· DCE ^ 二氯乙烧 DCM = 二氯甲烷 DMF N，N-二甲基甲醯胺 DMSO ^ 二曱亞颯 LAH 氫化鋁鋰 MTBE ^ 曱基第三丁基醚 THF ^ 四氫吱喊 TLC ^ 薄層層析法 i根據本發明之化合物有至少一個對掌中心時其可 據此存在為對掌異獅。當化合物有二❹瓣掌中心時 其可據此存在為非對掌異構物。當然全部這些異構物及其 ，合物都包括在本發明之範_。而且，化合物之部份結 曰曰升/式可存在為多晶形物且也包括在本發明之範圍内。此 外，部份化合物可與水或常用有機溶劑形成溶劑化物(例如 水合物），且這些溶劑化物也包括在本發明之範圍内。 例中使用的縮 ,在藥劑中使用時，本發明化合物之鹽類係指無毒的「藥 學上可接受的鹽類」。但是，其他鹽類可以用在製備根據 本發明之化合物或其藥學上可接受的鹽類。化合物之合適 的藥學上可接受的鹽類包括酸加成鹽，其可經由例如將化 200808300 合物之溶液與藥學上可接受的酸例如氫氯酸、硫酸、富馬 酸、馬來酸、琥珀酸、醋酸、苯曱酸、擰檬酸、酒石酸、 碳酸或鱗酸之溶液混合而形成。而且，當本發明化合物帶 有一個酸性基團時，其合適的藥學上可接受的鹽類包括鹼 金屬鹽類，例如鈉或鉀鹽；鹼土金屬鹽類，例如鈣或鎂鹽； 及與合適的有機配體形成的鹽類，例如四級銨鹽。據此， 代表性的藥學上可接受的鹽類包括下列： 醋酸鹽、苯磺酸鹽、苯曱酸鹽、碳酸氫鹽、硫酸氫鹽、 酒石酸氫鹽、删酸鹽、溴化物、依地酸舞、右旋樟腦續酸 鹽、碳酸鹽、氣化物、克拉維酸鹽、擰檬酸鹽、二氫氯化 物、依地酸鹽、乙二磺酸鹽、依拉酸鹽、乙磺酸鹽、富馬 酸鹽、葡庚糖酸鹽、葡糖酸鹽、谷胺酸鹽、乙醇醯阿散酸 鹽、己基間本一酴酸鹽、海巴胺(hydrabamine)、漠酸鹽、 氯酸鹽、羥基萘酸鹽、碘化物、異氰酸鹽、乳酸鹽、乳糖 备I鹽、月私鹽、頻果酸鹽、馬來酸鹽、扁桃酸鹽、甲 磺酸鹽、曱基溴、硝酸曱酯、硫酸甲酯、黏酸鹽、萘磺酸 鹽、硝酸鹽、N-甲基還原葡糖胺銨鹽、油酸鹽、巴莫酸鹽(雙 海奈酸鹽）、棕搁酸鹽、泛酸鹽、磷酸鹽/磷酸氫鹽、聚半乳 糖盤酸鹽、水揚酸鹽、硬脂酸鹽、硫酸鹽、驗式醋酸鹽、 琥珀酸鹽、丹寧酸鹽、酒石酸鹽、茶氯酸鹽(te〇clate)、甲 苯磺酸鹽、三乙基破及戊酸鹽。 可以在製備藥學上可接受的鹽類中使用的代表性酸及 鹼包括下列： 酸包括醋酸、2,2-二氣醋酸、醯基化的胺基酸、己二酸、 200808300 深朊酸、抗壞血酸、L-天冬胺酸、苯續酸、苯甲酸、4-乙 ，胺基苯甲酸、（+)-樟腦酸、樟腦磺酸、樟腦-1〇_ 石戸九癸酸、己酸、辛酸、肉桂酸、檸檬酸、環己胺基石黃 酉=、十一烷基硫酸、乙烷β1，2_二磺酸、乙磺酸、2_羥基_乙 續酸二甲酸、f馬酸、耗糖二酸、龍膽酸、葡庚糖酸、 右旋葡糖酸、右旋葡萄糖魏、左旋_谷胺酸、α•酮基_戊 了I、乙醇酸、馬尿酸、氫溴酸、氫氯酸、卜)_L_乳酸、(士)_DL_ 乳®^、乳糖醛酸、馬來酸、㈠_L_蘋果酸、丙二酸、（土)dl_ 爲桃，、甲石頁酸、奈_2_石黃酸、萘二石黃酸、！·經基_2_蒸 ，、終驗酸、擰檬酸、油酸、乳清酸、草酸、棕櫚酸、巴 1、磷酸、左旋-焦谷胺酸、水揚酸、4_胺基冰楊酸癸 =酸、硬麟、琥峨、硫酸、丹寧酸、（+)_左旋酒石酸 4氰酸、P-甲苯磺酸及十一碳烯酸；且 、 鹼包括氨、左旋精胺酸、苄胺、乙二午 丹醇、二挪、二乙胺、 力乙—胺、N_甲基·逛原葡糖胺、海巴胺、出 左疑·賴胺酸、氫氧化鎂、4你經基乙基)_嗎福〇林丄、 0井、虱氡化鉀、1-(2-經基乙基p比咯咬、二、吡 納、三乙醇胺、胺基丁三醇及氫氧化鋅。、、氧乳化 備。式ω化合物其中A是偶-可根據圖示1概述的方法製 42 .200808300The following is in this manual especially in the illustration and implementation · DCE ^ Dichloroethane DCM = dichloromethane DMF N, N-dimethylformamide DMSO ^ Diterpenoid LAH lithium aluminum hydride MTBE ^ 曱Tributyl ether THF ^ Tetrahydropyrene TLC ^ Thin layer chromatography i The compound according to the present invention has at least one pair of palms when it can be present as a pair of lions. When the compound has a center of the second palm, it can be present as a non-parentomer. Of course, all of these isomers and their compounds are included in the scope of the present invention. Moreover, a portion of the compound can be present as a polymorph and is also included within the scope of the invention. Further, some of the compounds may form solvates (e.g., hydrates) with water or a common organic solvent, and such solvates are also included in the scope of the present invention. As used in the examples, the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". However, other salts may be used in the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may be, for example, by reacting a solution of the compound 200808300 with a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, It is formed by mixing a solution of succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or scaly acid. Moreover, when the compound of the present invention bears an acidic group, suitable pharmaceutically acceptable salts thereof include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; Salts formed by organic ligands, such as quaternary ammonium salts. Accordingly, representative pharmaceutically acceptable salts include the following: acetate, besylate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, acid salt, bromide, lysine Sour dance, dextrorotatory citrate, carbonate, vapor, clavulanate, citrate, dihydrochloride, edetate, ethanedisulfonate, ylide, ethanesulfonic acid Salt, fumarate, glucoheptonate, gluconate, glutamate, ethanol oxalate, hexyl phthalate, hydrabamine, oxalate, chlorine Acid salt, hydroxynaphthoate, iodide, isocyanate, lactate, lactose I salt, monthly salt, frequency phosphate, maleate, mandelate, methanesulfonate, sulfonium bromide , decyl nitrate, methyl sulfate, acid salt, naphthalene sulfonate, nitrate, N-methyl reduced glucosamine ammonium salt, oleate, bamo acid salt (double sea narate), brown Acid salt, pantothenate, phosphate/hydrogen phosphate, polygalactose salt, salicylate, stearate, sulfate, acetate, succinate, tannin Tartrate, teoclate (te〇clate), tosylate, triethiodide and valerate broken. Representative acids and bases which may be employed in the preparation of pharmaceutically acceptable salts include the following: Acids include acetic acid, 2,2-di-acetic acid, thiolated amino acids, adipic acid, 200808300 decanoic acid, Ascorbic acid, L-aspartic acid, benzoic acid, benzoic acid, 4-ethyl, aminobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, camphor-1〇_石戸九癸酸, caproic acid, caprylic acid , cinnamic acid, citric acid, cyclohexylamine ruthenium xanthine, undecyl sulfate, ethane β1,2_disulfonic acid, ethanesulfonic acid, 2-hydroxyl-ethylidene dicarboxylic acid, f-acid, consumption Saccharic acid, gentisic acid, glucoheptonic acid, d-gluconic acid, d-glucose Wei, L-glutamic acid, α-keto-penta-I, glycolic acid, hippuric acid, hydrobromic acid, hydrogen Chloric acid, Bu) _L_lactic acid, (士)_DL_乳®^, lactanoic acid, maleic acid, (a) _L_malic acid, malonic acid, (soil) dl_ is peach, sapphire acid, nai_2 _hemeic acid, naphthalene tartrazine,! ·Based on 2_ steam, final acid, citric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, bar 1, phosphoric acid, levo-pyroglutamic acid, salicylic acid, 4_Amino ice Salicylic acid yttrium = acid, hard lin, sulphur, sulphuric acid, tannic acid, (+) _ tartaric acid 4 cyanic acid, P-toluene sulfonic acid and undecylenic acid; and alkali, including ammonia, L-arginine , Benzylamine, Ethylene glycol, Ernwine, Diethylamine, Lithium-amine, N-methyl, Glucosamine, Haibaamine, Xieyu, Lysine, Magnesium Oxide, 4 You pass through the base ethyl) _ 福福〇林丄, 0 well, potassium telluride, 1-(2-ethylidene p to bite, di, pyran, triethanolamine, aminobutyric triol and hydrogen Zinc oxide, oxygen emulsification, formula ω compound wherein A is even - can be made according to the method outlined in Figure 1. 42.200808300

圖示1Figure 1

據此，將經適當取代的式(V)化合物，其係一種已知的 化合物或經由已知方法製備的化合物，與經適當取代的式 (VI)化合物，其係 一種已知的化合物或經由已知方法製備 的化合物，其中式(VI)化合物之存在量是約2至約5當量， 在有機溶劑例如乙醇、曱醇、二4烧等中，在無水的有機 溶劑中，較宜在約50°C至約100°C範圍之升溫下，較宜在 約迴流溫度下反應，得到對應的式(la)化合物。 式(I)化合物也可替代地根據圖示2概述的方法製備。Accordingly, an appropriately substituted compound of the formula (V) which is a known compound or a compound prepared by a known method, and an appropriately substituted compound of the formula (VI) which is a known compound or via A compound prepared by a known method, wherein the compound of the formula (VI) is present in an amount of from about 2 to about 5 equivalents, preferably in an organic solvent such as ethanol, decyl alcohol, bis- 4 or the like, in an anhydrous organic solvent. Preferably, the reaction is carried out at a temperature of from about 50 ° C to about 100 ° C at about reflux temperature to provide the corresponding compound of formula (la). Compounds of formula (I) may alternatively be prepared according to the methods outlined in Scheme 2.

/ R4 R3 圖示2 據此，將經適當取代的式(νπ)化合物，其係一種已知 的化合物或經由已知方法製備的化合物，與經適當取代的 式(VI)化合物，其係一種已知的化合物或經由已知方法製 43 200808300 備的化合物，其中式(VI)化合物之存在量是約2至钓5當 量，在有機溶劑例如THF、二畤烷等中，在無水的有機溶 劑中，較宜在約5(TC至約100°C範圍之升溫下，較宜在約 迴流溫度下反應，得到對應的式(I)化合物。 式(VII)化合物其中A是_〇12-可例如根據圖示3概述 的方法製備。/ R4 R3 Figure 2 Accordingly, an appropriately substituted compound of the formula (νπ) which is a known compound or a compound prepared by a known method, and an appropriately substituted compound of the formula (VI), which is a a known compound or a compound prepared by a known method, wherein the compound of the formula (VI) is present in an amount of from about 2 to 5 equivalents in an organic solvent such as THF, dioxane or the like in an anhydrous organic solvent. Preferably, the reaction is carried out at a temperature of about 5 (TC to about 100 ° C, preferably at about reflux temperature to give the corresponding compound of the formula (I). The compound of the formula (VII) wherein A is _〇12- For example, prepared according to the method outlined in Figure 3.

圖示3 醯氯、績醯氯等反應， 等在有機溶劑例如THF 到對應的式(IX)化合物< 據此，將經適當取代的式(VIII)化合物，其係一種已知 # H匕口物或經由已知方法製備的化合物，與活化劑例如草 且隨後與胺來源例如氨、氫氧化銨 ’、乙喊、DCM、DCE等中反應，得 式（DC)化合物I痛杳4S裡:ΛΑ 1菩K丸丨Figure 3 shows the reaction of ruthenium chloride, ruthenium chloride, etc., in an organic solvent such as THF to the corresponding compound of formula (IX) < Accordingly, an appropriately substituted compound of formula (VIII), which is a known #H匕Oral or a compound prepared by a known method, reacted with an activator such as grass and then with an amine source such as ammonia, ammonium hydroxide, B, DCM, DCE, etc., to obtain a compound (DC) compound I in 4S :ΛΑ1菩蒲丸

ί 麵其巾Α是颂卿,如根據圖示 在有 化合π 圖示4 概述的方法製備。 44 200808300ί The face is made by 颂 ,, as prepared according to the method outlined in Figure 4, which is outlined in Figure 4. 44 200808300

圖示4 據此，將經適當取代的式(X)化合物，其係一種已知的 化合物或經由已知方法製備的化合物，與甲醯胺及甲酸之 混合物，其中甲醯胺及甲酸之混合物存在量是大於約1當 量，較宜在大於約5當量之過量下，在約150°C之升溫下 反應，得到對應的式(XI)化合物。 式(XI)化合物經由與濃HC1、濃H2S04等在升溫下反 應而水解，較宜在迴流溫度，得到對應的式(Vllb)化合物。 式(VII)化合物可替代地根據圖示5概述的方法製備。Figure 4 According to this, an appropriately substituted compound of the formula (X) which is a known compound or a compound prepared by a known method, a mixture with formamide and formic acid, wherein a mixture of formamidine and formic acid is used. The amount is greater than about 1 equivalent, more preferably in an excess of greater than about 5 equivalents, at a temperature of about 150 ° C to provide the corresponding compound of formula (XI). The compound of the formula (XI) is hydrolyzed by reaction with concentrated HC1, concentrated H2SO4 or the like at elevated temperature, preferably at reflux temperature to give the corresponding compound of the formula (V11b). The compound of formula (VII) can alternatively be prepared according to the method outlined in Figure 5.

