TW200808298A - Use of benzo-heteroaryl sulfamide derivatives as neuroprotective agents - Google Patents

Abstract

The present invention is directed to a use of a therapeutically effective amount of one or more novel benzo-heteroaryl sulfamide derivatives of formula (I) as herein defined for the manufacture of a medicament for neuroprotection, for treating an acute neurodegenerative disorder, for treating a chronic neurodegenerative disorder and/or for preventing neuron death or damage following brain, head and/or spinal cord trauma or injury.

Description

200808298 九、發明說明： 【發明所屬之技術領域】 本發明有關於苯并-雜芳基磺醯二胺衍生物 (benzo-heteroaryl sulfamide derivatives)作為神 經保護劑 5 (neuroprotective agents)的用途。本發明進一步有關於苯并 -雜芳基磺醯二胺衍生物的用途，其用於治療急性和/或慢 性神經退化性疾病，更特別地用於治療以神經元損傷或死 g 亡（neuron damage or death)為特徵的急性或慢性神經退化 性疾病。 10 【先前技術】 神經退化性病況（neurodegenerative conditions)在美 國或國外均苦惱著許許多多不同的個體。舉例來說，許多 個體受神經退化性疾病（neurodegenerative diseases)所 15 古。這些疾病包括一群嚴重哀弱的病況（seriously debilitating conditions)，諸如帕金森氏症（parkinson，s ® disease)、肌萎縮性偏側硬化症（aniy〇trophic lateral sclerosis，ALS，、、Lou Gehrig’s disease")、多發性硬化症 (multiple sclerosis)、杭 丁頓氏舞蹈症（Huntington，s 20 · disease)、阿茲海默症（Alzheimer’s disease)、糖尿病性視 網膜病變（diabetic retinopathy)、多發性梗塞失智症 (multi-infarct dementia)、黃斑退化(macular degeneration)，以及類似的病況。 人類逐漸增加的壽命已造成對神經退化性疾病盛行 5 200808298 的體認提高。這些疾病的相對高發生率（報導落入介於 2-15%之70歲以上的族群範圍）對罹患者、看護人，以及 一般大眾造成顯著的醫學性、社會性，以及財政性沉重負 擔。這些疾病發生後，它們非常快速地導致死亡，或取代 5 的是，它們可慢慢地進展超過一為數年的期間，通常在需 要被細心照護的患者中為最多。 被診斷出帶有神經退化性疾病之患者的機率隨著族 • 群年齡而急劇地增加，特別是那些患有身體退化者（諸如 阿热'/母默症）°帶有阿兹海默症之個體數目係呈指數地成 10 長且被評估當今全世界可能有多達兩千四百萬的個體罹 患此病況 阿茲海默症（AD)係由病患的一退化性演進 (degenerative process)所引起，其特徵在於源自基底前腦 (basal forebrain)、大腦皮質（cerebral cortex)以及其它腦區 15 (brain areas)而來之細胞進行性喪失(progressive loss)。傳 送乙醯膽驗（acetylcholine)的神經元且它們的標乾神經 (target nerves)尤受到影響。老年斑（senile plaques)與神經 原纖維糾結（neurofibrillary tangles)出現。除了較慢的臨床 進程（clinical course)以及經定義之萎縮（circumscribed 20 atrophy)不同外，匹克氏病（Pick’s disease)具有一類似於阿 茲海默症之主要地影響額葉以及顳葉（frontal and temporal lobes)的臨床表現（clinical picture)。關於阿茲海 默症以及其它失智症的一動物模式顯示:朝向此等斑形成 的遺傳傾向（hereditary tendency)。被認為，若是一藥物在 200808298 此模式中具有效果，其可能有利於阿茲海默症或匹克氏病 的至少某些型式。目前雖有舒減療法(palliative treatments) 但並沒有修復阿茲海默氏症患者之功能的方法。 帕金森氏症(PD)，為一種中年或老年的疾病，具有非 5 常漸進式的進展（very gradual progression)以及一個延長 的過程（prolonged course)。哈瑞森氏内科醫學原理 (HARRISON’S PRINCIPLES OF INTERNAL MEDICINE, _ Vol· 2，23d ed·，Ed by Isselbacher，Braunwald，Wilson， Martin，Fauci and Kasper，McGraw-Hill Inc” New York io City，1994, pg· 2275·)。最經常地被發現於帶有帕金森氏症 之患者中的變化為腦幹（brainstem)[黑質（substantia nigra)，藍斑20(locus 20 coeruleus)]中堆積含黑色素的神 經細胞（melanin-containing nerve cells)，腦幹處有不同程 度的神經細胞流失伴隨反應性神經膠瘤病（reactive 15 gliosis)(最常於黑質被判定出）還有明顯的嗜酸性球性細 胞質内包含（eosinophilic intracytoplasmic inclusions)。於 其完整發病模式（fully developed form)中，PD在患者中很 容易地被認出，其中的共通特徵為彎曲的姿勢（stooped posture)、僵直（stifness)以及動作遲緩（31(^11633〇£ 20 movement)、臉部表情固定（fixity of facial expression)、肢 體的節律性震顫（rhythmic tremor of the limbs)，這些於主 動意志運動（active willed movement)或完全放鬆(complete relaxation)時消失。通常，伴隨著完全發展疾病的其它特 徵為急促步態（festinating gait)，令病患以一似乎是要趕上 200808298 身體重心之加快節奏的快托步（quick shuffling steps at an accelerating pace)行進或行走。 藥理學上以左旋多巴（levodopa)結合立體定位手術 (stereotactic surgery)來治療帕金森氏症地最好也只顯示 5 局部的治癒（partial cure)。許多潛在的治療困難處是關於 一個事實：這些治療法(therapeutic measures)沒有一個是 對潛在疾病演進（其由神經退化所構成者）具有效果。最 p 後，藥理學得以不再抵銷基神經節多巴胺的流失（the l〇ss of basal ganglia dopamine) — 點似乎必須被達成。 10 其它困擾人類的神經退化性病況至少一部分是由中 風或其它創傷或受傷所引起或被造成。根據一來源，每年 有多達700,000個中風新案例發生。在美國，每分鐘就有 一次中風發生。絕大多數的中風病患遭受永久性失能 (permanent disability)，且中風是影響3-4百萬美國公民之 15 成人的神經性失能（neurological disability)的主因。 _ 仍有提供一種用於急性與慢性神經退化性疾病之有 效治療的需要。再者，仍有關於作為神經保護性之藥劑且 因此應用於預防神經元死亡及/或損傷的需要。 20 【發明内容】 本發明有關於一治療有效數量之具有化學式d)的 化合物或其一藥學上可接受鹽類的用途，其供製造用於神 經保護的一醫藥品 8 200808298200808298 IX. Description of the Invention: [Technical Field of the Invention] The present invention relates to the use of benzo-heteroaryl sulfamide derivatives as neuroprotective agents. The invention further relates to the use of a benzo-heteroarylsulfonamide derivative for the treatment of acute and/or chronic neurodegenerative diseases, more particularly for the treatment of neuronal damage or death (neuron) Damage or death) is characterized by acute or chronic neurodegenerative diseases. 10 [Prior Art] Neurodegenerative conditions are annoying to many different individuals in the United States or abroad. For example, many individuals are affected by neurodegenerative diseases. These diseases include a group of seriously debilitating conditions, such as parkinson (s ® disease), ay 〇 trophic lateral sclerosis (ALS, ,, Lou Gehrig's disease" ), multiple sclerosis, Huntington's disease, Alzheimer's disease, diabetic retinopathy, multiple infarction Multi-infarct dementia, macular degeneration, and similar conditions. The gradual increase in human life has led to an increase in the prevalence of neurodegenerative diseases 5 200808298. The relatively high incidence of these diseases (reported to fall within the range of 2-15% of those over the age of 70) poses significant medical, social, and financial burdens for deaf patients, caregivers, and the general public. After these diseases occur, they cause death very quickly, or instead, they can slowly progress over a period of more than a few years, usually the most patients who need to be carefully cared for. The chances of being diagnosed with a neurodegenerative disease increase dramatically with the age of the group, especially those with degenerative conditions (such as A hot '/ maternal syndrome) with Alzheimer's disease The number of individuals is exponentially 10 long and is estimated to be as many as 24 million individuals worldwide may suffer from this condition. Alzheimer's disease (AD) is a degenerative process of the patient. Caused by a progressive loss of cells derived from the basal forebrain, cerebral cortex, and other brain regions. Neurons that transmit acetylcholine and their target nerves are particularly affected. Senile plaques and neurofibrillary tangles appear. In addition to the slower clinical course and the defined circumscribed 20 atrophy, Pick's disease has a predominantly affecting frontal and temporal frontal lobe similar to Alzheimer's disease. And temporal lobes) clinical picture. An animal model of Alzheimer's disease and other dementias shows a hereditary tendency toward these plaques. It is believed that if a drug is effective in this mode in 200808298, it may be beneficial for at least some types of Alzheimer's or Pick's disease. Although there are currently palliative treatments, there is no way to repair the function of Alzheimer's patients. Parkinson's disease (PD), a middle-aged or elderly disease, has a very gradual progression and a prolonged course. HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, _ Vol. 2, 23d ed·, Ed by Isselbacher, Braunwald, Wilson, Martin, Fauci and Kasper, McGraw-Hill Inc. New York io City, 1994, pg · 2275 ·). The most frequently found in patients with Parkinson's disease is the brainstem (brastem) [substantia nigra, locus 20 (locus 20 coeruleus)] Melanin-containing nerve cells, varying degrees of neuronal loss in the brainstem with reactive 15 gliosis (most often judged by the substantia nigra) and significant eosinophilicity Eosinophilic intracytoplasmic inclusions. In its fully developed form, PD is easily recognized in patients, with common features such as stooped posture, stifness, and Slow movement (31 (^11633〇 £ 20 movement), fixation of facial expression, rhythmic tremor of limbs The limbs), these disappear when active willed movement or complete relaxation. Usually, with the other characteristics of fully developed disease is the stagnation gait, the patient seems to be To catch up with 200808298 quick shuffling steps at an accelerating pace. Pharmacologically treat levodopa with stereotactic surgery to treat Parkinson's disease. It is best to show only 5 partial cures. Many potential treatment difficulties are related to the fact that none of these therapeutic measures have a potential disease progression (which is made up of neurodegeneration) After the most p, pharmacology can no longer offset the loss of the basal ganglia dopamine (the l〇ss of basal ganglia dopamine) - the point seems to have to be reached. 10 Other neurodegenerative conditions that afflict humans are caused, at least in part, by or caused by stroke or other trauma or injury. According to one source, as many as 700,000 new stroke cases occur each year. In the United States, a stroke occurs every minute. The vast majority of stroke patients suffer from permanent disability, and stroke is the leading cause of neurological disability affecting 15 adults in 3-4 million US citizens. _ There is still a need to provide an effective treatment for acute and chronic neurodegenerative diseases. Furthermore, there is still a need for a neuroprotective agent and thus for preventing neuronal death and/or injury. 20 SUMMARY OF THE INVENTION The present invention relates to the use of a therapeutically effective amount of a compound of formula d) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product for neuroprotection 8 200808298

其中among them

Rl是選自於由氫、鹵素、羥基、曱氧基、三氟甲基、 硝基與氰基所組成之群組； χ-γ 是選自於由-S-CH-、-S-C(CH3)-、、 -〇-C(CH3)-、_n(CH3)-CH-以及-CKNCH-CH-所組成之群 組； 15 A為選自於由-CHr以及_CH(CH3)-所組成的群組； R疋選自於由氫及甲基所組成的群組； R3以及R4係分別獨立地選自於由氫及Ci_4烷基 成的群組； 夂 另擇地，R3以及R4還有它們所連接的氮原子形成一 =5至7員、飽和的、局科飽和的或芳麵環狀結構， ^擇地含有一至三個額外的雜原子（個別地選自於由 0、N以及N所組成的群組）。 、 例如本發明㈣ϋ療有效數量之 a物的用途，其供製造用於神經保護之一醫藥口 在-個實财，本發明㈣_種—治療有^數量之上 9 200808298 述任一化合物的用途，其供製造用於治療急性神經退化性 疾病之一醫藥品。在另一個實例中，本發明有關於一種一 治療有效數量之上述任一化合物的用途，其供製造用於治 療慢性神經退化性疾病的一醫藥品。 5 更例如本發明是一種上述任一種化合物之用途，其供 製造用於預防對一腦部、中樞神經系統或週邊神經系統之 侵犯或受傷後的神經元死亡或損害之一醫藥品。 _ 本發明有關於一種一治療有效數量之具有化學式（I) 的化合物或其一藥學上可接受鹽類的用途，其供製造用於 10 神經保護之一醫藥品R1 is selected from the group consisting of hydrogen, halogen, hydroxy, decyloxy, trifluoromethyl, nitro and cyano; χ-γ is selected from -S-CH-, -SC (CH3 a group consisting of -, - -〇-C(CH3)-, _n(CH3)-CH-, and -CKNCH-CH-; 15 A is selected from the group consisting of -CHr and _CH(CH3)- Group of R 疋 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; 夂 alternatively, R 3 and R 4 are also The nitrogen atoms to which they are attached form a =5 to 7 membered, saturated, organosaturated or aromatic ring structure, optionally containing one to three additional heteroatoms (optionally selected from 0, N, and a group of N). For example, the present invention (4) uses a therapeutically effective amount of a substance for the manufacture of one of the medical treatments for neuroprotection, and the present invention (four) _ species-treatment has a number of above 9 200808298 Use for the manufacture of a medicament for the treatment of acute neurodegenerative diseases. In another embodiment, the invention relates to the use of a therapeutically effective amount of any of the foregoing compounds for the manufacture of a medicament for the treatment of chronic neurodegenerative diseases. Further, for example, the present invention is a use of any of the above compounds for the manufacture of a medicament for preventing the death or damage of neurons after invasion or injury to a brain, central nervous system or peripheral nervous system. The invention relates to a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in 10 neuroprotection

其中^^^^以^尺蚁^-以及人是如此處所定義。 本發明更有關一種一治療有效數量之具有化學式(I )的 20 化合物或其一藥學上可接受鹽類的用途，其供製造用於治 療急性或慢性神經退化性疾病之一醫藥品。本發明進一步 有關於一種一治療有效數量之具有化學式（I )的化合物 或其一藥學上可接受鹽類的用途，其供製造用以預防在受 傷後的神經元死亡或損傷之一醫藥品。 10 200808298 如此處所用的 ''神經保護(neuroprotection) 〃 一詞應 代表保護腦部、中樞神經系統或週邊神經系統内（較佳地 在腦或脊髓中）的神經元免於死亡及/或損傷。較佳地，該 等神經元係受到保護以免於因氧化壓力（例如氧自由基） 5 所造成的死亡或損傷。 被含括於本發明之方法内的％急性神經退化性疾病 (acute neurodegenerative disorders)77 包括，但不限定於： g 各種不同種類與神經元死亡或損傷相關之急性神經退化 性疾病[包括腦jk管循環不良（cerebrovascular 10 insufficiency)、局部腦創傷（£〇〇&11>^111奸公11111&)、擴散性腦 損傷（diffuse brain damage)，以及脊縫損傷]，亦即含括栓 塞性閉塞（embolic occlusion)與血栓性閉塞（thrombotic occlusion)的大腦缺血（cerebral ischemia)或梗塞 (infarction)、急性缺企（acute ischemia)後的再灌注 15 (reperfusion)、產期缺氧性-缺血性損傷（？61^1^&1 hypoxic-ischemic injury)、心在兆停止（cardiac arrest)，還有 馨 任何類型的顧内出血（intracranial hemorrhage)[包括但不 限於硬膜上（epidural)、硬膜下（subdural)、餘7蛛膜下 (subarachonoid)以及大腦内（intracerebral)]，與顱内及脊椎 20 内損傷（intracranial and intravertebral lesions)[包括但不限 於挫傷（contusion)、貫穿傷（penetration)、刮傷（shear)、壓 傷（compression)與裂傷（laceration)]，及嬰幼兒腦震盪搖晃 症候群（whiplash shaken infant syndrome)。較佳地，該急 性神經退化性疾病為中風、急性缺血性損傷（acute 11 200808298 ischemic injury)、頭部受傷或脊驗受傷的結果。 被含括於本發明之方法内的％慢性神經退化疾病 (chronic neurodegenerative disorders)” 包括，但不限於： 阿茲海默症、匹克氏病、泛發性路易體疾病（diffuse Lewy 5 body disease)、進行式核上麻痒（progressive supranuclear palsy) (Steel-Richardson syndrome，史-禮二氏症候群）、 多系統退化（multisystem degeneration) (Shy-Drager p syndrome，夏-達拉格症候群）、與神經退化有關的慢性癲 癇病況（chronic epileptic conditions associated with 10 neurodegeneration)、運動神經元疾病包括肌萎縮性偏侧硬 化症、退化性萎縮症（degenerative ataxias)、皮質基底核 退化症（cortical basal degeneration)、關島複合型 ALS-帕 金森氏-失智症（ALS-Parkinson，s-Dementia complex of Guam)、亞急性硬化泛腦炎（subacute sclerosing 15 PanencePhalitis)、杭丁頓氏舞蹈症、帕金森氏症、共核蛋 馨 白病（synucleinoPathies)[包括多發性系統退化症（multiple system atrophy)]、原發性進行式失語症（primary progressive aphasia)、紋狀體黑質退化症（striat〇nigrai degeneration)、馬卡度-約瑟夫症（Machado-Joseph disease)/ 20 弟3型脊聽小腦萎縮症（Spinocerebenar ataxia type 3)以及 橄欖體橋腦小腦退化（〇liVOp〇nt〇cerebellar degeneration)、妥瑞氏病（Gines De La Tourette’s disease)、延版性與假延髓性麻痒and pseudobulbar palsy)、脊知性及脊趙延髓性肌肉萎縮症（Kennedy’s 12 200808298 disease，甘迺迪氏症）、多發性硬化症、原發性側索硬化 症(primary lateral sclerosis)、家族性痙孿性截癱（familial spastic paraplegia)、沃尼克-霍夫曼症（Werdnig-Hoffman disease)、庫格勃-韋蘭德症（Kugelberg-Welander disease)、 5 泰薩氏症（Tay-Sachs disease )、山多夫氏病（Sandhoff s disease)、家族性痙孿症（familial spastic disease)、沃法特 -庫格勃-韋蘭德症（Wohlfart-Kugelberg-Welander _ disease)、痙攣性下肢無力（spasticpaΓapaΓesis)、進行性多 處腦白 質病 （progressive multifocal ίο leukoencephalopathy)、家族性自主神經障礙（familial dysautonomia) (Riley-曰 syndrome，賴利-戴症候群），以 及病原性蛋白顆粒疾病（prion disease)[包括但不限於庫賈 氏 （Creutzfeldt-Jakob) 、 GSS 氏 病 (Gerstmann-Straussler-Scheinker disease)、克魯病（Kuru) 15 及家族性失眠症（familial insomnia)]。較佳地，該慢性神 經退化性疾病係選自於阿茲海默症、帕金森氏症，多發性 @硬化症或腦性麻痒。 意欲被含括於本發明方法内的其它表示神經元死亡 或損傷以及諸如此類者的疾病包括癡呆症、不論潛伏性病 20 因（包括年齡-相關聯的癡呆症以及其他癡呆症），以及具記 憶喪失之病況[包括與阿茲海默症有關的癡呆症、血管性 癡呆症（vascular dementia)、泛發性白質病變（diffuse white matter disease)(賓旺格氏症，Binswanger’s disease)，内分 泌或代謝起因之癡呆症、頭部創傷與泛發性腦部損傷之癡 13 200808298 呆症、拳擊家癡呆症（dementia pugilistica)與額葉療呆症 (frontal lobe dementia)] 〇 亦被含括於本發明内者為於腦部、中拖神經系統或週 邊神經系統受傷後的神經保護方法（亦即用以預防神經元 死亡及/或損傷的方法），其中該損傷係起因自化學性、毒 性、感染性、輻射性及/或創傷性損傷。較佳地，本發明 ^方法有關於在腦部、頭部及/或脊賴傷或損傷後防止 神經元死亡或損傷，不論任何原因。 乳動患^ 一詞係指-動物，較佳 此處所用的、、治療有效ί:療二祭^驗的對象。 或藥劑之數量引起—由公：7”代表活性化合物 床人員所;^夺六一、九貝、獸醫師、醫師或其它臨 效性反庫組織系統、動物或人類上的生物性或藥 15 包括減缓被治療之疾病或病變的症候。 社本發明之一且體你ΙΦ ^ ^ 選自於群組，其中/、 ，，、有化學式（I)的化合物是 r1是選自於由氫、鹵夺 、，& 確基與氣基所組心素、龜、甲氧基、三氣甲基、 x々是選自於由4 〇-c(ch3)〜n(ch、r:CH、各C(CH3)_、-0-CH-、 組； 3) H_ U及-CH=CH-CH-所組成之群 R2:是3^自自:1领2_以及~CH(CH3)_所組成的群組； d氫及甲基所組成的群組； 係刀別獨立地選自於由氫及甲基所組成的 14 200808298 群組； 另擇地，R3以及R4還有它們所連接之氮原子形成一 個5至7員、飽和的、局部不飽和的或芳族的環狀結構， 可選擇地含有一至兩個額外的雜原子（個別地選自於由 5 Ο、N以及S所組成的群組)。 在本發明之另一具體例中，具有化學式（I)的化合物 及其藥學上可接受鹽類是選自於群組，其中 _ R1是選自於由氫以及鹵素所組成之群組； X-Y 是選自於由-S_CH·、-S，C(CH3)-、-0-CH_、 ίο -0-C(CH3)-、-N(CH3)_CH-以及-CH=CH-CH•所組成之群 組； A為選自於由名112-以及-(：11(€113)-所組成的群組； R2是選自於由氫及曱基所組成的群組； R3以及R4係分別獨立地選自於由氫及甲基所組成的 15 群組。 在本發明之另一具體例中，具有化學式（I)的化合物 及其藥學上可接受鹽類是選自於群組，其中 R1是選自於由氫以及鹵素所組成之群組，其中該鹵 素是被連結至4-、5-或7-位置； 20 X-Y 是選自於由-0_CH-、-0-C(CH3)-、-S-CH-、 -S-C(CH3)-、-N(CH3)-CH-以及-CH=CH-CH-所組成之群 組； A為選自於由-CH2-以及-CH(CH3)_所組成的群組； R2為氫； 15 200808298 R3以及R4係分別地為氫。 在本發明之另一具體例中，具有化學式（I)的化合物 及其藥學上可接受鹽類是選自於群組，其中 R1為氫； 5 X-Y 是選自於由 _0-CH-、-0-C(CH3)-、-S-CH-、 -S-C(CH3)-、-N(CH3)-CH-以及-CH=CH_CH-所組成之群 組； _ A為選自於由-CH2-以及-CH(CH3)-所組成的群組； R2為氫； ίο R3以及R4係分別為氫。 在本發明之另一具體例中，具有化學式（I)的化合物 及其藥學上可接受鹽類是選自於群組，其中 R1是選自於由氫、鹵素、羥基、甲氧基、三氟甲基、 硝基與氰基所組成之群組；較佳地，R1是選自於由氫與 15 鹵素所組成之群組；更佳地，R1是選自於由氫與鹵素所 組成之群組，其中該鹵素是被連結至4-、5-或7-位置； • X-Y 為-S-CH-; A為選自於由-CH2-以及-CH(CH3)-所組成的群組； R2是選自於由氫及曱基所組成的群組；較佳地，R2 20 為鼠， R3以及R4係分別獨立地選自於由氫及鹵素所組成的 群組；較佳地，R3以及R4係分別獨立地為氫。 在本發明的一具體例中R1是選自於由氫、氯、氟以 及溴所組成的群組。在本發明的另一具體例中，該R1基 16 200808298 團是氫以外的並且被連結於4_、5_或7_位置，較佳地在 5位置在本發明的仍一具體例中，該Ri基團是氫以外 的並且被連結於5-、6-或8-位置，較佳地在6_位置。在 本發明的仍—具體财，Rl是選自於由氫以及鹵素所組 成的群組^在本發明的仍一具體例中，Rl是選自於由羥 基以及甲氧基所組成的群組。在本發明的仍一且體例中， R1是選自於由氫、鹵素以及三氟甲基所組成之群組。在 本發明的仍一具體例中，Rl是選自於由氫、鹵素、三氟 甲基、氰基以及硝基所組成的群組。在本發明的仍一具體 =中’R1是選自於由氫、鹵素、三氟？基以及氰基所組 ，的群組。在本發明的仍一具體例中，Rl是選自於由三 氟甲基以及氰基所組成的群組。在本發明的仍—具體 15 20 中，R1是選自於由氫、‘溴、5_氯、5_氟、5·溴、：三氟 甲基、5-氰基以及7-氰基所組成的群組。 在本發明的一具體例中，R2為氫。在本發明的另一 -體例中R以及R分別為氫。在本發明的仍— R2為氫，R3為氫且R、氫。 』例中 ^本發明的-具體例中，r3以及r4是分別獨立地為 k自於虱以及Cm烷基所組成之群組。在本發明的且 ，例中’R3以及"有氮原子(r3以及以接至它)被抓 在—起（taken together)以形成一個5至7員、飽和 ==口==，狀結構’任擇地含有一個或兩個額 ^的雜原子（其個別地選自料〇、N以及8所組 17 200808298Where ^^^^ is defined by the ant ant ^ - and the person is so defined. The invention further relates to the use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an acute or chronic neurodegenerative disease. The invention further relates to the use of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention of neuronal death or injury following injury. 10 200808298 As used herein, the term 'neuroprotection' should mean the protection of neurons from the brain, central nervous system or peripheral nervous system (preferably in the brain or spinal cord) from death and/or injury. . Preferably, the neuronal systems are protected from death or damage caused by oxidative stress (e.g., oxygen free radicals). The % acute neurodegenerative disorders 77 included in the method of the present invention include, but are not limited to: g various acute neurodegenerative diseases associated with neuronal death or injury [including brain jk Cerebrovascular 10 insufficiency, local brain trauma (£ 〇〇 & 11 > ^ 111 traitor 11111 &), diffuse brain damage (diffuse brain damage), and spinal injury], ie including embolism Embryal occlusion and thrombocytic occlusion of cerebral ischemia or infarction, reperfusion after acute ischemia, hypoxia-deficiency during birth Blood damage (?61^1^&1 hypoxic-ischemic injury), cardiac arrest (cardiac arrest), and any type of intracranial hemorrhage (including but not limited to epidural) , subdural, residual 7 subarachonoid (subarachonoid) and intracerebral (intracerebral), and intracranial and spinal 20 lesions (intracranial and intraverte Bral lesions) [including but not limited to contusion, penetration, shear, compression and laceration], and whiplash shaken infant syndrome . Preferably, the acute neurodegenerative disease is the result of a stroke, acute ischemic injury (acute 11 200808298 ischemic injury), head injury or spine injury. % chronic neurodegenerative disorders included in the methods of the invention include, but are not limited to: Alzheimer's disease, Pick's disease, diffuse Lewy 5 body disease Progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Drager p syndrome, Xia-Dalag syndrome), and nerve Chronic epileptic conditions associated with 10 neurodegeneration, motor neuron diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, Guam Compound ALS-Parkinson, s-Dementia complex of Guam, subacute sclerosing 15 Panence Phalitis, Huntington's disease, Parkinson's disease, total Nuclear egg white disease (synucleinoPathies) [including multiple systemic degeneration (multiple syst) Em atrophy)], primary progressive aphasia, striat〇nigrai degeneration, Machado-Joseph disease / 20 brother type 3 ridge Spinocerebenar ataxia type 3 and oligopononcebra degeneration (〇liVOp〇nt〇cerebellar degeneration), Gines De La Tourette's disease, extended and pseudobulbar itch and pseudobulbar ), spinal sensation and medullary medullary muscular dystrophy (Kennedy's 12 200808298 disease, Gandido's disease), multiple sclerosis, primary lateral sclerosis, familial spastic (familial spastic) Paraplegia), Werdnig-Hoffman disease, Kugelberg-Welander disease, 5 Tay-Sachs disease, Sandov's disease (Sandhoff s Disease), familial spastic disease, wohlfart-Kugelberg-Welander _ disease, spastic lower limbs Force (spasticpaΓapaΓesis), progressive multifocal ίο leukoencephalopathy, familial dysautonomia (Riley-曰syndrome), and pathogenic protein granule disease (prion disease) ) [including but not limited to Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuru 15 and familial insomnia]. Preferably, the chronic neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple sclerosis or cerebral itch. Other diseases which are intended to be included in the method of the invention, which represent neuronal death or injury, and the like, include dementia, regardless of latent disease 20 (including age-associated dementia and other dementias), and memory loss. Conditions [including dementia associated with Alzheimer's disease, vascular dementia, diffuse white matter disease (Binswanger's disease), endocrine or metabolic causes Dementia, head trauma and generalized brain injury 13 200808298 Dementia, dementia pugilistica and frontal lobe dementia are also included in the present invention. Is a neuroprotective method (ie, a method for preventing neuronal death and/or injury) after injury to the brain, the middle tread nervous system, or the peripheral nervous system, wherein the injury is caused by self-chemical, toxic, infectious Radiation and/or traumatic injury. Preferably, the method of the invention relates to preventing neuronal death or injury after the brain, head and/or ridges are injured or damaged, for whatever reason. The term "milk-motivated" means the animal, preferably the one used here, and the treatment is effective. Or the quantity of the medicinal agent - by the public: 7" represents the active compound bed personnel; ^ 六 、, 九 九, veterinarian, physician or other effective anti-library system, animal or human biological or pharmaceutical 15 Including one of the symptoms of the disease or disease to be treated. One of the inventions and the body ΙΦ ^ ^ is selected from the group, wherein /, ,,, the compound of formula (I) is that r1 is selected from hydrogen , halogen, and &qi; the base and gas base of the group, turtle, methoxy, trimethyl, x 々 is selected from 4 〇-c (ch3) ~ n (ch, r: CH , each C(CH3)_,-0-CH-, group; 3) H_U and -CH=CH-CH- group R2: is 3^ from: 1 collar 2_ and ~CH(CH3) a group of _; a group consisting of d hydrogen and methyl; the knives are independently selected from the group consisting of hydrogen and methyl 14 200808298; alternatively, R3 and R4 are also The nitrogen atom to be bonded forms a 5 to 7 membered, saturated, partially unsaturated or aromatic cyclic structure, optionally containing one to two additional heteroatoms (optionally selected from 5 Ο, N, and S) Group of groups). In this In another specific embodiment, the compound of formula (I) and a pharmaceutically acceptable salt thereof are selected from the group consisting of _R1 selected from the group consisting of hydrogen and halogen; XY is selected from the group consisting of a group consisting of -S_CH·, -S, C(CH3)-, -0-CH_, ίο -0-C(CH3)-, -N(CH3)_CH-, and -CH=CH-CH• ; A is selected from the group consisting of 112- and - (: 11 (€113)-; R2 is selected from the group consisting of hydrogen and sulfhydryl; R3 and R4 are independently selected From 15 groups consisting of hydrogen and methyl. In another embodiment of the invention, the compound of formula (I) and pharmaceutically acceptable salts thereof are selected from the group wherein R1 is selected From the group consisting of hydrogen and halogen, wherein the halogen is bonded to the 4-, 5- or 7-position; 20 XY is selected from -0_CH-, -0-C(CH3)-, - a group consisting of S-CH-, -SC(CH3)-, -N(CH3)-CH-, and -CH=CH-CH-; A is selected from -CH2- and -CH(CH3)_ a group consisting of; R2 is hydrogen; 15 200808298 R3 and R4 are respectively hydrogen. In another embodiment of the present invention, The compound of formula (I) and pharmaceutically acceptable salts thereof are selected from the group consisting of wherein R1 is hydrogen; 5 XY is selected from _0-CH-,-0-C(CH3)-, - a group consisting of S-CH-, -SC(CH3)-, -N(CH3)-CH-, and -CH=CH_CH-; _A is selected from -CH2- and -CH(CH3)- a group consisting of; R2 is hydrogen; ίο R3 and R4 are respectively hydrogen. In another embodiment of the present invention, the compound of the formula (I) and a pharmaceutically acceptable salt thereof are selected from the group consisting of, wherein R1 is selected from the group consisting of hydrogen, halogen, hydroxy, methoxy, and tri a group consisting of a fluoromethyl group, a nitro group and a cyano group; preferably, R1 is selected from the group consisting of hydrogen and 15 halogen; more preferably, R1 is selected from hydrogen and halogen. a group wherein the halogen is bonded to the 4-, 5- or 7-position; • XY is -S-CH-; A is selected from the group consisting of -CH2- and -CH(CH3)- And R 2 is selected from the group consisting of hydrogen and sulfhydryl; preferably, R 2 20 is a mouse, and R 3 and R 4 are each independently selected from the group consisting of hydrogen and halogen; preferably The R3 and R4 systems are each independently hydrogen. In a specific embodiment of the invention, R1 is selected from the group consisting of hydrogen, chlorine, fluorine, and bromine. In another embodiment of the present invention, the R1 group 16 200808298 group is other than hydrogen and is bonded to the 4_, 5_ or 7_ position, preferably at the 5 position in still another embodiment of the present invention, The Ri group is other than hydrogen and is attached to the 5-, 6- or 8-position, preferably at the 6-position. In still another embodiment of the present invention, R1 is selected from the group consisting of hydrogen and halogen. In still another embodiment of the present invention, R1 is selected from the group consisting of a hydroxyl group and a methoxy group. . In still another aspect of the invention, R1 is selected from the group consisting of hydrogen, halogen, and trifluoromethyl. In still another embodiment of the invention, R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, cyano and nitro. In still another specific embodiment of the present invention, 'R1 is selected from hydrogen, halogen, and trifluoro? Group of groups based on cyano group. In still another embodiment of the invention, R1 is selected from the group consisting of trifluoromethyl and cyano. In still-specific 15 20 of the present invention, R1 is selected from the group consisting of hydrogen, 'bromine, 5-chloro, 5-fluoro, 5·bromo, trifluoromethyl, 5-cyano and 7-cyano. The group consisting of. In a specific embodiment of the invention, R2 is hydrogen. In another embodiment of the invention, R and R are each hydrogen. In the present invention - R2 is hydrogen, R3 is hydrogen and R, hydrogen. In the specific example of the present invention, r3 and r4 are each independently a group consisting of k from 虱 and Cm alkyl. In the present invention, and in the example, 'R3 and " have nitrogen atoms (r3 and to which it is attached) are taken together to form a 5 to 7 member, saturation == mouth ==, structure 'Optionally containing one or two heteroatoms (each selected individually from the group, N and 8 groups 17 200808298