(V") a〜Nh2 圖示5 45 200808300 據此，將經適當取代的式(XII)化合物，其中L是釋離 基例如Br、C1、I、甲苯磺醯酯基、甲磺醯酯基等，其係一 種已知的化合物或經由已知方法製備的化合物，與疊氮化 鈉在有機溶劑例如dmf、dmso、甲醇、乙醇等t反應， 得到對應的式(XIII)化合物。 式(XIII)化合物與適當選擇的還原劑例如LAH、三苯 基膦、H2(g)等根據已知方法反應，得到對應的式(VII)化合 物。 式(VII)化合物其中a是CH2且X-Y是-0-CH2-可例如 根據圖示6概述的方法製備。 σ(V") a~Nh2 Figure 5 45 200808300 Accordingly, an appropriately substituted compound of the formula (XII) wherein L is a cleavage group such as Br, C1, I, tolsulfonate, methanesulfonate And the like, which is a known compound or a compound prepared by a known method, and reacted with sodium azide in an organic solvent such as dmf, dmso, methanol, ethanol or the like to obtain a corresponding compound of the formula (XIII). The compound of the formula (XIII) is reacted with a suitably selected reducing agent such as LAH, triphenylphosphine, H2 (g) or the like according to a known method to give the corresponding compound of the formula (VII). Compounds of formula (VII) wherein a is CH2 and X-Y is-0-CH2- can be prepared, for example, according to the procedure outlined in Scheme 6. σ

圖示6 據此，將經適當取代的酚、式(XIV)化合物，其係一種 已知的化合物或經由已知方法製備的化合物，與溴丙酮之 已知化合物，在鹼例如K2C〇3、Na2C03、NaH、三乙胺、 吼啶等存在下，在有機溶劑例如乙腈、 DMF、THF等中反 應，視需要在升溫下進行，得到對應的式(χν)化合物。 式(XV)化合物與酸例‘聚磷酸、硫酸、氬氯酸等，較 宜與聚麟酸，較宜在無溶劑(從事此項技藝者瞭解聚磷酸作 46 200808300 為溶劑)下反應，得到對應的式(XVI)化合物。 &，(xviMt合物_來_如㈣代琥賴亞胺在過Figure 6 Accordingly, an appropriately substituted phenol, a compound of the formula (XIV), which is a known compound or a compound prepared by a known method, and a known compound of bromoacetone, in a base such as K2C〇3, In the presence of Na2C03, NaH, triethylamine, acridine or the like, it is reacted in an organic solvent such as acetonitrile, DMF, THF or the like, and if necessary, is carried out at elevated temperature to obtain a corresponding compound of the formula (??). The compound of the formula (XV) and the acid example 'polyphosphoric acid, sulfuric acid, argonic acid, etc., are preferably reacted with polylinic acid, preferably in the absence of a solvent (the person skilled in the art knows that polyphosphoric acid is used as a solvent for 2008 200808300), Corresponding compound of formula (XVI). &,(xviMt compound_来_如(四)代琥赖亚亚

氧化苯醯、Bf2等，在有機溶·i如四氣化碳、氯仿、DCM 等中反應，較宜在i化有機溶射，制對應的細νπ) 化合物。 式(XVII)化合物與疊氮化鈉在考機溶劑例如DMF、 DMSO、甲醇、乙醇等中反應，得到對應的式(χνπι)化合 物。 式(XVIII)化合物與適當選擇的還原劑例如LAH、三苯 基膦、等根據已知方法反應，得到對應的式(viic)化合 物。 式(V)化合物其中Χ_γ是^名沁可例如根據圖示7概述 的方法製備。 00¾ R1- xSH R1^YS^ ο 一以 ---- (XIX) (XX) R1- _τγ\ 一-Cc (XXI) 圖示7 (Va) 、〇CHiBenzoyl benzoquinone, Bf2, etc., are reacted in an organic solvent such as tetra-carbonized carbon, chloroform, DCM, etc., and it is preferred to use an organic solvent to prepare a corresponding fine νπ) compound. The compound of the formula (XVII) is reacted with sodium azide in an experimental solvent such as DMF, DMSO, methanol, ethanol or the like to give the corresponding compound of the formula (?νπι). The compound of the formula (XVIII) is reacted with a suitably selected reducing agent such as LAH, triphenylphosphine, etc. according to known methods to give the corresponding compound of the formula (viic). Compounds of formula (V) wherein Χ γ is 沁 can be prepared, for example, according to the method outlined in Scheme 7. 003⁄4 R1- xSH R1^YS^ ο One to ---- (XIX) (XX) R1- _τγ\ One-Cc (XXI) Figure 7 (Va), 〇CHi

S 據此，將經適當取代的式(XIX)化合物，其係一種已知 的化合物或經由已知方法製備的化合物，與氣乙盤二甲基 縮醛或溴乙醛二甲基縮醛之已知化合物，在鹼例如第三丁 醇鉀、第三丁醇鈉、碳酸鉀、氫氧化鉀等存在在有機 47 .200808300 命制例如THF、DMF、乙腈等巾反應，得到對應的式(χχ) 化合物。 式(XX)化合物與酸例如聚磷酸、硫酸、氫氯酸等，較 宜與聚麟酸，在鮮存在下，較宜在無_(從事此項技藝 者瞭解聚鱗酸及/或氯苯可作為溶劑)下，在從約·。C至 200°C範圍之升溫下，較宜在約迴流溫度之升溫下反應，得 到對應的式(XXI)化合物。 式(XXI)化合物與曱酿化劑例如二氯甲基甲基醚等，在 路易士酸觸媒例如四氯化鈦、三氣化铭、四氣化錫等存在 下，在有機溶劑例如DCM、氯仿等中，在從約〇。〇至約室 溫範圍之溫度下反應，得到對應的式(Va)化合物。 式(I)化合物其中R3及/或R4不是氫或R3及R4與和其 鍵結的氮形成環結構，可例如根據圖示8概述的方法製備。According to this, an appropriately substituted compound of the formula (XIX) which is a known compound or a compound prepared by a known method, and a gas dimethyl acetal or bromoacetaldehyde dimethyl acetal Known compounds, in the presence of a base such as potassium t-butoxide, sodium butoxide, potassium carbonate, potassium hydroxide, etc., in the organic 47.200808300, such as THF, DMF, acetonitrile, etc., to obtain the corresponding formula (χχ ) Compound. The compound of the formula (XX) and the acid such as polyphosphoric acid, sulfuric acid, hydrochloric acid, etc., are preferably combined with polylinic acid, in the presence of fresh, preferably in the absence of _ (the person skilled in the art knows about polylactic acid and/or chlorobenzene) Can be used as a solvent), from about. When the temperature is raised from the range of C to 200 ° C, it is preferred to carry out the reaction at a temperature of about reflux temperature to obtain a corresponding compound of the formula (XXI). A compound of the formula (XXI) and an emulsification agent such as dichloromethyl methyl ether or the like are present in an organic solvent such as DCM in the presence of a Lewis acid catalyst such as titanium tetrachloride, tri-gasification, tetra-tin-iron or the like. , chloroform, etc., from about 〇. The reaction is carried out at a temperature in the range of about room temperature to obtain the corresponding compound of the formula (Va). Compounds of formula (I) wherein R3 and/or R4 are other than hydrogen or R3 and R4 form a ring structure with the nitrogen to which they are bonded may, for example, be prepared according to the procedure outlined in Scheme 8.

圖示8 據此，將經適當取代的式(Ib)化合物，與經適當取代 .的胺、秘XU)化合物，其係—種已知的化合物或經由已 知方法製備的化合物，在水或有機溶侧如二极、乙醇、 THF、異丙醇等中反應，先決條件是式⑽化合物及雄观 48 200808300 化合物是至少部份滚:龃名★ a +,,, ΜFigure 8 Accordingly, an appropriately substituted compound of the formula (Ib), with an appropriately substituted amine, a secret XU) compound, a known compound or a compound prepared by a known method, in water or The organic soluble side is reacted in a dipole, ethanol, THF, isopropanol or the like, and the prerequisite is that the compound of the formula (10) and the male watch 48 200808300 are at least partially rolled: anonymous ★ a +,,, Μ

，在從約室溫至 ，得到對應的式 從事此藝者還可了解其中本發明之 在多種溶劑或溶劑系統中進行時，該肩 適的溶劑或溶劑系統之混合物中進行。 明之一個反應步驟可以 該反應步驟也可以在合 當用於製備根據本發明化合物之方法產生立體豈構物 之混合物時，這些異構物可經由方便的技術例如製備級層 析法分離。化合物可製備糾消旋物形式，或可經由立體 特異性合成或經由解離而製備個別的對掌異構物。化合物 可例如經由標準技術解離成其成份對掌異構物，例如經由 與光學活性酸例如㈠_二_對_甲苯酿基_D_酒石酸及/或⑴- 二-對-甲苯目石酸之鹽形成而形成非對掌異構物 對，隨後經由逐步結晶及再生自由態鹼。解離化合物也可 經由形成非對掌異構性酯類或醯胺類，隨後經由層析分離 並去除對掌性輔劑，或者是，使用對掌性HpLC管柱解離。 在用於製備本發明化合物之任何方法中，可能需要及/ 或必要保護相關分子上的敏性或反應性基此可經由傳統的 保τι蒦基達成，例如揭不在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，保護基可在方便的後 續階段使用此項技藝中的已知方法去除。 本發明提供治療致癲性之方法，不論其引起原因及發 49 200808300 展階段，包括將醫療有效量本文說明之式⑴化合物投藥 至對其有需要之受實驗者。本發明方法因此提供抑制癲癇 發作、抽搐或類似與癲癇發作相關的症狀且同時防止至癲 癇性進展之能力，所以可以防止引起疾病之進展或惡化或 非癲癇發作傾向的神經組織致癲性歷程之募集。為了完成 此目標，本發明之化合物或組成物必須在下面說明的正確 醫療有效量或劑量下使用。 —從事此項技藝者可以很容易地決定最適化劑量及投 藥4間表，且將隨著使用的特定化合物、投藥模式、製劑 強度、及疾病情开>之進展而改變。此外，與被治療的特定 病人相關的因子，包括病人年齡、體重、飲食及投藥時間， 將&致需要調整劑量。 在本發明之一個具體實施例中，使用式(I)化合物之治 療，，法可以在曾經有赫發作足以證明為癲癇的診斷 之受實驗者或病人㈣。在此频實關巾，本發明化合 物可乂’、AED s同時使用，在認出是癲癇發作障礙或癲 癇的病人抑·癇發作。但是，關於此點，根據本發明之 方法，這些化合物是在適當劑量範圍内使用，以便另外提 供抗致癲性效應(AEGD效應)並防止神經組織受到癲癇 發作活性之延伸及擴展及疾病之後續惡化。 、在另-個具體實施例中，使用本發明化合物之治療攝 生法可以在例如受實驗者罹患腦部傷害性損傷或其他最 rf傷但是在受實驗者尚未被辑有癲癇之制始，例如 又貝驗者有第-或第二次癲癇發作之前。在_個具體實施 50 200808300 例中，被肢合物例如精神性_治療之有致癲性可能的 受^驗者’或有與發展_的風險相_疾賴如自閉症 之文實驗者，可以用本發明揭示之式(化合物開始治療 攝生法。 μ 在另-個频實施财，使財發魏合物之治療攝 生法可以在神經純沒有發生任何骸或損傷之前但是 在當此傷害或損傷可以預期或將要發生時開始。例如此 •=攝生法可以在受實驗者進行神經外科手術時或可能 遭X其他形式或頭或腦部創傷時開始，例如拳擊、激烈運 動或競赛、再發生的中風、TIA，s等。 在另一個具體實施例中，本文揭示之化合物在腦部傷 ，性損傷或最初發作後投藥—段時間(週、月、年）。臨床 百生將知道如何決定本文揭示之化合物已經達到醫療有 j私度，例如病人的臨床檢查，或經由測量血液或腦-脊 體液中的_濃度。從事此項技藝者經由身 #副作關如語言不清、_或受細協調功能之餘^ 重性，可以決定最大容忍劑量。 、本發明還包括含一或多種式(I)化合物與藥學上可接受 $載劑之醫藥組成物。製備含有本發明說明的—或多種化 -勿作為活丨生成份的醫樂組成物，可以根據傳統醫藥混合 技術將化合物或化合物群與藥學載劑密切混合。決定於所 要的投藥路徑(例如口服、不經腸道），該载劑可以有多種 不同的$式。據此，對於液體口服製劑例如懸浮液、酿劑 及;谷液，合適的載劑及添加劑包括水、二醇、油、醇、調 51 200808300 未背!、防腐劑、女疋劑、染色劑等；對於固體口服製劑例 如私切、膠展劑及片劑，合適的載劑及添力口劑包括殿粉、 糖、稀釋劑、粒化劑、潤滑劑、黏著劑、分解劑等。固體 口服衣劑也可以關如麵物質包衣或腸包衣用以調節吸 附的主要位置。對於不經腸道投藥，載劑通常包括無菌的 水=加使增加溶解度或防腐性的其他成份。注射的懸浮 液或冷液也可以利用水性载劑以及適當的添加劑製備。 • 雜本發明的醫藥組成物時，根據傳統醫藥混合技術 將作為活性成份的本發明之一或多種化合物與藥學載劑穷 切混合’決定於所要的投藥路徑，該載劑可以有多種不同 的七式。在製備口服給藥形式之組成物時，可以使用任何 々用的醫藥介質。據此，對於液體口服製劑，例如懸浮液、 酏劑及溶液，合適的載劑及添加劑包括水、二醇、油、醇1 凋味劑、防腐劑、安定劑、染色劑等；對於固體口服製巧 例如粉劑、谬囊劑、囊片、膠囊錠及片劑，合適的载劑及 •、添加劑包括殿粉、糖、稀釋劑、粒化劑、潤滑劑、黏著^ 分解劑等。因為其容易投藥，片劑及膠囊劑代表最有利月的 口服給樂單元形式，在此情形下，明顯是使㈣體醫率載 劑。如果需要時，可以經由標準技術將片劑糖包衣或腸包 衣。對於不經腸道的藥劑，载劑通常包括無菌的水，雖缺 可以添加其他成份，例如用於輔助溶解度或防腐之目的“。、、 也可以製備注射的懸浮液，在此情形下，可以使用合適 液體載劑、懸浮劑等。本文的醫藥組成物之每個給藥單元 例如片劑m粉劑、注射劑、茶匙劑等將含有需要 52 200808300 ^达上述有效劑量之活性成份的量。本文的醫藥組成物之 母個給藥單元例如片劑、膠囊劑、粉劑、注射劑、苹匙劑 專將含有從約αι·ι_毫克且相在㈣G毫克/ 公斤/天之劑量下給予，較宜從約〇1至1〇〇亳克/公斤/天， 更且從、、.勺0.5-50笔克/公斤/天，更宜從約j 〇 〇毫克/公 斤/天或其中的任何範圍。但是決定於病人的需求、所要治 療的，情之嚴重度及使用的化合物，可以改變劑量。可以 φ 使用母日投藥或在一段時間後投藥。 、較宜這些組成物是在單元給藥形式，例如片劑、丸劑、 ，囊劑、粉劑、粒劑、錢不經腸道的溶液或懸浮液、計 置的噴霧劑或液體嘴霧劑、滴劑、瓶劑、自動注射器裝置 或栓劑；供口服、不經腸道、鼻内、舌下或直腸用藥，或 ^由吸入或吹人用I或者是，組成物可存在為合適每週 一次或每月-次用藥之形式；例如可順應成活性化合物之 不溶解的鹽，例如癸酸鹽，提供儲積製劑供肌肉内注射。 修 f悔製備固體組成物例如片劑，是將主要活性成份盘醫寧 載，例如傳統製造片劑的成份例如玉米驗、乳糖、嚴糖、 甘露醇、滑石、硬脂酸、硬脂酸鎂、碟酸二約或膠體及盆 .他醫藥稀釋劑例如水混合，形成含本發明化合物或1華學 切接受_的均勻混合物之固體_製組成物。當提到 翻製喊物是均自時，係指雜成份平均分散在整 個組成物使得組成物容易再分成同等有效的給藥形式例如 片劑、丸劑及膠囊齊卜然後將此固體預調製組成物再分成 上述形式之給藥形式，其中含從〇1至約1〇〇〇毫克本發明 53 200808300 供得到延長活性的優點之給轉广;ζ。,^ 口而& .^ ^ 口梁形式0例如，片劑或由密,1可 έ内部給藥及外部給藥成 3、 、/ 者。，後者疋以封套形式包覆前 解沛办7711、祕層隔離，其係在胃中作為阻止分 所可成份完整進人十二指腸或延遲釋放。多種物 =;1腸溶性層或包衣使用，此種物質包括多種聚合 ^與此物質例如蟲膠、魏醇及醋酸纖維素醋。 /、中可則本發明之新穎組成物供π服或經由注射 投樂之液體形式包括水性溶液、適當調味的漿液、水性或 j性懸祕、及时用油例如棉籽油、芝麻油、椰子油或 t生油以及關及類似的藥學媒劑之調味懸浮液。用於水 性懸浮液之合適的分散或祕劑，包括合成及天然的 膠體 列如西頁蓍膠、***膠、藻酸鹽、葡聚糖、緩甲基纖維 素鈉、甲基纖維素、聚乙稀基比洛酮或明膠。 ^本發明方法也可以使用含有本文中定義的任何化合物 及樂學上可接受的載劑之醫藥組成物進行。該醫藥組成物 可含有約0.1毫克及1000毫克之間的化合物，較宜約50 至500毫克，且可以調製成合適用於選擇的投藥模式之任 何形式。載劑包括需要且惰性的醫藥賦形劑，包括但不限 於黏著劑、懸浮劑、潤滑劑、調味劑、甜化劑、防腐劑、 染劑及塗料。合適用於口服投藥之組成物包括固體形式， 例如片劑、丸劑、囊片、膠囊劑(各包括立即釋放、定時釋 放及持續釋放的調配物）、粒劑及粉劑，及液體形式，例如 溶液、漿劑、酏劑、乳液、及懸浮液。可用於不經腸道投 54 200808300 藥的形式包括無菌的溶液、乳液及懸浮液。 每二2lfci物有利於在單-每曰劑量下投藥，或將總 片里刀成母天'一、二或四次劑量下招藥 :::r以在從事一般此項技藝者熟知的經由局部= 二=鼻内媒劑在鼻㈣式或經由經皮的皮膚貼布投藥。 .......經皮輸送的系統形式投藥，在整個給藥攝生法中的 投藥劑量當妓連如不是騎。絲生法中的 例如，對於在片劑或膠囊劑形式之 =以與鳴毒的藥學上可接受的情性;劑;= 著巧^水等結合。而且，當必要或需要時，合適的黏 =、潤滑劑、分解劑及染色劑也可以摻混至混合物中。 著劑包括但不限於殿粉、明膠、天然糖類例如葡 主箸糖、玉米甜化劑、天然及合成膠例如***膠、 :耆膝或油酸納、硬脂酸鈉、硬脂酸鎂、苯甲酸納、醋酸 ❿ #减鱗。分解劑包括但不限於殿粉、甲基纖維素、 瓊月曰、膨潤土、黃原膠等。 、液體是在適當調味的懸浮劑或分散劑中形成，例如合 成及天然膠例如黃蓍膠、***膠、曱基纖維素等。用於 不經腸道投藥時，需要無菌的懸浮液及溶液。當需要靜脈 内投藥^是使用通常含有合適的防腐劑之等滲性製劑。 不而疋茜要冶療或預防偏頭痛時，本發明化合物可以 在任何上述的組成物並根據此項技藝中建立的給藥攝生法 投藥。 / 此產品之每日劑量可以在每個成人每天從讀至200 55 200808300 毫克/公斤之廣大範圍内變化。對於口服投藥，組成物較宜 在含 〇.〇1、0.05、0.1、0.5、1.0、2,5、5.0、10.0、15.0、25 〇、 5〇.〇、100、150、200、250、500 及 1〇〇〇 毫克活性成份之 片劑形式提供，供根據症狀調整需要治療的病人之劑量。 藥劑之有效量通常是在每天從約〇.01亳克/公斤至約15〇〇 毫克/公斤體重之劑量範圍供應。該範圍較宜是每天從約 0.1至約100.0毫克/公斤體重，更宜是每天從約〇 5亳克/ φ A斤至约50毫克/公斤，再更宜是每天從約ΐ·〇至約25 〇 毫克/公斤體重。此化合物可以在每天1至4次之攝生法下 投藥。 從事此項技藝者將可了解本發明化合物之醫療有效量 可包括在延長的治療攝生法内重複給藥以產生臨床明顯的 結果，預防、逆轉、停止或抑制致癲性。 伙事此項技藝者將可了解使用合適、已知且普遍接受 的細胞及/或動物模式之活體内及試管内試驗，可預期受測 試的化合物治療或預防特定症狀之能力。從事此項技藝者 還可了解人體臨床試驗，包括第一次在人體、劑量範圍及 功效試驗，在健康實驗者及/或罹患特定疾病者，可以根據 在臨床及醫學技藝中熟知的方法完成。 有效劑塁之決定通常是根據動物模式研究，隨後是人 類臨床試驗且係經由在受實驗者中明顯減低標的暴露症狀 或情形之發生或嚴重性決定有效劑量及投藥建議案引導。 關於此點，合適的模式包括例如鼠、大鼠、豬、貓、不是 人的靈長類及此項技藝中已知的其他可接受的動物模式受 56 200808300 者是’有效劑量可以使用試管内模式測試(例如 管及躺賊種㈣，只有一般的計 正*㉔叫定適當㈣歧齡以投藥醫療 性#j(例如鼻内有效、經皮有效、靜脈内有 、或肌^有效以產生所要的反應之量）。 例疋陳述以幫助瞭解本發明，且不是要也不能 可式下作為在下面專利申請範圍中陳述的本發明之 限制。 【實施方式】 實例1The corresponding formula is obtained from about room temperature to the present, and those skilled in the art can also understand that the present invention is carried out in a mixture of solvent or solvent systems in a variety of solvents or solvent systems. One of the reaction steps may be such that the reaction step may also be separated by a convenient technique such as preparative stratification when the mixture is used to produce a stereoscopic cleavage in accordance with the process of the present invention. Compounds can be prepared in the form of racemates, or individual palmomerisomers can be prepared via stereospecific synthesis or via dissociation. The compound can be dissociated into its constituents, for example via standard techniques, for example via an optically active acid such as (i)-di-p-toluene-based _D_tartaric acid and/or (1)-di-p-toluene tartaric acid. The salt forms to form a pair of non-parent isomers, followed by gradual crystallization and regeneration of the free base. The dissociated compound can also be dissociated via the formation of a palmitic HpLC column by the formation of a non-palphalinic isomer or a guanamine, followed by separation and removal of the palmitic adjuvant by chromatography. In any of the methods used to prepare the compounds of the invention, it may be necessary and/or necessary to protect the susceptibility or reactivity of the relevant molecule via a conventional oxime group, for example, 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, protecting groups can be removed at a convenient subsequent stage using methods known in the art. . The present invention provides a method of treating epilepticity, regardless of the cause and the stage of the 2008 2008300, including administering a medically effective amount of a compound of the formula (1) described herein to a subject in need thereof. The method of the present invention thus provides the ability to inhibit seizures, seizures or similar symptoms associated with seizures while preventing progression to epilepticity, thereby preventing the progression of neurological tissue that causes disease progression or worsening or non-seizure tendency. raise. To accomplish this, the compounds or compositions of the invention must be used in the correct medically effective amount or dosage as described below. - Those skilled in the art can easily determine the optimal dosage and administration schedule, and will vary with the particular compound used, the mode of administration, the strength of the formulation, and the progression of the disease. In addition, the factors associated with the particular patient being treated, including the patient's age, weight, diet, and time of administration, will require a dose adjustment. In a specific embodiment of the invention, the treatment with a compound of formula (I) can be carried out in a subject or patient who has had a diagnosis of seizure sufficient to prove epilepsy (4). In this case, the compound of the present invention can be used simultaneously, and the AED s can be used at the same time to recognize seizures in patients who are suffering from seizure disorders or epilepsy. However, in this regard, according to the method of the present invention, these compounds are used in an appropriate dosage range to additionally provide an anti-epileptic effect (AEGD effect) and prevent the extension and expansion of the nervous tissue from seizure activity and the follow-up of the disease. deterioration. In another embodiment, the therapeutic regimen using a compound of the invention may be initiated, for example, by a subject suffering from a brain injury or other most rf injury, but in the subject having not yet had epilepsy, for example Another tester has a first or second seizure before. In the case of _ a specific implementation 50 200808300, a subject who is likely to be epileptically ill by a limb, such as a psychiatric _ treatment, may have a risk of developing _ a disease such as autism, The formula disclosed in the present invention can be used (the compound begins to be treated by the method. μ is implemented in another frequency, so that the therapeutic method of the fertilization can be used before the nerve pureness does not cause any defects or damage but when it is damaged or The injury can be expected to occur or will occur. For example, the • birth method can be initiated when the subject undergoes neurosurgery or when other forms of X or head or brain trauma, such as boxing, intense exercise or competition, The occurrence of stroke, TIA, s, etc. In another specific embodiment, the compounds disclosed herein are administered in the event of a brain injury, sexual injury or initial onset - a period of time (week, month, year). Clinical 100 students will know how It is decided that the compounds disclosed herein have reached a medical level of privacy, such as a clinical examination of a patient, or by measuring the concentration of _ in blood or brain-spinal fluid. The maximum tolerated dose may be determined by unclear, _ or by the fine coordination function. The present invention also encompasses a pharmaceutical composition comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier. A pharmaceutical composition containing the present invention, or a plurality of compounds, which are not active ingredients, may be intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical mixing techniques, depending on the desired route of administration (eg, oral, Intestinal), the carrier can be used in a variety of different forms. Accordingly, for liquid oral preparations such as suspensions, broths, and troughs, suitable carriers and additives include water, glycols, oils, alcohols. , adjusted 51 200808300 not back!, preservatives, pedicures, dyes, etc.; for solid oral preparations such as private cuts, gels and tablets, suitable carriers and additives include temple powder, sugar, diluted Agents, granulating agents, lubricants, adhesives, decomposers, etc. Solid oral coatings can also be used as a surface coating or enteric coating to regulate the main site of adsorption. For parenteral administration, carriers usually Including none Water = other ingredients that increase solubility or corrosion resistance. Injectable suspensions or cold liquids can also be prepared using aqueous carriers and appropriate additives. • When mixed with the pharmaceutical composition of the present invention, according to traditional pharmaceutical mixing techniques The active ingredient of one or more of the compounds of the present invention is miscellaneously mixed with the pharmaceutical carrier, which is determined by the desired route of administration. The carrier may have a plurality of different formulas. Any of the compositions of the oral administration form may be used. Pharmaceutical media for use. Accordingly, suitable liquid carriers and additives for liquid oral preparations such as suspensions, elixirs and solutions include water, glycols, oils, alcohols, scenting agents, preservatives, stabilizers, dyeing Agents, etc.; for solid oral preparations such as powders, cachets, caplets, capsules and tablets, suitable carriers and additives, including temple powder, sugar, thinner, granulating agent, lubricant, adhesive ^ Decomposing agent, etc. Because of their ease of administration, tablets and capsules represent the most promising monthly oral administration unit form, in which case it is apparent that the (four) body rate carrier. If desired, the tablet may be sugar coated or enteric coated via standard techniques. For parenteral agents, the carrier usually comprises sterile water, although other ingredients may be added, for example for the purpose of aiding solubility or preservation. Alternatively, an injection suspension may be prepared, in which case Use a suitable liquid carrier, suspending agent, etc. Each of the administration units of the pharmaceutical compositions herein, such as a tablet, a powder, an injection, a teaspoon, etc., will contain an amount of active ingredient that requires 52 200808300 ^ to achieve the above effective amount. The parental administration unit of the pharmaceutical composition such as tablets, capsules, powders, injections, and apples will be administered from a dose of about αι·ι_mg and at a dose of (four) G mg/kg/day, preferably from About 〇1 to 1 gram / kg / day, and more from,,. spoon 0.5-50 gram / kg / day, more preferably from about j 〇〇 mg / kg / day or any range of them. Depending on the patient's needs, the severity of the treatment, the severity of the condition, and the compound used, the dosage may be varied. It may be administered on a parental day or after a period of time. Preferably, these components are administered in unit form, for example Tablets, pills, capsules, powders, granules, parenteral solutions or suspensions, metered sprays or liquid mouth sprays, drops, vials, autoinjector devices or suppositories; for oral administration , parenteral, intranasal, sublingual or rectal administration, or by inhalation or inhalation, or the composition may be in the form of a weekly or monthly-time administration; for example, compliant activity An insoluble salt of a compound, such as a citrate, provides a depot preparation for intramuscular injection. The preparation of a solid composition, such as a tablet, is the preparation of a main active ingredient, such as a traditional tablet-making ingredient such as corn. Test, lactose, sucrose, mannitol, talc, stearic acid, magnesium stearate, dishoate or colloidal and pots. It is mixed with a pharmaceutical diluent such as water to form a compound containing the present invention or 1 The solid mixture of the homogeneous mixture. When it is mentioned that the transcripts are all self-contained, it means that the components are evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective administration forms such as tablets, pills and Capsule Thereafter, the solid pre-modulation composition is subdivided into a form of administration of the above form, which contains from the 〇1 to about 1 〇〇〇mg of the invention 53 200808300 for the advantage of prolonging the activity; & .^ ^ Oral beam form 0, for example, tablets or dense, 1 can be internally administered and externally administered into 3, / /. The latter is wrapped in the form of an envelope before the release of 7711, the secret layer Isolation, which is used in the stomach as a component to prevent the complete entry of the duodenum or delayed release. Multiple substances =; 1 enteric layer or coating, this substance includes a variety of polymerizations and such substances such as shellac, furan And cellulose acetate vinegar. /, may be the novel composition of the present invention for π or liquid form by injection, including aqueous solution, properly flavored slurry, aqueous or j-septic, timely oil such as cottonseed oil , sesame oil, coconut oil or t-oil and a flavored suspension of a similar pharmaceutical vehicle. Suitable dispersing or secreting agents for aqueous suspensions, including synthetic and natural colloids such as gelatin, gum arabic, alginate, dextran, sodium methacrylate, methylcellulose, poly Ethyl pirinone or gelatin. The method of the invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 1000 mg of the compound, preferably about 50 to 500 mg, and may be formulated in any form suitable for the chosen mode of administration. Carriers include the required and inert pharmaceutical excipients including, but not limited to, adhesives, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms such as tablets, pills, caplets, capsules (each comprising immediate release, timed release and sustained release formulations), granules and powders, and liquid forms such as solutions , slurries, tinctures, lotions, and suspensions. Can be used for parenteral administration 54 200808300 The form of the drug includes sterile solutions, emulsions and suspensions. Every 2 2 lfci is beneficial for administration at a single-per-dose dose, or a total of one, two or four doses of the mother-in-law is applied to the mother's day:::r is known to those skilled in the art. Top = 2 = intranasal vehicle is administered in nasal (four) form or via a transdermal skin patch. .... The systemic form of transdermal delivery, the dose of the drug in the whole drug delivery method, if the Qilian is not riding. For example, in the form of a tablet or a capsule, it is combined with a pharmaceutically acceptable condition of the agent; the agent; Moreover, suitable viscosities, lubricants, decomposers and dyes can also be incorporated into the mixture when necessary or desired. Agents include, but are not limited to, powders, gelatin, natural sugars such as Portuguese sugar, corn sweeteners, natural and synthetic gums such as acacia, knee or sodium oleate, sodium stearate, magnesium stearate, Sodium Benzoate, Barium Acetate #减鳞. Decomposers include, but are not limited to, temple powder, methyl cellulose, qiongyue, bentonite, xanthan gum, and the like. The liquid is formed in a suitably flavored suspending or dispersing agent, such as synthetic and natural gums such as tragacanth, acacia, decyl cellulose and the like. For parenteral administration, sterile suspensions and solutions are required. When intravenous administration is required, an isotonic preparation which usually contains a suitable preservative is used. When it is desired to treat or prevent migraine, the compounds of the invention may be administered in any of the above compositions and according to the administration regime established in the art. / The daily dose of this product can vary from a maximum of 200 55 200808300 mg / kg per adult per day. For oral administration, the composition is preferably contained in 〇.〇1, 0.05, 0.1, 0.5, 1.0, 2, 5, 5.0, 10.0, 15.0, 25 〇, 5 〇.〇, 100, 150, 200, 250, 500. And a tablet form of 1 mg of the active ingredient is provided for the purpose of adjusting the dosage of the patient in need of treatment according to the symptoms. The effective amount of the agent is usually supplied in a dosage range of from about 0.101 g/kg to about 15 mg/kg body weight per day. The range is preferably from about 0.1 to about 100.0 mg/kg body weight per day, more preferably from about 5 g/φ A kg to about 50 mg/kg per day, and more preferably from about ΐ·〇 to about every day. 25 〇 mg / kg body weight. This compound can be administered in a regimen of 1 to 4 times per day. Those skilled in the art will appreciate that a medically effective amount of a compound of the invention can include repeated administration within an extended therapeutic regimen to produce clinically significant results, preventing, reversing, arresting, or inhibiting epilepticity. Those skilled in the art will be able to understand in vivo and in vitro tests using appropriate, known and generally accepted cell and/or animal models to predict the ability of the tested compound to treat or prevent a particular condition. Those skilled in the art will also be able to understand human clinical trials, including the first in human, dose range and efficacy tests, in health practitioners and/or those with specific diseases, which can be done according to methods well known in the clinical and medical arts. The determination of the effective agent is usually based on animal model studies, followed by human clinical trials and is guided by the effective dose and dosing recommendations determined by the subject's apparent reduction in the symptoms or severity of the exposure or severity of the condition. In this regard, suitable modes include, for example, rats, rats, pigs, cats, non-human primates, and other acceptable animal models known in the art. 56 200808300 are 'effective doses that can be used in vitro. Mode test (such as tube and thief species (four), only the general meter is *24 called appropriate (four) aging to drug administration medical #j (such as intranasal effective, transdermal effective, intravenous, or muscle effective to produce The amount of the desired reaction is exemplified to help the understanding of the present invention, and is not intended to be construed as a limitation of the invention as set forth in the following claims.