在t發明的—具體例中，r3以及r4是分別獨立地選 於由氫、甲基以及乙基所組成的群組。在本發明 一 具體例中’ R3以及r4是分別獨立地選自於由氫以及甲基 所'、且成的群組。在本發明的仍-具體例中，R3以及R4 a 刀別獨立地返自於由氫以及乙基所組成的群組。在本 的仍一具體例中，R3為氫且R4為乙基。 X 、在4本發明的一具體例中，R3以及R4還有氮原子（R3 鲁 連接至它）被抓在-起以形成-個5至7員、飽和 1〇的、局部不飽和的或芳族的環狀結構’任擇地含有一至兩 個附加的雜原子（其個別地選自於由〇、N以及S所組成 的群，）。在本發明的另一具體例中，R3以及R4還有氮原 子(R以及R4連接至它）被抓在一起以形成一個5至7 的飽和環狀結構，任擇地含有一至兩個附加的雜原盆 Μ :別地選自於由〇、N以及s所組成的群組）。在本發明 的另一具體例中，R3以及R4還有氮原子(R3以及Μ連接 # 至它）被抓在-起以形成—個5至7員的芳族環狀結構， 任擇地含有一至兩個附加的雜原子（其個別地選自於由 〇、N以及s所組成的群組）。 、 泊 較佳地’R3以及R4還有氮原子（R3以及R4連接至它 ^皮抓在-起以形成-個5至6員之飽和的，局部不飽和或 芳族的環狀結構，任擇地含有一至兩個額外的雜原子 個別地選自於由0、N以及S所組成的群組）。更佳地了 V以及V還有氮原？（R3以及❻接至它）被抓在一起以 形成-個6員之飽和、局部不飽和或芳族的環狀結構，任 18 200808298 擇地含有-至兩個附加的雜原子（其個別地選自於由〇、n 以及S所組成的群組）。 較佳地’ R3以及R4還有氮原子（R3以及R4連接至它） 被抓在-起以形成-個5至7 (更佳地為5至6)員之飽和 5的或芳族的環狀結構，任擇地含有—至兩個（較佳地為一 個）額外的雜原子（其個別地選自於由〇、s以及N所组成 的群組，較佳地為Ο或N，更佳地為N)。 • 在本發明的另一具體例中，R3以及R4還有氮原子（R3 以及R4連接至它）被抓在-起以形成_個5至6員之飽和 10的或芳族的環狀結構，任擇地含有—至兩個（較佳地為一 個）額外的雜原子（其個別地選自於由〇、smN所組成 的群組，較佳地為Ο或N，更佳地為N)。 較佳地’該5至7員之飽和的、局部不飽和的或芳族 的環狀結構含有0至1個額外的雜原子（其個別地選自於 15由G、S以及N所組成的群組）。較佳地，該雜原子是獨 立地選自於由Ο以及N所組成的群組，更佳地，該雜原 子為N 〇 該5至7員之飽和的、局部不飽和的或芳族的環狀結 構[其可任擇地含有一至兩個額外雜原子（個別地選自於 20 由〇、3以及N所組成之群組）]之適當的實例包括，但不 限定於：吡咯基(pyrrolyl)、吡咯啶基❻^⑺丨记化”卜吡咯 啉基（pyrrolinyl)、嗎琳基（m〇rph〇linyl)、哌啶基 (piperidinyl)、六氫吼畊基（piperazinyl)、咪唑基 (lmidazolyl) “比唑基（pyraz〇lyl)、σ比啶基（pyridyl)、咪唑 19 200808298 5In the specific embodiment of the invention, r3 and r4 are each independently selected from the group consisting of hydrogen, methyl and ethyl. In a specific example of the present invention, 'R3 and r4 are each independently selected from the group consisting of hydrogen and a methyl group. In still another embodiment of the invention, R3 and R4a are independently returned from a group consisting of hydrogen and ethyl. In still another embodiment of this invention, R3 is hydrogen and R4 is ethyl. X, in a specific embodiment of the invention, R3 and R4 also have a nitrogen atom (R3 is connected to it) to be caught - to form - 5 to 7 members, saturated 1 〇, partially unsaturated or The aromatic cyclic structure 'optionally contains one to two additional heteroatoms (which are individually selected from the group consisting of ruthenium, N and S). In another embodiment of the invention, R3 and R4, and also nitrogen atoms (R and R4 are attached thereto), are clamped together to form a saturated cyclic structure of 5 to 7, optionally containing one to two additional Heterogeneous pots: Otherly selected from the group consisting of 〇, N, and s). In another embodiment of the present invention, R3 and R4 further have a nitrogen atom (R3 and Μ linkage # to it) are captured to form a 5- to 7-membered aromatic cyclic structure, optionally containing One to two additional heteroatoms (each selected individually from the group consisting of 〇, N, and s). Preferably, 'R3 and R4 have a nitrogen atom (R3 and R4 are attached to it to form a saturated, partially unsaturated or aromatic ring structure of 5 to 6 members). Optionally, one or two additional heteroatoms are individually selected from the group consisting of 0, N, and S). Better V and V and nitrogen? (R3 and spliced to it) are clamped together to form a 6-membered saturated, partially unsaturated or aromatic ring structure, any 18 200808298 optionally containing - to two additional heteroatoms (each individually Selected from a group consisting of 〇, n, and S). Preferably, 'R3 and R4 have a nitrogen atom (R3 and R4 are attached to it) are captured to form - a 5 to 7 (more preferably 5 to 6) member of a saturated 5 or aromatic ring a structure, optionally containing - to two (preferably one) additional heteroatoms (each selected individually from the group consisting of 〇, s and N, preferably Ο or N, more Good land is N). • In another embodiment of the invention, R3 and R4 have a nitrogen atom (where R3 and R4 are attached) are captured to form a saturated 10 or aromatic cyclic structure of 5 to 6 members. Optionally containing - to two (preferably one) additional heteroatoms (each selected individually from the group consisting of hydrazine, smN, preferably hydrazine or N, more preferably N ). Preferably, the 5 to 7 membered saturated, partially unsaturated or aromatic cyclic structure contains 0 to 1 additional heteroatoms (each individually selected from 15 consisting of G, S and N) Group). Preferably, the hetero atom is independently selected from the group consisting of ruthenium and N, and more preferably, the hetero atom is N 〇 saturated, partially unsaturated or aromatic of 5 to 7 members Suitable examples of cyclic structures [which may optionally contain one to two additional heteroatoms (individually selected from the group consisting of 20, 3, and N) include, but are not limited to, pyrrolyl ( Pyrrolyl), pyrrolidinyl ❻^(7) 丨""pyrrolinyl, m〇rph〇linyl, piperidinyl, piperazinyl, imidazolyl (lmidazolyl) "pyraz〇lyl, σ pyridyl, imidazole 19 200808298 5

10 15 20 基（imidazolyl)、硫嗎琳基（thi〇m〇rph〇iinyi)、吼 σ井基 (pyrazmyl)、二卩井基(triazinyl)、氮呼基(azepinyl)以及類似 者。較佳的5至7員之飽和的、局部不飽和的或芳族的環 狀結構[其可任擇地含有一至兩個額外雜原子（獨立地選 自於由0、S以及n所組成之群組）]包括，但不限定於： 咪唑基、吡咯啶基、哌啶基以及嗎琳基。 在本發明的—具體例中，A為-CH2-。 在本發明的—具體例中，X-Y是選自於下列群組： _S-CH-、4CH·、_〇_c(CH士、_N(CH3)-CH-以及 -CH=CH-CH-。在本發明的另一具體例中，χ-γ是選自於 下列群組：-S-CH-、-O-CH-、-0-C(CH3)·以及-CH=CH-CH-。在本發明的又一個具體例中，χ-γ是選自於下列群 組：-S-CH-、、-〇_c(CH3)-以及-N(CH3)-CH-。在 本發明的另一個具體例中，χ_γ是選自於下列群組： -S-CH-、-0-CH·、-Ν(αΗ[3>α^ 以及 。在本 發明的又一個具體例中，Χ-Υ是選自於下列群組： 各CH-、-0-CH-以及-CH=CH_CH_。在本發明的又一個具 體例中’ X_Y是選自於下列群組：-S-CH-以及-O-CH-。在 本發明的又一具體例中，χ_γ是選自於下列群組：S_CH_、 -S-C(CH3)-、-0—CH-、-〇-C(CH3)-以及-N(CH3)-CH-。 在本發明的一具體例中，X-Y為-S-CH-。在本發明的 另一具體例中，χ_γ為_€11=:(：：11=€11_。在本發明的又一個 具體例中’ Χ-Υ為-N(CH士CH-。在本發明的又一個具體 例中’ χ-γ疋選自於下列群組：_〇_CH_以及-〇_c(CH士。 20 200808298 在一具體例中，本發明有關於一種選自於由下列群組 的化合物及其藥學上可接受鹽類：Λ「-(苯并[6]噻吩-3-基曱 基)磺醯二胺;1[(5-氯苯并[Ζ>]噻吩-3-基）曱基]磺醯二胺； ，(3-苯并呋喃基曱基)磺醯二胺；，[(5-氟苯并[Ζ7]噻吩-3-5 基）甲基]磺醯二胺；ΑΚ1-苯并Θ]噻吩-3-基乙基）磺醯二 胺；豕（1-萘甲基)磺醯二胺；，[(2-甲基-3·苯并呋喃）甲基] 磺醯二胺；j[(5-溴苯并[Ζ>]噻吩-3-基）甲基]磺醯二胺； _ 豕[(4-溴苯并[Ζ>]噻吩-3-基)曱基]磺醯二胺；，[(7-氯苯并 〇]噻吩-3-基）曱基]磺醯二胺；，[(1-甲基-1//-吲哚-3-基) 10 曱基]磺醯二胺；，[(4-三氟曱基苯并[Ζ>]噻吩-3-基）甲基] 磺醯二胺；豕[(4-氰基苯并〇]噻吩胃3-基）甲基]磺醯二胺； ，[(苯并|>]噻吩-3-基）甲基]胺磺醯啦咯啶；，[(苯并[办] 噻吩-3-基）曱基]-ΑΓ-乙基磺醯二胺；咪唑-1-磺酸[(苯并[办] 噻吩-3-基）曱基]-醯胺；以及其藥學上可接受鹽類。 15 本發明的額外具體例，包括那些其中有關一個或多個 如此處所定義之經選定的變化例（亦即R1、R2、R3、R4， ® Χ-Υ以及A)，是獨立地被選定為任何個別取代基或如此 處所定義被選自於下列完整列表的任何取代基之次組。 被應用為神經保護劑的代表性化合物係如以下表1 20 及2中所列示者。 21 200808298 表1 :具有化學式（i)之代表性化合物10 15 20 imidazolyl, thi〇m〇rph〇iinyi, σ σ pyrazmyl, triazinyl, azepinyl and the like. A preferred 5 to 7 membered saturated, partially unsaturated or aromatic cyclic structure [which may optionally contain one to two additional heteroatoms (independently selected from the group consisting of 0, S and n) Groups]] include, but are not limited to, imidazolyl, pyrrolidinyl, piperidinyl and morphinyl. In a specific embodiment of the invention, A is -CH2-. In a specific embodiment of the invention, XY is selected from the group consisting of _S-CH-, 4CH·, _〇_c (CH, _N(CH3)-CH-, and -CH=CH-CH-. In another embodiment of the invention, χ-γ is selected from the group consisting of -S-CH-, -O-CH-, -0-C(CH3)., and -CH=CH-CH-. In still another embodiment of the present invention, χ-γ is selected from the group consisting of -S-CH-, -〇_c(CH3)-, and -N(CH3)-CH-. In the present invention In another specific example, χ_γ is selected from the group consisting of: -S-CH-, -0-CH·, -Ν(αΗ[3>α^ and. In still another specific example of the present invention, Χ- Υ is selected from the following groups: each CH-, -0-CH-, and -CH=CH_CH_. In still another embodiment of the present invention, 'X_Y is selected from the following groups: -S-CH- and - O-CH-. In still another embodiment of the present invention, χ_γ is selected from the group consisting of S_CH_, -SC(CH3)-, -0-CH-, -〇-C(CH3)-, and -N (CH3)-CH-. In a specific example of the present invention, XY is -S-CH-. In another embodiment of the present invention, χ_γ is _€11=:(::11=€11_. In still another embodiment of the present invention, 'Χ-Υ is -N(CH士CH-. In still another embodiment of the present invention, 'χ-γ疋 is selected from the group consisting of: _〇_CH_ and -〇_c (CH. 20 200808298. In one specific example, the present invention relates to one selected from a compound of the following group and a pharmaceutically acceptable salt thereof: Λ "-(benzo[6]thiophen-3-ylindenyl)sulfonyldiamine; 1[(5-chlorobenzo[Ζ>]thiophene 3-yl)mercapto]sulfonyldiamine; (3-benzofuranylfluorenyl)sulfonamide; [[5-fluorobenzo[Ζ7]thiophene-5-yl)methyl] Sulfonamide; ΑΚ1-benzopyrene]thiophen-3-ylethyl)sulfonyldiamine; hydrazine (1-naphthylmethyl)sulfonyldiamine; [(2-methyl-3·benzofuran) Methyl] sulfonamide diamine; j[(5-bromobenzo[Ζ>]thiophen-3-yl)methyl]sulfonamide diamine; _ 豕[(4-bromobenzo[Ζ>]thiophene- 3-yl)mercapto]sulfonyldiamine;,[(7-chlorobenzoindole]thiophen-3-yl)indolyl]sulfonyldiamine;,[(1-methyl-1//-吲哚-3-yl) 10 fluorenyl] sulfonyl diamine;, [(4-trifluoromethyl benzo[Ζ>]thiophen-3-yl)methyl] sulfonium diamine; hydrazine [(4-cyano) Benzopyrene]thiophene-3-yl)methyl]sulfonamide; ,[(benzo[>]thiophen-3-yl)methyl]aminesulfonate咯 ;;,[(benzo[io]thiophen-3-yl)indolyl]-oxime-ethylsulfonyldiamine;imidazol-1-sulfonic acid[(benzo[io]thiophen-3-yl)indole And guanidine; and pharmaceutically acceptable salts thereof. 15 Additional specific examples of the invention, including those in which one or more selected variants (i.e., R1, R2, R3, R4, ® Χ-Υ, and A) as defined herein are independently selected as Any individual substituent or subgroup of any substituent selected from the full list below, as defined herein. Representative compounds that are employed as neuroprotective agents are as listed in Tables 1 20 and 2 below. 21 200808298 Table 1: Representative compounds of formula (i)

〇A"° N—r3 R4 編號 R1 -Χ-Υ- A R3 R4 1 Η -S-CH- -CH2- H H 3 5-C1 -S-CH- -ch2- H H 6 Η -0-CH- -ch2- H H 7 Η -n(ch3)-ch- -ch2- H H 8 5-F -S-CH- -ch2- H H 9 Η -S-CH- -CH(CH3)- H H 10 Η -CH=CH-CH- -ch2- H H 13 Η -0-C(CH3) -ch2- H H 15 5·Βτ -S-CH- -ch2- H H 17 4-Βγ -S-CH- -ch2- H H 18 7-F -S-CH- -ch2- H H 19 5-CF3 -S-CH- -ch2- H H 20 5-CN -S-CH- -CH2- H H 21 Η -S-CH- -ch2- H 乙基 22 200808298〇A"° N—r3 R4 No. R1 -Χ-Υ- A R3 R4 1 Η -S-CH- -CH2- HH 3 5-C1 -S-CH- -ch2- HH 6 Η -0-CH- - Ch2- HH 7 Η -n(ch3)-ch- -ch2- HH 8 5-F -S-CH- -ch2- HH 9 Η -S-CH- -CH(CH3)- HH 10 Η -CH=CH -CH- -ch2- HH 13 Η -0-C(CH3) -ch2- HH 15 5·Βτ -S-CH- -ch2- HH 17 4-Βγ -S-CH- -ch2- HH 18 7-F -S-CH- -ch2- HH 19 5-CF3 -S-CH- -ch2- HH 20 5-CN -S-CH- -CH2- HH 21 Η -S-CH- -ch2- H ethyl 22 200808298

此處所用％i素〃應表示氯、溴、氟及碘。 此處所用v'烷基〃一詞包括直鏈及支鏈，不論單獨或 5 者作為一取代基團的部分使用。例如，烧自由基包括甲 基、乙基、丙基、異丙基、丁基、異丁基、二級-丁基、 _ 三級-丁基、戊基以及類似者。除非另提及，"Cm烷基" 代表一為1 -4個碳原子的碳鍵組成物。 當一特定基團 '經取代（substituted)"(例如烧基、 ίο 苯基、芳基、、雜烧基、雜芳基），那基團可具有一個或 多個獨立地選自於取代基列表的取代基，較佳地由一至五 個取代基，更佳地由一至三個取代基，最佳地由一至兩個 取代基。 關於取代基，v、獨立地（independently)〃一詞表示當 15 超過一個此類取代基係可行時，此類取代基可為相同的或 23 200808298 彼此不同的。 為了提供一個更為明確的說明，此處被給予的某些數 量表示並不會以“大約（about)”一詞來描述。被理解的是： 不論‘大約” 一詞是否被明確地使用，此處被給予的每個 5 數量意欲為意指實際給予數量，並且其也意欲為意指有關 此給予數量的近似值，該近似值可合理地根據該項技藝中 的一般技藝被推論出，包括有關於此給予數量之實驗和/ 鲁 或測里條件的近似值。 除非另提及，如此處所用“脫離基(leaving gr0Up)”應 10 表示一個帶電荷或不帶電荷的原子或基團，其在一取代或 替代反應期間脫離。適當的實例包括，但不限定為Br、The %i used herein shall mean chlorine, bromine, fluorine and iodine. The term v'alkyl" as used herein includes both straight and branched chains, whether used alone or as part of a substituted group. For example, calcined free radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 1,3-tert-butyl, pentyl and the like. Unless otherwise mentioned, "Cm alkyl" represents a carbon bond composition of from 1 to 4 carbon atoms. When a particular group is 'substituted' (for example, alkyl, ί phenyl, aryl, heteroalkyl, heteroaryl), the group may have one or more independently selected from the substitution. The substituents of the base list are preferably one to five substituents, more preferably one to three substituents, most preferably one to two substituents. With respect to substituents, v, the term "independently" means that when more than one such substituent is feasible, such substituents may be the same or 23 200808298 different from each other. In order to provide a more explicit description, some of the numerical representations given herein are not described by the word "about". It is understood that whether or not the word 'about' is used explicitly, each 5 quantity given herein is intended to mean the actual amount given, and it is also intended to mean an approximation of the quantity given, the approximation It may be reasonably inferred from the general skill in the art, including approximations of the experimental and/or linguistic conditions for the amount given herein. Unless otherwise mentioned, "leaving gr0Up" as used herein shall be 10 represents a charged or uncharged atom or group that cleaves during a substitution or substitution reaction. Suitable examples include, but are not limited to, Br,

Cl、I、曱石夤酸鹽（mesylate)、曱苯磺酸（tosylate)，以及類 似之物。 除非另提及，R1取代基所連結的位置將透過開始自 15 X_Y位置為1、2以一順時針方向環繞該核心結構計算並 且從它們如下列繼續而被決定：Cl, I, mesylate, tosylate, and the like. Unless otherwise mentioned, the position to which the R1 substituent is attached will be calculated by starting from the 15 X_Y position of 1, 2 in a clockwise direction around the core structure and proceeding from them as follows:

、右X Υ取代基為_CH=CH_CH_，則基團將被計數 為1 2 3並且繼而如前述順時針地環繞該核心結構地繼 24 200808298The right X Υ substituent is _CH=CH_CH_, then the group will be counted as 1 2 3 and then circled clockwise around the core structure as described above.