將硫茚-3-醛(1·62克，10.0毫莫耳)溶解在無水乙醇(5〇 宅升）。加入績gt二胺(4.0克，42毫莫耳)並將混合物加熱 至迴流經16小時。使混合物冷卻至室溫。加入硼氫化鈉 (0.416克，11.0毫莫耳)並將混合物在室溫攪拌3小時。 將反應用水(50毫升)稀釋並用氯仿(3x75毫升)萃取。將萃 取液濃縮並層析(在DCM中的5%曱醇），得到標題化合物 之白色固體。 咕 NMR (DMSO-d6)，心 7·98 (1H，dd，J=6.5, 2.3 Hz)， 57 200808300 7·92 (1H，dd，>6·6, 2·4 Ηζ)，7·62 (1H，s)，7·36·7·45 (2H，m)， 7·〇8 (1H，t，J二6·3 Hz)，6·72 (2H，s)，4·31 (2H，d，J=6.3 Hz)。 實例2The thioindole-3-aldehyde (1·62 g, 10.0 mmol) was dissolved in absolute ethanol (5 宅 liter). The gt diamine (4.0 g, 42 mmol) was added and the mixture was heated to reflux for 16 hours. The mixture was allowed to cool to room temperature. Sodium borohydride (0.416 g, 11.0 mmol) was added and the mixture was stirred at room temperature for 3 hr. The reaction was diluted with water (50 mL) and EtOAc. The extract was concentrated and purified (EtOAc EtOAc)咕NMR (DMSO-d6), heart 7·98 (1H, dd, J=6.5, 2.3 Hz), 57 200808300 7·92 (1H, dd, >6·6, 2·4 Ηζ), 7.62 (1H, s), 7·36·7·45 (2H, m), 7·〇8 (1H, t, J 2 6. 3 Hz), 6·72 (2H, s), 4·31 (2H , d, J = 6.3 Hz). Example 2

MiHl-氣笨#基）甲某1-碏醯二胺(化合物#3、MiHl-qi stupid #基)甲一1-碏醯 diamine (compound #3,

將(5-氯小笨并噻吩各基)曱胺(〇·820克，4·15毫莫耳） 及磺酿二胺(2.5克，26毫莫耳)在無水二畤烷(50毫升）中 混合並將混合物加熱至迴流經4小時。使反應冷卻並用水 (50笔升)稀釋。將溶液用氣仿(3χ75毫升)萃取。將萃取液 濃縮並層析(在DCM中的5%曱醇），得到標題化合物之白 色固體。 4 NMR (DMSO-d6)，5 : 8·05 (2Η，m)，7·74 (1Η，s)，7·40 (1Η，d，J=6.5 Ηζ)，7·07 (m，t，J=6.3 Ηζ)，6·72 (2Η，s)，4·26 (2H，d，J=6.4 Hz)。 實例3 IH(i-甲基-iH-喷兔^基）甲基\碏醯二胺(化合物#7)(5-Chlorobenzophenanyl) decylamine (〇·820 g, 4·15 mmol) and sulfonamide (2.5 g, 26 mmol) in anhydrous dioxane (50 ml) The mixture was mixed and the mixture was heated to reflux for 4 hours. The reaction was allowed to cool and diluted with water (50 liters). The solution was extracted with a gas imitation (3 χ 75 mL). The extract was concentrated and purified (EtOAc EtOAc) 4 NMR (DMSO-d6), 5: 8·05 (2Η, m), 7·74 (1Η, s), 7·40 (1Η, d, J=6.5 Ηζ), 7·07 (m,t, J=6.3 Ηζ), 6.72 (2Η, s), 4·26 (2H, d, J=6.4 Hz). Example 3 IH (i-methyl-iH-spray) methyl hydrazine diamine (compound #7)

200808300 將N-甲基吲哚各醛(1.66克，1〇·4毫莫耳)溶解在無 水乙醇(50毫升）。加入績醯二胺(4·5克，47毫莫耳)並將 混合物加熱至迴流經16小時。再度加入磺醯二胺(ι·〇克， 10.4晕莫耳)並將混合物加熱至迴流經24小時。使混合物 冷卻至室溫。加入硼氫化鈉(0.722克，12.5毫莫耳)並將 混合物在室溫攪拌1小時。將反應用水(5〇毫升)稀釋並用 DCM (3x75毫升)萃取。將萃取液濃縮並加入約1毫升甲 醇以產生稠漿，將其過濾後得到標題化合物之白色粉末。 H NMR (CD3ODX δ : 7.67 (1Η, d5 J=5.9 Hz), 732 (1H5 d, J=6.2 Hz)，7·14-7.19 (2H，m)，7·06 (1H，dt，J=7.7, 0·7 Hz)， 4·36 (2H，s)，3·75 (3H，s)。 MS (M-Hy 237.6 〇 實例4 苯并口夫喃基甲基h磺醯二胺g h厶铷叫200808300 N-methyl oxime aldehyde (1.66 g, 1 〇 4 mmol) was dissolved in anhydrous ethanol (50 mL). Dimethyl diamine (4.5 g, 47 mmol) was added and the mixture was heated to reflux for 16 hours. Sulfonamide (Ig., 10.4 Halo) was added again and the mixture was heated to reflux for 24 hours. The mixture was allowed to cool to room temperature. Sodium borohydride (0.722 g, 12.5 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (5 mL) and extracted with DCM (3. The extract was concentrated and about 1 ml of methanol was added to give a thick powder which was filtered to give the title compound as white powder. H NMR (CD3ODX δ : 7.67 (1Η, d5 J=5.9 Hz), 732 (1H5 d, J=6.2 Hz), 7·14-7.19 (2H, m), 7·06 (1H, dt, J=7.7 , 0·7 Hz), 4·36 (2H, s), 3·75 (3H, s) MS (M-Hy 237.6 〇 Example 4 Benzo-f-butylmethyl-h-sulfonyl diamine gh 厶铷

將苯并呋喃-3-羧酸(1.91克，π·8毫莫耳)懸浮在無水 DCM(75毫升）。依序加入草醯氯(2 〇馗在1)(：]^，6·48 笔升)及一滴一甲基甲醯胺。將溶液在室溫攪拌2小時， 然後加入氫氧化銨(濃縮，10毫升）。將所得的混合物用水 (100毫升)稀釋並用DCM(3xl00毫升)萃取。將萃取液濃 59 200808300 縮成灰色固體並溶解在無水THF (100毫升）。加入氫化鋁 經(1·0 Μ在丁HF，ΐι·8毫升）。將混合物在室溫攪拌 小時。依序加入少量飽和的NaHC03水溶液及MgS〇4。 將混合物過濾後用1NHC1萃取。將水性萃取液用3N NaOH調整至pH 14並用DCM萃取。將有機萃取液用硫 I鎂乾燥並丨辰縮成無色的油。將油溶解在二崎烧毫升） ，加入磺醯二胺(3·7克，38毫莫耳）。將混合物加熱至迴 φ 流經4小時，冷卻至室溫並濃縮。將所得的固體層析(在 DCM中的5%甲醇），得到標題化合物之淡黃色固體。 H NMR (CD3〇D)，5 ·· 7·53 (1H，d，J=5.7 Ηζ)，7·44 (1H，d， >6.0 Hz)，717.26 (2H，m)，6.73(m，s)，4.35 (2H，s)。’ ’ 實例5 M=『(5-萌，丰开『bl嗉嗯-3-基）甲基1_石蓊醢二胺(化合物狀）The benzofuran-3-carboxylic acid (1.91 g, π·8 mmol) was suspended in anhydrous DCM (75 mL). Add oxalic acid chloride (2 〇馗 at 1) (:]^, 6.48 liters) and one drop of methyl methamine. The solution was stirred at room temperature for 2 hours, then ammonium hydroxide (concentrated, 10 mL) was added. The resulting mixture was diluted with water (100 mL) The extract concentrated 59 200808300 was reduced to a gray solid and dissolved in dry THF (100 mL). Add aluminum hydride (1·0 Μ in butyl HF, ΐι·8 ml). The mixture was stirred at room temperature for an hour. A small amount of saturated aqueous NaHC03 solution and MgS〇4 were added in sequence. The mixture was filtered and extracted with 1N HCl. The aqueous extract was adjusted to pH 14 with 3N NaOH and extracted with DCM. The organic extract was dried over sulphur I magnesium and condensed into a colorless oil. Dissolve the oil in two kiwis and add sulfonamide (3. 7 g, 38 mmol). The mixture was heated to return to φ for 4 hours, cooled to room temperature and concentrated. The resulting solid was chromatographed (EtOAc EtOAc) H NMR (CD3〇D), 5 ··················································· s), 4.35 (2H, s).例 例 5 M=『(5-萌,丰开『bl嗉-3-yl)methyl 1_Dendrobium diamine (compound form)

將5-氟-3-曱基苯并噻吩(U4克，6·83毫莫耳)、過氧 化笨醯(0.165克，0·68毫莫耳)及]^_溴代琥珀醯亞胺(1·7〇 克，7.52毫莫耳)在四氯化碳(25亳升）中混合並將混合物 加熱至迴流經3小時。使黃色溶液冷卻，用水稀釋並用 DCM (2x50毫升)萃取。將萃取液用鹽水(1〇〇毫升)清洗， 用硫酸鎂乾燥，並濃縮成橙色固體。將固體溶解在無水 60 200808300 DMF。加入疊氮化鈉(4.0克，61毫莫耳)並將混合物在室 溫攪拌16小時。將反應用水(100亳升)稀釋並用***(2χ75 毫升)萃取。將萃取液用鹽水(100毫升)清洗，用硫酸鎂乾 燥，並濃縮成黃色油。將油溶解在THF (50毫升)與水(5 毫升)之混合物中。加入三苯基膦(3.60克，13·7毫莫耳）。 將混合物在至攪拌16小時。將反應濃縮並層析(在dcm 中的2至5/〇甲醇）。將所得的c_(5-氟·苯并[b]n塞嗯_3_基)_ 甲胺(1.04克，5·73毫莫耳)溶解在無水二崎烧(5〇毫升)並 加入磺醯二胺(2.75克，28·7毫莫耳）。將反應加熱至迴流 經4小時，冷卻至室溫，並濃縮成固體，將其層析(在DCM 中的5%甲醇），得到標題化合物之白色固體。 H NMR (CD3〇D)，5 : 7.85 (1H，dd，J=6.6, 3·6 Hz)，7.66 (1Η，dd，风4, 1·8 Ηζ)，7·62 (1Η，s)，7.13-7·18 (1Η，m)，4·40 (2H，s)。 ，， 實例6 N-(k_蒸并『b~|6基)-確醯二脍价厶物，5-Fluoro-3-mercaptobenzothiophene (U4 g, 6.83 mmol), albino peroxide (0.165 g, 0·68 mmol) and ]^-bromoarene quinone ( 1·7 g, 7.52 mmol) was mixed in carbon tetrachloride (25 liters) and the mixture was heated to reflux for 3 hours. The yellow solution was cooled, diluted with water and extracted with EtOAc EtOAc. The extract was washed with brine (1 mL) dried over magnesium sulfate. Dissolve the solid in anhydrous 60 200808300 DMF. Sodium azide (4.0 g, 61 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction was diluted with water (100 mL) and extracted with diethyl ether (2 EtOAc). The extract was washed with brine (100 ml) dried over magnesium sulfate. The oil was dissolved in a mixture of THF (50 mL) and water (5 mL). Triphenylphosphine (3.60 g, 13.7 mmol) was added. The mixture was stirred until 16 hours. The reaction was concentrated and chromatographed (2 to 5 / methanol in dcm). The obtained c_(5-fluorobenzo[b]n-single_3_yl)-methylamine (1.04 g, 5.73 mmol) was dissolved in anhydrous bisaki (5 mL) and added with sulfonate. Decane diamine (2.75 g, 28. 7 mmol). The reaction was heated to EtOAc (3 mL). H NMR (CD3〇D), 5: 7.85 (1H, dd, J=6.6, 3·6 Hz), 7.66 (1Η, dd, wind 4, 1·8 Ηζ), 7·62 (1Η, s), 7.13-7·18 (1Η, m), 4·40 (2H, s). ,, Example 6 N-(k_vapor and "b~|6 base" - confirm the price of the bismuth,

將3_乙醯基硫昂(3.00克，n〇毫莫耳)添加至甲酸(1〇 毫升)及甲醯胺(ίο,毫升)之混合物中。將溶液加熱至15(rc 經8小時。使反應冷卻至室溫，用水(5〇毫升)稀釋並用乙 61 2008083003_Ethylsulfonamide (3.00 g, n〇 mmol) was added to a mixture of formic acid (1 mL) and formazan (mL). Heat the solution to 15 (rc for 8 hours. Allow the reaction to cool to room temperature, dilute with water (5 mL) and use B.

醚(3x50毫升)萃取。將***萃取液用飽和的NaHC03水溶 液及鹽水清洗。將溶液濃縮並層析(在DCM中的5%甲 醇），得到N-(l-苯并[b]噻嗯各基-乙基)-曱醯胺(7.6克)之 白色固體，將其懸浮在濃HC1 (30毫升）。將混合物加熱 至迴流經1.5小時後用水(1〇〇毫升)稀釋。加入3NNaOH 直到pH是14。將混合物用***(3xl00毫升)萃取，然後 用石;1酸鎂乾燥並濃縮成撥色油。將油溶解在無水二σ号烧 (75 I升)並加入&酿一胺。將混合物加熱至迴流經2小時 後用水(50毫升)稀釋。將溶液用醋酸乙酯(2χ5〇毫升)萃 取，用硫酸鎂乾燥，濃縮並層析(在DCM中的2.5%至5% 曱醇），得到標題化合物之白色固體。 H NMR (CD3〇D)3 : 8·01 (1Η，dd，J=5.5, 0·7 Ηζ)， 7.85 (1Η，dt，>6·0, 〇·6 Ηζ)，7.49 (1Η，s)，7.31-7.40 (2Η，m)， 4·95 (1H，q，Kl Hz)，1·67 (3H，d，>5·1 Hz)。 實例7 射甲基)-磺(化合物#1〇、Ether (3 x 50 ml) was extracted. The ether extract was washed with a saturated aqueous NaHCO3 solution and brine. The solution was concentrated and chromatographed (5% MeOH in EtOAc EtOAc) In concentrated HC1 (30 ml). The mixture was heated to reflux for 1.5 hours and then diluted with water (1 mL). 3N NaOH was added until the pH was 14. The mixture was extracted with diethyl ether (3×10 mL) and then dried with EtOAc EtOAc. The oil was dissolved in anhydrous sigma (75 I) and & The mixture was heated to reflux for 2 hours and then diluted with water (50 mL). The solution was extracted with ethyl acetate (2 mL EtOAc)EtOAc. H NMR (CD3〇D) 3 : 8·01 (1Η, dd, J=5.5, 0·7 Ηζ), 7.85 (1Η, dt, >6·0, 〇·6 Ηζ), 7.49 (1Η, s ), 7.31-7.40 (2Η, m), 4·95 (1H, q, Kl Hz), 1.67 (3H, d, > 5·1 Hz). Example 7 shot methyl)-sulfonate (compound #1〇,

將!-萘甲胺⑽克，12.7毫莫耳)及俩二胺⑽克， 笑莫耳)在無水二贼⑽料)中齡並將混合物加 :農時。使反應冷卻至室溫並過渡。將過渡液 _成□肢朗水清洗至TLC顯示沒有植二胺殘留在 62 200808300Will be --naphthylamine (10) grams, 12.7 millimoles) and two diamines (10 grams), laughing in the middle of the water in the second thief (10)) and add the mixture: agricultural time. The reaction was allowed to cool to room temperature and transitioned. Wash the transition solution _ into the limbs to the TLC to show no phytodiamine residues in the 62 200808300

色固體。Color solid.

Ηζ)，4·58 (1H，br s)，4·51 (2H，br s) 實例8 N-『(2-甲一基_-3_丰开吱喃基）甲基石兔胺(化合物#^Ηζ), 4·58 (1H, br s), 4·51 (2H, br s) Example 8 N- "(2-methyl-based _-3_Fengkai mercapto) methyl glutamine (compound) #^

將2-曱基苯并吱喃-3-酸(0·51克，3·18毫莫耳)溶解在 無水乙醇(25毫升）。加入續醯二胺(1·5克，16毫莫耳)並 將混合物加熱至迴流經4天。使混合物冷卻至室溫。加入 氫化鈉(0·132克，3·50毫莫耳)並將混合物在室溫擾拌 24小時。將反應用水(100毫升)稀釋並用DCM (3x75毫 升)萃取。將萃取液濃縮並懸浮在少量的DCM中，過濾 後得到標題化合物之白色固體。 !H NMR (DMSOd6)，5 : 7·65 (1Η，dd，J=6.4, 2·6 Ηζ)， 7.43-7.47 (1Η，m)，7.19-7.23 (2Η，m)，6·87 (1Η，t，J=6.2 Hz), 6·68 (2H，s)，4·11 (2H，d，J=6.2 Hz)，2·42 (3H，s)。 實例9 N-「(5 -溴茉莽「bl嚓處:1:基）甲基確酸二胺(化合物# 15) 63 2008083002-Mercaptobenzopyran-3- acid (0.51 g, 3.18 mmol) was dissolved in absolute ethanol (25 mL). Dihydrodiamine (1.5 g, 16 mmol) was added and the mixture was heated to reflux for 4 days. The mixture was allowed to cool to room temperature. Sodium hydride (0. 132 g, 3.50 mmol) was added and the mixture was stirred at room temperature for 24 hours. The reaction was diluted with water (100 mL) and extracted with DCM (3.times. The extract was concentrated and suspended in aq. !H NMR (DMSOd6), 5: 7·65 (1Η, dd, J=6.4, 2·6 Ηζ), 7.43-7.47 (1Η,m), 7.19-7.23 (2Η,m),6·87 (1Η , t, J = 6.2 Hz), 6·68 (2H, s), 4·11 (2H, d, J = 6.2 Hz), 2·42 (3H, s). Example 9 N-"(5-bromomophyllin "bl嚓: 1: base" methyl acid diamine (compound # 15) 63 200808300

將5-溴苯并噻吩(1·60克，7·51毫莫耳)及二氯甲基甲 基醚(1·29克，11·3毫莫耳)溶解在無水ι，2-二氣乙烧(75 毫升）。加入四氣化鈦(2·14克，11.3毫莫耳），溶液變成深 色。在室溫經1小時後，將反應倒入飽和的NaHC03水溶 液與冰之混合物中。將混合物攪拌約30分鐘後用DCM (2x100毫升)萃取。將萃取液濃縮並層析(在己烷中的〇至 5%醋酸乙酯），得到5-溴-苯并[b]噻嗯-3-醛(1.32克）。將 5-溴-苯并[b]噻嗯-3-醛(1·20克，4.98毫莫耳)及磺醯二胺 (4.0克，42宅莫耳)在無水乙酵(25毫升）中混合並加熱至 迴流經3天。使反應冷卻至室溫並加入硼氳化鈉(〇·2〇7克， 5.47毫莫耳）經5小時後，加入水(50毫升)並將溶液用 氯仿(3x50毫升)萃取。將萃取液濃縮，懸浮在少量的DCM 中，過濾後得到標題化合物之黃色固體。 NMR (DMSO-d6)，5 : 8.12 (1Η，d，J=L8 Ηζ)，7.97 (1Η，d，】=8·6 Ηζ)，7·71 (1Η，s)，7.52 (lH，dd，J=8.6, 1·9 Ηζ)， 7·12 (1H，d，J=6.3 Hz), 6.72 (2H，s)，4·28 (2H，d，J=6.2 Hz)。 實例10 N4(4-溴茉#『bl噻嗯基）甲某i-碏醯二胺(化合物#17、 64 200808300Dissolve 5-bromobenzothiophene (1·60 g, 7.51 mmol) and dichloromethyl methyl ether (1·29 g, 11.3 mmol) in anhydrous ι, 2-二气Ethylene (75 ml). Titanium tetraoxide (2·14 g, 11.3 mmol) was added and the solution turned dark. After 1 hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then extracted with DCM (2×100 mL). The extract was concentrated and chromatographed (EtOAc EtOAc EtOAc EtOAc) 5-Bromo-benzo[b]thiazolaldehyde (1·20 g, 4.98 mmol) and sulfonamide (4.0 g, 42 house Mo) in anhydrous ethyl acetate (25 ml) Mix and heat to reflux for 3 days. The reaction was cooled to room temperature and sodium borohydride (5 g, 5.47 mmol) was added over 5 hrs, then water (50 ml) was added and the solution was extracted with chloroform (3 x 50 ml). The extract was concentrated, suspended in EtOAc (EtOAc)EtOAc. NMR (DMSO-d6), 5: 8.12 (1Η,d,J=L8 Ηζ), 7.97 (1Η,d,]=8·6 Ηζ),7·71 (1Η,s),7.52 (lH,dd, J=8.6, 1·9 Ηζ), 7·12 (1H, d, J=6.3 Hz), 6.72 (2H, s), 4·28 (2H, d, J=6.2 Hz). Example 10 N4 (4-bromomox #『bl thiophene) A certain i-quinone diamine (compound #17, 64 200808300

將4-/臭苯并嚷吩仏⑽克，8·45毫莫耳)及二氯甲基甲 基醚(1.46克，12·7笔莫耳)溶解在無水DCM(1〇〇毫升）。 ⑩ 加入四氯化鈦(2.40克，12·7毫莫耳），溶液變成深色。在 至ι經30分鐘後，將反應倒入飽和的NaHC〇3水溶液與 冰之混合物中。將混合物攪拌約3〇分鐘後用DCm (2xl50 笔升)萃取。將萃取液濃縮並層析(在己烷中的〇至15%醋 酸乙酯），得到4-溴-苯并[b]噻嗯_3-醛(〇·9ΐ〇克）。將4-溴-苯并[b]噻嗯-3-醛(0.910克，3.77毫莫耳)及磺醯二胺(3·〇 克，31毫莫耳)在無水乙醇(25毫升)中混合並加熱至迴流 經3天。使反應冷卻至室溫並加入侧氫化納(〇157克，屯15 φ 宅莫耳）。經5小時後，加入水(5〇毫升)並將溶液用氯仿 (3x50毫升)萃取。將萃取液濃縮，懸浮在少量的dCm中， 過濾後得到標題化合物之黃色固體。 NMR (DMSO-d6)? δ : 8-05 (1H? dd, J=8.19 0.8 Hz), 7·78 (1H，s)，7·64 (1H，dd，J=7.6, 0·8 Hz)，7·27 (1H，t，：Ν7·9 Hz)，7·13 (1H，t，J=6.3 Hz)，6·72 (2H，br s)，4.65 (2H，d， J=5.3 Hz) 〇 實例11 H17-氟笨并「bl喧嗯-3-基）甲基l·續醯二胺(化合物#18) 65 2008083004-(Oxobenzoin) (10) g, 8.45 mmol, and dichloromethyl methyl ether (1.46 g, 12.7 mol) were dissolved in dry DCM (1 mL). 10 Titanium tetrachloride (2.40 g, 12.7 mmol) was added and the solution turned dark. After a period of 30 minutes, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 3 minutes and then extracted with DCm (2 x 150 liters). The extract was concentrated and chromatographed (yield in hexanes to 15% ethyl acetate) to afford 4-bromo-benzo[b]- </RTI> <RTIgt; 4-Bromo-benzo[b]thiazolaldehyde (0.910 g, 3.77 mmol) and sulfonamide (3 gram, 31 mmol) in absolute ethanol (25 mL) It was heated to reflux for 3 days. The reaction was allowed to cool to room temperature and side sodium hydride (〇 157 g, 屯 15 φ house mole) was added. After 5 hours, water (5 mL) was added and the solution was extracted with chloroform (3×50 mL). The extract was concentrated, suspended in aq. NMR (DMSO-d6)? δ : 8-05 (1H? dd, J=8.19 0.8 Hz), 7·78 (1H, s), 7·64 (1H, dd, J=7.6, 0·8 Hz) ,7·27 (1H,t,:Ν7·9 Hz),7·13 (1H,t,J=6.3 Hz),6·72 (2H,br s),4.65 (2H,d, J=5.3 Hz) 〇Example 11 H17-Fluoro-p- and "bl喧-3-yl)methyl l·Continuation of diamine (Compound #18) 65 200808300

FF

NH2 將2~敦0塞吩(4.14克，32·6毫莫耳)溶解在無水THF (100毫升）。加入第三丁醇鉀(1〇M在THF，35·8毫升） 並將懸浮液在室溫攪拌15分鐘。加入氣乙醛二曱基縮醛 並將混合物攪拌3天。加入水(100毫升)並將溶液用*** (3x100毫升)萃取。將萃取液濃縮成黃色油並層析(在己烷 中的5至20%醋酸乙酯），得到1-(2,2-二甲氧基-乙基硫烷 基)-；2-氟-苯(6.42克)之無色油。將氯苯⑻毫升)加熱至迴 流並加入聚磷酸(1毫升）。然後緩慢加入1_(2,2_二曱氧基_ 乙基硫胺基)丨氟-苯(6.42克），溶液變成深色。加熱3小 時後，使反應冷卻至室溫並用水(50毫升)稀釋。將溶液用 苯(2x50毫升)萃取。將萃取液濃縮並層析(在己烷中的〇 至15%醋酸乙酯），得到7-氟苯并噻吩(〇·77克）。將7-氟 苯并噻吩(0.77克，5.1毫莫耳)及二氣甲基甲基醚(〇.872 克，7.6毫莫耳)溶解在無水DCM (25毫升）。加入四氯化 鈦(1·0 Μ在DCM，7·6毫升，7.6毫莫耳），溶液變成深色。 在室溫經30分鐘後，將反應倒入飽和的NaHC03水溶液 與冰之混合物中。將混合物攪拌約30分鐘後用DCM (2x50毫升)萃取。將萃取液濃縮並層析(在己烷中的〇至 15%醋酸乙酯），得到7-氟苯并噻吩-3-醛(0.642克）。將7- 66 200808300 氟苯并噻吩-3省(〇·642克，3·77毫莫耳)及磺醯二胺(17 克，18毫莫耳)在無水乙醇(2〇毫升）中混合並加熱至迴流 經3天。使反應冷卻至室溫並加入硼氫化鈉(〇148克，3 92 笔莫耳）。經2小時後，加入水(25毫升)並將溶液用氯仿 (3x25毫升)萃取。將萃取液濃縮，懸浮在少量的DCM中， 過濾後得到標題化合物之黃色固體。 lB NMR (DMSO-d6), (5 : 7.78 (1H, d, J=8.0 Hz), 7·43·7·50 (1H，m)，7.27 (1H，dd，J二 10.3, 7.9 Hz)，7·14 (1H， t，J=6.4 Hz)，6·74 (2H，br s)，4.31 (2H，d，J=6.4 Hz)。 實例12 三氟甲基装莽塞嗯-3-基）甲基1-石簧醯二胺(化合物 #19)NH2 2~~0 cetin (4.14 g, 32·6 mmol) was dissolved in dry THF (100 mL). Potassium tert-butoxide (1 M in THF, 35.8 ml) was added and the suspension was stirred at room temperature for 15 min. Glycolaldehyde didecyl acetal was added and the mixture was stirred for 3 days. Water (100 ml) was added and the solution was extracted with diethyl ether (3×100 mL). The extract is concentrated to a yellow oil and chromatographed (5 to 20% ethyl acetate in hexane) to give 1-(2,2-dimethoxy-ethylsulfanyl)-; A colorless oil of benzene (6.42 g). The chlorobenzene (8 ml) was heated to reflux and polyphosphoric acid (1 mL) was added. Then, 1_(2,2-dimethoxy-ethylthioamino)phosphonium-benzene (6.42 g) was slowly added, and the solution turned dark. After heating for 3 hours, the reaction was cooled to room temperature and diluted with water (50 mL). The solution was extracted with benzene (2 x 50 mL). The extract was concentrated and chromatographed (yield in hexanes to 15% ethyl acetate) to afford 7-fluorobenzothiophene (77 g). 7-Fluorobenzothiophene (0.77 g, 5.1 mmol) and dimethyl methyl methyl ether (〇.872 g, 7.6 mmol) were dissolved in dry DCM (25 mL). Titanium tetrachloride (1.00 Torr in DCM, 7.6 ml, 7.6 mmol) was added and the solution turned dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHC03 and ice. The mixture was stirred for about 30 minutes then extracted with DCM (2×50 mL). The extract was concentrated and chromatographed (eluent to 15% ethyl acetate in hexane) to afford 7-fluorobenzothiophene-3- aldehyde (0.642 g). 7-66 200808300 fluorobenzothiophene-3 (〇·642 g, 3.77 mmol) and sulfonamide diamine (17 g, 18 mmol) mixed in absolute ethanol (2 mL) Heat to reflux for 3 days. The reaction was allowed to cool to room temperature and sodium borohydride ( 148 g, 3 92 moles) was added. After 2 hours, water (25 ml) was added and the solution was extracted with chloroform (3×25 ml). The extract was concentrated, suspended in aq. lB NMR (DMSO-d6), (5: 7.78 (1H, d, J = 8.0 Hz), 7·43·7·50 (1H, m), 7.27 (1H, dd, J 20.3, 7.9 Hz), 7·14 (1H, t, J=6.4 Hz), 6.74 (2H, br s), 4.31 (2H, d, J = 6.4 Hz). Example 12 Trifluoromethyl 莽 -3- -3- )methyl-1-石弹簧醯Diamine (Compound #19)