於此通篇揭示的標準命名下，被指明側鏈的末端部分 將首先被描述’繼而為接近連接點（point of attachment)的 相鄰官能性（adjacent functionality)。因此，舉例來說，一 5 '苯基CVQ烷基胺基羰基烷基〃取代基係指具有 下列化學式之一個基團：Under the standard nomenclature disclosed throughout this specification, the end portion of the indicated side chain will first be described 'and then the adjacent functionality of the point of attachment. Thus, for example, a 5 'phenyl CVQ alkylaminocarbonylalkylhydrazine substituent refers to a group having the formula:

10 8lkyl10 8lkyl

slkyl·Slkyl·

本說明書中所用縮寫，特別是反應途徑(Schemes)以 及實施例（Examples)， 係如下： DCE = 二氯乙烷 15 DCM = 二氯甲烷 DMF = N，N-二曱基甲醯胺 • DMSO = 二甲亞砜 LAH = 銘氳化裡 MTBE = 甲基-四敛-丁酯 20 THF = 四氫呋喃 TLC = 薄層層析法 若根據此發明之該等化合物具有至少一手性中心 (chiral center)，它們因而可呈鏡像異構物（enantiomers)存 在。若該等化合物具有兩個或多個手性中心，它們可額外 25 200808298 地呈非鏡像異構物（diastereomers)存在。要被理解的是： 所有此類異構物及其混合物被含括於本發明之範疇内。再 者，關於這些化合物的某些結晶型式（crystalline ^印^可 呈同貝多晶型體(polymorphs)存在且意欲被包含於本發明 5 中。此外，該等化合物的某些可與水或常見有機溶劑形成 溶劑合物（亦即與水則為水合物），且此類溶劑合物亦被意 欲含括於本發明之範缚中。 瞻關於醫學上的用途，本發明的化合物之鹽類係指無毒 的藥學上可接受鹽類/Z。然而，其它鹽類可應用於製備 10 根據本發明的化合物或它們的藥學上可接受鹽類。該等化 合物的適當藥學上可接受鹽類包括酸式加成鹽（acid addition salts)，其例如可透過混合該化合物之一溶液與一 藥學上可接受酸之溶液（諸如鹽酸、硫酸、延胡索酸、馬 來酸、琥珀酸、乙酸、苯曱酸、檸檬酸、酒石酸、碳酸或 15 磷酸）而形成。再者，若本發明之化合物帶有一酸性部分 (acidic moiety)，其適當的藥學上可接受鹽類包括鹼金屬 鹽類（例如鈉鹽或鉀鹽）；鹼土金屬鹽類（例如鈣鹽或鎂 鹽）；以及與適當有機酸配位子所形成的鹽類（例如四級胺 鹽）。因此，代表性的藥學上可接受鹽類包括下列： 2〇 乙酸鹽、苯磺酸鹽、苯曱酸鹽、碳酸氬鹽、硫酸氫鹽、 酒石酸鼠鹽、删酸鹽、〉臭鹽、依地酸轉（calcium edetate)、 樟腦磺酸鹽（camsylate)、碳酸鹽、氯鹽、克拉維酸鹽 (clavulanate)、檸檬酸鹽、二氩氯酸鹽、依地酸鹽卜(16丨316)、 乙二磺酸鹽（edisylate)、依托度酸鹽（est〇iate)、曱磺酸鹽 26 200808298The abbreviations used in this specification, in particular the Schemes and Examples, are as follows: DCE = dichloroethane 15 DCM = dichloromethane DMF = N, N-dimercaptoamine • DMSO = Dimethyl sulfoxide LAH = Methyl sulfonamide MTBE = methyl-tetrahydro-butyl ester 20 THF = tetrahydrofuran TLC = thin layer chromatography. If the compounds according to the invention have at least one chiral center, they Thus it can exist as enantiomers. If the compounds have two or more chiral centers, they may be present as additional diastereomers in 200808298. It is to be understood that all such isomers and mixtures thereof are included within the scope of the invention. Furthermore, certain crystalline forms of these compounds may be present in the form of polymorphs and are intended to be included in the present invention 5. In addition, some of these compounds may be associated with water or common The organic solvent forms a solvate (i.e., hydrates with water), and such solvates are also intended to be encompassed by the present invention. For the medical use, the salts of the compounds of the present invention Means a non-toxic pharmaceutically acceptable salt / Z. However, other salts may be employed in the preparation of 10 compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of such compounds include Acid addition salts, for example, by mixing a solution of one of the compounds with a solution of a pharmaceutically acceptable acid (such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid) Formed with citric acid, tartaric acid, carbonic acid or phosphoric acid. Further, if the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts include alkalis. a salt (such as a sodium salt or a potassium salt); an alkaline earth metal salt (such as a calcium salt or a magnesium salt); and a salt formed with a suitable organic acid ligand (for example, a quaternary amine salt). The pharmaceutically acceptable salts include the following: 2-indole acetate, besylate, benzoate, argon carbonate, hydrogen sulfate, tartaric acid rat salt, acid salt, odor salt, edetate ( Calcium edetate), campylate, carbonate, chloride, clavulanate, citrate, diarchlorate, edetate (16丨316), ethanedisulfonate Acid salt (edisylate), etodoate (est〇iate), sulfonate sulfonate 26 200808298

10 15 20 (esylate)、延胡索酸鹽、葡庚酸鹽（giuceptate)、葡糖酸_ (gluconate)、 麩胺酸鹽、乙内醯砷酸鳞 (glycollylarsanilate)、己基收斂酸(heXyiresorcinate)、海巴 胺(hydrabamme)、氫溴酸鹽、氫氯酸鹽、羥萘酸鹽、碘鹽、 異硫磺酸鹽、乳酸鹽、乳酸糖鹽（lact〇bi〇nate)、月桂酸鹽、 蘋果酸鹽、馬來酸鹽、杏仁酸鹽、甲磺酸鹽、甲基溴鹽、 甲基硝酸鹽、曱基硫酸鹽、黏液酸鹽(mucate)、萘磺酸鹽、 硝酉夂鹽、N-甲基還原葡萄糖胺銨鹽、油酸鹽、帕莫酸鹽（恩 波酉夂鹽）孝人月曰西夂鹽、泛酸鹽、石粦酸鹽/二磷酸鹽、聚半乳 糖盤孤纟楊|^鹽、硬脂酸鹽、硫酸鹽、次乙酸鹽、破拍 馱鹽鞣i夂鹽/酉石酸鹽、茶氯酸鹽⑽、甲苯石黃酸、 三乙蛾鹽以及戊酸鹽。 可被用於製備藥惠μ > ^ t 梁子上可接受鹽類的代表性酸與鹼包 括下列： 酸包括乙酸、2 - * — a , _ ，-—虱乙酸、經醯化胺基酸、已二酸、 澡酸、抗壞企酸、T I p 大門冬胺酸、苯石蔷酸、笨甲酸、4-乙醯胺苯甲酸、嫱評撕 )樟細奴、樟腦磺酸、（+)-(lS)-樟腦-10-石頁酸、癸酸、己酸、去於而 宁自夂、肉桂酸、擰檬酸、環拉酸（cyclamic acid)、十二烷硫酸、？ 己規-1，2-一石買酸、乙二石蔷酸、2-經基 -乙二磺酸、曱酴、μ如也 ^ „ I月索酸、半乳糖二酸、龍膽酸、葡 一 ^葡§曼、葡萄糖搭酸、L-糙胺酸、α-側氧_戊 酉夂严乙I夂馬尿酸㈣她a灿）、氫溴酸、氫氯酸、 (+)-L-乳酸、（±)七τ， ^礼§文、乳糖醛酸、馬來酸、㈠-L蘋 果酸、丙二酸、（±彳m # V hUL-古杏仁酸、曱磺酸、萘·>磺酸、 27 200808298 萘-1，5·二磺酸、1-羥基-2-萘曱酸、菸鹼酸、硝酸、油酸、 乳清酸、草酸、棕櫚酸、帕莫酸、磷酸、L-焦麩酸、水楊 酸、4-胺基-水揚酸、施巴酸（sebaic acid)、硬脂酸、破珀 酸、硫酸、鞣酸、（+)-L-酒石酸、硫氰酸、對-甲苯磺酸及 5 Η 稀酸；以及 驗包括氨、L-精胺酸、苯明（benethamine)、苄星青 (benzathine)、氫氧化I弓、膽驗、單醇（deanol)、二乙醇胺、 0 二乙胺、2-(二乙胺）-乙醇、乙醇胺、乙二胺、N-曱基-還 原葡萄糖胺、海巴胺（hydrabamine)、1咪唾、L-離胺酸、 1〇 氫氧化鎂、4-(2-羥乙基）-啉、哌、氫氧化鉀、1-(2-羥 乙基）-吡咯啶、二級胺、氫氧化鈉、三乙醇胺、胺基丁三 醇以及氫氧化鋅。 其中A為-CH2-之具有化學式（I)的化合物可根據概 述於反應途徑1之步驟所製備。10 15 20 (esylate), fumarate, giuceptate, gluconate, glutamate, glycollylarsanilate, hexyiresorcinate, seaba Amine (hydrabamme), hydrobromide, hydrochloride, hydroxynaphate, iodide, isosulfonate, lactate, lactate, lactate, garrate, malate, Maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, sulfhydryl sulfate, mucate, naphthalene sulfonate, nitronium salt, N-methyl Reducing Glucosamine Ammonium Salt, Oleate, Pamoate (Enboline Salt) Xiaoren Yuexixi Salt, Pantothenate, Dendrobate/Diphosphate, Polygalactose Disk Lonely Populus | ^ Salt, stearate, sulphate, hypoacetate, sputum salt 酉i夂 salt / strontium salt, tea chlorate (10), toluene, acid, triethyl moth salt and valerate. Representative acids and bases which can be used in the preparation of pharmaceutically acceptable salts < ^ t acceptable salts include the following: Acids include acetic acid, 2 - * - a, _, - hydrazine acetic acid, deuterated amino acids , adipic acid, bath acid, anti-bad acid, TI p-aspartic acid, benzoic acid, benzoic acid, 4-ethylguanidinium benzoic acid, 嫱 撕 tear) 樟 fine slave, camphor sulfonic acid, (+ )-(lS)- camphor-10-street acid, citric acid, hexanoic acid, decoction, cinnamic acid, citric acid, cyclamic acid, dodecane sulphate, ? Acquired -1,2-one stone to buy acid, succinic acid, 2- carbyl-ethanedisulfonic acid, hydrazine, μ as well „ I lauric acid, galactose diacid, gentisic acid, Portuguese ^························································································ Lactic acid, (±) seven τ, ^ § text, lacturonic acid, maleic acid, (a)-L malic acid, malonic acid, (±彳m # V hUL-almondic acid, sulfonic acid, naphthalene · gt Sulfonic acid, 27 200808298 naphthalene-1,5·disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, palmitic acid, phosphoric acid, L-pyroic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, spearic acid, sulfuric acid, citric acid, (+)-L-tartaric acid, thiocyanate, P-toluenesulfonic acid and 5 稀 dilute acid; and including ammonia, L-arginine, benethamine, benzathine, hydroxide I bow, gallstone, deanol, two Ethanolamine, 0 diethylamine, 2-(diethylamine)-ethanol, ethanolamine, ethylenediamine, N-mercapto-reducing glucosamine, Hydrabamine, 1 mil saliva, L-lysine, 1 〇magnesium hydroxide, 4-(2-hydroxyethyl)-phenyl, piperazine, potassium hydroxide, 1-(2-hydroxyethyl) Pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide. The compound of formula (I) wherein A is -CH2- can be prepared according to the procedure outlined in Scheme 1 .

反應途徑1 因此，在一有機溶劑如乙醇、曱醇、二噚烷，以及類 似者，較佳地在一無水有機溶劑中，較佳地以一落在約 28 200808298 50°C至約1〇〇°C的範圍之昇高溫度，更佳地於約回流溫 度，一具有化學式（V)之適當地經取代化合物（一種已知化 合物或藉著已知方法所製備的化合物），與一適當之經取 代的具有化學式（VI)的化合物（一種已知化合物或藉著已 5 知方法所製備的化合物）反應，其中該具有化學式（VI)的化 合物數量以約2至約5當量的範圍存在，以產生具有化學 式（I a)的對應化合物。 _ 具有化學式（1)的化合物可另擇地根據概述於反應 途徑2中的步驟被製備。 10Reaction route 1 Thus, in an organic solvent such as ethanol, decyl alcohol, dioxane, and the like, preferably in an anhydrous organic solvent, preferably one falls at about 28 200808298 50 ° C to about 1 Torr. An elevated temperature in the range of 〇 ° C, more preferably at about reflux temperature, a suitably substituted compound of formula (V) (a known compound or a compound prepared by known methods), and a suitable a substituted compound of the formula (VI) (a known compound or a compound prepared by a known method) wherein the amount of the compound of the formula (VI) is present in the range of from about 2 to about 5 equivalents To produce the corresponding compound of formula (I a). The compound of formula (1) can alternatively be prepared according to the procedure outlined in Scheme 2. 10

1515

反應途徑2 因此，在一有機溶劑諸如THF、二今院，以及類似者 中，較佳地在一無水有機溶劑中，較佳地以一為約50°C 2〇 至約100°C的範圍的昇高溫度，更佳地於約回流溫度下， 一具有化學式（W)之適當地經取代化合物（一種已知化合 物或藉著已知方法所製備的化合物)與一適當之經取代的 具有化學式（VI)的化合物（一種已知化合物或藉著已知方 法所製備的化合物）反應，其中具有化學式（VI)的化合物以 29 200808298 ^里為約2至約5當量的範圍存在，以產生具有化學式（I 的對應化合物。Reaction route 2 Therefore, in an organic solvent such as THF, Erjinyuan, and the like, it is preferably in an anhydrous organic solvent, preferably in a range of from about 50 ° C to about 100 ° C. An elevated temperature, more preferably at about reflux temperature, a suitably substituted compound of formula (W) (a known compound or a compound prepared by known methods) and a suitably substituted a compound of the formula (VI), a known compound or a compound prepared by a known method, wherein the compound of the formula (VI) is present in the range of from about 2 to about 5 equivalents in 29 200808298 ^ to produce A corresponding compound of the formula (I).

JL Φ Λ VL # '、 為之具有化學式（ΥΠ)的化合物可，例妒 精著根據概•反應途徑3的步驟被製備。 R1JL Φ Λ VL # ', a compound having the chemical formula (ΥΠ), can be prepared according to the procedure of the reaction route 3. R1

ΝΗ, 反應途徑 因此’於一諸如 THF、：：_、DCM、DCE，0^ _ 類似者的有機溶劑中，一具有化學式（Μ)之適當地經取代 化合物（一種已知化合物或藉著已知方法所製備之化合物） 與一活化劑[諸如草醯氯(oxa〗yl chl〇ride)、磺醯氯（sulfonyl chloride)以及類似之物]，繼而與一胺源（amine source)[諸 如氣（ammonia)、氫氧化銨（ammonium hydroxide)，以及类貝 似之物]反應，以產生具有化學式（K)之對應化合物。 具有化學式（K)之化合物於一如THF、二***，以及 類似者的有機溶劑中，與一適當地經擇定的還原齊彳如 LAH、硼烷，及類似之物反應，以產生具有化學式（处^ 30 200808298 的對應化合物。 其中A為-CH(CH3)-之具有化學式（W)的化合物可， 例如根據概述於反應途徑4的步驟被製備。ΝΗ, the reaction pathway is thus in an organic solvent such as THF, :::, DCM, DCE, 0^ _, a suitably substituted compound of the formula (Μ) (a known compound or by means of Known as the compound prepared by the method) and an activator [such as oxa yl chl〇ride, sulfonyl chloride and the like], followed by an amine source [such as gas (Ammonia), ammonium hydroxide, and a shell-like reaction are reacted to produce a corresponding compound of the formula (K). The compound of the formula (K) is reacted with an appropriately selected reducing hydrazine such as LAH, borane, and the like in an organic solvent such as THF, diethyl ether or the like to give a chemical formula. (Compounds corresponding to 30 200808298. Compounds of formula (W) wherein A is -CH(CH3)- can be prepared, for example, according to the procedure outlined in Reaction Scheme 4.

因此，於一為大約150°C的經提高溫度下，一具有化 15 學式（X)之適當地經取代化合物（一種已知化合物或藉著 已知方法所製備之化合物）與一曱醯胺及甲酸的混合物反 ® 應，以產生具有化學式（X I )之對應化合物，其中該曱醯 胺及甲酸的混合物是呈一高於大约為1當量的數量存 在，較佳地，呈一高於大約為5當量的過量數量。Thus, at an elevated temperature of about 150 ° C, a suitably substituted compound (a known compound or a compound prepared by known methods) having a formula (X) A mixture of an amine and a formic acid is reacted to produce a corresponding compound of formula (XI) wherein the mixture of guanamine and formic acid is present in an amount greater than about 1 equivalent, preferably above one Approximately an excess of 5 equivalents.

2〇 於一提高溫度下（較佳地於回流溫度），具有化學式（X I )之化合物藉著與濃HC1、濃H2S04，以及類似之物反 應而被水解，以產生具有化學式（Wb)的對應化合物。 具有化學式（.）的化合物可另擇地根據如概述於反 應途徑5中的步驟被製備。 3 1 2008082982. At a raised temperature (preferably at reflux temperature), the compound of formula (XI) is hydrolyzed by reaction with concentrated HC1, concentrated H2S04, and the like to produce a corresponding chemical formula (Wb). Compound. The compound of formula (.) can alternatively be prepared according to the procedure as outlined in Scheme 5. 3 1 200808298

55

反應途徑5 10 因此，於一有機溶劑（諸如一 DMF、DMSO、曱醇、 乙醇，以及類似者）中，一具有化學式（ΧΠ)之適當經取代 的化合物（一種已知化合物或藉著已知方法所製備之化合 物，其中L為一個諸如Br、Cl、I、曱苯磺酸、曱磺酸， 15 以及類似物的脫離基)與疊氮化鈉（sodium azide)反應以產 生具有化學式（XU)的化合物。 ® 該具有化學式（xm)的化合物與一適當經選定的還原 劑[諸如 LAH、三苯膦（triphenylphosphine)、H2(g)，以及 類似者]根據已知方法反應，以產生具有化學式（W)的化合 20 物。 其令Α為CH2且Χ-Υ為-0-CH2-之具有化學式（W)的 化合物可例如根據如概述於反應途徑6中的步驟被製備。 32 200808298 ΟReaction route 5 10 Thus, in an organic solvent (such as a DMF, DMSO, decyl alcohol, ethanol, and the like), a suitably substituted compound of the formula (ΧΠ) (a known compound or by known A compound prepared by the method wherein L is a cleavage group such as Br, Cl, I, benzenesulfonic acid, sulfonic acid, 15 and the like, and reacted with sodium azide to produce a chemical formula (XU) )compound of. ® The compound of formula (xm) is reacted with a suitably selected reducing agent [such as LAH, triphenylphosphine, H2 (g), and the like] according to known methods to produce a chemical formula (W) The combination of 20 things. The compound of the formula (W) wherein Α is CH2 and Χ-Υ is -0-CH2- can be prepared, for example, according to the procedure as outlined in Reaction Scheme 6. 32 200808298 Ο

反應途徑6 10 因此，在一鹼（諸如K2C〇3、Na2C〇3、NaH、三乙胺、 比口疋，以及類似之物）的存在下，於一有機溶劑（諸如乙 腈、DMF、THF ’以及類似者）中，選擇性地於一提高溫 度下，—適當地經取代之盼(phenol)，一具有化學式XIV) 的化合物（一種已知化合物或藉著已知方法所製備之化合 15 物）與溴丙酮(brom〇acetone)(—種已知化合物）反應，以產 ⑩ 生具有化學式（X V)的化合物。 較佳地在無溶劑存在下（習於本技藝者將認知到多磷 酸作為溶劑），具有化學式（XV)的化合物與一酸（諸如多 磷酸、硫酸、鹽酸，以及類似之物，較佳地為多磷酸）反 20 應’以產生具有化學式（XVI)的對應化合物。 在過氧化苯甲醯（benzoyiperoxide)、Br2，以及類似者 的存在下’於一有機溶劑[諸如四氯化碳（carbon tetrachloride)、氯仿、DCM，以及類似者，較佳地為一種 、、二鹵化的有機溶劑]中，較佳地一經鹵化有機溶劑中，具 33 200808298 有化學式（XVI)的化合物與一溴源[諸如N-溴琥珀醯亞胺 (N-bromosuccinimide)]反應，以產生具有化學式（ΧΥΠ)的 對應化合物。 於一有機溶劑（諸如一 DMF、DMSO、甲醇、乙醇， 5 以及類似者）中，具有化學式（XW)的化合物與疊氮化鈉反 應，以產生具有化學式（XM)的對應化合物。 具有化學式（XM)的化合物與一適當經選定的還原 g 劑[諸如LAH、三苯膦、H2(g)，以及類似者]根據已知方 法反應，以產生具有化學式（VDc)的對應化合物。 ίο 其中X-Y為-S-CH-之具有化學式（V)的化合物可例 如根據如概述於反應途徑7中的步驟被製備。 15Reaction route 6 10 Thus, in the presence of a base such as K2C〇3, Na2C〇3, NaH, triethylamine, specific oxime, and the like, in an organic solvent (such as acetonitrile, DMF, THF) And a similar compound, optionally at an elevated temperature, a suitably substituted phenol, a compound of formula XIV (a known compound or a compound 15 prepared by known methods) It is reacted with brom acetone (a known compound) to produce a compound of the formula (XV). Preferably, in the absence of a solvent (the skilled person will recognize polyphosphoric acid as a solvent), a compound of formula (XV) and a monoacid (such as polyphosphoric acid, sulfuric acid, hydrochloric acid, and the like, preferably For the polyphosphoric acid, the reverse 20 should be 'to produce the corresponding compound of the formula (XVI). In the presence of benzoyiperoxide, Br2, and the like, in an organic solvent [such as carbon tetrachloride, chloroform, DCM, and the like, preferably one, two, In a halogenated organic solvent, preferably in a halogenated organic solvent, having 33 200808298, a compound of formula (XVI) is reacted with a source of bromine [such as N-bromosuccinimide] to produce A corresponding compound of the formula (ΧΥΠ). In an organic solvent such as a DMF, DMSO, methanol, ethanol, 5 and the like, the compound of the formula (XW) is reacted with sodium azide to produce the corresponding compound of the formula (XM). The compound of formula (XM) is reacted with a suitably selected reducing agent [such as LAH, triphenylphosphine, H2 (g), and the like] according to known methods to produce the corresponding compound of formula (VDc). The compound of formula (V) wherein X-Y is -S-CH- can be prepared, for example, according to the procedure as outlined in Reaction Scheme 7. 15

反應途徑7 20 因此，於一鹼[諸如第三丁基醇鉀 (potassium-tert-butoxide) 、 第三丁 基醇鈉 (sodium-tert-butoxide)、碳酸卸、氳氧化鉀，以及類似之 34 200808298 物]的存在下，於一有機溶劑（諸如THF、DMF、乙腈，以 及類似者）中，一具有化學式(XIX)之適當經取代的化合物 (一種已知化合物或藉著已知方法所製備之化合物）與氯 乙醛縮二甲醇（chloroacetaldehyde dimethyl acetal)或溴乙 5 盤縮二曱醇（bromoacetaldehyde dimethyl acetal)(—種已知 化合物）反應，以產生具有化學式（XX)的對應化合物。Reaction route 7 20 Thus, in a base [such as potassium-tert-butoxide, sodium-tert-butoxide, carbonic acid unloading, potassium ruthenium oxide, and the like 34 In the presence of 200808298, an appropriately substituted compound of formula (XIX) (a known compound or prepared by known methods) in an organic solvent such as THF, DMF, acetonitrile, and the like The compound) is reacted with chloroacetaldehyde dimethyl acetal or bromoacetaldehyde dimethyl acetal (a known compound) to produce the corresponding compound of formula (XX).

在一溶劑不存在下（習於該項技藝者將認知到：多磷 p 酸和/或氣苯可當作溶劑），於一落在自大約1〇〇至2〇〇°C 的範圍内之經提高溫度（較佳地於大約回流溫度的提高溫 1〇 度），該具有化學式（XX)的化合物與酸（諸如多填酸、疏 酸、鹽酸，以及類似者）反應，較佳地與多碟酸於存在氯 苯下反應，以產生具有化學式（XXI)之對應化合物。 在路易斯酸催化劑（Lewis acid catalyst)[諸如四氯化 鈦（titanium tetrachloride)、四氯化鋁（aiuminum 15 trichloride)、四氯化錫(^1116打&〇:111〇1^(16)，以及類似者]存 在下，於一有機溶劑（諸如DCM、氣仿，以及類似者）中， 於一落在大約0°C至大約室溫範圍内的溫度，具有化學式 (XXI)之化合物與一甲醯基化劑（formylating reagent)[諸 如二氯曱醚(dichloromethyl methyl ether)，以及類似者]反 2〇 應，以產生具有化學式(Va)的對應化合物。 其中R3和/或R4為氫以外者或R3和R4還有氮原子（R3 和R4連接至它)一起形成一個環狀結構之具有化學式（I ) 的化合物，可任擇地根據概述於反應途徑8中的步驟被製 備0 35 200808298In the absence of a solvent (as will be appreciated by those skilled in the art: polyphosphoric acid and/or benzene can be used as a solvent), falling within a range of from about 1 Torr to about 2 °C. Preferably, the compound of formula (XX) is reacted with an acid (such as a polyacid, an acid, a hydrochloric acid, and the like) by increasing the temperature (preferably by an increase in temperature of about 1 Torr). The reaction with a multi-disc acid in the presence of chlorobenzene produces the corresponding compound of formula (XXI). In a Lewis acid catalyst [such as titanium tetrachloride, aiuminum 15 trichloride, tin tetrachloride (^1116 dozen & 〇: 111〇1^(16), And in the presence of a similar compound, in an organic solvent (such as DCM, gas, and the like), a compound of formula (XXI) and a temperature falling within a range of from about 0 ° C to about room temperature A forylating reagent [such as dichloromethyl methyl ether, and the like] is reacted to produce a corresponding compound of formula (Va) wherein R3 and/or R4 are other than hydrogen. Or a compound of formula (I) wherein R3 and R4, together with a nitrogen atom (to which R3 and R4 are attached), form a cyclic structure, optionally prepared according to the procedure outlined in Reaction Scheme 8 0 35 200808298

反應途徑8 因此，假設具有化學式（lb)的化合物以及具有化學式 (XXII)的化合物是至少一部分地可溶於水中或有機溶劑 中，在水或一有機溶劑（諸如二崎烷、乙醇、THF、異丙 醇’以及類似者)中，於一落入大約室溫至大約回流的溫 度範圍（較佳地於回流溫度），具有化學式（lb)之適當地經 取代的化合物與一適當地經取代的胺，具有化學式（XXII) 的化合物（一種已知化合物或藉著已知方法所製備之化合 物）反應，以產生具有化學式（Ic)之對應化合物。 習於此技藝者將認知到··本發明的其中一個反應步驟 可在各種不同溶劑或溶劑系統中被執行，該反應步驟亦可 於該適當溶劑或溶劑系統的一混合物中被執行。 若用於製備根據本發明化合物之步驟產生立體異構 物的混合物，這些異構物可透過習用技術（如製備型層析 法)被分離。該等化合物可呈消旋物的型式被製備，或個 別鏡像異構物可以透過不論是光學純度合成 (enantiospecific synthesis)或透過離析（resolution)所製 36 200808298 備。該等化合物可’舉例來說，透過標準技術[諸如 成（透過以一光學活性酸(如㈠-二-對-甲笨曱酿基_d:石 酸及/或（+)_一-對-甲苯甲醯基酒石酸繼而部分结晶以 及自由鹼的再生）的非鏡像對形成]被離析於它們分 5鏡像異構物中。該等化合物亦可藉由非鏡像異構醋或酸胺 的形成，繼而層析分離且移除手性輔助體（chiral auxiHary) 而被離析。可替代地，該專化合物可使用一手性HPLC管 g 柱所離析。 在用以本發明化合物之任何製備步驟中，保護所涉及 ίο 任一分子上的敏感性或反應基團是必要及/或所欲。這可 透過習知保5蒦基團的方法（如那些描述於Protective Groups in Organic Chemistry, ed· J.F.W· McOmie，Plenum Press，1973;以及 T.W· Greene & P.G.M. Wuts，Protective Groups in Organic Synthesis. John Wiley & Sons，1991 者) 15 而達成。這些保護基團可於一習知的後續階段使用該項技 _ 藝中已知方法被移除。 本發明進一步含有具化學式（I )之一種或多種化合 物以及一藥學上可接受載體的藥學組成物。含有一種或多 種此處所述作為有效成分的本發明化合物的藥學組成物 可透過嫺熟地混合該化合物或該等化合物與一根據習知 藥學上化合技術的藥學上可接受載體而被製備。該載體可 根據所欲投藥途徑（例如口服的、非經口的）採用各種不同 型式。因而用於液態口服製備物（如懸浮液、酏劑以及溶 液劑），適當载體以及添加劑包括水、乙二醇、油、酒精、 37 200808298 香料劑、防腐劑、安定劑、著色劑以及類似者；用於固態 口服製備物（諸如散劑、囊劑以及錠劑），適當載劑以及添 加劑包括殿粉、糖、稀釋劑、粒化劑、潤滑劑、黏結劑、 崩解劑以及類似者。固態口服製備物亦可由諸如糖的物質 5 所包覆或為包覆腸衣以調節主要吸收位置。用於非經口的 投藥，該載劑將通常地由無菌水所組成所構成且其他成分 可被加入以提供溶解度或保存。注射型懸浮液或溶液劑亦 _ 可使用水性載體還有適當添加劑被製備。 為製備本發明之藥學組成物，作為有效成分的本發明 10 之一種或多種化合物係嫻熟地與一根據習知藥學化合技 術的藥學載劑混合，載體可根據所欲用以投藥之製備物型 式（諸如口服或如肌肉内的非經口型式）]採用各種不同型 式。於製備呈口服劑量型式的組成物，任一種常用藥學媒 介可被採用。因此，用於液態口服製備物諸如例懸浮液、 15 酏劑以及溶液劑，適當載體以及添加劑包括水、乙二醇、 油、酒精、香料劑、防腐劑、著色劑以及類似者；用於固 ® 態口服製備物諸如例散劑、囊劑、膠囊（caplets)、膠囊鍵 (gelcaps)以及錠劑，適當的載劑以及添加劑包括澱粉、 糖、稀釋劑、粒化劑、潤滑劑、黏結劑、崩解劑以及類似 20 者。因在投藥上的便利性，錠劑及囊劑代表最為有利的口 服劑量單位型式，於該例中固態藥學載體被明顯地採用。 若所欲，錠劑可以透過標準技術為糖所包覆或以腸衣包 覆。用於非經口的，該載劑將通常地含有無菌水，經由其 他成分（舉例來說，為了如增進溶解度或為保存）可被含括 38 200808298 在内。注射型的懸浮液亦可被製備’於該例中適當的液恶 載體、懸浮劑與類似者可被選伟。此處之藥學組成物叮包 含，每劑量單位（如錠劑、囊齊彳、散劑、注射、茶匙里與 類似者）所需以實現如上述〆有效劑量之一有效成分數 5 量。此處之藥學組成物可包含’母劑里單位（諸如蘇Μ 囊劑、散劑、注射、栓劑、茶匙量與類似者）自約0·1 — 1麵 mg且可被預定為一自約〇·〇1-2〇〇·〇 mg/kg/曰的劑耋，較 佳地自約0.1-100 mg/kg/日’更佳地自約〇·5-50 rflg/kg/ 日，更佳地自約1.0-25.0 mg/kg/曰或其内任何範®被給 10 予。然而該劑量可根據病患需求、所治療病況的嚴重性以 及所用化合物而改變。不論是每日投藥或後-週期性給藥 (post-periodic dosing)之用途 < 被採用。 較佳地這些組成物係呈諸如键劑、丸劑、囊劑、散劑、 膠囊、無菌非經口的溶液劑或懸浮液、定量喷霧劑 15 (metered aerosol)或液態喷霧劑、滴劑、針劑（ampoules)、 自動注射器裝置（autoinjector devices)或检劑的單位劑量 ® 型式；用於口服、注射、鼻内（intranasal)、舌下（sublingual) 或直腸投藥，或用於藉著吸入（inhalation)或通氣 (insufflation)的投藥。任擇地，該組成物可被呈現為一適 2〇 於每週一次或每月一次投藥的型式；例如，該活性化合物 之一不溶鹽（諸如癸酸鹽，decanoate salt)，可被採用以提 供一用於肌肉内注射的保存製備物。為製備固態組成物 (諸如錠劑），該主要有效成分混合一藥學上載劑（諸如傳統 成錠成分如玉米澱粉、乳糖、蔗糖、山梨醇、滑石、硬脂 39 200808298 酸、硬脂酸鎂、磷酸二鈣或樹膠），以及其它藥學上稀釋 劑（諸如水）以形成一固態前處方組成物（S〇lid preformulation composition)，該固態前處方組成物含有一 本發明之一化合物，或其一藥學上可接受鹽類之均質化混 5 合物。當意指這些前處方組成物為均質化時，它代表著該 有效成分係平均地被分散於組成物，故該組成物易於被再 分為相等有效劑量的型式（諸如錠劑、丸劑或囊劑）。此固 _ 態前處方組成物係繼而被細分為上述類型的單位劑量型 式’其含有自0·1至約1000 mg之本發明的有效成分。該 ίο 新穎組成物之錠劑或丸劑可被包覆或被合成以提供可供 延長作用益處的一劑量型式。舉例來說，該鍵劑或丸劑可 含有一内劑量以及一外劑量組分（an inner dosage and an outer dosage component)，後者呈一包覆前者之套膜型 式。此二種組分可被一腸衣層（enteric iayer)所分隔，該腸 15 衣層在胃中作為抗崩解(resist disintegration)並允許内組 分完整地通過十二指腸或被延長地釋放。各種不同的材料 可被用於此腸衣層或塗層（coatings)，此類材料包括一些 具如蟲膠（shellac)、十六醇（cetyl alcohol)或乙酸纖維素之 原料的聚合酸(polymeric acids)。 20 該液態型式，於其中本發明之新穎組成物可被併入供 口服地或藉著注射投藥者，包括水性溶液劑、經適當調味 的糖膠、水性或油性懸浮液，以及具有可食用油（如棉花 軒油、芝麻油、椰子油或花生油）之經調味的乳化劑，還 有酿劑以及類似藥學上載體(vehicle)。用於水性懸浮液之 40 200808298 適當分散或懸浮劑，包括合成或天然樹膠如膠黃耆樹膠 (tragacanth)、亞拉伯樹膠（acacia)、藻酸鹽（alginate)、聚 葡糖、魏曱纖維素納、曱基纖維素、聚乙烯-°比略唆酮 (polyvinyl，pyrrolidone)或明膠。 本發明之方法亦可使用含有如此處所述任一種化合 物及一藥學上可接受載體的一藥學組成物而被實施。該藥 學組成物可含有介於約0.1 mg及1000 mg的化合物，較 佳地約50至500 mg，且可被構成為任何適於供經擇定投 藥模式的型式。載體包括必須的以及惰性的藥學賦型劑， 包括但不限於黏結劑、懸浮劑、潤滑劑、調味劑、甜味劑、 防腐劑、染料及塗層。適於口服投藥的組成物包括固體型 式[諸如丸劑、錠劑、膠囊、囊劑（每一者包括立即釋放、 分時釋放或缓釋配方）、粒劑以及散劑]、液體型式（諸如 溶液劑、糖漿、酏劑、乳化劑，以及懸浮液）。應用於非 經口投藥之型式包括無菌溶液劑，乳化劑以及懸浮液。 有利地，本發明之化合物可呈每日單一劑量被投藥， 或每日總劑量被分為每日二、三或四次地投藥。再者，用 於本發明之化合物可以一鼻内型式經由適當鼻内載體的 局部使用，或經由那些為本技藝中一般技術者所知的穿皮 皮膚貼藥（transdermal skin patches)來被投藥。作為呈一穿 皮投遞系統的型式來被投藥，該劑量投藥在整個劑量攝生 法中當然將為連續性而非間續性。 例如，用於呈一錠劑或囊劑為型式的口服投藥，該活 性藥物組分可結合一口服，無毒性藥學上可接受的惰性載 41 ] 200808298 體如乙醇、甘油、水或類似者。再者，當如所欲或需要時， 適當黏結劑、潤滑劑、崩解劑及著色劑可被併入混合物 中°適當的黏結劑包括但未限定地為澱粉、明膠、天然糖 (如葡萄糖或貝他一乳糖）、玉米甜味劑、天然及合成樹膠 5 如亞拉伯樹膠、膠黃耆樹膠或油酸鈉、硬脂酸鈉、硬脂酸 鎮、笨甲酸鈉、乙酸鈉、氯化鈉與類似之物。崩解劑包括 但未限定地為澱粉、曱基纖維素、瓊脂、膨土、三仙膠與 | 類似之物。 在適當地經調味的懸浮或分散劑中的液態型式如合 10 成或天然樹膠，例如，膠黃耆樹膠、亞拉伯樹膠、甲基纖 維素與類似之物。用於非經口的投藥，無菌懸浮液及溶液 劑是所欲的。當靜脈内注射為所欲時，通常地含有適當防 腐劑之等張製備物被採用。 當神經保護為需要時，本發明之化合物可以呈任何前 15 述組成物並根據該技藝中已建立的劑量攝生法來被投藥。 該等產物的每日劑量可於一每曰每位成人自0.01至 ⑩ 200 mg/kg的廣泛範圍中變化。用於口服投藥，該組成物 較佳地呈含有 0·(Π、0.05、0·；1、0.5、1·0、2·5、5.0、1〇.〇、 15·0、25·0、50·0、100、150、200、250、500 及 1000 毫 2〇 克的有效成份之錠劑型式被提供而用於治療病患的症狀 調整。該藥物的一有效數量係通常地以一為自約每日每公 斤體重0·01 mg/kg至約200 mg/kg的一劑量水準被提供。 較佳地，該範圍係自約每日每公斤體重0.1至約100,0 mg/kg，更佳地自約每曰每公斤體重〇·5 mg/kg至約50 42 200808298 更佳地自約每曰每公斤體重1 .〇至約A。病。 该化合物可呈-為每日！至4次的攝生法被投藥。 投藥之最佳化劑量可由那些f於本項技藝者所易於 決疋，^將隨著所用蚊化合物、投藥模式、製備物的強 度、投I#模式m餘況的進展而改變。此外，與被 ί療病患相關的因f ’包括病患年紀、體重、飲食以及投 樂日寸間’將造成調整劑量的需要。Reaction Scheme 8 Thus, it is assumed that the compound of formula (lb) and the compound of formula (XXII) are at least partially soluble in water or an organic solvent, in water or an organic solvent (such as diazane, ethanol, THF, In isopropanol 'and the like, a suitably substituted compound of formula (lb) is suitably substituted with a temperature ranging from about room temperature to about reflux (preferably at reflux temperature). An amine having a compound of the formula (XXII), a known compound or a compound prepared by a known method, is reacted to give a corresponding compound of the formula (Ic). It will be appreciated by those skilled in the art that one of the reaction steps of the present invention can be carried out in a variety of different solvent or solvent systems, and the reaction step can also be carried out in a mixture of the appropriate solvent or solvent system. If the mixture used to prepare the compounds according to the invention produces a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in the form of a racemate, or the individual mirror isomers may be prepared by either enantiospecific synthesis or by resolution (200808298). Such compounds may, for example, be passed through standard techniques [such as by (through (through) an optically active acid (eg, (i)-di-p-to- 曱 曱 _d: lithic acid and/or (+) _ a-pair - Non-mirromeric pair formation of toluamyl tartaric acid followed by partial crystallization and regeneration of the free base] is segregated in their 5 mirror image isomers. These compounds may also be formed by the formation of non-image isomerized vinegar or acid amine And chromatographically separating and removing the chiral auxiHary to be isolated. Alternatively, the specific compound can be isolated using a chiral HPLC tube g column. In any of the preparation steps used in the compounds of the invention, It is necessary and/or desirable to protect the sensitivities or reactive groups on any molecule involved. This can be done by conventional methods of protecting groups (such as those described in Protective Groups in Organic Chemistry, ed·JFW· McOmie, Plenum Press, 1973; and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991) 15. These protective groups can be used in a later stage of the convention _ Art The method of the invention further comprises a pharmaceutical composition comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier, a pharmaceutical composition comprising one or more of the compounds of the invention as described herein as an active ingredient. The compound can be prepared by skillfully mixing the compound or the compound with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. The carrier can be administered according to the desired route of administration (eg, oral, parenteral). Various types. Thus used in liquid oral preparations (such as suspensions, elixirs and solutions), suitable carriers and additives include water, glycols, oils, alcohols, 37 200808298 fragrances, preservatives, stabilizers, Colorants and the like; for solid oral preparations (such as powders, sachets, and lozenges), suitable carriers and additives, including powders, sugars, diluents, granulating agents, lubricants, binders, disintegrants And similarly, the solid oral preparation may also be coated with a substance 5 such as sugar or coated with a casing to adjust the main absorption site. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to provide solubility or preservation. Injectable suspensions or solutions may also be used with aqueous carriers and suitable additives. To prepare the pharmaceutical composition of the present invention, one or more compounds of the present invention 10 as an active ingredient are skillfully mixed with a pharmaceutical carrier according to a conventional pharmaceutical compounding technique, and the carrier can be administered according to the desired composition. The preparation form (such as oral or intramuscular non-oral) is in a variety of different forms. For the preparation of a composition in an oral dosage form, any of the usual pharmaceutical media can be employed. Thus, for use in liquid oral preparations such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, perfumes, preservatives, colorants, and the like; ® oral preparations such as powders, sachets, caplets, gelcaps, and lozenges, suitable carriers and additives including starch, sugars, diluents, granulating agents, lubricants, binders, Disintegrants and similar 20 people. Because of the ease of administration, tablets and sachets represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are clearly employed. If desired, the lozenge can be coated with sugar or coated with a casing by standard techniques. For parenteral use, the carrier will typically contain sterile water, which may be included via other ingredients (for example, to enhance solubility or for preservation). Injectable suspensions may also be prepared. In this case, suitable liquid carriers, suspensions and the like may be selected. The pharmaceutical composition herein contains, per dosage unit (e.g., tablets, capsules, powders, injections, teaspoons, and the like) required to achieve an effective amount of one of the effective doses as described above. The pharmaceutical composition herein may comprise 'the parental unit (such as a sputum capsule, powder, injection, suppository, teaspoon amount and the like) from about 0·1 to 1 side mg and may be predetermined as a self-approximately 〇 〇 〇〇 〇〇 〇 〇 mg / kg / 曰 耋 耋, preferably from about 0.1-100 mg / kg / day 'better than 〇 · 5-50 rflg / kg / day, better The ground is given from about 1.0-25.0 mg/kg/曰 or any of its formulas. However, the dosage will vary depending on the needs of the patient, the severity of the condition being treated, and the compound employed. Whether it is daily dosing or post-periodic dosing use < is employed. Preferably, these compositions are in the form of, for example, a key, a pill, a sachet, a powder, a capsule, a sterile parenteral solution or suspension, a metered aerosol or a liquid spray, a drop, A unit dose® type of ampoules, autoinjector devices or testosteres; for oral, injection, intranasal, sublingual or rectal administration, or for inhalation Or administration of insufflation. Optionally, the composition can be presented in a form that is administered once a week or once a month; for example, one of the active compounds insoluble salts (such as decanoate salt) can be employed A preservation preparation for intramuscular injection is provided. To prepare a solid composition such as a tablet, the main active ingredient is mixed with a pharmaceutically acceptable carrier such as a conventional ingot ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearin 39 200808298 acid, magnesium stearate, a dicalcium phosphate or gum), and other pharmaceutically acceptable diluents (such as water) to form a solid pre-formulation composition comprising a compound of the invention, or a compound thereof A homogenized mixture of pharmaceutically acceptable salts. When it is meant that these pre-prescription compositions are homogenized, it means that the active ingredients are evenly dispersed in the composition, so that the composition is easily subdivided into equal effective dosage forms (such as tablets, pills or sachets). Agent). The pre-prescription composition is then subdivided into a unit dosage form of the above type which contains from 0 to 1 mg of the active ingredient of the present invention. The tablets or pellets of the novel compositions can be coated or synthesized to provide a dosage form for the benefit of prolongation. For example, the bond or pellet may contain an inner dosage and an outer dosage component which is in the form of a sheath covering the former. The two components can be separated by an enteric iayer which acts as a resist disintegration in the stomach and allows the inner component to pass intact through the duodenum or prolonged release. A variety of different materials can be used for this casing layer or coatings, including some polymeric acids with raw materials such as shellac, cetyl alcohol or cellulose acetate. ). 20 a liquid form wherein the novel composition of the invention may be incorporated for oral administration or by injection, including aqueous solutions, suitably flavored gums, aqueous or oily suspensions, and edible oils Flavored emulsifiers such as cotton sesame oil, sesame oil, coconut oil or peanut oil, as well as broths and similar pharmaceutically acceptable vehicles. For aqueous suspensions 40 200808298 Suitable dispersion or suspending agents, including synthetic or natural gums such as tragacanth, acacia, alginate, polyglucose, Weiwei fiber Suona, thiol cellulose, polyethylene-pyralidone or gelatin. The method of the present invention can also be practiced using a pharmaceutical composition comprising any of the compounds described 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 into any form suitable for the selected mode of administration. The carrier includes both necessary and inert pharmaceutical excipients including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms [such as pills, troches, capsules, sachets (each including immediate release, time-release or sustained release formulations), granules and powders], liquid forms (such as solutions) , syrups, tinctures, emulsifiers, and suspensions). Suitable types for parenteral administration include sterile solutions, emulsifiers and suspensions. Advantageously, the compounds of the invention may be administered in a single daily dose, or the total daily dose may be divided into two, three or four daily doses. Furthermore, the compounds of the present invention can be administered in an intranasal form via topical use of a suitable intranasal vehicle, or via transdermal skin patches known to those of ordinary skill in the art. As a form of delivery in a transdermal delivery system, the dosage administration will of course be continuous rather than continuous throughout the dosage regimen. For example, for oral administration in the form of a lozenge or sachet, the active pharmaceutical ingredient can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water or the like. Further, suitable binders, lubricants, disintegrants, and color formers can be incorporated into the mixture as desired or desired. Suitable binders include, but are not limited to, starch, gelatin, natural sugars (eg, glucose) Or beta-lactose), corn sweetener, natural and synthetic gums such as gum arabic gum, gum tragacanth or sodium oleate, sodium stearate, stearic acid, sodium benzoate, sodium acetate, chlorination Sodium and similar things. Disintegrators include, but are not limited to, starch, sulfhydryl cellulose, agar, bentonite, triterpene, and the like. The liquid form in a suitably seasoned suspension or dispersing agent is, for example, a 10% natural gum or a natural gum, for example, gum arabic gum, gum arabic, methyl cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. When intravenous injection is desired, an isotonic preparation, usually containing a suitable preservative, is employed. When neuroprotection is desired, the compounds of the invention can be administered in any of the compositions described above and administered according to established dosage regimens in the art. The daily dose of such products can vary from 0.01 to 10 200 mg/kg per adult per subject. For oral administration, the composition preferably contains 0·(Π, 0.05, 0·; 1, 0.5, 1·0, 2. 5, 5.0, 1〇.〇, 15·0, 25.0, A dosage form of 50, 0, 100, 150, 200, 250, 500 and 1000 ng of active ingredient is provided for the treatment of symptom adjustment of the patient. An effective amount of the drug is usually one A dose level of from about 0.01 mg/kg to about 200 mg/kg per kilogram of body weight per day is provided. Preferably, the range is from about 0.1 to about 100,0 mg/kg per kilogram of body weight per day. More preferably from about 5 mg/kg per kg body weight to about 50 42 200808298 more preferably from about 1 kg per kg body weight to about A. Disease. The compound can be - daily! The 4 times of the birth method is administered. The optimal dosage for administration can be easily determined by those skilled in the art, and will follow the mosquito compound used, the mode of administration, the strength of the preparation, and the I# mode. In addition, the cause associated with the patient being treated with ί, including the age, weight, diet, and the amount of time spent on the music will cause a need to adjust the dose.