將4-三氟甲基苯并噻吩(0.276克，1·37毫莫耳)及二 氯甲基甲基醚(0.236克，2.06毫莫耳)溶解在無水DCM (10 毫升）。加入四氯化鈦(1.0 Μ在DCM，2·1毫升，2.1毫莫 耳)，溶液變成深色。在室溫經30分鐘後，將反應倒入飽 和的NaHC03水溶液與冰之混合物中。將混合物攪拌約 30分鐘後用DCM (2x50毫升)萃取。將卒取液濃縮並層析 (在己烷中的0至15%醋酸乙酯），得到冬三氟甲基苯并噻 67 200808300 吩-3-駿。 將4-二氟〒基苯并嗔吩_3_卿226克，❹搬毫莫耳) 及磺醯二胺(0.471克，4.91毫莫耳)在無水乙醇(5毫升）中 混合並加熱至迴流經24小時。使反應冷卻至室溫並加入 硼氫化納(0.056克，！.47毫莫耳）。經5小時後，加入水 (1〇毫升)並將溶液用·(3xl0毫升)萃取。將萃取液濃縮 並層析(在DCM中的5〇/〇甲醇)，得到標題化合物之白 體。 J=8.4 Hz)，7.84 (1H，s)，7.68 (1H，dd，J=8.5, 1.4 Hz)，， 6.7-6.9 (2H，br s)，4.4-4.5 (1H，br s)，4·37 (2H，s)。 實例13 NrJ(4-氰基苯并间嚓聲士基好基城醯二脸γ化合物#2〇、4-Trifluoromethylbenzothiophene (0.276 g, 1.37 mmol) and dichloromethyl methyl ether (0.236 g, 2.06 mmol) were dissolved in dry DCM (10 mL). Titanium tetrachloride (1.0 Torr in DCM, 2.1 ml, 2.1 mmol) was added and the solution turned dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHC03 and ice. The mixture was stirred for about 30 minutes and then extracted with DCM (2×50 mL). The stroke liquid was concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to give the winter trifluoromethylbenzothiazide 67 200808300. Mix 4-difluorodecylbenzobenzophenone _3_qing 226 g, hydrazine and sulfonamide (0.471 g, 4.91 mmol) in absolute ethanol (5 ml) and heat to The reflux was carried out for 24 hours. The reaction was allowed to cool to room temperature and sodium borohydride (0.056 g, EtOAc. After 5 hours, water (1 mL) was added and the solution was extracted with (3×10 mL). The extract was concentrated and purified (5 EtOAc / EtOAc) J=8.4 Hz), 7.84 (1H, s), 7.68 (1H, dd, J=8.5, 1.4 Hz),, 6.7-6.9 (2H, br s), 4.4-4.5 (1H, br s), 4· 37 (2H, s). Example 13 NrJ (4-cyanobenzoindole 嚓 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基

'H NMR (DMSO-d6), ^ : 8.30 (1H, s), 8.25 (1H, d, 將氰基苯并噻吩(1.15克，7·22毫莫耳)及二氯曱基曱 基醚(1·25克，1〇·8毫莫耳)溶解在無水DCM (100毫升）。 加入四氣化鈦(1·〇 Μ在DCM，10.8毫升，1〇·8毫莫耳）， 溶液變成深色。在室溫經30分鐘後，將反應倒入飽和的 NaHC〇3水溶液與冰之混合物中。將混合物攪拌約3〇分 鐘後用DCM (2x50毫升)萃取。將萃取液濃縮並層析(在 68 200808300 己烷中的0至15%醋酸乙酯），得到4_氰基苯并噻吩冬醛。 將4-氰基苯并噻吩各越(0.298克，1.59毫莫耳)及磺 醯二胺(0.766克，7.97毫莫耳)在無水乙醇(2〇毫升）中混 合並加熱至迴流經24小時。使反應冷卻至室溫並加入硼 氫化鈉(0.091克，2.39毫莫耳)。經5小時後，加入水(2〇 耄升)並將溶液用氯仿(3x20毫升)萃取。將萃取液濃縮並 層析(在DCM中的5%曱醇），得到標題化合物之白色固 體。 NMR (DMSO-d6)9 δ : 8.37 (1H? s)9 8.30 (1H, d, J=8.4 Hz), 7.87 (1H，s)，7·70 (1H，dd，J=8.5, 1.4 Hz)， 6.7-6.9 (2H，br s)，4.4-4.5 (1H，br s)，4·40 (2H，s) 〇 實例14'H NMR (DMSO-d6), ^: 8.30 (1H, s), 8.25 (1H, d, cyanobenzothiophene (1.15 g, 7.22 mmol) and dichloroindenyl decyl ether ( 1·25 g, 1 〇·8 mmol) dissolved in anhydrous DCM (100 ml). Add titanium tetrahydrate (1·〇Μ in DCM, 10.8 ml, 1 〇·8 mmol), the solution becomes deep After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHC.sub.3 solution and ice. The mixture was stirred for about 3 minutes and then extracted with DCM (2×50 mL). 4- to cyanobenzothioxanthaldehyde was obtained in 68 200808300 hexanes in hexane. 4-cyanobenzothiophene each (0.298 g, 1.59 mmol) and sulfonamide The amine (0.766 g, 7.97 mmol) was combined in dry ethanol (2 mL) and heated to reflux for 24 h. The reaction was cooled to room temperature and sodium borohydride (0.091 g, 2.39 m. After 5 hours, water (2 liters) was added and EtOAc (3 mL, EtOAc). DMSO-d6)9 δ : 8.37 (1H s)9 8.30 (1H, d, J=8.4 Hz), 7.87 (1H, s), 7·70 (1H, dd, J=8.5, 1.4 Hz), 6.7-6.9 (2H, br s), 4.4 -4.5 (1H, br s), 4·40 (2H, s) 〇 Example 14

將N-[(笨并[b]噻嗯-3-基）甲基]-續醯二胺(0 25()克， 1.03宅莫耳)及吼咯。定(〇·25毫升)在無水二4燒(5毫升）中 混合並加熱至迴流經32小時。將反應蒸發並用在dcm 中的5%甲醇層析後得到標題化合物之白色固體。 H NMR (CDC13), δ : 7.84-7.89 (2Η, m)9 7.38-7-45 (3Η? m)，4.49 (3Η，br s)，3·25 (4Η，t，J=4.0 Ηζ)，1·8〇 (4Η，t，J=4.0 69 200808300N-[(stupid[b]thia-3-yl)methyl]--indole diamine (0 25 () g, 1.03 house mole) and oxime. The mixture (25 ml) was combined and dried under reflux for 24 hours. The reaction was evaporated and purified with EtOAc EtOAc EtOAc H NMR (CDC13), δ : 7.84-7.89 (2Η, m)9 7.38-7-45 (3Η? m), 4.49 (3Η, br s), 3·25 (4Η, t, J=4.0 Ηζ), 1·8〇(4Η,t,J=4.0 69 200808300

將N-[(苯并[b]噻嗯-3-基）甲基]-磺醯二胺(〇·250克， 1·03毫莫耳)及乙胺(70〇/〇在Η2〇, 〇 1〇毫升)在無水二呤烷 (5毫升）中混合並加熱至迴流經32小時。將反應蒸發並用 在DC1V[中的5%曱醇層析後得到標題化合物之白色固體。 ln NMR (CDC13), 5 : 7.83-7.90 (2H, m)? 7.36-7.47 (3H5 m)，4·51 (2H，s)，2·90 (2H，q，JN7 Ηζ)，1·〇3 (3H，t，J=7 Hz)。 實例16 曱某1-醯胺(化合物#102)N-[(benzo[b]thiazol-3-yl)methyl]-sulfonimide (〇·250 g, 1.03 mmol) and ethylamine (70〇/〇 in Η2〇, 〇1〇ml) was mixed in anhydrous dioxane (5 ml) and heated to reflux for 32 hours. The reaction was evaporated and purified with EtOAc EtOAc elut elut Ln NMR (CDC13), 5 : 7.83-7.90 (2H, m)? 7.36-7.47 (3H5 m), 4·51 (2H, s), 2·90 (2H, q, JN7 Ηζ), 1·〇3 (3H, t, J = 7 Hz). Example 16 曱一1-醯amine (Compound #102)

將苯并噻嗯基曱胺及夂(咪唑-i-磺醯基)-卜甲基 3H 2唑4_鏑三氟曱基磺酸鹽在無水乙腈中混合。將溶 夜在至/m攪拌過從，濃縮，並層析(在中的甲醇）， 70 200808300 得到標題化合物之褐色固體。 NMR (DMSO-d6)，5 : 8·05 (1H，dd，ΊΜ7·0, 1.6 Hz)， 7·99 (1Η，dd，】=7·1，1·7 Ηζ)，7.85 (1Η，s)，7·66 (1Η，s)， 7·42-7·65 (5H，m)，4·34 (2H，s)。 實例17 活體内扁桃腺激發試驗The benzothiazolidine and hydrazine (imidazole-i-sulfonyl)-methyl-3H 2 azole 4 - fluorenyltrifluorosulfonate were mixed in anhydrous acetonitrile. The title compound was obtained as a brown solid. mp. NMR (DMSO-d6), 5: 8·05 (1H, dd, ΊΜ7·0, 1.6 Hz), 7·99 (1Η, dd, 】=7·1,1·7 Ηζ), 7.85 (1Η, s ), 7·66 (1Η, s), 7·42-7·65 (5H, m), 4·34 (2H, s). Example 17 In vivo activating test of tonsils

扁桃腺激發之發展是致癲性的一個建立模式(Arnano K，Hamada K，Yagi K，Seino Μ· Antiepileptic effects of topiramate on amygdaloid kindling in rats. Epilepsy Res. 1998 Jul;31(2): 123-8; Barton ME，White HS. The effect of CGX-1007 and CL· 1041，novel NMD A receptor antagonists， on kindling acquisition and expression. Epilepsy Res. 2004 Mar;59(l):l-12; Loscher W，Honack D，Rundfeldt C. Antielepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. J Pharmacol Exp Ther. 1998 Feb;284(2):474-9; McNamara JCX Analyses of the molecular basis of kindling development. Psychiatry Clin Neurosci. 1995 Jime;49(3):S175-8· Review·; Morimoto K，Katayama K, Inoue K9 Sato K. Effects of competitive and noncompetitive NMDA receptor antagonists on kindling and LTR Pharmacol Biochem Behav. 1991 Dec;40(4):893-9; Racine, RJ. 1972. Modification pf seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr. 71 200808300The development of tonsil stimulation is a model for epilepsy (Arnano K, Hamada K, Yagi K, Seino Anti · Antiepileptic effects of topiramate on amygdaloid kindling in rats. Epilepsy Res. 1998 Jul; 31(2): 123-8 Barton ME, White HS. The effect of CGX-1007 and CL·1041, novel NMD A receptor antagonists, on kindling acquisition and expression. Epilepsy Res. 2004 Mar;59(l):l-12; Loscher W,Honack D , Rundfeldt C. Antielepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. J Pharmacol Exp Ther. 1998 Feb;284(2):474-9; McNamara JCX Analyses of the molecular basis of kindling Development. Psychiatry Clin Neurosci. 1995 Jime;49(3):S175-8· Review·; Morimoto K, Katayama K, Inoue K9 Sato K. Effects of competitive and noncompetitive NMDA receptor antagonists on kindling and LTR Pharmacol Biochem Behav. 1991 Dec 40(4):893-9; Racine, RJ. 1972. Modification pf seizure activity by electrical stimulation. II. Motor seizure. Electro Encephalogr. 71 200808300

Clin. Neurophysiol· 32, 281-294)。部份癲癇之激發的大鼠 模式是致癲性之一個被接受的模式(McNamara JO. Analyses of the molecular basis of kindling development. Psychiatry Clin Neurosci. 1995 June;49(3):S175-8.Clin. Neurophysiol· 32, 281-294). The partial rat model of epilepsy is an accepted mode of epilepsy (McNamara JO. Analyses of the molecular basis of kindling development. Psychiatry Clin Neurosci. 1995 June; 49(3): S175-8.

Review·) 〇 簡要地說，測試法之步驟如下。實驗步驟中使用得自Review·) 简要 Briefly, the steps of the test method are as follows. Used in the experimental steps

Charles River，Wilmington，MA 且體重在 250-300 克之間 的成年雄性Sprague-Dawley大鼠。除了從飼養籠子取出 用於實驗步驟之外，全部動物是飼養在12:12的白晝黑暗 循環且容許自由得到食物(Pr〇lab RMH 3000)及水。在溫 度控制、無農藥的設備中，動物照顧是吻合詳細列在 National Research Council Publication, &quot;Guide for the Care and Use of Laboratory Animals” 的建議。在早上 9 點至下 午2點之間例行性地進行激發刺激以避免任何晝夜變化。 化合物#1在少量體積的〇·5%曱基纖維素中搗碎，超 音波處理10分鐘，並用〇·5%甲基纖維素調整至最終體 積。將化合物在0.04毫升/10克體重之體積下全身性投藥 (腹膜内）且全部測試是在預先測定時間之腹膜内投藥後 〇·5小時的最大效應下進行。 測定化合物#1阻止表現扁桃腺激發的癲癇發作之能 力。對於此研究，用***（120毫克/公斤，腹膜内）及甲 苯噻嗪(12毫克/公斤，腹膜内）混合劑將大鼠麻醉。在無 菌的情形下，將雙極電極(Plastic 0ne，R〇an〇ke，VA)腦立 體測定地植入右底外側的扁桃腺(αρ_2·2, ΜΙ^4 7, 72 200808300Adult male Sprague-Dawley rats of Charles River, Wilmington, MA with a body weight between 250 and 300 grams. Except for removal from the feeding cages for the experimental procedure, all animals were housed in a 12:12 dark cycle and allowed free access to food (Pr〇lab RMH 3000) and water. In temperature-controlled, pesticide-free equipment, animal care is consistent with the recommendations detailed in the National Research Council Publication, &quot;Guide for the Care and Use of Laboratory Animals." Routine between 9 am and 2 pm Excitation stimulation was performed to avoid any diurnal variation. Compound #1 was chopped in a small volume of 〇·5% thiol cellulose, sonicated for 10 minutes, and adjusted to final volume with 〇·5% methylcellulose. The compound was administered systemically (intraperitoneal) at a volume of 0.04 ml/10 g body weight and all tests were performed under the maximum effect of 5 hours after intraperitoneal administration at a predetermined time. Determination of Compound #1 prevented the performance of the tonsil challenge The ability of seizures. For this study, the rats were anesthetized with a mixture of ketamine (120 mg/kg, ip) and xylazine (12 mg/kg, ip). In the case of sterility, the bipolar Electrodes (Plastic 0ne, R〇an〇ke, VA) were implanted stereotactically into the right abdomen of the right abdomen (αρ_2·2, ΜΙ^4 7, 72 200808300