10 15 、=於該技藝者當認知到，使用適#、已知以及普遍地 被接受之細胞及/或動物模式的活體内（以或活體外 ㈨試驗兩者係對測試一化合物治療或預防一特定 疾病的能力來說具有預見性。 ^ 該技藝者更當認知到，在健康病患及/或那些遭 受一預定疾病者中，包括首見於人類（first_in_human)、劑 夏範圍以及藥效測試的人類臨床測試可根據已知於臨床 以及醫學技藝的方法而被完成。 【實施方式】 下列實施例被提出以協助理解本發明，且並未意欲也 不應被認為限定於之後的申請專利範圍所提出之本發明。 實施例1 K苯并ΙΉ噻吩-3-某甲基)磺醯二胺（化合物#1) 43 20080829810 15 , = as the artist knows, using the appropriate, and generally accepted cell and / or animal model of the in vivo (or or in vitro (nine) test for the test of a compound treatment or prevention Predictive for the ability of a particular disease. ^ The artist is more aware of the fact that in healthy patients and/or those who suffer from a predetermined disease, including first sight in humans (first_in_human), summer range, and efficacy testing The human clinical test can be performed according to methods known in the clinical and medical arts. [Embodiment] The following examples are presented to assist in understanding the present invention and are not intended or intended to be limited to the scope of the following claims. The present invention has been proposed. Example 1 Kbenzoquinthiophen-3-methylsulfonate diamine (Compound #1) 43 200808298

5 NH2 苯并 口塞吩-3-曱經（thianaphthene-3-carboxaldehyde) g (1.62g，10·0 mmol)被溶解於無水乙醇（50 mL)中。將續酸 二胺（4.0g，42 mmol)加入且該混合物被加熱至回流歷時 ίο 16小時。該混合物被冷卻至室溫。棚氫化鈉（sodium borohydride) (0.416 g，11.0 mmol)被加入混合物中並於室 溫下攪拌混合物歷時3小時。該反應以水（50 mL)稀釋且 以氯仿（3 X 75 mL)萃取。該萃取物被濃縮並經層析 (chromatographed) (5%曱醇配於DCM中）以產生如一白 15 色固態的標題化合物。 4 NMR (DMSO-A)，δ7·98(1Η，dd，J = 6·5, 2·3 Hz)， 春 7·92(1Η，dd，6.6, 2.4 Ηζ)，7·62(1Η，s)，7·36_7·45(2Η，m)， 7·08(1Η，t，/ = 6·3 Hz)，6·72(2Η，s)，4·31(2Η，d，/ = 6·3 Hz). 20 實施例2 『(5-氣笨升『办1p塞吩-3-基）甲暮i石黃酿二胳（化合物#3) 44 2008082985 NH2 benzoxetene-3-carboxaldehyde g (1.62 g, 10·0 mmol) was dissolved in absolute ethanol (50 mL). The acid extended diamine (4.0 g, 42 mmol) was added and the mixture was heated to reflux for 16 hours. The mixture was cooled to room temperature. Sodium borohydride (0.416 g, 11.0 mmol) was added to the mixture and the mixture was stirred at room temperature for 3 hours. The reaction was diluted with water (50 mL) and extracted with chloroform (3 X 75 mL). The extract was concentrated and chromatographed (5% sterol in DCM) to give the title compound as a white solid. 4 NMR (DMSO-A), δ7·98 (1Η, dd, J = 6·5, 2·3 Hz), spring 7.92 (1Η, dd, 6.6, 2.4 Ηζ), 7·62 (1Η, s ), 7·36_7·45(2Η,m), 7·08(1Η,t,/ = 6·3 Hz),6·72(2Η,s),4·31(2Η,d,/ = 6· 3 Hz). 20 Example 2 『(5-气笨升『1p stopper-3-yl) formazan i stone yellow wine two (compound #3) 44 200808298

(5- 氣-1· 苯并噻吩 -3- 基）甲胺 [(5-chloro-1 -benzothiophene-3-yl)methylamine] (0.820 g， 4·15 mmol)以及磺醯二胺（2.5 g，26 mmol)被化合於無水二 噚烷（50 mL)中且該混合物被加熱至回流歷時4小時。該 反應被冷卻至室溫且以水（50 mL)稀釋。以氣仿（3 X 75 mL) 萃取該溶液。萃取物被濃縮且經層析（5%甲醇配於DCM 中）以產生如一白色固態的標題化合物。 NMR (DMSO-A)，δ 8·05(2Η，m)，7·74(1Η，s)， 7.40(1H，d，6·5 Hz)，7·07(1Η，t，6·3 Hz)，6·72(2Η，s)， 4.26(2H，d，6.4 Hz). 實施例i 基-If吲哚-3-基）甲某1碏醯二胺（化合物#7)(5-chloro-1 -benzothiophene-3-yl)methylamine (0.820 g, 4·15 mmol) and sulfonamide (2.5 g) , 26 mmol) was combined in anhydrous dioxane (50 mL) and the mixture was heated to reflux for 4 hours. The reaction was cooled to room temperature and diluted with water (50 mL). The solution was extracted with a gas imitation (3 X 75 mL). The extract was concentrated and purified by chromatography (EtOAc EtOAc) NMR (DMSO-A), δ 8·05 (2Η, m), 7.74 (1Η, s), 7.40 (1H, d, 6·5 Hz), 7·07 (1Η, t, 6·3 Hz ), 6.72 (2 Η, s), 4.26 (2H, d, 6.4 Hz). Example i yl-If吲哚-3-yl)methyl 1 碏醯diamine (compound #7)

45 200808298 N-甲基’ °朵-3 -曱酸（1.66 g，10.4 mmol)被溶解於無水 乙醇（50 mL)中。將石頁酿二胺（4· 5 g，47 mmol)加入並且加 熱該混合物至回流歷時16小時。將額外的確醯二胺（ί ο g， 10.4 mmol)加入且混合物被加熱至回流歷時24小時。該 5 混合物被冷卻至室溫。將删鼠化納（0.722g，12.5 mmol)加 入且該混合物於室溫下攪拌歷時1小時。該反應以水（50 mL)稀釋並以DCM(3 X 75 mL)萃取。萃取物被濃縮且加入 大約1 mL的甲醇以製造出一漿:液（slurry)，該漿液經過濾 而產生如一白色粉末的標題化合物。 10 !H NMR (CD3OD): δ 7.67(1H, d, J - 5.9 Hz), 7.32(1H, d，J = 6·2 Hz)，7·14-7.19(2Η，m)，7·06(1Η，dt，J = 7·7, 0·7 Hz)，4·36(2Η，s)，3·75(3Η，s). MS(M-H)_237.6· 15 實施例4 ，『(3-茉并呋喃甲基1碏醯二胺（化合物#3)45 200808298 N-Methyl<0>> - decanoic acid (1.66 g, 10.4 mmol) was dissolved in anhydrous ethanol (50 mL). The stone diamine (4.5 g, 47 mmol) was added and the mixture was heated to reflux for 16 hours. An additional decane diamine (ί ο g, 10.4 mmol) was added and the mixture was heated to reflux for 24 hours. The 5 mixture was cooled to room temperature. The mutated sodium (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 (50 mL) and EtOAc (EtOAc) The extract was concentrated and about 1 mL of methanol was added to make a slurry which was filtered to give the title compound as a white powder. 10 !H NMR (CD3OD): δ 7.67 (1H, d, J - 5.9 Hz), 7.32 (1H, d, J = 6.2 Hz), 7·14-7.19 (2Η, m), 7·06 ( 1Η, dt, J = 7·7, 0·7 Hz), 4·36 (2Η, s), 3·75 (3Η, s). MS(MH)_237.6· 15 Example 4, “(3 -Momofuranylmethyl 1 碏醯diamine (Compound #3)

苯并吱喃-3-叛酸（1.91 g，11.8 mmol)被懸浮於無水 00^(75 1111〇中。加入草醯氯(2.〇]^配於〇€]^中，6.48 111£) 46 200808298 與繼而一滴的二甲基曱醯胺（dimethylformamide)。該溶液 於室溫下攪拌歷時2小時，繼而加入氮氧化銨（濃縮的， 10mL)。所形成的混合物以水（l〇〇mL)稀釋並以DCM(3 X 100 mL)萃取。萃取物被濃縮至一灰色固體並溶解於無水 5 THF(100 mL)中。加入鋁氳化鋰（1·〇 Μ配於THF中，11.8 mL)。該混合物於室溫下被攪拌歷時16小時。加入少量 的飽和水性NaHC03並且繼而MgS04。該混合物被過濾 • 並且繼而以IN HC1萃取。該水性萃取物以3N NaOH調 整至pH 14並以DCM萃取。有機萃取物以硫酸鎂乾燥並 10 濃縮成一無色的油。該油被溶解於二崎烧（50 mL)並加入 磺醯二胺(3. 7 g，38 mmol)。該混合物被加熱至回流歷時4 小時、冷卻至室溫，並且濃縮。所形成的固體被層析（5% 曱醇配於DCM中）以產生如一淡黃色固體的標題化合物。 iH NMR (CD3OD): δ 7·53(1Η，d，J 二 5·7 Ηζ)，7·44(1Η， 15 d，6·0 Hz)，7·16-7·26(2Η，m)，6.73(1H，s)，4·35(2Η，s)· ⑩實施例5 #-『(5-氩_苯并⑻嘆吩-3-某）甲基μ甚醯二胺（化合物#8)Benzopyran-3-one acid (1.91 g, 11.8 mmol) was suspended in anhydrous 00^(75 1111 。. Add oxalic acid (2.〇)^ in 〇€]^, 6.48 111 £) 46 200808298 followed by a drop of dimethylformamide. The solution was stirred at room temperature for 2 hours, then ammonium oxychloride (concentrated, 10 mL) was added. The resulting mixture was taken with water (1 mL) Diluted and extracted with DCM (3 X 100 mL). The extract was concentrated to a gray solid and dissolved in anhydrous 5 THF (100 mL). Aluminium lithium hydride was added (1·〇Μ in THF, 11.8 mL) The mixture was stirred at room temperature for 16 hours. A small amount of saturated aqueous NaHC03 was added and then MgS04. The mixture was filtered and then extracted with IN HCl. The aqueous extract was adjusted to pH 14 with 3N NaOH and DCM. The organic extract was dried over magnesium sulfate and concentrated to give a colorless oil. The oil was dissolved in EtOAc (50 mL) and sulfonamide (3.7 g, 38 mmol) was added. The reflux was carried out for 4 hours, cooled to room temperature and concentrated. The solid formed was chromatographed (5% dec. DCM) to give the title compound as a pale yellow solid. iH NMR (CD3OD): δ 7·53 (1 Η, d, J 5.2 Ηζ), 7·44 (1 Η, 15 d, 6·0 Hz) ,7·16-7·26(2Η,m),6.73(1H,s),4·35(2Η,s)·10Example 5#-『(5-argon-benzo(8) sinter-3- Methyl) quinone diamine (compound #8)

47 200808298 5- 氟 -3- 曱基 苯并噻 吩 (5-fluoro-3-mehtylbenzothiopliene)(L14 g，6·83 mmol)、過 氧化苯甲醯（benzoyl peroxide)(0· 165 g，0.68 mmol)以及 N-漠號蓝亞胺（1·70 g，7.52 mmol)被化合於四氯化石炭（25 mL)中且該混合物被加熱至回流歷時3小時。黃色液體被 冷卻、以水稀釋，並以DCM(2 X 50 mL)萃取。萃取物以 鹽水（100 mL)洗滌、以硫酸鎂乾燥，並濃縮成一橙色固 體。該固體溶解於無水DMF中。將疊氮化鈉（4.0 g，61 mmol)加入且於室溫下攪拌該混合物歷時16小時。該反 應以水（100 mL)稀釋並以二***（2x75 mL)萃取。萃取物 以鹽水（100 mL)洗滌、以硫酸鎂乾燥，並濃縮成一為黃色 的油。該油被溶解於THF(50 mL)與水（5 mL)的混合物中。 加入三苯膦（3·60 g，13.7 mmol)。該混合物於室溫下被攪 拌歷時16小時。該反應被濃縮並且經層析（2至5%甲醇 配於DCM中）。所形成的C-(5-氟-苯并[6]噻吩-3-基)-甲胺 (1·04 g，5·73 mmol)被溶解於無水二00(50 mL)且加入磺 醯一胺（2· 75 g，28.7 mmol)。該反應被加熱至回流歷時4 小時、冷卻至室溫，並濃縮成一固體，該固體經層析 甲醇配於DCM中）以產生一如白色固態的標題化合物。 NMR (CD3OD): δ 7.85(1H, dd5 J = 6.6, 3.6 Hz), 7.66(1H，dd，7.4, 1·8 Hz)，7·62(1Η，s)，7·13-7·18(1Η，m)， 4·40(2Η，s)· 實施例6 48 200808298 7^『（1-笨并『办1嘍吩-3-基乙基）-磺醯二胺（化合物#9)47 200808298 5-fluoro-3-mehtylbenzothiopliene (L14 g, 6.83 mmol), benzoyl peroxide (0·165 g, 0.68 mmol) And N-Moline Blueimine (1·70 g, 7.52 mmol) was combined in carbon tetrachloride (25 mL) and the mixture was heated to reflux for 3 hours. The yellow liquid was cooled, diluted with water and extracted with DCM (2 X 50 mL). The extract was washed with brine (100 mL), dried over magnesium sulfate and evaporated. The solid was dissolved in anhydrous DMF. Sodium azide (4.0 g, 61 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction was diluted with water (100 mL) and extracted with diethyl ether (2×75 mL). The extract was washed with brine (100 mL), dried over magnesium sulfate and evaporated. 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 at room temperature for 16 hours. The reaction was concentrated and chromatographed (2 to 5% methanol in DCM). The C-(5-fluoro-benzo[6]thiophen-3-yl)-methylamine (1·04 g, 5.73 mmol) formed was dissolved in anhydrous 20 (50 mL) and sulfonate was added. Amine (2·75 g, 28.7 mmol). The reaction was heated to reflux for 4 h, cooled to rt. NMR (CD3OD): δ 7.85 (1H, dd5 J = 6.6, 3.6 Hz), 7.66 (1H, dd, 7.4, 1·8 Hz), 7.62 (1Η, s), 7·13-7·18 ( 1Η,m), 4·40(2Η,s)· Example 6 48 200808298 7^『(1-Bist and 喽1喽-3-ylethyl)-sulfonamide (Compound #9)

• 3-乙醯苯并嗟吩（3-acetylthianaplithene)(3.00 g，17.0 mmol)被加入至一為曱酸（1〇 mL)與曱醯胺（1〇 mL)的混合 ίο 物中。該溶液被加熱至150°C歷時8小時。該反應被冷卻 至室溫、以水（50 mL)稀釋，以二***（3 X 50 mL)萃取。 以飽合水性NaHC03與鹽水洗滌該醚萃取物。該溶液被濃 縮並經層析（5°/。甲醇配於DCM中）以產生如一白色固體的 ，(1-苯并[6]噻吩-3-基-乙基)-甲醯胺（1.76 g)，其被懸浮於 15 濃鹽酸（30 mL)中。該混合物被加熱至回流歷時1.5小時 繼而以水（100 mL)稀釋。3N的NaOH被加入直到pH為 馨 14。以二***(3 X 100 mL)萃取混合物繼而以硫酸鎮乾燥 並濃縮成一為橙色的油。該油被溶解於無水二巧炫(75 mL) 中並加入績醯二胺。該混合物被加熱至回流歷時2小時並 20 且以水（50 mL)稀釋。以乙酸乙酯（2 X 50 mL)萃取該溶 液、以硫酸鎂乾燥、濃縮，並經層析（2.5至5%的甲醇配 於DCM中）以產生如一白色固體的標題化合物。 !H NMR (CD3OD): δ 8.01(1H5 dd, J = 5.5, 0.7 Hz), 7·85(1Η，dt，6·0, 0·6 Hz)，7·49(1Η，s)，7·31-7·40(2Η，m)， 49 200808298 4.95(1H, q,/- 5.1 Hz), 1.67(3H, d5 J- 5.1 Hz). 實施例7 Ν-Π-萘甲基）磺醯二胺（化合物#10)• 3-acetylthianaplithene (3.00 g, 17.0 mmol) was added to a mixture of citric acid (1 〇 mL) and guanamine (1 〇 mL). The solution was heated to 150 ° C for 8 hours. The reaction was cooled to room temperature, diluted with water (50 mL) andEtOAc. The ether extract was washed with saturated aqueous NaHC03 and brine. The solution was concentrated and chromatographed (5 ° / methanol in DCM) to give (1-benzo[6]thiophen-3-yl-ethyl)-carbamide (1.76 g) as a white solid. ), it was suspended in 15 concentrated hydrochloric acid (30 mL). The mixture was heated to reflux for 1.5 hours and then diluted with water (100 mL). 3N NaOH was added until the pH was 14 . The mixture was extracted with diethyl ether (3×100 mL) and then dried with sulphuric acid and concentrated to give an orange oil. The oil was dissolved in anhydrous dihydrate (75 mL) and the diamine was added. The mixture was heated to reflux for 2 hours and 20 and diluted with water (50 mL). The solution was extracted with EtOAc (EtOAc (EtOAc)EtOAc. !H NMR (CD3OD): δ 8.01 (1H5 dd, J = 5.5, 0.7 Hz), 7·85 (1Η, dt, 6·0, 0·6 Hz), 7·49 (1Η, s), 7· 31-7·40(2Η,m), 49 200808298 4.95(1H, q,/- 5.1 Hz), 1.67(3H, d5 J- 5.1 Hz). Example 7 Ν-Π-naphthylmethyl)sulfonate II Amine (Compound #10)

ίο 1，萘曱胺（l-naplithanlenemethylamine)(2.00 g，12.7 mmol)以及石黃醯二胺（5.0 g，52 mmol)被化合於無水二口咢烧 (100 mL)中且該混合物被加熱至回流歷時6小時。該反應 被冷卻至室溫並且被過濾。濾液被濃縮成一固體並以水洗 滌，直到TLC標示在該固態中沒有殘留微量磺醯二胺。 15 經收集的固體於真空下被乾燥以產生如一白色固體的標 題化合物。 • NMR (CDCI3)： δ 8.09(1H? d, J = 6.3 Hz), 7.86(1H, dd，12.9, 6、2 Hz)，7·42-7.61(4Η，m)，4·75(2Η，d，4·4 Hz)，4·58(1Η，br s)，4·51(2Η，br s). 20 實施例8 ，『(2-甲基-3-茉共呋喃）甲基1磺醯二胺（化合物#13) 50 200808298Ίο 1, l-naplithanlenemethylamine (2.00 g, 12.7 mmol) and scutellarin diamine (5.0 g, 52 mmol) were combined in anhydrous bismuth (100 mL) and the mixture was heated to The reflux lasted for 6 hours. The reaction was cooled to room temperature and filtered. The filtrate was concentrated to a solid and washed with water until TLC indicated that there was no trace of sulfonamide in the solid. The collected solid was dried under vacuum to give the title compound as a white solid. • NMR (CDCI3): δ 8.09 (1H? d, J = 6.3 Hz), 7.86 (1H, dd, 12.9, 6, 2 Hz), 7.42-7.61 (4Η, m), 4·75 (2Η, d, 4·4 Hz), 4·58 (1Η, br s), 4·51 (2Η, br s). 20 Example 8, "(2-methyl-3-moslicanyl)methyl 1 sulfonate Diamine (Compound #13) 50 200808298

55

10 1510 15

2- 甲基苯 并呋喃 -3- 曱醛 (2-methylbenzofuran-3-carbaldehyde) (0.51 g，3· 18 mmol) 被溶解於無水乙醇（25 mL)中。加入磺醯二胺（1.5 g，16 mmol)並加熱該混合物至回流歷時4天。混合物被冷卻至 室溫。將·氫化納（0.132 g，3.50 mmol)加入且該混合物於 室溫下攪拌歷時24小時。該反應以水（100 mL)稀釋並以 DCM(3 X 75 mL)萃取。萃取物被濃縮且懸浮於少量的 DCM中並經過濾以產生如一白色固體的標題化合物。 4 NMR (DMSO-A): δ 7·65(1Η，dd，J = 6·4, 2·6 Hz)， 7·43-7.47(1Η，m)，7.19-7·23(2Η，m)，6·87(1Η，t，6·2 Ηζ)， 6·68(2Η，s)，4·11(2Η，d，6·2 Ηζ)，2·42(3Η，s)· 實施例9 ，『(5-溴笨并⑻噻吩-3-基）甲基1磺醯二胺（化合物#15)2-methylbenzofuran-3-carbaldehyde (0.51 g, 3·18 mmol) was dissolved in absolute ethanol (25 mL). Sulfonamide (1.5 g, 16 mmol) was added and the mixture was heated to reflux for 4 days. The mixture was cooled to room temperature. The 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 X 75 mL). The extract was concentrated and suspended in a small amount of DCM and filtered to give the title compound as a white solid. 4 NMR (DMSO-A): δ 7·65 (1Η, dd, J = 6·4, 2·6 Hz), 7·43-7.47 (1Η, m), 7.19-7·23 (2Η, m) ,6·87(1Η,t,6·2 Ηζ), 6.68(2Η,s), 4·11(2Η,d,6·2 Ηζ), 2·42(3Η,s)·Example 9 , "(5-Bromo-(8)thiophen-3-yl)methyl 1 sulfonamide (Compound #15)

5 1 200808298 5_溴苯并嗟吩（5-bromobenzothiophene) (1.60 g，7·51 mmol)以及二氣甲基***（ι·29 g，11·3 mmol)被溶解於無 水1，2-二氯乙烷（75mL)中。將四氯化鈦（2.14g，11.3mmol) 加入，令該溶液變為暗色。於室溫下歷經1小時後，飽和 5 的水性NaHC03以及冰的一混合物被倒入該反應中。該混 合物被攪拌歷時30分鐘並且繼而以DCM(2 X 100 mL)萃 取。該萃取物被濃縮且經層析（0至5%的乙酸乙酯配於己 _ 烷中）以產生5-溴-笨并[&]噻吩-3-甲醛（L32g)。該5-溴苯 并噻吩-3-甲醛（1.20 g，4.98 mmol)以及磺醯二胺（4·0 g，42 ίο mmol)被化合於無水乙醇(25 mL)中並且被加熱回流歷時3 天。該反應被冷卻至室溫並且加入硼氫化鈉（0.207 g，5·47 mmol)。五個小時後，將水（50 ml)加入並且以氯仿（3 χ 50 mL)萃取。該萃取物被濃縮、懸浮於少量DCM中，且經 過濾以提供一如黃色固體的標題化合物。 15 lR NMR (DMSO-i/5): δ 8.12(1Η? ά, J = L8 Hz),5 1 200808298 5-bromobenzothiophene (1.60 g, 7.51 mmol) and di-gas methyl ether (ι·29 g, 11.3 mmol) were dissolved in anhydrous 1,2-di In ethyl chloride (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added to make the solution dark. After 1 hour at room temperature, a mixture of saturated 5 aqueous NaHC03 and ice was poured into the reaction. The mixture was stirred for 30 minutes and then extracted in DCM (2×100 mL). The extract was concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield 5-bromo- <RTI ID=0.0>> The 5-bromobenzothiophene-3-carbaldehyde (1.20 g, 4.98 mmol) and the sulfonium diamine (4·0 g, 42 ίο mmol) were combined in absolute ethanol (25 mL) and heated to reflux for 3 days. . The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol). After five hours, water (50 ml) was added and extracted with chloroform (3 χ 50 mL). The extract is concentrated, suspended in a small amount of DCM and filtered to give the title compound as a yellow solid. 15 lR NMR (DMSO-i/5): δ 8.12 (1Η? ά, J = L8 Hz),

7·97(1Η，d，J = 8·6Ηζ)，7·71(1Η，s)，7·52(1Η，dd，J = 8.6, ⑩ 1.9 Hz)，7.12(1H，t，6·3 Hz), 6·72(2Η，s)，4·28(2Η，d，J =6·2 Hz)· 20 實施例10 #二『(4-溴茉#mi嚓吩-3-某）甲基1磺醯二胺（化合物#17) 52 2008082987·97(1Η,d,J=8·6Ηζ),7·71(1Η,s),7·52(1Η,dd,J=8.6, 10 1.9 Hz), 7.12(1H,t,6·3 Hz), 6·72(2Η, s), 4·28(2Η,d,J=6·2 Hz)·20 Example 10 #二『(4-Brommo#mi嚓-3-1) Base 1 sulfonium diamine (compound #17) 52 200808298

4-漠苯并嗟吩（1.80 g，8.45 mmol)以及二氯甲基*** (1·46 g，12·7 mmol)被溶解於無水DCM(100 mL)中。將四 氯化鈦（2.40 g，12.7 mmol)加入，令該溶液變為暗色。於 室溫下歷經30分鐘後，飽和的水性NaHCQ3以及冰的一 混合物被倒入該反應中。該混合物被攪拌歷時30分鐘並 且繼而以DCM(2x 150mL)萃取。該萃取物被濃縮且經層 析（0至15%的乙酸乙酯配於己烷中）以產生4-溴苯并噻吩 -3-曱醛（0.910 g)。該4-溴苯并噻吩-3-甲醛（0.910 g，3·77 mmol)以及磺醯二胺（3·〇 g，31 mmol)被化合於無水乙醇 (25 mL)中並且被加熱回流歷時3天。該反應被冷卻至室 溫並且加入硼氬化鈉（0.157 g，4·15 mmol)。五個小時後， 將水（50 ml)加入並且以氯仿（3 X 50 mL)萃取。該萃取物被 濃縮、懸浮於少量DCM中，且經過濾以產生一如黃色固 體的標題化合物。 !H NMR (DMSO-ί/ί)： δ 8.05(1H5 dd, J = 8.1, 0.8 Hz)? 7·78(1Η，s)，7·64(1Η，dd，J = 7·6, 0·8 Hz)，7·27(1Η，t，/ = 7·9 Hz)，7.13(1H，t，6·3 Hz)，6·72(2Η，br s)，4·65(2Η，d， J = 5.3 Hz). 53 200808298 實施例11 HT7-乱苯异『Z>1隹吩-3-基）甲基1確酿二胺（化合物#18)4- Desert benzophenone (1.80 g, 8.45 mmol) and dichloromethylether (1·46 g, 12.7 mmol) were dissolved in dry DCM (100 mL). Titanium tetrachloride (2.40 g, 12.7 mmol) was added to make the solution dark. After 30 minutes at room temperature, a mixture of saturated aqueous NaHCQ3 and ice was poured into the reaction. The mixture was stirred for 30 minutes and then extracted with DCM (2 x 150 mL). The extract was concentrated and subjected to chromatography (0 to 15% ethyl acetate in hexanes) to afford 4-bromobenzothiophene-3-furaldehyde (0.910 g). The 4-bromobenzothiophene-3-carbaldehyde (0.910 g, 3.77 mmol) and the sulfonium diamine (3·〇g, 31 mmol) were combined in absolute ethanol (25 mL) and heated to reflux for 3 day. The reaction was cooled to room temperature and sodium borohydride (0.157 g, 4.15 mmol) was added. After five hours, water (50 ml) was added and extracted with chloroform (3 X 50 mL). The extract is concentrated, suspended in a small amount of DCM and filtered to give the title compound as a yellow solid. !H NMR (DMSO-ί/ί): δ 8.05 (1H5 dd, J = 8.1, 0.8 Hz)? 7·78(1Η, s), 7·64 (1Η, dd, J = 7·6, 0· 8 Hz), 7·27 (1Η, t, / = 7·9 Hz), 7.13 (1H, t, 6·3 Hz), 6.72 (2Η, br s), 4·65 (2Η, d, J = 5.3 Hz). 53 200808298 Example 11 HT7-disorganized benzene "Z>1 隹-phen-3-yl)methyl 1 is a diamine (compound #18)

2-氟硫酚（2-fluorotliiophenol)(4.14 g，32.6 mmol)被溶 解於無水THF(100 mL)中。將第三丁基醇鉀（1.0 Μ配於 THF中，35\8mL)加入並且將懸浮液（suspension)於室溫下 攪拌歷時15分鐘。加入2-氯乙醛縮二曱醇且攪拌混合物 歷時3天。將水（100 mL)加入並且以二***（3 X 100 mL) 萃取。萃取物被濃縮至一黃色油並經層析（5至20%乙酸 乙酯配於己烷中）以產生如一無色油的1-(2,2-二甲氧基-乙 基 石黃 酿 基 ）-2- 氣-苯 n^(252-dimethoxy-ethylsulfanyl)-2-fluoro-benzene](6.42 g)。將氣苯(25 mL)加熱至回流並加入多磷酸（1 mL)。繼而 加入1-(2,2-二甲氧基-乙基磺醯基)-2-氟-苯以緩慢地令該 溶液轉變成暗色。經過3個小時的加熱後，該反應被冷卻 到至溫並以水（50 mL)稀釋。以本（2 X 50 mL)卒取該溶 液。萃取物被濃縮且經層析（0至15%的乙酸乙酯配於己 燒中）以產生7-氟苯并噻吩(0.77 g)。該7_氟苯并噻吩(0.77 §，5.1 mmol)以及二氯曱醚（0.872 g，7·6 mmol)被溶解於無 54 200808298 水DCM(25 mL)中。將四氯化鈦（1〇 μ配於DCM中，7.6 mL，7·6 mmol)加入，令該溶液轉為暗色。於室溫經過3〇 分鐘後，飽和的水性NaHC〇3以及冰的一混合物被倒入該 反應中。該混合物被攪拌歷時約30分鐘並且繼而以 5 DCM(2 X 50 mL)萃取。該萃取物被濃縮且經層析（〇至15% 的乙酸乙酯配於己烷中）以產生7-氟苯并噻吩-3-曱醛 (0.642 g)。該 7-氟苯并噻吩冬甲醛（0.642 g，3.77 mmol) 以及績酸二胺（1·7 g，18 mmol)被化合於無水乙醇（20 mL) 中並且被加熱回流歷時三天。該反應被冷卻至室溫並且加 ίο 入硼氫化鈉（〇·148 g，3·92 mmol)。兩個小時後，將水（25 ml) 加入並且以氯仿（3 X 25 mL)萃取該溶液。該萃取物被濃 縮、懸浮於少量DCM中，且經過濾以產生一如黃色固體 的標題化合物。 4 NMR (DMSO-A): δ 7·78(1Η，d，J = 8·0 Hz)， 15 7·43-7·50(1Η，m)，7·27(1Η，dd，1〇·3, 7·9 Ηζ)，7.14(1Η， t，/== 6、4 Ηζ)，6·74(2Η，br s)，4·31(2Η，d，6·4 Ηζ). 膏施例12 ΑΜΪ4-三氟甲基笨并「办1噻吩-3-基）甲篡1磺醯二胺 2〇 (化合物#18)2-fluorotliiophenol (4.14 g, 32.6 mmol) was dissolved in dry THF (100 mL). Potassium tert-butylate (1.0 Torr in THF, 35\8 mL) was added and the suspension was stirred at room temperature for 15 minutes. 2-Chloroacetaldehyde decyl alcohol was added and the mixture was stirred for 3 days. Water (100 mL) was added and extracted with diethyl ether (3×100 mL). The extract is concentrated to a yellow oil and chromatographed (5 to 20% ethyl acetate in hexanes) to give 1-(2,2-dimethoxy-ethyl sylvestin) as a colorless oil. -2- gas-benzene n^(252-dimethoxy-ethylsulfanyl)-2-fluoro-benzene] (6.42 g). Gas benzene (25 mL) was heated to reflux and polyphosphoric acid (1 mL) was added. Then, 1-(2,2-dimethoxy-ethylsulfonyl)-2-fluoro-benzene was added to slowly convert the solution to a dark color. After 3 hours of heating, the reaction was cooled to warmness and diluted with water (50 mL). The solution was taken in this (2 X 50 mL). The extract was concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophene (0.77 g). The 7-fluorobenzothiophene (0.77 §, 5.1 mmol) and chlorinated ether (0.872 g, 7·6 mmol) were dissolved in a water-free DCM (25 mL). Titanium tetrachloride (1 〇 μ in DCM, 7.6 mL, 7.6 mmol) was added to turn the solution to a dark color. After 3 minutes at room temperature, a mixture of saturated aqueous NaHC〇3 and ice was poured into the reaction. The mixture was stirred for about 30 minutes and then extracted with 5 DCM (2 X 50 mL). The extract was concentrated and chromatographed (purified to 15% ethyl acetate in hexanes) to afford 7-fluorobenzothiophene-3-furaldehyde (0.642 g). The 7-fluorobenzothiophene winter formaldehyde (0.642 g, 3.77 mmol) and the acid diamine (1.7 g, 18 mmol) were combined in absolute ethanol (20 mL) and heated to reflux for three days. The reaction was cooled to room temperature and added with sodium borohydride (〇·148 g, 3.92 mmol). After two hours, water (25 ml) was added and the solution was extracted with chloroform (3×25 mL). The extract was concentrated, suspended in a small amount of DCM and filtered to give the title compound as a yellow solid. 4 NMR (DMSO-A): δ 7·78 (1Η, d, J = 8·0 Hz), 15 7·43-7·50 (1Η, m), 7·27 (1Η, dd, 1〇·· 3, 7·9 Ηζ), 7.14 (1Η, t, /== 6, 4 Ηζ), 6.74 (2Η, br s), 4·31 (2Η, d, 6·4 Ηζ). 12 ΑΜΪ4-trifluoromethyl stupid and "do 1 thiophen-3-yl"carboxamidine 1 sulfonamide diamine 2 化合物 (compound #18)

55 200808298 4-三氟甲基苯并嗟吩(〇·276 g，1.37 mmol)以及二氯甲 醚（0·236 g，2·06 mmol)被溶解於無水DCM(10 mL)中。將 四氯化鈦（1·0 Μ配於DCM中，2.1 mL，2·1 mmol)，令該 溶液轉為暗色。於室溫經過30分鐘後，飽和的水性 5 NaHC03以及冰的一混合物被倒入該反應中。該混合物被 攪拌歷時30分鐘並且繼而以DCM(2 X 25 mL)萃取。該萃 取物被濃縮且經層析（0至15%的乙酸乙酯配於己烷中）以 產生4-三氟甲基苯并噻吩-3-曱醛。 ® 該4_三氟甲基苯并噻吩-3-曱醛（0.226 g，0.982 mmol) !〇 以及續酿二胺（0.471 g，4.91 mmol)被化合於無水乙醇（5 mL)中並且被加熱回流歷時24小時。該反應被冷卻至室 溫並且加入硼氫化鈉（0.056 g，1·47 mmol)。五個小時後， 將水（10 ml)加入並且以氯仿（3 X 10 mL)萃取。該萃取物被 濃縮，且經層析（5%甲醇配於DCM中）以產生一如白色固 15 體的標題化合物。 lU NMR (DMSO-^): δ 8.30(1Η9 s), 8,25(1Η, d, 8·4 馨 Ηζ)，7·84(1Η，s)，7·68(1Η，dd，/= 8.5, 1·4 Ηζ)，6·76'9(2Η， br s)，4·4-4·5(1Η，br s)，4·37(2Η，s)· 20 實施例13_ 沁ΙΪ4-氰基茉并[bl噻吩-3-某）甲基1-磺醯二胺 (化合物#20) 56 20080829855 200808298 4-Trifluoromethylbenzophenone (〇·276 g, 1.37 mmol) and methylene chloride (0·236 g, 2·06 mmol) were dissolved in dry DCM (10 mL). Titanium tetrachloride (1·0 Μ in DCM, 2.1 mL, 2.1 mmol) was turned into a dark color. After 30 minutes at room temperature, a mixture of saturated aqueous 5 NaHC03 and ice was poured into the reaction. The mixture was stirred for 30 minutes and then extracted with DCM (2 X 25 mL). The extract was concentrated and chromatographed (0 to 15% ethyl acetate in hexanes) to yield 4-trifluoromethylbenzothiophene-3-furfural. ® 4_Trifluoromethylbenzothiophene-3-furaldehyde (0.226 g, 0.982 mmol) 〇 and continuous diamine (0.471 g, 4.91 mmol) were combined in absolute ethanol (5 mL) and heated The reflux lasted for 24 hours. The reaction was cooled to room temperature and sodium borohydride (0.056 g, 1.47 mmol). After five hours, water (10 ml) was added and extracted with chloroform (3×10 mL). The extract was concentrated and chromatographed (5% MeOH in DCM) to give the title compound as white solid. lU NMR (DMSO-^): δ 8.30 (1Η9 s), 8,25 (1Η, d, 8·4 Ηζ), 7.84 (1Η, s), 7.68 (1Η, dd, /= 8.5 , 1·4 Ηζ),6·76'9(2Η, br s), 4·4-4·5(1Η,br s),4·37(2Η,s)·20 Example 13_沁ΙΪ4-Cyanide Kemo [blthiophene-3-)methyl 1-sulfonate diamine (compound #20) 56 200808298

4-氰基苯并噻吩（1.15 g，7.22 mmol)以及二氯甲醚 _ (1·25 g，1〇·8 mmol)被溶解於無水DCM(10 mL)中。將四氯 化鈦（1·0 Μ 配於 DCM 中，ΐ〇·8 mL，10·8 mmol)，令該溶 10 液轉為暗色。於室溫經過30分鐘後，飽和的水性NaHC03 以及冰的一混合物被倒入該反應中。該混合物被擾拌歷時 30分鐘並且繼而以DCM(2 X 50 mL)萃取。該萃取物被濃 縮且經層析（〇至15%的乙酸乙酯配於己烷中）以產生4-氰 基苯并噻吩-3-曱醛。 15 該4-氰基苯并嗟吩-3-甲酸(〇、298 g，1·59 mmol)以及 磺醯二胺（〇·766 g，7.97 mmol)被化合於無水乙醇（20 mL) 馨 中並且被加熱至回流歷時24小時。該反應被冷卻至室溫 並且加入硼氫化鈉（0.091 g，2·39 mmol)。五個小時後’將 水（20 ml)加入並且以氯仿（3 X 20 mL)萃取該溶液。該％取 20 物被濃縮，且經層析（5%曱醇配於DCM中）以產生一如白 色固體的標題化合物。 4 NMR (DMSO-d6): δ 8.37(1H，s)，8·30(1Η，d，/= 8·4 Ηζ)，7·87(1Η，s)，7·70(1Η，dd，8·5, 1·4 Ηζ)，6·76-6·9(2Η， br s)，4本4·5(1Η，br s)，4.40(2Η, s)· 57 200808298 實施例14 TV-「笨并噻吩-3-基）曱基1胺磺醯吡咯啶（化合物#101)4-Cyanobenzothiophene (1.15 g, 7.22 mmol) and chloroform ether _ (1·25 g, 1 〇·8 mmol) were dissolved in anhydrous DCM (10 mL). Titanium tetrachloride (1·0 Μ in DCM, ΐ〇·8 mL, 10·8 mmol) was used to turn the solution into a dark color. After 30 minutes at room temperature, a mixture of saturated aqueous NaHC03 and ice was poured into the reaction. The mixture was scrambled for 30 minutes and then extracted with DCM (2 X 50 mL). The extract was concentrated and chromatographed (to 15% ethyl acetate in hexanes) to give 4-cyanobenzothiophene-3-furfural. 15 4-Cyanobenzophenone-3-carboxylic acid (〇, 298 g, 1.59 mmol) and sulfonium diamine (〇·766 g, 7.97 mmol) were combined in absolute ethanol (20 mL) It was heated to reflux for 24 hours. The reaction was cooled to room temperature and sodium borohydride (0.091 g, 2. 39 mmol). After five hours, water (20 ml) was added and the solution was extracted with chloroform (3 X 20 mL). The % of the product was concentrated and purified by chromatography (EtOAc EtOAc) 4 NMR (DMSO-d6): δ 8.37 (1H, s), 8·30 (1Η, d, /= 8·4 Ηζ), 7·87 (1Η, s), 7·70 (1Η, dd, 8 ·5,1·4 Ηζ),6·76-6·9(2Η, br s), 4 books 4·5(1Η, br s), 4.40(2Η, s)· 57 200808298 Example 14 TV- Stupid thiophen-3-yl) fluorenyl 1 amine sulfonium pyrrolidine (compound #101)

NHNH

，[苯并[办]噻吩-3-基）曱基]胺磺醯（0.250 g，1.03 ίο mmol)以及吼口各唆（0·25 mL)被化合於無水二4烧（5 mL)中 並且被加熱至回流歷時32小時。該反應被蒸發並經由以 5%曱醇（配於DCM中）被層析以產生如一白色固體的標題 化合物。 !H NMR (CDC13)： δ 7.84-7.89(2H, m), 7.38-7.45(3H, is m)，4·49(3Ή，br s)，3·25(4Ή，t，J = 4·0 Hz)，1·80(2Η，t，J = 4.0 Hz). 實施例15 沁『苯并[Z>1噻吩-3-基）甲基1-ΛΓ-乙基磺醯二胺 2〇 (化合物#21), [Benzene] thiophen-3-yl) sulfhydrazine (0.250 g, 1.03 ίο mmol) and 吼 唆 (0·25 mL) were combined in anhydrous 2 4 (5 mL) It was heated to reflux for 32 hours. The reaction was evaporated and purified by EtOAc EtOAc (EtOAc) !H NMR (CDC13): δ 7.84-7.89 (2H, m), 7.38-7.45 (3H, is m), 4·49 (3Ή, br s), 3·25 (4Ή, t, J = 4·0 Hz), 1·80 (2Η, t, J = 4.0 Hz). Example 15 苯 "Benzo[Z>1thiophen-3-yl)methyl 1-indole-ethylsulfonyldiamine 2 oxime (compound) #twenty one)

58 200808298 队[苯并〇]噻吩-3-基）甲基]胺石黃二醯（0.250 g，ΐ·〇3 mmol)以及乙胺（70%配於Η20中，〇· 10 mL)被化合於無水 二噚烷（5 mL)中並且被加熱至回流歷時32小時。該反應 被蒸發並經由以5%甲醇（配於DCM中）被層析以產生如一 白色固體的標題化合物。 NMR (CDC13): δ 7·83<7·90(2Η，m)，7·36-7·47(3Η， m)，4·51(2Η，s)，2.90(2Η，q，J = 7 Ηζ)，1·03(3Η，t，J = 7 Hz)· 10 16 逢逵二1-磺酸『茉并『办1噻吩-3-基）甲基1-醯胺 ^^^#102)58 200808298 Team [benzopyrene]thiophen-3-yl)methyl]amine pyroxigmine (0.250 g, ΐ·〇 3 mmol) and ethylamine (70% in Η20, 〇· 10 mL) were combined It was dried in anhydrous dioxane (5 mL) and heated to reflux for 32 h. The reaction was evaporated and purified eluting with EtOAc EtOAc EtOAc NMR (CDC13): δ 7·83 <7·90 (2Η, m), 7·36-7·47 (3Η, m), 4·51 (2Η, s), 2.90 (2Η, q, J = 7 Ηζ),1·03(3Η,t,J = 7 Hz)· 10 16 逵二1-sulfonic acid 『Mu 『 办 1 thiophen-3-yl)methyl 1- oxime ^^^#102)

3-苯并噻吩甲胺以及3-(咪唑-1-磺醯基）-1-甲基 咪唑·1-三氟曱磺酸被化合於無水乙腈中。該溶液於室溫 下被攪拌過夜、經濃縮，且經層析（5%曱醇配於DCM中） 以產生如一棕色固體的標題化合物。 4 NMR (DMSO-A): δ 8·05(1Η，dd，J = 7·0, 1·6 Hz)、 7·99(1Η，dd，J = 7·1，1·7 Ηζ)，7·85(1Η，s)，7·66(1Η，s)， 59 200808298 7·42_7·65(5Η，m)，4·34(2Η，s)· 實施例17 ggll Titer Glo/細胞活性活體外分析法 5 該分析係根據購自Promega之套組内的插頁（參見本 申請案文末之附件）中所列示操作程序而被進行。 細胞培養如下列所製備。經解離之海馬回以及皮質細 g 胞培養物自胚胎第18天的大鼠胎兒（day 18 rat fetuses)被 建立該等胎兒經由剖腹產（cesarean section)自以根據美 1〇 國獸醫協會安樂死委員會（AVMA Panel on Euthanasia)的 哈樂先（halothane)麻醉之雌親（dams) (Harlan Sprague-Dawley)被取出。小動物被斷頭且腦被移除並置 放於漢克斯平衡鹽類溶液（Hank，s Balanced Salt solution， lx HBSS; Gibco, Rockville，MD)。該海馬回及皮質被分解 15 且根據組織-類型被集中。組織經胰蛋白酶化(trypsinized) 歷時 15 分鐘（1 mg/ml trypsin-HBSS; Worthington， ⑩ Lakewood，NJ)，以新鮮HBSS清洗，培養於胰蛋白晦抑 制劑（1 mg/ml; Sigma, St· Louis，MO)中歷時 5 分鐘，再度 以新鮮HBSS清洗且繼而以一經火拋光的玻璃滴管於1 20 ml新鮮HBSS中被研磨。經解離細胞以10,000 cells/well 被植種至經聚離胺酸塗層且具補充有26 mM NaHC03(Sigma)、40 mM 葡萄糖（Sigma)、20 mM KCl(Sigma)、1 mM 丙酮酸鈉（Sigma)、10%(v/v)經加熱的 不活化胎牛血清（Hyclone，Logan，UT)，以及0.001%硫酸 60 200808298 建它黴素（gentamicin sulfate，Sigma)(pH 7.4)的 100 μΐ/well 鷹氏最少養分培養基（Eagle’s Minimal Essential Media， MEM; Gibco)的 96-井平盤（BD BioScience，Bedford， MA)。無血清培養物被平盤培養並維持於神經基礎培養基 5 +B27 補充物（Neurobasal medium + B27 supplement,3-Benzothiophenemethylamine and 3-(imidazolium-1-sulfonyl)-1-methylimidazole·1-trifluoroanthracenesulfonic acid were combined in anhydrous acetonitrile. The solution was stirred at rt overnight, EtOAc (EtOAc) 4 NMR (DMSO-A): δ 8·05 (1Η, dd, J = 7·0, 1·6 Hz), 7·99 (1Η, dd, J = 7·1,1·7 Ηζ), 7 85 (1Η, s), 7.66 (1Η, s), 59 200808298 7·42_7·65 (5Η, m), 4·34 (2Η, s)· Example 17 ggll Titer Glo/cell activity in vitro Analytical Method 5 This analysis was performed according to the operating procedures listed in the inserts from the Promega set (see attachment at the end of the text of this application). Cell culture was prepared as follows. The dissociated hippocampus and cortical fine-cell cultures were established from the 18th day of the embryonic rat fetus (day 18 rat fetuses). The fetuses were esarean section according to the US 1 veterinary association euthanasia committee ( The dams (Harlan Sprague-Dawley) of the halothane anesthesia of AVMA Panel on Euthanasia were taken out. The small animals were decapitated and the brain was removed and placed in a Hanks, s Balanced Salt solution (lx HBSS; Gibco, Rockville, MD). The hippocampus and cortex are decomposed 15 and concentrated according to the tissue-type. Tissues were trypsinized for 15 minutes (1 mg/ml trypsin-HBSS; Worthington, 10 Lakewood, NJ), washed with fresh HBSS, and cultured in trypsin inhibitor (1 mg/ml; Sigma, St· It took 5 minutes in Louis, MO), was again washed with fresh HBSS and then ground in a 20% fresh HBSS with a polished glass dropper. Dissociated cells were seeded at a dose of 10,000 cells/well to a polylysine coating supplemented with 26 mM NaHC03 (Sigma), 40 mM glucose (Sigma), 20 mM KCl (Sigma), 1 mM sodium pyruvate ( Sigma), 10% (v/v) heated inactivated fetal bovine serum (Hyclone, Logan, UT), and 0.001% sulfuric acid 60 200808298 gentamicin sulfate (Sigma) (pH 7.4) 100 μΐ/ Well 96-well plate (BD BioScience, Bedford, MA) of Eagle's Minimal Essential Media (MEM; Gibco). Serum-free cultures were plated and maintained in neurobasal medium 5 + B27 supplement (Neurobasal medium + B27 supplement,

Gibco)。於實驗處理前，細胞被允許於一經濕化37°C 5% C02的培養箱中貼附歷時24小時。 g 測試化合物如下被製備：10 mM的各個化合物儲備液 (stock)(配於DMSO中）以1:50被稀釋於DPBS中以產生 ίο 一為200 μΜ的最終儲備液。該儲備液進一步被稀釋於 DPBS中以在每一個為100 gL的井中獲得一為〇」、i以 及120 μΜ的化合物最終濃度。等量的载體(vehicle)或經 稀釋之化合物被加入每一培養井内。Gibco). Prior to the experimental treatment, cells were allowed to attach to a humidified 37 ° C 5% C02 incubator for 24 hours. g Test compounds were prepared as follows: 10 mM of each compound stock (in DMSO) was diluted 1:50 in DPBS to produce a final stock of ίο 200 μΜ. The stock solution was further diluted in DPBS to obtain a final concentration of the compound of 〇, i and 120 μΜ in each well of 100 gL. An equal amount of vehicle or diluted compound is added to each well.