Paxinos and Watson)。腹面-背面及側面測量是從前囪，而 背部-腹部測量是從頭顱骨表面。植入無菌的頭顱骨螺釘 (3-4)用於中性的參考電極。使用牙科用的膠合劑及丙烯 酸將電極固定。然後使用無菌的18/8 Michel缝線夾子 (Roboz，Gaithersburg，MD)將傷口閉合。將新黴素抗生素 軟貧施加至傷口並將單一劑量之青黴素(6〇,〇〇〇 ILJ，加，Paxinos and Watson). The ventral-back and lateral measurements were taken from the anterior humerus, while the back-abdominal measurements were taken from the skull surface. A sterile skull screw (3-4) is implanted for the neutral reference electrode. The electrode is fixed using a dental cement and acrylic acid. The wound was then closed using a sterile 18/8 Michel suture clip (Roboz, Gaithersburg, MD). Apply neomycin antibiotics to the wound and apply a single dose of penicillin (6〇, 〇〇〇 ILJ, plus,

AgriLabs)投藥至各大鼠後，將其放回到乾淨的籠子經一 星期之手術後恢復。 然後根據下面的提案(Barton and White，2004)進行扁 桃腺激發。簡要地說，在記錄室内經短暫適應新環境(&lt;5 分鐘)後，得到基線 EEG 記錄(MP 1〇〇, Bi〇pac Systems Inc·，After being administered to each rat, AgriLabs was returned to a clean cage and recovered after a week of surgery. The amygdala challenge was then performed according to the following proposal (Barton and White, 2004). Briefly, baseline EEG records were obtained after a brief adaptation to the new environment (&lt;5 minutes) in the recording room (MP 1〇〇, Bi〇pac Systems Inc.,

Goleta，CA)。然後使大鼠隨意地接受媒劑(〇 5%曱基纖維 素)或化合物#1 (100毫克/公斤，腹膜内)(每組n=1〇隻大 鼠）。在實驗當天，在扁桃腺激發(2〇〇微安培經2秒)前 30分鐘，投藥單一劑量之化合物#1或〇.5%甲基纖維素。 在各處理組中記錄大鼠的行為癲癇發作得分及AD持續 時間使用Racine尺度測定行為癲癇發作得分，也就是扣 無反應；程度l=gr〇⑽ing/活動亢進；程度2=點頭/顏抖； 程度3=單向前肢陣攣；程度4=上升的陣攣；及程度5== 上升及下降的全面性緊張-陣攣性癲癇發作(Radne， 1972)。在刺激串連後數位化記錄放電後(AD)活性經 秒並測量主要AD的持續時間。當顯現五個連續程度4 或5次全面性癲癇發作時，大鼠視為完全激發。在全部三 組中持續每曰刺激經13天，直到在媒劑處理組中的大鼠 73 200808300 完全》(也就是五次連續程度4或5細發作）。此時， ，，部大鼠有一週無刺激及藥劑期，然後在擷取期(也就 疋弟1 13天)使其在無樂劑下使用相同的刺激物再度刺 激。用化合物#1處理的大鼠隨後每天刺激一次直到其到 達完全激發階段。 在媒劑及化合物#1組中的AD持續時間都顯示在激 發擷取期的過程中持續增加。處理組中沒有觀察到統計上 的差異。 β化合物#1防止得到全面性激發的癲癇發作。此結論 是根據發現在無藥航織物綱結束後，赫發作程度 保持明顯低於媒劑處理組中的大鼠(化合物#1=〇 1±〇11 且媒劑=4.6±0.24)。而且，當在無藥劑下刺激時，在化合 物#1處理組的大鼠之癲癇發作程度之增加速率與在媒劑 處理的大鼠中觀察的相同-支持化合物#1延遲數天得到激 發之結論. 本研究的結果刻化合_具有在雜_的扁桃 腺激發的大鼠模式中改善激發之能力。這些結果也與化合 物#1具有疾病-改善效應的結論吻合。此結論是根據發現 在無藥劑及触物躺結束後，化合細組中的大鼠之 癲癇發作程度，保持明顯低於媒劑處理的大鼠。而且，一 旦在沒有藥劑恢復刺激後，進行的癲癇發作程度與在媒劑 處理的大鼠相同。 &gt;部份癲癇之激發的大鼠模式是致癲性之一個被接受 的模式(McNamara，1995)。在無刺激物及藥劑下經i週後， 74 200808300 化合物處理組中的癲癇發作程度而不是放電後持續時間 是明顯低於媒劑處理組之發現，建議化合物#1防止得到 第一期全面性的癲癇發作而不是局部的癲癇發作。在本研 究中用化合物#1得到的結果與用抗癲癇劑丙戊酸(Silver etal·，1991)、***(silver etal，1991)、里維地(L〇scher et al·，1998)、多比瑞(Amano et al·，1998)及 NMDA 受體拮 抗劑MK-801 (Morimotoetal·，1991)得到的結果有類似的 • 大小。雖然不是很決定性，本發明結果建議化合物#1可 防止癲癇在容易受影響的病人中發展。Goleta, CA). The rats were then given ad libitum with vehicle (〇 5% mercaptocellulose) or Compound #1 (100 mg/kg, intraperitoneal) (n = 1 大 each mouse). On the day of the experiment, a single dose of Compound #1 or 5%.5% methylcellulose was administered 30 minutes before the tonsil challenge (2 〇〇 microamperes for 2 seconds). Rats' behavioral seizure scores and AD duration were recorded in each treatment group using the Racine scale to measure behavioral seizure scores, ie, no response; degree l=gr〇(10)ing/activity hyperactivity; degree 2=nodding/shake; Degree 3 = one-way forelimb clonic; degree 4 = ascending clonic; and degree 5 == generalized tension of ascending and descending - clonic seizures (Radne, 1972). After the stimulation was serially recorded, the recording (AD) activity was measured in seconds and the duration of the primary AD was measured. Rats were considered to be fully challenged when five consecutive levels of 4 or 5 overall seizures appeared. Stimulation per sputum was continued for 13 days in all three groups until the rats in the vehicle-treated group 73 200808300 Complete (ie, five consecutive degrees of 4 or 5 fine seizures). At this time, the rats had no stimulation and pharmacy for one week, and then they were stimulated again with the same stimulator under the nourishing agent during the sampling period (i.e., 13 days). Rats treated with Compound #1 were then stimulated once a day until they reached the full challenge phase. The duration of AD in both the vehicle and Compound #1 groups showed a continuous increase during the aggressive capture period. No statistical differences were observed in the treatment group. Beta Compound #1 prevents a seizure that is fully stimulated. This conclusion is based on the finding that the degree of seizures remained significantly lower in the vehicle treated group (Compound #1 = 〇 1 ± 〇 11 and vehicle = 4.6 ± 0.24) after the end of the drug-free aerial fabric. Moreover, when stimulated without the drug, the rate of increase in the degree of seizure in the rats in the compound #1 treatment group was the same as that observed in the vehicle-treated rats - the conclusion that the support compound #1 was delayed for several days was excited. The results of this study engraved _ with the ability to improve stimulation in a rat model stimulated by the amygdala. These results are also consistent with the conclusion that Compound #1 has a disease-improving effect. This conclusion is based on the finding that the degree of seizure in the rats in the combined group after the absence of the drug and the end of the touch was kept significantly lower than that of the vehicle treated. Moreover, once the stimulation was not resumed, the degree of seizure was performed in the same manner as in the vehicle-treated rats. &gt; The partial rat model of epilepsy is an accepted mode of epilepsy (McNamara, 1995). After i weeks without irritation and agents, the degree of seizures in the 2008 2008300 compound treatment group, rather than the post-discharge duration, was significantly lower than that of the vehicle-treated group. It is recommended that compound #1 prevent the first phase of comprehensiveness. Seizures rather than local seizures. The results obtained with Compound #1 in this study were compared with the antiepileptic valproic acid (Silver et al., 1991), phenobarbital (silver et al, 1991), and rivieri (L〇scher et al., 1998). ), Dolphi (Amano et al., 1998) and the NMDA receptor antagonist MK-801 (Morimoto et al, 1991) have similar results. Although not very decisive, the results of the present invention suggest that Compound #1 can prevent epilepsy from developing in susceptible patients.

iMJA 作為口服組成物之一個特定具體實施例，將1〇〇毫克 根據貫例1製備的化合物#1用足夠微細分粒的乳糖調配 而仵到總量是580至590毫克而填入〇號硬質膠囊内。 &gt;、雖然上述說明揭示本發明之原理，提供的實例是作為 =明之目的，當然實施本發明包括下列申請專利範圍及同 • ’事項包括的範圍之全部常用的變化、調適及/或修改。iMJA As a specific embodiment of the oral composition, 1 mg of Compound #1 prepared according to Example 1 was formulated with a sufficiently finely divided amount of lactose to a total amount of 580 to 590 mg and filled with a nickname hard Inside the capsule. &lt;RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;

Claims (1)