一為30%的過氧化氫(H2〇2; Sigma)儲備溶液以DpBS 15 呈1:10〇地稀釋以產生一為3 mM的儲備溶液。5微升的 載體或也〇2儲備溶液被加入每1〇〇 μ1培養井中以產生一 胃為150 μΜ的最終濃度。 化合物#1係根據此處所述的操作程序被測試，社果 如列於下表4及5。注意的是，下列所示數據中' 每二平 20 盤係為三重複地執行而得到一為η = 9的總數。 61 200808298 表4 :以150 uM的H，Ch侵犯大鼠的海馬回培養物 載體 化合物#1 化合物#1 化合物# 1 (vehicle) 0.1 μΜ 1 μΜ 10 μΜ 平盤1 0.5 28 30 41 平盤2 0.6 16 12 46 平盤3 0.5 17 13 45 平均值 0.5 20 18 44 標準偏差 0.1 7 10 3 表5 :以150 ιιΜ的侵犯大鼠皮質培養物 載體 化合物#8 化合物#8 化合物#8 (vehicle) 0.1 μΜ 1 μΜ 10 μΜ 平盤1 1.2 16 13 22 平盤2 1 43 24 27 平盤3 0.8 19 12 30 平均值 1 26 16 26* 標準偏差 0.2 15 7 4 5 具有鄧恩氏事後檢定（Dunn’s post-hoc test)之克魯斯 卡-沃利斯多重比較（Kruskal-Wallis multiple comparisons)； *，ρ<0·05 **，ρ<0·01 因此，數據顯示：化合物#1就保護神經元免於因氧 10 化壓力或氧化傷害（例如一氧/過氧化物自由基的結果）造 成的死亡及/或損傷是有效的。 62 200808298 實施例18 如一口服組成物的特定具體例，如實施例1所製備之 100 mg的化合物# 1係與足量精細分配的乳糖經配方以提 供一為580至590 mg的總量俾以充填一為Ο尺寸的硬膠 5 囊。 雖然前述說明書以提供說明為目的之實施例敎示本 發明之主要原理，將被理解的是：本發明之實施含括所有 如落入下列申請專利範圍或它們之等效性範圍内的通常 變化、適應變化及/或修飾。 10 【圖式簡單說明】 無 【主要元件符號說明】 15 無A 30% hydrogen peroxide (H2〇2; Sigma) stock solution was diluted 1:10 in DpBS 15 to yield a 3 mM stock solution. Five microliters of carrier or also 储备2 stock solution was added to each 〇〇μ1 culture well to produce a final concentration of 150 μΜ for the stomach. Compound #1 was tested according to the procedure described herein and is shown in Tables 4 and 5 below. Note that in the data shown below, 'every two flats are performed in three repetitions to obtain a total of η = 9. 61 200808298 Table 4: Hippocampal culturing culture carrier compound #1 Compound #1 Compound # 1 (vehicle) 0.1 μΜ 1 μΜ 10 μΜ Flat plate 1 0.5 28 30 41 Flat plate 2 0.6 with 150 μM H, Ch invasion of rat hippocampus 16 12 46 Flat plate 3 0.5 17 13 45 Average 0.5 20 18 44 Standard deviation 0.1 7 10 3 Table 5: Invasion of rat cortical culture carrier compound with 150 ιιΜ #8 Compound #8 Compound #8 (vehicle) 0.1 μΜ 1 μΜ 10 μΜ Flat plate 1 1.2 16 13 22 Flat plate 2 1 43 24 27 Flat plate 3 0.8 19 12 30 Average 1 26 16 26* Standard deviation 0.2 15 7 4 5 With Dunn's post-hoc check (Dunn's post-hoc Test) Kruskal-Wallis multiple comparisons; *,ρ<0·05 **,ρ<0·01 Therefore, the data shows that Compound #1 protects neurons from Death and/or damage due to oxygen 10 pressure or oxidative damage (eg, the result of mono/peroxide radicals) is effective. 62 200808298 Example 18 As a specific example of an oral composition, 100 mg of Compound #1 prepared as in Example 1 is formulated with a sufficient amount of finely divided lactose to provide a total amount of 580 to 590 mg. Fill a hard rubber 5 capsule with a size of Ο. While the foregoing specification has been presented for purposes of illustration, the embodiments of the invention Adapt to changes and/or modifications. 10 [Simple diagram description] None [Main component symbol description] 15 None

6363

Claims (1)

200808298 、申請專利範圍： 1· 一具有一治療有效數量的下列化學式（1)之化合物或 其一藥學上可接受鹽類的用途，其供製造用於神經保 護之一醫藥品：200808298, Patent Application Range: 1. A use of a therapeutically effective amount of a compound of the following formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in neuroprotection: 〇々〇 n、r3 R (I) .其中 氟甲 R1是選自於由氫、鹵素、羥基、甲氧基、 基、靖基與氰基所組成之群組； 15 X-Y 是選自於由 ICH-、-S-C(CH3)-、-0-CH-、 -〇-C(CH3)-、-N(CH3)-CH-以及-CH=CH-CH-所組成之 群組； A為選自於由-CH2·以及_CH(CH3)_所組成的群 組； R2是選自於由氫及甲基所組成的群組； R3以及I係分別獨立地選自於由氫及c广4烷基 所組成的群組； 土 另擇地，R3以及R4還有它們所連接之氮原子形成 二個5至7 、飽和的、局部不飽和或㈣的環狀結 構，可選擇地含有一至兩個額外的雜原子，該雜原子 64 200808298 是個別地選自於由Ο、N以及S所組成的群組。 2.如申請專利範圍第1項之用途，其中 R1是選自於由氫、鹵素、三氟曱基、氰基以及硝 基所組成之群組； 5 X-Y 是選自於由-S-CH-、…O-CH-、-0-C(CH3)-、 -N(CH3)-CH-以及-CH=CH-CH-所組成之群組； A為選自於由-CH2_以及-CH(CH3)-所組成的群 組； R2是選自於由氳及曱基所組成的群組； 10 R3以及R4係分別獨立地選自於由氫、曱基以及乙 基所組成的群組； 或其一藥學上可接受鹽類。 3·如申請專利範圍第2項之用途，其中 R是選自於由氮、齒素、二氣甲基以及氛基所組 15 成之群組； X-Y 是選自於由-S-CH-、-O-CH-、-0-C(CH3)-、 ⑩ -N(CH3)-CH-以及-CH=CH-CH-所組成之群組； A為選自於由-CH2-以及-CH(CH3)-所組成的群 組； 2〇 R2為氫； R3以及R4係分別獨立地選自於由氬及乙基所組 成的群組， 或其一藥學上可接受鹽類。 4·如申請專利範圍第3項之用途，其中 65 200808298 Π1是選自於由氫、5-氯、5·氟、5-溴、4-溴、7-氟、5-三氟曱基以及5-氰基所組成之群組； Χ-Υ 是選自於由-S-CH-、-0-CH…-0-C(CH3)-、 -N(CH3)-CH-以及-CH二CH-CH-所組成之群組； 5 A為選自於由-CH2-以及-CH(CH3)-所組成的群 .組； R2為氫； _ R3以及R4係分別獨立地為氫；任擇地R3為氬而 R4為乙基； 1〇 或其一藥學上可接受鹽類。 5. 如申請專利範圍第1項之用途，其中 R1是選自於由氫、鹵素、三氟甲基與氰基所組成 之群組； X-Y 是選自於由-S-CH-、-0-CH-、-0-C(CH3)-、 is -N(CH3)-CH-以及-CH=CH-CH-所組成之群組； A為選自於由-CH2-以及-CH(CH3)-所組成的群 ® 組； R2是選自於由氳及甲基所組成的群組； R3以及R4還有它們所連接之氮原子形成一個5 20 至7員、飽和的、局部不飽和或芳族的環狀結構，可 選擇地含有一至兩個額外的雜原子，該雜原子是個別 地選自於由Ο、N以及S所組成的群組； 或其一藥學上可接受鹽類。 6. 如申請專利範圍第5項之用途，其中 66 200808298 ,r是選自於m素、三氟甲基與氰基所組成 之群組， 5〇々〇n, r3 R (I). wherein the fluorinated group R1 is selected from the group consisting of hydrogen, halogen, hydroxy, methoxy, benzyl, jing and cyano; 15 XY is selected from ICH a group consisting of -, -SC(CH3)-, -0-CH-, -〇-C(CH3)-, -N(CH3)-CH-, and -CH=CH-CH-; A is selected from the group consisting of a group consisting of -CH2· and _CH(CH3)_; R2 is selected from the group consisting of hydrogen and methyl; R3 and I are independently selected from hydrogen and c4 a group of alkyl groups; alternatively, R3 and R4 and the nitrogen atom to which they are attached form two 5 to 7, saturated, partially unsaturated or (iv) cyclic structures, optionally containing one to two An additional heteroatom, the hetero atom 64 200808298 is individually selected from the group consisting of Ο, N, and S. 2. The use of claim 1, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, cyano and nitro; 5 XY is selected from -S-CH a group consisting of -, O-CH-, -0-C(CH3)-, -N(CH3)-CH-, and -CH=CH-CH-; A is selected from -CH2_ and - a group consisting of CH(CH3)-; R2 is selected from the group consisting of ruthenium and osmium; 10 R3 and R4 are each independently selected from the group consisting of hydrogen, sulfhydryl and ethyl. Group; or a pharmaceutically acceptable salt thereof. 3. The use of the second item of the patent application, wherein R is selected from the group consisting of nitrogen, dentate, di-methyl methyl and aryl groups; XY is selected from -S-CH- a group consisting of -O-CH-, -0-C(CH3)-, 10-N(CH3)-CH-, and -CH=CH-CH-; A is selected from -CH2- and - CH(CH3)- group consisting of; 2〇R2 is hydrogen; R3 and R4 are each independently selected from the group consisting of argon and ethyl, or a pharmaceutically acceptable salt thereof. 4. The use of claim 3, wherein 65 200808298 Π1 is selected from the group consisting of hydrogen, 5-chloro, 5·fluoro, 5-bromo, 4-bromo, 7-fluoro, 5-trifluorodecyl and a group consisting of 5-cyano groups; Χ-Υ is selected from the group consisting of -S-CH-, -0-CH...-0-C(CH3)-, -N(CH3)-CH-, and -CH a group consisting of CH-CH-; 5 A is selected from the group consisting of -CH2- and -CH(CH3)-; R2 is hydrogen; _ R3 and R4 are each independently hydrogen; Alternatively, R3 is argon and R4 is ethyl; 1 hydrazine or a pharmaceutically acceptable salt thereof. 5. The use of claim 1, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano; XY is selected from -S-CH-, -0 a group consisting of -CH-, -0-C(CH3)-, is-N(CH3)-CH-, and -CH=CH-CH-; A is selected from -CH2- and -CH(CH3) ) - group of groups consisting of; R2 is selected from the group consisting of hydrazine and methyl; R3 and R4 and the nitrogen atom to which they are attached form a 5 20 to 7 member, saturated, partially unsaturated Or an aromatic cyclic structure optionally containing one to two additional heteroatoms selected individually from the group consisting of ruthenium, N and S; or a pharmaceutically acceptable salt thereof . 6. For the purposes of application No. 5 of the scope of patent application, 66 200808298, r is selected from the group consisting of m, trifluoromethyl and cyano, 5 1010 20 X-Y 是選自於由-S-CH-、-0_CH·、_0_C(CH3)·、 -N(CH3)-CH-以及-CH=CH_CH_所組成之群組，· 电.A為選自於由偶_以及_CH(CH3)_所組成的群 %是選自於由氫及甲基所組成的群組； R。3以及R4財它們所連接之氮原子形成一個5 至6員、飽和的或芳族的環狀結構，可選擇地含有一 至兩個額外的雜原子，該雜原子是個別地選自於由 〇、Ν以及s所組成的群組； 或其一藥學上可接受鹽類。 如申請專利範圍第6項之用途，其中 R1為氫； Χ-Υ 為-S-CH-; Α 為-CH2_ ; R2為氫； R3以及R4還有它們所連接之氮原子形成一個5 貝的環狀結構’該環狀結構可選擇地選自於由鱗咬 或咪唑所組成的群組； 或其一藥學上可接受鹽類。 如申請專職圍第2項之用途，其中具有化學式⑴ 的化口物疋選自於下列所組成的群H(苯并[外塞吩 •3-基甲基)％醯二胺；1[(5、氣苯并[6]嗟吩冬基）甲基] 67 200808298 磺醯二胺；，[(3-苯并呋喃甲基]磺醯二胺；，[(5-氟苯 并[办]噻吩-3-基）曱基]磺醯二胺；，[(1-苯并[&]噻吩-3-基乙基)-磺醯二胺；ΛΚ1-萘曱基)磺醯二胺；沁[(2-曱基 -3-苯并呋喃）曱基]磺醯二胺；ΛΚ(5-溴苯并[Z>]噻吩-3-5 基）甲基]磺醯二胺；，[(4-溴苯并|>]噻吩-3-基）甲基]磺 醯二胺；Λ4(7-氟苯并[6]噻吩-3-基）曱基]磺醯二胺； 曱基-li/-吲哚_3_基）甲基]磺醯二胺；，[(4-三氟 _ 曱基苯并[&]噻吩-3-基）甲基]磺醯二胺;尽[(4-氰基苯并 [办]噻吩-3-基）曱基]_磺醢二胺；，[苯并[办]噻吩-3-基） 1〇 曱基]胺磺醯吡咯啶；，[苯并|>]噻吩-3-基）曱基]-AT- 乙基磺醯二胺；咪唑-1-磺酸[苯并[6]噻吩-3-基）曱基]-醯胺；以及其藥學上可接受鹽類。 9·如申請專利範圍第1項之用途，其中具有化學式（I ) 的化合物是選自於下列所組成的群組：ΛΚ苯并[6]噻吩 15 -3-基甲基)磺醯二胺；，[(5-氟苯并[办]噻吩-3-基）甲基] 磺醯二胺；以及其藥學上可接受鹽類。 ® 10·—治療有效數量之化合物於製造用以神經保護的一醫 藥品之用途，該化合物是選自於下列所構成之群組： ，(苯并|>]噻吩-3-基曱基)磺醯二胺與其藥學上可接受 20 鹽類。 11.一治療有效數量之具有化學式（I )的化合物與其藥學 上可接受鹽類的用途，其供製造一治療急性神經退化 性疾病的醫藥品 68 20080829820 XY is selected from the group consisting of -S-CH-, -0_CH·, _0_C(CH3)·, -N(CH3)-CH-, and -CH=CH_CH_, · Electric. A is selected from The group % consisting of even_ and _CH(CH3)_ is selected from the group consisting of hydrogen and methyl; R. 3 and R4, the nitrogen atom to which they are attached forms a 5 to 6 membered, saturated or aromatic ring structure, optionally containing one to two additional heteroatoms, which are individually selected from a group consisting of Ν, s, and s; or a pharmaceutically acceptable salt thereof. For example, the use of the scope of claim 6 wherein R1 is hydrogen; Χ-Υ is -S-CH-; Α is -CH2_; R2 is hydrogen; R3 and R4 and the nitrogen atom to which they are attached form a 5-shell Cyclic structure 'The cyclic structure is optionally selected from the group consisting of scale bites or imidazoles; or a pharmaceutically acceptable salt thereof. For the purpose of applying for the second item of the full-time, the chemical substance of the formula (1) is selected from the group H (benzo[extopon-3-ylmethyl)% guanidine diamine; 1[( 5, gas benzo[6] fluorenyl winter base) methyl] 67 200808298 sulfonamide diamine;, [(3-benzofuranmethyl] sulfonamide diamine;, [(5-fluorobenzo[[]] Thiophen-3-yl)indolyl]sulfonyldiamine;,[(1-benzo[&]thiophen-3-ylethyl)-sulfonamide;ΛΚ1-naphthyl)sulfonamide;沁[(2-Mercapto-3-benzofuran)indolyl]sulfonyldiamine; hydrazine (5-bromobenzo[Z>]thiophene-3-5yl)methyl]sulfonamide;(4-bromobenzo->]thiophen-3-yl)methyl]sulfonamide;Λ4(7-fluorobenzo[6]thiophen-3-yl)indolyl]sulfonyldiamine;-li/-吲哚_3_yl)methyl]sulfonyldiamine;,[(4-trifluoro-mercaptobenzo[&]thiophen-3-yl)methyl]sulfonamide;[(4-cyanobenzo[io]thiophen-3-yl)indolyl]-sulfonyldiamine;, [benzo[thiophen-3-yl) 1indolyl]sulfonopyrrolidine; , [Benzene|>]thiophen-3-yl)indenyl]-AT-ethylsulfonyldiamine; imidazole-1-sulfonic acid [benzo[6]thiophen-3-yl) Yl] - Amides; and pharmaceutically acceptable salts thereon. 9. The use of the first aspect of the patent application, wherein the compound of formula (I) is selected from the group consisting of indolo[6]thiophene-15-3-ylmethyl)sulfonamide ;, [(5-fluorobenzo[thiophen-3-yl)methyl]sulfonamide; and pharmaceutically acceptable salts thereof. ® 10 - The use of a therapeutically effective amount of a compound for the manufacture of a medicament for neuroprotection, the compound being selected from the group consisting of: (benzo[|]|thiophen-3-ylindenyl Sulfodiamine and its pharmaceutically acceptable 20 salts. 11. Use of a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of acute neurodegenerative diseases 68 200808298 其中among them 10 1510 15 20 R1是選自於由氫、鹵素、羥基、曱氧基、三氟甲 基、碗基與氰基所組成之群組； X-Υ 是選自於由-S-CH-、-S-C(CH3)-、、 -0-C(CH3)…-N(CH3)-CH-以及-CH=CH-CH-所組成之 群組； A為選自於由ΤΗπ以及-CH(CH3)-所組成的群 組； R2是選自於由氳及甲基所組成的群組； R3以及R4係分別獨立地選自於由氫及cr4烷基 所組成的群組； 一另擇地，R3以及R4還有它們所連接之氮原子形成 -個5至7員、飽和的、局部不飽和或芳族的環狀結 構，其可選擇地含有一至兩個額外的雜原子，該雜原 子是個別地選自於由0、N以及3所組成组。 12.如申請專利範圍第11項之用途，其中 、 二氟甲基、氰基與硝基 R是選自於由氫、鹵素、 所組成之群組； 69 200808298 Χ-Υ 是選自於由-S-CH-、-O-CH-、-0C(CH3)-、 -N(CH3)-CH-以及-CH=CH-CH-所組成之群組； A為選自於由-CH2-以及-CH(CH3)-所組成的群 組； 5 R2是選自於由氫及曱基所組成的群組； R3以及R4係分別獨立地選自於由氫、甲基以及乙 基所組成的群組； g 或其一藥學上可接受鹽類。 13·如申請專利範圍第2項之用途，其中 ίο R1是選自於由氫、鹵素、三氟甲基與氰基所組成 之群組； X-Y 是選自於由-S-CH-、-O-CH-、-0-C(CH3)… -N(CH3)-CH-以及-CH=CH-CH-所組成之群組； A為選自於由_CH2-以及-CH(CH3)-所組成的群 15 組； R2為氫； ® R3以及R4係分別獨立地選自於由氫以及乙基所 組成的群組； 或其一藥學上可接受鹽類。 20 14·如申請專利範圍第13項之用途，其中 R1是選自於由氫、5-氯、5-敗、5-漠、4-溴、7-氟、5·三氟甲基以及5-氰基所組成之群組； X-Y 是選自於由-S-CH-、-0-CH-、-0-C(CH3)-、 -N(CH3)-CH-以及-CH二CH-CH-所組成之群組； 70 200808298 A為選自於由-CH2-以及-CH(CH3)-所組成的群 組； R2為氫； R3以及R4係分別獨立地為氫；任擇地R3為氫而 5 R4為乙基； 或其一藥學上可接受鹽類。 15.如申請專利範圍第11項之用途，其中 _ R1是選自於由氫、鹵素、三氟曱基與氰基所組成 之群組； ίο X-Y 是選自於由-S-CH-、-0_CH-、_0-C(CH3)-、 -N(CH3)-CH-以及-CH二CH-CH-所組成之群組； A為選自於由-CH2-以及-CH(CH3)-所組成的群 組； R2是選自於由氫及甲基所組成的群組； 15 R3以及R4還有它們所連接之氮原子形成一個5 至7員、飽和的、局部不飽和或芳族的環狀結構，其 ^ 可選擇地含有一至兩個額外的雜原子，該雜原子是獨 立地選自於由Ο、N以尽S所組成的群組； 或其一藥學上可接受鹽類。 2〇 16·如申請專利範圍第11項之用途，其中 R1是選自於由氫、鹵素、三氟曱基與氰基所組成 之群組； X-Y 是選自於由-S-CH-、-0-CH-、-0-C(CH3)-、 -N(CH3)-CH-以及-CH=CH-CH-所組成之群組； 71 200808298 組 A為選自於由—CH2-以及· CH(CH3)_所組成的群 疋選自於由氫及甲基所組成的群組； 520 R1 is selected from the group consisting of hydrogen, halogen, hydroxy, decyloxy, trifluoromethyl, bowl and cyano; X-Υ is selected from -S-CH-, -SC ( CH3)-, -0-C(CH3)...-N(CH3)-CH- and -CH=CH-CH-; group A is selected from ΤΗπ and -CH(CH3)- a group consisting of; R2 is selected from the group consisting of hydrazine and methyl; R3 and R4 are each independently selected from the group consisting of hydrogen and a cr4 alkyl group; alternatively, R3 and R4 also has a nitrogen atom to which they are attached to form a 5- to 7-membered, saturated, partially unsaturated or aromatic cyclic structure which optionally contains one to two additional heteroatoms which are individually It is selected from the group consisting of 0, N and 3. 12. The use of claim 11, wherein the difluoromethyl group, the cyano group and the nitro group R are selected from the group consisting of hydrogen and halogen; 69 200808298 Χ-Υ is selected from a group consisting of -S-CH-, -O-CH-, -0C(CH3)-, -N(CH3)-CH-, and -CH=CH-CH-; A is selected from -CH2- And a group consisting of -CH(CH3)-; 5 R2 is selected from the group consisting of hydrogen and sulfhydryl; R3 and R4 are each independently selected from hydrogen, methyl and ethyl. a group; g or a pharmaceutically acceptable salt thereof. 13. The use of claim 2, wherein ίο R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano; XY is selected from -S-CH-, - a group consisting of O-CH-, -0-C(CH3)...-N(CH3)-CH- and -CH=CH-CH-; A is selected from _CH2- and -CH(CH3) - Group 15 consisting of; R2 is hydrogen; ® R3 and R4 are each independently selected from the group consisting of hydrogen and ethyl; or a pharmaceutically acceptable salt thereof. 20 14. The use of claim 13 wherein R1 is selected from the group consisting of hydrogen, 5-chloro, 5-defene, 5-ear, 4-bromo, 7-fluoro, 5·trifluoromethyl and 5 a group consisting of cyano groups; XY is selected from the group consisting of -S-CH-, -0-CH-, -0-C(CH3)-, -N(CH3)-CH-, and -CH di CH- a group consisting of CH-; 70 200808298 A is selected from the group consisting of -CH2- and -CH(CH3)-; R2 is hydrogen; R3 and R4 are each independently hydrogen; optionally R3 Is hydrogen and 5 R4 is ethyl; or a pharmaceutically acceptable salt thereof. 15. The use of claim 11, wherein _R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano; ίο XY is selected from -S-CH-, a group consisting of -0_CH-, _0-C(CH3)-, -N(CH3)-CH-, and -CH2CH-CH-; A is selected from -CH2- and -CH(CH3)- a group consisting of; R2 is selected from the group consisting of hydrogen and methyl; 15 R3 and R4 and the nitrogen atom to which they are attached form a 5 to 7 member, saturated, partially unsaturated or aromatic a cyclic structure, optionally containing one to two additional heteroatoms independently selected from the group consisting of hydrazine, N, and S; or a pharmaceutically acceptable salt thereof . 2. The use of claim 11, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano; XY is selected from -S-CH-, a group consisting of -0-CH-, -0-C(CH3)-, -N(CH3)-CH-, and -CH=CH-CH-; 71 200808298 Group A is selected from -CH2- and · The group consisting of CH(CH3)_ is selected from the group consisting of hydrogen and methyl; 5 10 1510 15 20 ^収R4财它朗賴之氮原子形成-個5 員飽和的、局部不飽和或芳族的環狀結構，並 地含有—至兩_外的雜原子，該雜原子是獨 選自於由Ο、N以及S所組成的群組； 或其一藥學上可接受鹽類。 17·如申請專利範圍第16項之用途，其申 R1為氫； Χ_γ 為·S-CH-; Α 為-CIV; R為氫； 。R3以及R4還有它們所連接之氮原子形成一個5 貝的城結構’該環狀結構可選自於由吡 所構成的群組； 4中坐 或一藥學上可接受鹽類。 18’如申請專利範圍第12項之用途’其中具有化學式⑴ 的化合物是選自於下列所構成之群組：仏(苯并[冲塞吩 卞基曱基)石黃酿m氯苯并[冲塞吩冬基）甲基] 石尹、醯一胺，"_[(3_苯并呋喃甲基]磺醯二胺；尽[(孓氟苯 并肿塞吩·3-基）甲基]續醯二胺；沁[(1-苯并肿塞吩_3· 基乙基）-磺醯二胺；ΑΚ1-萘甲基)磺醯二胺；沁[(2•甲基 -3-苯并呋喃）曱基]磺醯二胺；沁[(5_溴苯并噻吩 72 200808298 基)甲基]磺醯二胺；，[(4-溴苯并[6]噻吩-3-基）甲基]磺 醯二胺；Λ4(7-氟苯并[6]噻吩-3-基）曱基]磺醯二胺； ，[(1-曱基-17/-吲哚-3_基)甲基]磺醯二胺；，[(4-三氟 甲基苯并[办]噻吩-3-基)曱基]磺醯二胺；，[(4-氰基苯并 5 [办]噻吩-3-基）甲基]-磺醯二胺；，[苯并[办]噻吩-3-基) 甲基]胺磺醯°比咯啶；，[苯并[办]噻吩-3-基）曱基]-AT-乙基磺醯二胺；咪唑-1-磺酸[苯并[i>]噻吩-3-基）甲基]-醯胺；以及其藥學上可接受鹽類。 19·如申請專利範圍第11項之用途，其中具有化學式（I ) 1〇 的化合物是選自於下列所構成之群組：豕（苯并|>]噻吩 -3-基曱基)磺醯二胺；，[(5-氟苯并[6]噻吩-3-基）甲基] 磺醯二胺；以及其藥學上可接受鹽類。 20. —治療有效數量之化合物於製造治療一急性神經退化 性疾病之醫藥品的用途，該化合物選自於由ΛΚ苯并[Z>] 15 噻吩-3-基曱基）磺醯二胺以及其藥學上可接受鹽類所 組成之群組。 ® 21·—治療有效數量之具有化學式（I )的化合物或其一藥 學上可接受鹽類的用途，其供製造治療一慢性神經退 化性疾病之醫藥品20 ^R4 is formed by a nitrogen atom forming a 5-membered saturated, partially unsaturated or aromatic ring structure, and containing - to a hetero atom outside the two, the hetero atom is selected from a group consisting of Ο, N, and S; or a pharmaceutically acceptable salt thereof. 17. If the application of claim 16 is used, the application R1 is hydrogen; Χ_γ is · S-CH-; Α is -CIV; R is hydrogen; R3 and R4 also have a nitrogen atom to which they are attached to form a 5 Å city structure. The cyclic structure may be selected from the group consisting of pyridin; 4 or a pharmaceutically acceptable salt. 18 'Use as claimed in item 12 of the patent application' wherein the compound of formula (1) is selected from the group consisting of hydrazine (benzo[indenyl] fluorenyl) feldspar, m-chlorobenzo[冲 吩 冬 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基a diamine; hydrazine [(1-benzothiazepine-3-ylethyl)-sulfonyldiamine; ΑΚ1-naphthylmethyl)sulfonamide; 沁[(2•methyl-3) -benzofuran)fluorenyl]sulfonyldiamine; hydrazine[(5-bromobenzothiophene 72 200808298)methyl]sulfonyldiamine;,[(4-bromobenzo[6]thiophen-3-yl Methyl]sulfonamide diamine; Λ4(7-fluorobenzo[6]thiophen-3-yl)indolyl]sulfonyldiamine; ,[(1-mercapto-17/-吲哚-3_yl) Methyl] sulfonamide; [(4-trifluoromethylbenzo[io]thiophen-3-yl)indolyl]sulfonyldiamine;,[(4-cyanobenzo-5) Thiophen-3-yl)methyl]-sulfonyldiamine;,[benzo[thiophen-3-yl)methyl]amine sulfonium pyrrole;,[benzo[thio]thiophene-3- Alkyl]-AT-ethylsulfonyldiamine; imidazole-1-sulfonic acid [benzo[i>]thiophen-3-yl) And guanidine; and pharmaceutically acceptable salts thereof. 19. The use of claim 11 wherein the compound of formula (I) 1 is selected from the group consisting of hydrazine (benzo[>]thiophen-3-ylindenyl)sulfonate Decanediamine; [(5-fluorobenzo[6]thiophen-3-yl)methyl]sulfonamide; and pharmaceutically acceptable salts thereof. 20. Use of a therapeutically effective amount of a compound selected from the group consisting of anthraquinone [Z>] 15 thiophen-3-ylmercapto)sulfonamide and a medicament for the treatment of an acute neurodegenerative disease a group consisting of pharmaceutically acceptable salts thereof. ® 21 - The use of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a chronic neurodegenerative disease 20 73 (I) 200808298 其中 Rl是選自於由氫、鹵素、羥基、曱氧基、三氣甲 基、硝基與氰基所組成之群組； χ-γ 是選自於由-S-CH-、-S-C(CH3>、、 5 e〇-C(CH3)…-N(CH3)-CH·以及-CH=CH-CH-所組成之 群組； A為選自於由-CH2·以及-CH(CH3·)-所組成的群 • ； R2是選自於由氫及甲基所組成的群組； 10 r3以及R4係分別獨立地選自於由氫及Cl_4垸基 所組成的群組； ^a 另擇地，R3以及R4還有它們所連接之氮原子形成 一個5至7員、飽和的、局部不飽和或芳族的環狀結 15 構，其可選擇地含有一至兩個額外的雜原子，該雜原 子疋獨立地選自於由〇、N以及S所組成的群組。、 φ 22.如申請專利範園第21項之用途，其中 R1是選自於由氫、鹵素、三氟甲基、氰基與硝基 所組成之群組； 土 X_Y 是選自於由-S-CH-、-O-CH-、-〇-c(CH3)-、 20 -N(CH3)-CH-以及-CH=CH-CH-所組成之群組；3 A為選自於由七出-以及^與^^-所組成的群 組； R2是選自於由氳及甲基所組成的群組； R3以及R4係分別獨立地選自於由氫、甲基以及乙 74 200808298 基所組成的群組； 或其一藥學上可接受鹽類。 23. 如申請專利範圍第22項之用途，其中 R1是選自於由氫、鹵素、三氟甲基以及氰基所組 5 成之群組； X-Y 是選自於由-S讎CH-、-Ο睡CH_、-0-C(CH3)-、 -N(CH3)-CH-以及-CH二CH-CH-所組成之群組； A為選自於由-CH2-以及-CH(CH3)-所組成的群 組； ίο R2為氫； R3以及R4係分別獨立地選自於由氫以及乙基所 組成的群組； 或其一藥學上可接受鹽類。 24. 如申請專利範圍第23項之用途，其中 is R1是選自於由氫、5-氯、5-氟、5-溴、4-溴、7- 氟、5-三氟曱基以及5-氰基所組成之群組； 馨 X-Y 是選自於由-S-CH-、-0-CH-、-0-C(CH3)-、 -N(CH3)-CH-以及-CH=CH-CH-所組成之群組； A為選自於由-CH2-以及-CH(CH3)-所組成的群 20 組； R2為氫； R3以及R4係分別獨立地為氫；任擇地R3為氫而 R4為乙基； 或其一藥學上可接受鹽類。 75 200808298 25. 如申請專利範圍第21項之用途，其中 R1是選自於由氫、鹵素、三氟甲基與氰基所組成 之群組； X-Y 是選自於由-S-CH-、-0-CH-、-OC(CH3)-、 5 -N(CH3)-CH-以及-CH二CH-CH-所組成之群組； A為選自於由-CH2-以及-CH(CH3)-所組成的群 組； R2是選自於由氫及曱基所組成的群組； ® R3以及R4還有它們所連接之氮原子形成一個5 ίο 至7員、飽和的、局部不飽和或芳族的環狀結構，其 可選擇地含有一至兩個額外的雜原子，該雜原子是獨 立地選自於由Ο、N以及S所組成的群組； 或其一藥學上可接受鹽類。 26. 如申請專利範圍第25項之用途，其中 is R1是選自於由氫、鹵素、三說曱基與氰基所組成 之群組； ⑩ X-Y 是選自於由-S_CH-、-0-CH·、-0-C(CH3)-、 -N(CH3)-CH-以及-CH=CH-CH-所組成之群組； A為選自於由-CH2-以及-CH(CH3)-所組成的群 20 組； R2是選自於由氫及甲基所組成的群組； R3以及R4還有它們所連接之氮原子形成一個5 至6員、飽和的或芳族的環狀結構，其可選擇地含有 一至兩個額外的雜原子，該雜原子是獨立地選自於由 76 200808298 〇、N以及S所組成的群組，· 或其一藥學上可接受鹽類。 27·如申請專利範圍第26項之用途，其中 R1為氫； 520 73 (I) 200808298 wherein R1 is selected from the group consisting of hydrogen, halogen, hydroxy, decyloxy, trimethylmethyl, nitro and cyano; χ-γ is selected from -S- a group consisting of CH-, -SC(CH3>, 5 e〇-C(CH3)...-N(CH3)-CH· and -CH=CH-CH-; A is selected from -CH2· And a group consisting of -CH(CH3.)-; R2 is selected from the group consisting of hydrogen and methyl; 10 r3 and R4 are independently selected from hydrogen and Cl_4 thiol. Groups; ^a Alternatively, R3 and R4, together with the nitrogen atom to which they are attached, form a 5 to 7 membered, saturated, partially unsaturated or aromatic ring structure, optionally containing one to two An additional heteroatom, the hetero atom is independently selected from the group consisting of 〇, N, and S., φ 22. For use in claim 21, wherein R1 is selected from hydrogen a group consisting of halogen, trifluoromethyl, cyano and nitro; soil X_Y is selected from -S-CH-, -O-CH-, -〇-c(CH3)-, 20-N a group consisting of (CH3)-CH- and -CH=CH-CH-; 3 A is selected from a group consisting of - and ^ and ^^-; R2 is selected from the group consisting of hydrazine and methyl; R3 and R4 are independently selected from hydrogen, methyl and B. A group consisting of: or a pharmaceutically acceptable salt thereof. 23. The use of claim 22, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, and cyano. Group of XY is selected from the group consisting of -S雠CH-, - Sleeping CH_, -0-C(CH3)-, -N(CH3)-CH-, and -CH two CH-CH- a group; A is selected from the group consisting of -CH2- and -CH(CH3)-; ίο R2 is hydrogen; R3 and R4 are each independently selected from the group consisting of hydrogen and ethyl; Or a pharmaceutically acceptable salt thereof. 24. The use of claim 23, wherein is R1 is selected from the group consisting of hydrogen, 5-chloro, 5-fluoro, 5-bromo, 4-bromo, 7- a group consisting of fluorine, 5-trifluoromethyl and 5-cyano; XY is selected from -S-CH-, -0-CH-, -0-C(CH3)-, -N ( a group consisting of CH3)-CH- and -CH=CH-CH-; A is selected from the group consisting of -CH2- and -CH(CH3)- Group 20; R2 is hydrogen; R3 and R4 are each independently hydrogen; optionally R3 is hydrogen and R4 is ethyl; or a pharmaceutically acceptable salt thereof. 75 200808298 25. The use of claim 21, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano; XY is selected from -S-CH-, a group consisting of -0-CH-, -OC(CH3)-, 5-N(CH3)-CH-, and -CH2CH-CH-; A is selected from -CH2- and -CH(CH3) a group consisting of; R2 is selected from the group consisting of hydrogen and sulfhydryl; ® R3 and R4 and the nitrogen atom to which they are attached form a 5 ίο to 7 member, saturated, partially unsaturated Or an aromatic cyclic structure optionally containing one to two additional heteroatoms independently selected from the group consisting of ruthenium, N and S; or a pharmaceutically acceptable salt thereof class. 26. The use of claim 25, wherein is R1 is selected from the group consisting of hydrogen, halogen, sulfonium and cyano; 10 XY is selected from -S_CH-, -0 a group consisting of -CH·, -0-C(CH3)-, -N(CH3)-CH-, and -CH=CH-CH-; A is selected from -CH2- and -CH(CH3) - Group 20 consisting of; R2 is selected from the group consisting of hydrogen and methyl; R3 and R4 and the nitrogen atom to which they are attached form a 5- to 6-membered, saturated or aromatic ring A structure optionally containing one to two additional heteroatoms independently selected from the group consisting of 76 200808298 〇, N and S, or a pharmaceutically acceptable salt thereof. 27. The use of claim 26, wherein R1 is hydrogen; 1010 20 入-Y 為; Α 為-CH2_; R為氯； ^以及R4還有它們所連接之氮原子形成一個$ 貝的¥狀結構’該環狀結構可選自於由対唆或味唾 所組成的群組； 或其一藥學上可接受鹽類。 冰如申請專利第22項之用途’其中具有化學式⑴ 的化合物是選自於下列所構成的群組：ΛΚ笨并[_吩 ^基甲基）磺醯二胺；尽[(5_氯苯并噻吩_3_基）甲基] 石κ I一胺，ΛΓ-[(3-苯并呋喃甲基]磺醯二胺；f [(孓氟苯 并P]噻吩-3-基）甲基]磺醯二胺；沁[(1_苯并[6]噻吩_3_ 基乙基）_石黃酿二胺；萘甲基)石黃醯二胺；尽[(2_甲基 •3·苯并吱喃）曱基]磺醯二胺；沁[(5_溴苯并噻吩_3_ 基）曱基]磺醯二胺；ΛΓ-[(4-溴苯并[办]噻吩基）甲基]磺 酸二胺；ΛΚ(7·氟苯并[Z>]噻吩_3_基）甲基]磺醯二胺； ^[(1-甲基-li/-吲哚冬基）曱基]磺醯二胺；，[(4_三氟 甲基苯并[δ]售吩冬基）甲基]磺醯二胺；尽[(4_氰基苯并 0]噻吩-3-基）曱基；h磺醯二胺；，[苯并⑼噻吩冬基） 甲基]胺磺各咬；iV-[苯并[5]ϋ塞吩-3-基）曱基]_#二 77 200808298 乙基磺醯二胺；咪唑-1-磺酸[苯并[办]噻吩-3-基）曱基]-醯胺；以及其藥學上可接受鹽類。 520 is -Y is; Α is -CH2_; R is chlorine; ^ and R4 and the nitrogen atom to which they are attached form a $-shell structure. The cyclic structure may be selected from the group consisting of a group consisting of; or a pharmaceutically acceptable salt thereof. The use of the ice as in the application of the patent item 22 wherein the compound of the formula (1) is selected from the group consisting of: ΛΚ 并 [ _ _ _ ; ; ; ; ; ; ( ( ( ( ( And thiophene-3-yl)methyl]glycol I-amine, ΛΓ-[(3-benzofuranmethyl)sulfonyldiamine; f [(孓fluorobenzo-P)thiophen-3-yl)methyl Sulfonated diamine; hydrazine [(1_benzo[6]thiophene-3-ylethyl)_Calcium diamine; naphthylmethyl) scutane diamine; do [(2_methyl•3· Benzopyran) sulfonyldiamine; hydrazine [(5-bromobenzothiophene-3-yl)indolyl]sulfonyldiamine; hydrazine-[(4-bromobenzo[io]thiophenyl) Diamine]sulfonic acid diamine; hydrazine (7·fluorobenzo[Z>]thiophene-3-yl)methyl]sulfonyldiamine; ^[(1-methyl-li/-indoleyl)fluorenyl Sulfonamide; [(4_trifluoromethylbenzo[δ] phenylheptyl)methyl]sulfonamide; amine [(4-cyanobenzo[0]thiophen-3-yl) Sulfhydryl; h sulfonium diamine;, [benzo(9) thiophenymidyl) methyl]amine sulfonate each bit; iV-[benzo[5]decanphen-3-yl)indolyl]_#二77 200808298 Ethylsulfonium diamine; imidazole-1-sulfonic acid [benzo[thiophen-3-yl)indenyl]-decylamine; And pharmaceutically acceptable salts thereof. 5 10 1510 15 20 29·如申請專利範圍第21項之用途，其中具有化學式（I) 的化合物是選自於下列所組成之群組：，（苯并[6]噻吩 -3-基甲基)磺醯二胺；，[(5-氟苯并[办]噻吩-3-基）甲基] 磺醯二胺；以及其藥學上可接受鹽類。 30· —治療有效數量之化合物於製造治療一慢性神經退化 性疾病之醫藥品的用途，該化合物選自於由ΛΚ苯并[办] 噻吩-3-基甲基）磺醯二胺以及其藥學上可接受鹽類所 組成之群組。 31·—治療有效數量之具有化學式（I )的化合物或其藥學 上可接受鹽類的用途，其供製造用於預防在腦部、頭 部或脊髓創傷或受傷後的神經元死亡或損傷之一醫藥 品20 29. The use of claim 21, wherein the compound of formula (I) is selected from the group consisting of: (benzo[6]thiophen-3-ylmethyl)sulfonate An amine;, [(5-fluorobenzo[thiophen-3-yl)methyl]sulfonamide; and a pharmaceutically acceptable salt thereof. 30. Use of a therapeutically effective amount of a compound for the manufacture of a medicament for the treatment of a chronic neurodegenerative disease selected from the group consisting of benzophenone-3-ylmethyl)sulfonamide and its pharmacy A group consisting of acceptable salts. 31. Use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a neuronal death or injury following trauma or injury to the brain, head or spinal cord a pharmaceutical product Nsr3 R4 (I) /其中 R1是選自於由氫、鹵素、經基、甲氧基、三氟曱 基、硝基與氰基所組成之群組； X-Y 是選自於由-S-CH-、-S-C(CH3)-、-0-CH-、 78 200808298 -0-C(CH3)-、-N(CH3)-CH-以及-CH=CH-CH-所組成之 群組； A為選自於由-CH2-以及-CH(CH3)-所組成的群 組； 5 R2是選自於由氫及曱基所組成的群組； R3以及R4係分別獨立地選自於由氫及Ci-4烷基 所組成的群組； 另擇地，R3以及R4還有它們所連接之氮原子形成 一個5至7員、飽和的、局部不飽和或芳族的環狀結 1〇 構，其可選擇地含有一至兩個附加的雜原子，該雜原 子是獨立地選自於由Ο、N以及S所組成的群組。 32·如申請專利範圍第31項之用途，其中 R1是選自於由氫、鹵素、三氟曱基、氰基與硝基 所組成之群組； 15 X-Y 是選自於由-S-CH-、-O-CH-、-0-C(CH3)-、 -N(CH3)-CH-以及-CH=CH-CH所組成之群組； ⑩ A為選自於由-CH2-以及-CH(CH3)-所組成的群 組； R2是選自於由氫及甲基所組成的群組； 20 R3以及R4係分別獨立地選自於由氫、曱基以及乙 基所組成的群組， 或其一藥學上可接受鹽類。 33·如申請專利範圍第32項之用途，其中 R1是選自於由氩、鹵素、三氟曱基以及氰基所組 79 200808298 成之群組， X-Y 是選自於由-S-CH-、-0-CH-、-0-C(CH3)-、 -N(CH3)-CH-以及-CH=CH-CH-所組成之群組； A為選自於由-CH2-以及-CH(CH3)-所組成的群 5 組； R2為氫； R3以及R4係分別獨立地選自於由氫以及乙基所 組成的群組， 或其一藥學上可接受鹽類。 10 34·如申請專利範圍第33項之用途，其中 R1是選自於由氫、5-氯、5-氟、5-溴、4-溴、7-氣、5 -二氣曱基以及5 -氣基所組成之群組， X-Y 是選自於由-S-CH-、-0-CH-、-0-C(CH3)-、 -N(CH3)-CH-以及-CH二CH-CH-所組成之群組； 15 A為選自於由<112-以及-(：11((：113)-所組成的群 組； • R2為氳； R3以及R4係個別為氫；任擇地R3為氫而R4為乙 基； 20 或其一藥學上可接受鹽類。 35·如申請專利範圍第31項之用途，其中 R1是選自於由氫、鹵素、三氟曱基與氰基所組成 之群組； X-Y 是選自於由-S-CH-、-0-CH-、-0-C(CH3)-、 80 \ Λ 200808298 -N(CH3)-CH-以及-CH二CH-CH-所組成之群組； A為選自於由-CH2-以及-CH(CH3)-所組成的群 組； R2是選自於由氫及甲基所組成的群組； 5 R3以及R4還有它們所連接之氮原子形成一個5 至7員、飽和的、局部不飽和或芳族的環狀結構，其 可選擇地含有一至兩個額外的雜原子，該雜原子是獨 _ 立地選自於由0、N以及S所組成的群組； 或其一藥學上可接受鹽類。 ίο 36·如申請專利範圍第35項之用途，其中 R1是選自於由氫、鹵素、三氟甲基與氰基所組成 之群組； X-Y 是選自於由-S-CH-、-0-CH-、-0-C(CH3)-、 -N(CH3)-CEl·以及-CH=CH-CH-所組成之群組； 15 A為選自於由-CH2-以及-CH(CH3)-所組成的群 組； ® R2是選自於由氫及甲基所組成的群組； R3以及R4還有它們所連接之氮原子形成一個5 至6員的、飽和的或芳族的環狀結構，其可選擇地含 20 有一至兩個額外的雜原子，該雜原子是獨立地選自於 由Ο、N以及S所組成的群組； 或其一藥學上可接受鹽類。 37·如申請專利範圍第36項之用途，其中 R1為氫； 8 1 200808298 Χ-Υ 為 _S-CH-; A 為-CH2-; R2為氫； R3以及R4還有它們所連接之氮原子形成一個5 5 員的環狀結構，該環狀結構可選自於由吡咯啶或咪唑 所組成的群組； 或其一藥學上可接受鹽類。 _ 38·如申請專利範圍第32項之用途，其中具有化學式（I ) 的化合物是選自於下列所構成之群組：，（苯并|>]噻吩 10 -3-基甲基）磺醯二胺；，[(5-氯苯并[6]噻吩-3-基）甲基] 磺醯二胺；，[(3-苯并呋喃曱基]磺醯二胺；，[(5-氟苯 并〇]噻吩-3-基）曱基]磺醯二胺；苯并[6]噻吩-3-基乙基)-磺醯二胺；，（1-萘甲基)磺醯二胺；，[(2-甲基 -3-苯并呋喃）甲基]磺醯二胺；沁[(5-溴苯并〇]噻吩-3-15 基）甲基]磺醯二胺；沁[(4-溴苯并[6]噻吩-3-基）曱基]磺 醯二胺；，[(7-氟苯并[办]噻吩-3-基）甲基]磺醯二胺； * 曱基-1//-吲哚-3-基）甲基]磺醯二胺；，[(4-三氟 曱基苯并[6]噻吩-3-基）甲基]磺醯二胺；，[(4-氰基苯并 [办]噻吩-3-基）甲基]-磺醯二胺；7V-[苯并[6]噻吩-3-基） 20 甲基]胺磺醯吼咯啶；沁[苯并〇]噻吩-3-基）甲基]-ΛΓ- 乙基磺醯二胺；咪唑-1-磺酸[苯并[>]噻吩-3-基）甲基]-醯胺；以及其藥學上可接受鹽類。 39·如申請專利範圍第31項之用途，其中具有化學式（I ) 的化合物是選自於下列所構成之群組：豕（苯并|>]噻吩 82 200808298 -3-基曱基)磺醯二胺；沁[(5-氟苯并[6]噻吩-3-基）甲基] 磺醯二胺；以及其藥學上可接受鹽類。 40·—治療有效數量之化合物供製造一用以預防在腦部、 頭部或脊髓創傷或受傷後的神經元死亡或損傷之醫藥 5 品的用途，該化合物選自於由，（苯并[6]噻吩-3-基曱 基）磺醯二胺以及其藥學上可接受鹽類所組成之群組。Nsr3 R4 (I) / wherein R1 is selected from the group consisting of hydrogen, halogen, thiol, methoxy, trifluoromethyl, nitro and cyano; XY is selected from -S-CH a group consisting of -, -SC(CH3)-, -0-CH-, 78 200808298 -0-C(CH3)-, -N(CH3)-CH-, and -CH=CH-CH-; Selected from the group consisting of -CH2- and -CH(CH3)-; 5 R2 is selected from the group consisting of hydrogen and sulfhydryl; R3 and R4 are each independently selected from hydrogen and a group consisting of Ci-4 alkyl groups; alternatively, R3 and R4 and the nitrogen atom to which they are attached form a 5 to 7 membered, saturated, partially unsaturated or aromatic ring structure. It optionally contains one to two additional heteroatoms independently selected from the group consisting of ruthenium, N and S. 32. The use of claim 31, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, cyano and nitro; 15 XY is selected from -S-CH a group consisting of -, -O-CH-, -0-C(CH3)-, -N(CH3)-CH-, and -CH=CH-CH; 10 A is selected from -CH2- and - a group consisting of CH(CH3)-; R2 is selected from the group consisting of hydrogen and methyl; 20 R3 and R4 are each independently selected from the group consisting of hydrogen, sulfhydryl and ethyl Group, or a pharmaceutically acceptable salt thereof. 33. The use of claim 32, wherein R1 is selected from the group consisting of argon, halogen, trifluoromethyl and cyano groups 79 200808298, XY is selected from -S-CH- a group consisting of -0-CH-, -0-C(CH3)-, -N(CH3)-CH-, and -CH=CH-CH-; A is selected from -CH2- and -CH (CH3) - Group 5 consisting of; R2 is hydrogen; R3 and R4 are each independently selected from the group consisting of hydrogen and ethyl, or a pharmaceutically acceptable salt thereof. 10 34. The use of claim 33, wherein R1 is selected from the group consisting of hydrogen, 5-chloro, 5-fluoro, 5-bromo, 4-bromo, 7-, 5-dioxan and 5 a group consisting of gas groups, XY is selected from -S-CH-, -0-CH-, -0-C(CH3)-, -N(CH3)-CH-, and -CH two CH- a group consisting of CH-; 15 A is selected from the group consisting of <112- and -(:11((:113)-; R2 is 氲; R3 and R4 are each hydrogen; R3 is selected from the group consisting of hydrogen, halogen, trifluoromethane and a group consisting of cyano groups; XY is selected from -S-CH-, -0-CH-, -0-C(CH3)-, 80 \ Λ 200808298 -N(CH3)-CH- and -CH a group consisting of two 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 and the nitrogen atom to which they are attached form a 5 to 7 membered, saturated, partially unsaturated or aromatic ring structure, optionally containing one to two An additional heteroatom, which is selected from the group consisting of 0, N, and S; or a pharmaceutically acceptable salt thereof. ίο 36. The use of claim 35, Wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano; XY is selected from -S-CH-, -0-CH-, -0-C(CH3)- a group consisting of -N(CH3)-CEl· and -CH=CH-CH-; 15 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 and the nitrogen atom to which they are attached form a 5 to 6 membered, saturated or aromatic ring structure, optionally containing 20 to Two additional heteroatoms which are independently selected from the group consisting of hydrazine, N and S; or a pharmaceutically acceptable salt thereof. 37. The use of claim 36, Wherein R1 is hydrogen; 8 1 200808298 Χ-Υ is _S-CH-; A is -CH2-; R2 is hydrogen; R3 and R4 and the nitrogen atom to which they are attached form a 5 member ring structure, The ring structure can be selected from a group consisting of pyrrolidine or imidazole; or a pharmaceutically acceptable salt thereof. _ 38. The use of the compound of formula (I), wherein the compound of formula (I) is selected from the group consisting of Group: (benzo[>]thiophene 10-3-methylmethyl)sulfonyldiamine;,[(5-chlorobenzo[6]thiophen-3-yl)methyl]sulfonamide; [(3-benzofuranyl)sulfonyldiamine; [(5-fluorobenzopyrene]thiophen-3-yl)indolyl]sulfonyldiamine; benzo[6]thiophen-3-yl ()-sulfonyldiamine; (1-naphthylmethyl)sulfonamide; [(2-methyl-3-benzofuran)methyl]sulfonamide; 沁[(5-bromobenzene) And 〇]thiophen-3-l-yl)methyl]sulfonyldiamine; 沁[(4-bromobenzo[6]thiophen-3-yl)indolyl]sulfonyldiamine;,[(7-fluorobenzene) And [handle] thiophen-3-yl)methyl]sulphonic diamine; * mercapto-1//-indol-3-yl)methyl]sulphonyl diamine; [(4-trifluoromethyl) Benzo[6]thiophen-3-yl)methyl]sulfonyldiamine;,[(4-cyanobenzo[thiophen-3-yl)methyl]-sulfonamide; 7V-[benzene And [6]thiophen-3-yl) 20 methyl]amine sulfoxiranidine; 沁[benzopyrene]thiophen-3-yl Methyl] -ΛΓ- ethyl sulfonylurea diamine; imidazol-1-sulfonic acid [benzo [>] thiophen-3-yl) methyl] - Amides; and pharmaceutically acceptable salts thereon. 39. The use of claim 31, wherein the compound of formula (I) is selected from the group consisting of hydrazine (benzo[>]thiophene 82 200808298-3-ylindenyl)sulfonate Indole diamine; hydrazine [(5-fluorobenzo[6]thiophen-3-yl)methyl]sulfonamide; and pharmaceutically acceptable salts thereof. 40. A therapeutically effective amount of a compound for the manufacture of a pharmaceutical product for preventing the death or injury of a neuron in the brain, head or spinal cord after trauma or injury, the compound being selected from the group consisting of (benzo[ 6] A group consisting of thiophen-3-ylmercapto)sulfonamides and pharmaceutically acceptable salts thereof. 83 200808298 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： 益83 200808298 VII. Designation of representative representatives: (1) The representative representative of the case is the picture of (No). (2) A brief description of the symbol of the representative figure: 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: / κ R4 0)/ κ R4 0) 44