200808300 十、申請專利範圍： 1· 一種式(Ϊ)化合物200808300 X. Patent application scope: 1. A compound of formula (Ϊ) 〇 R2 N、r3 R4 Ο) • R1是選自包括氫、齒基、羥基、曱氧基、三氟甲基、 硝基及氰基， X-Y 是選自包括-S_CH-、-S-C(CH3)·、-0-CH-、 -0-C(CH3)-、-N(CH3)-CH-及-CH=CH-CH-; A是選自包括-CH2-及-CH(CH3)-; R2是選自包括氫及甲基； R3及R4是各獨立地選自包括氫及Ci 4烷基； ⑩ 或者是，R3及R4 一起與和其鍵結的氮原子形成5至 7員飽和、部份不飽和或芳族環結構，視需要一 個獨立地選自包括〇、N及S之其他雜原子； ^ , m ，在而要用抗癲性藥劑(AEGD) 治療的病人中用於治療致癲性之用途。 2·根據申請專利範圍第〗項之用途，其令 R1是選自包括氫、鹵基、三氟甲基 x，y是選自包括-s-CH' ·ααί n，基及蜗基， -n(ch3)-ch-及-CH=CH_CH、· 、…（ch3k 76 200808300 A是選自包括-CH2-及-CH(CH3)-; R2是選自包括氫及曱基； R3及R4是各獨立地選自包括氫、曱基及乙基； 或其藥學上可接受的鹽。 3. 根據申請專利範圍第2項之用途，其中 R1是選自包括氫、鹵基、三氟甲基及氰基； X-Y 是選自包括-S-CEK -0-CH-、-0-C(CH3；K -N(CH3)-CH-及-CH=CH-CH-; A是選自包括-CH2-及-CH(CH3)-; R2是氫； R3及R4是各獨立地選自包括氫及乙基； 或其藥學上可接受的鹽。 4. 根據申請專利範圍第3項之用途，其中 R1是選自包括氫、5-氯基、5-氟基、5-溴基、4-溴基、 7-氟基、5-三氟甲基及5-氰基； X-Y 是選自包括-S-CH-、-0-CH-、-0-C(CH3)-、 -N(CH3)-CH-及-CH=CH-CH“ A是選自包括-CH2-及-CH(CH3)-; R2是氫； R3及R4各是氫；或者是R3是氫且R4是乙基； 或其藥學上可接受的鹽。 5. 根據申請專利範圍第4項之用途，其中 R1是選自包括氫、鹵基、三氟曱基及氰基； X-Y 是選自包括-S-CH-、-0-CH-、-0-C(CH3K 77 200808300 -N(CH3)-CH-及-CHNCH-CH-; A是選自包括-Ch2-及-CH(CH3)_; R2是選自包括氫及甲基； R及R —起與和其鍵結的氮原子形成5至7員飽和、 部份不飽和或芳族環結構，視需要含有一至兩個獨立地選 自包括0、N及S之其他雜原子； 或其藥學上可接受的鹽。 % 6.根據申請專利範圍第5項之用途，其中 R1是選自包括氫、函基、三氟甲基及氰基； X-Y 是選自包括-S-CH、-OCH、-OC(CH3K -N(CH3)-CH-及-CI^CH-CH-; A是選自包括_CH2-及-CH(CH3)-; R2是選自包括氫及甲基； R3及R4—起與和其鍵結的氮原子形成5至6員飽和 或芳族環結構，視需要含有一至兩個獨立地選自包括〇、 鲁 N及S之其他雜原子； 或其藥學上可接受的鹽。 7·根據申請專利範圍第6項之用途，其中 R1是氫； X-Y 是 A 是-CH2-; R2是氫； R及R4 —起與和其鍵結的氮原子形成選自包括吡咯 啶基及咪嗤基之5員環結構； 78 200808300 或其藥學上可接受的鹽。 8·根據申請專利範圍第2項之用途，其中式⑴化合物是選 自包括 N-(苯并[b]噻嗯-3-基曱基)-磺醯二胺； Ν·[(5_氯苯并[b]噻嗯-3-基）曱基]-磺醯二胺； N-(3-苯并呋喃基曱基)-磺醯二胺； N_[(5-氟苯并[b]噻嗯-3-基)甲基]•磺醯二胺； N-(l-苯并[b]噻嗯-3-基乙基)-磺醯二胺； N-(l-萘基曱基)-磺醯二胺； N-[(2-甲基-3-苯并呋喃基）甲基]-磺醯二胺； N-[(5-溴苯并[b]噻嗯-3-基）曱基]-磺醯二胺； N-[(4-溴苯并[b]噻嗯-3-基）甲基]-磺醯二胺； N-[(7-氟苯并[b]噻嗯-3-基）甲基]-磺醯二胺； N-[(l-曱基·1Η·吲哚3-基）曱基]-磺醯二胺； 队[(4_三I甲基苯并[1)]喧嗯-3-基）曱基]石黃酿二胺； Ν-[(4-氰基苯并[b]噻嗯-3-基）曱基]-磺醯二胺； N-[(苯并[b]噻嗯各基）甲基]•胺磺醯基吡咯啶； N-[(苯弁[b]嗔嗯-3-基）曱基]-Ν’-乙基續酿二胺； 咪唑-1-磺酸[(苯并[b]噻嗯-3·基）甲基]•醯胺； 及其藥學上可接受的鹽類。 9·根據申請專利範圍第1項之用途，其中式⑴化合物是選 自包括N-(苯并[b]嗔嗯-3-基甲基)-石黃醯二胺;N-[(5-氟苯并 [b]噻嗯_3_基）甲基]-磺醯二胺；及其藥學上可接受的鹽類。 1〇·根據申請專利範圍第1項之用途，其中使得需要用抗癲 79 .200808300 性藥劑(AEGD)治療的病人之傾向因子是選自包括：任何種 、員對CNS之傷害或創傷，神經外科手術、有傷害風 險的活動，例如格鬥活動、赛車或赛馬及接觸運動包括拳 擊；脊柱創傷；CNS之感染；缺氧症，·中風(CVAs);暫時 缺血發作(TIA，S);騎脈狭f ;動脈粥樣硬化血管疾病的 歷史’肺栓基的歷史；末梢血管疾病；影響CNS之自發免 ，症，例如狼瘡；生產受傷，例如圍產期缺氧症；心跳驟 分’面療或移斷性血官手術過程，例如頸動脈内膜切除戋 大腦血管造影術；低血虔症；從栓塞、過高或過低灌流而 對fNS之傷害；低氧症；已知對細仏反應的障礙之已 运.傳ί員向’ CNS之空間佔據損傷；腦腫瘤，例如膠質 細胞瘤；在CNS内或周圍的流血或大量出血，例如大腦内 的流血或硬膜下的大量出血；腦水腫；熱痙攣；高體严. 暴露至毒性或有毒的藥财毒或戒除，例如古柯皿驗 去甲麻黃鹼或酒精；癲癇發作障礙或癲癇相關的類癲癇;、 作神經障礙或類似癲癇發作相關的障礙之家族 &lt; 二 態史；降低癲癇發作閾值的藥劑之目前治療，例如碳^ 托拉侮或克拉平；病人需要用抗癲劑治療的替代指標生 物指標之證據，例如MRU倾齡海馬硬化錢其他 病理，神經元降解產物之血清值提升、睫狀神經營+ (CNTF)之量增加或EEG輯的癲錢作障礙或癲痛 的類癲癇發作神_礙或類似的癲癇發作相關障礙 11.根射請專利範圍第丨項之用途，其中使得需要用 性藥劑(AEGD)治療的病人之傾向因子是 二癲 &lt; 9包括·密閉或 200808300 牙透!·生碩部觸；神射卜科手術、義脈狹窄、 外(CVA);痛痛狀態及cns之空間佔據 ♦Ό %專利範圍第1項之料，其中該傾向因子是密 才11頭销傷或穿透性頭部創傷或神經外科手術。 =.根據申請專利範圍第1項之用途，其中該傾向因子是中 =其他!4血管意外(CVA)、存在賴脈狹窄或 發作。〇R2 N,r3 R4 Ο) • R1 is selected from the group consisting of hydrogen, dentate, hydroxy, decyloxy, trifluoromethyl, nitro and cyano, and XY is selected from the group consisting of -S_CH-, -SC(CH3) ·, -0-CH-, -0-C(CH3)-, -N(CH3)-CH- and -CH=CH-CH-; A is selected from the group consisting of -CH2- and -CH(CH3)-; R 2 is selected from the group consisting of hydrogen and methyl; R 3 and R 4 are each independently selected from the group consisting of hydrogen and Ci 4 alkyl; 10 or R 3 and R 4 together with the nitrogen atom bonded thereto form a 5 to 7 member saturation, Partially unsaturated or aromatic ring structures, optionally selected from other heteroatoms including hydrazine, N and S; ^, m, for treatment in patients treated with anti-epileptic agents (AEGD) The use of epilepticity. 2. According to the use of the scope of the patent application, R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl x, and y is selected from the group consisting of -s-CH'-ααί n, yl and vortex, - n(ch3)-ch- and -CH=CH_CH, ·, ... (ch3k 76 200808300 A is selected from the group consisting of -CH2- and -CH(CH3)-; R2 is selected from the group consisting of hydrogen and sulfhydryl; R3 and R4 are Each is independently selected from the group consisting of hydrogen, sulfhydryl and ethyl; or a pharmaceutically acceptable salt thereof. 3. The use according to claim 2, wherein R1 is selected from the group consisting of hydrogen, halo, trifluoromethyl And cyano; XY is selected from the group consisting of -S-CEK -0-CH-, -0-C(CH3; K-N(CH3)-CH- and -CH=CH-CH-; A is selected from the group consisting of - And a pharmaceutically acceptable salt thereof; Wherein R1 is selected from the group consisting of hydrogen, 5-chloro, 5-fluoro, 5-bromo, 4-bromo, 7-fluoro, 5-trifluoromethyl and 5-cyano; XY is selected from the group consisting of -S-CH-, -0-CH-, -0-C(CH3)-, -N(CH3)-CH- and -CH=CH-CH "A is selected from the group consisting of -CH2- and -CH(CH3) )-; R2 is hydrogen; R3 R4 is each hydrogen; or R3 is hydrogen and R4 is ethyl; or a pharmaceutically acceptable salt thereof. 5. The use according to claim 4, wherein R1 is selected from the group consisting of hydrogen, halogen, and trifluoro Mercapto and cyano; XY is selected from the group consisting of -S-CH-, -0-CH-, -0-C (CH3K 77 200808300 -N(CH3)-CH- and -CHNCH-CH-; A is selected from Including -Ch2- and -CH(CH3)_; R2 is selected from the group consisting of hydrogen and methyl; R and R together with the nitrogen atom bonded thereto form a 5 to 7 member saturated, partially unsaturated or aromatic ring The structure, if necessary, contains one or two other heteroatoms independently selected from 0, N and S; or a pharmaceutically acceptable salt thereof. 6. The use according to item 5 of the patent application, wherein R1 is selected from Including hydrogen, a functional group, a trifluoromethyl group and a cyano group; XY is selected from the group consisting of -S-CH, -OCH, -OC(CH3K-N(CH3)-CH- and -CI^CH-CH-; A is Selected from the group consisting of _CH2- and -CH(CH3)-; R2 is selected from the group consisting of hydrogen and methyl; R3 and R4 together with the nitrogen atom bonded thereto form a 5- to 6-membered saturated or aromatic ring structure, It is necessary to contain one to two other heteroatoms independently selected from the group consisting of ruthenium, ruthenium N and S; A pharmaceutically acceptable salt thereof. 7. The use according to item 6 of the patent application, wherein R1 is hydrogen; XY is A is -CH2-; R2 is hydrogen; and R and R4 are formed together with a nitrogen atom bonded thereto and are selected from pyrrolidinyl groups and 5-membered ring structure of imipenyl; 78 200808300 or a pharmaceutically acceptable salt thereof. 8. The use according to item 2 of the patent application, wherein the compound of the formula (1) is selected from the group consisting of N-(benzo[b]then-3-ylindenyl)-sulfonyldiamine; Ν·[(5-chlorine) Benzo[b]thiazol-3-yl)indolyl]-sulfonyldiamine; N-(3-benzofuranylfluorenyl)-sulfonamide; N_[(5-fluorobenzo[b]] Thio-3-yl)methyl]•sulfonyldiamine; N-(l-benzo[b]thia-3-ylethyl)-sulfonyldiamine; N-(l-naphthylfluorenyl) - sulfonamide diamine; N-[(2-methyl-3-benzofuranyl)methyl]-sulfonyldiamine; N-[(5-bromobenzo[b]thiazol-3-yl N-[(4-bromobenzo[b]thia-3-yl)methyl]-sulfonyldiamine; N-[(7-fluorobenzo[b]] Thio-3-yl)methyl]-sulfonyldiamine; N-[(l-fluorenyl-1Η·吲哚3-yl)indolyl]-sulfonyldiamine; team[(4_三I甲) Benzo[1)]]-3-yl) fluorenyl] sulphate diamine; Ν-[(4-cyanobenzo[b]thia-3-yl)indolyl]-sulfonate Amine; N-[(benzo[b]thiophene)methyl]•aminesulfonylpyrrolidine; N-[(benzoquinone[b]嗔-3-yl)indolyl]-Ν'- Ethyl continuous diamine; imidazole-1-sulfonic acid [(benzo[b]thien-3-yl)methyl]•decylamine; Pharmaceutically acceptable salts. 9. The use according to the first aspect of the patent application, wherein the compound of the formula (1) is selected from the group consisting of N-(benzo[b]non-3-ylmethyl)-diazepine diamine; N-[(5- Fluorobenzo[b]thien-3-yl)methyl]-sulfonamide; and pharmaceutically acceptable salts thereof. 1〇· According to the use of the first application of the patent scope, the propensity factor of the patient who needs to be treated with the anti-epileptic 79.200808300 agent (AEGD) is selected from the group consisting of: any species, injury or trauma to the CNS, nerve Surgery, risk-taking activities such as fighting activities, racing or horse racing and contact sports including boxing; spinal trauma; infection with CNS; anoxia, stroke (CVAs); transient ischemic attack (TIA, S); Riding vein narrow f; history of atherosclerotic vascular disease 'history of pulmonary embolism; peripheral vascular disease; spontaneous immunity affecting CNS, such as lupus; production injury, such as perinatal hypoxia; heartbeat Facial or interruptive blood surgery, such as carotid endarterectomy, cerebral angiography; hypokalemia; damage to fNS from embolization, excessive or low perfusion; hypoxia; known to The obstacles to the fine reaction have been transported. The clerk occupies damage to the space of 'CNS; brain tumors, such as gliomas; bloody or massive bleeding in or around the CNS, such as a large amount of bleeding or subdural in the brain Bleeding Edema; enthusiasm; high body strictness. exposure to toxic or toxic drugs, toxic or abstinence, such as ***e test for mephedrine or alcohol; seizure disorder or epilepsy-related epilepsy;, neurological disorder or similar Family of seizure-related disorders&lt;synchronous history; current treatment of agents that reduce the threshold for seizures, such as carbon^tola or caratine; evidence of surrogate biomarkers for patients requiring antiepileptic treatment, such as MRU Other pathology of hippocampus hardening, increased serum value of neuronal degradation products, increased ciliary management + (CNTF) or EEG series of epileptic seizures or epileptic seizures Seizure-related disorders 11. The use of the scope of the patent application, in which the propensity factor for patients requiring treatment with an agent (AEGD) is two epilepsy &lt; 9 including · hermetic or 200,808,300 toothpaste! ;Shenzhen Bu Ke surgery, stenosis, external (CVA); pain state and cns space occupied ♦ Ό % patent range of the first item, which is the trend of 11 talent sales or penetration Head wound Injury or neurosurgery. =. Use according to item 1 of the scope of the patent application, wherein the propensity factor is medium = other! 4 vascular accident (CVA), presence of stenosis or seizure. 申請專利範㈣1項之賤，其巾該傾向因子是癲 ‘風、自包括N-(苯并[b]噻嗯冬基甲基)·續醯二胺及其 予上可接受的鹽類製造在需要用抗癲劑(AEGD)治療的 病人中治療致癲性的藥劑之用途。 1^·根據，請專利範圍第15項之用途，其中傾向因子使得 ^要用抗癲性藥劑(AEGD)治療的病人是選自包括：任何種 、員對CNS之傷害或創傷；神經外科手術、冑CNs傷害風 =的，動，例如格鬥活動、赛車或㈣及接觸運動包括拳 ，脊柱創傷；CNS之感染；缺氧症；中風(CVAs);暫時 缺血發作(TIA’S);頸動脈狹窄；動脈粥樣硬化血管疾病的 =史，肺栓塞的歷史；末梢血管疾病；影響CNSi自發免 =症’§例如狼瘡，生產受傷，例如圍產期缺氧症；心跳驟 τ ^邊療或诊斷性血管手術過程，例如頸動脈内膜切除或 血官造影術；低血壓症；從栓塞、過高或過低灌流而 S之傷害；低氧症；已知對AEGDs反應的障礙之已 知讀傾向；CNS之空間佔據損傷；腦腫瘤，例如膠質母 81 .200808300 細胞瘤；在CNS内或周圍的流血或大量出血 的流企或硬膜下的大量出灰；腦水腫；熱痙攣；岛内 暴露至毒性或有毒的藥物中毒或戒除，例如^ : ’ 去甲麻黃驗或鋪；癲癇發作障m断目_ =After applying for one of the patents (4), the tendency factor of the towel is epilepsy, including N-(benzo[b]thenylmethyl)diethylamine and its acceptable salts. The use of an agent that treats epilepticity in a patient in need of treatment with an anti-epileptic agent (AEGD). 1^·According to the use of the scope of the patent, the propensity factor is such that the patient to be treated with the anti-epileptic agent (AEGD) is selected from the group consisting of: any species, injury or trauma to the CNS; neurosurgery , 胄CNs injury wind =, move, such as fighting activities, racing or (four) and contact sports including boxing, spinal trauma; CNS infection; anoxia; stroke (CVAs); temporary ischemic attack (TIA's); carotid artery Stenosis; history of atherosclerotic vascular disease, history of pulmonary embolism; peripheral vascular disease; affecting CNSi spontaneous immunity = § such as lupus, production injury, such as perinatal anoxia; heartbeat τ ^ edge therapy or Diagnostic vascular procedures, such as carotid endarterectomy or blood angiography; hypotension; injury from embolization, excessive or hypoperfusion, S; hypoxia; known disorders of response to AEGDs Reading tendency; CNS space occupies damage; brain tumors, such as colloidal mother 81.200808300 cell tumor; bloody or massive bleeding in or around the CNS or subdural large amount of ash; brain edema; enthusiasm; Internal exposure to Poisoning or toxic or withdrawal, e.g. ^: 'Go lay phenylpropanolamine or inspection; seizures off mesh barrier _ = m 作神經障礙或類似癲癇發作相關的障礙之家族史、癲癎务 態史|降低癲癇發侧值的藥劑之目前治療，例如碳= 大 托拉侮或克拉平；病人需制抗細絲的替代指標或生 物指標之證據，例如MRI掃描顯示海馬硬化症或其他咖 病理，神經元降解產物之血清值提升、睫狀神經營養因子 (CNTF)之量增加或EEG建議的赫發作障礙或癲痛相關 的類癲癇發作神經障礙或類似的癲癇發作相關障礙。 17·根據申請專利範圍第15項之用途，其中使得需要用抗 癲=藥劑(AEGD)治療的病人之傾向因子是選自包括：密^ 或穿透性頭部創傷；神經外科手術、頸動脈狹窄、中風或 其他腦血管意外(CVA);癲癇狀態及CNS之空間佔據損 傷。 18·根據申請專利範圍第15項之用途，其中該傾向因子是 密閉性頭部創傷或穿透性頭部創傷或神經外科手術。 19·根據申請專利範圍第15項之用途，其中該傾向因子是 中風、其他腦血管意外(CVA)、存在頸動脈狹窄或暫時缺 血發4乍0 20·根據申請專利範圍第15項之用途，其中該傾向因子是 癲癇狀態。 21·根據申請專利範圍第1項之用途，其中該病人在該投藥 82 200808300 時尚未發展癲癇。 22. 根據申請專利範圍第1項之用途，其中該病人在該投藥 時是在發展癲癇之風險。 23. 根據申請專利範圍第15項之用途，其中該病人在該投 藥時尚未發展癲癇。 24. 根據申請專利範圍第15項之用途，其中該病人在該投 藥時是在發展癲癇之風險。 83 200808300 七、指定代表圖： (一) 本案指定代表圖為：第（無）圖。 (二) 本代表圖之元件符號簡單說明： 無Family history of neurological disorders or disorders associated with seizures, history of epilepsy | current treatment of agents that reduce the onset of seizures, such as carbon = tarsam or caratine; patients need to replace filaments Evidence for indicators or biomarkers, such as MRI scans showing hippocampal sclerosis or other coffee pathology, increased serum levels of neuronal degradation products, increased ciliary neurotrophic factor (CNTF), or EEG-recommended schizophrenia or epilepsy A seizure-like neurological disorder or a similar seizure-related disorder. 17. The use according to the scope of claim 15 wherein the propensity factor for a patient in need of treatment with an anti-epileptic = agent (AEGD) is selected from the group consisting of: dense or penetrating head trauma; neurosurgery, carotid artery Stenosis, stroke, or other cerebrovascular accident (CVA); seizure status and space in the CNS occupy damage. 18. Use according to item 15 of the scope of the patent application, wherein the propensity factor is a closed head trauma or penetrating head trauma or neurosurgery. 19. The use according to item 15 of the scope of the patent application, wherein the predisposing factor is stroke, other cerebrovascular accident (CVA), carotid stenosis or transient ischemic hair. 乍20. According to the application of claim 15 , wherein the propensity factor is an epileptic state. 21· According to the use of the scope of claim 1 of the patent, wherein the patient is not developing epilepsy in the administration of the drug 82 200808300. 22. The use according to item 1 of the scope of the patent application, wherein the patient is at risk of developing epilepsy at the time of administration. 23. The use according to item 15 of the scope of the patent application, wherein the patient has not developed epilepsy at the time of administration. 24. The use according to item 15 of the scope of the patent application, wherein the patient is at risk of developing epilepsy at the time of administration. 83 200808300 VII. Designation of representative representatives: (1) The representative representative of the case is: (No). (2) A brief description of the component symbols of this representative figure: None 八、本案若有化學式時，請揭示最能顯示發明特徵的化學 式：8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: