TWI335329B - 7-[2-[4-(6-fluoro-3-methyl-1,2-benzisoxazol-5-yl)-1-piperazinyl]ethyl]-2-(1-propynyl)-7h-pyrazolo-[4,3-e]-[1,2,4]-triazolo-[1,5-c]-pyrimidin-5-amine - Google Patents
7-[2-[4-(6-fluoro-3-methyl-1,2-benzisoxazol-5-yl)-1-piperazinyl]ethyl]-2-(1-propynyl)-7h-pyrazolo-[4,3-e]-[1,2,4]-triazolo-[1,5-c]-pyrimidin-5-amine Download PDFInfo
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- TWI335329B TWI335329B TW095134895A TW95134895A TWI335329B TW I335329 B TWI335329 B TW I335329B TW 095134895 A TW095134895 A TW 095134895A TW 95134895 A TW95134895 A TW 95134895A TW I335329 B TWI335329 B TW I335329B
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- BWPIARFWQZKAIA-UHFFFAOYSA-N protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 description 1
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
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- WEMNATFLVGEPEW-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1.C=1C=CSC=1 WEMNATFLVGEPEW-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
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- Psychology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
1335329 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種腺苷A：u受體拮抗劑7_[2_[4_(6_氟_3_甲 基-1，2-苯并異呤唑„5·基兴^哌畊基]乙基]_2_(1_丙炔基）_ 7H-吡唑并_[4,34]-[1，2,4]-三唑并[1，5<]嘧啶-5-胺，係關 於邊化合物在治療中樞神經系統病症中之用途，該等中樞 神經系統病症包括運動障礙，例如，帕金森氏病症、錐體
外徑症候群（Extra-Pyramidal Syndr〇me)、腿不寧症候群、 原發性震顫（essential trem〇r)及亨丁頓氏舞蹈症；注意力 病症，例如，注意力不足過動症、認知障礙及精神分裂症 之負性症狀；及其他中枢神經系統疾病，諸如，抑鬱症、 中風及精神病。本發明亦係關於包含該化合物之醫藥組合 物。 【先前技術】 已知腺苷為眾多生理機能之内源性調節劑。在心血管男 統水平上，腺苷為強血管舒張劑及心動抑制劑。在中樞书 經系統中’料誘導鎮定、抗焦慮及抗_效果。在呼明 系統中’腺苦誘導支氣管收縮。在腎臟系統中，其發揮雙 相作用，在低濃度時誘導血管收縮且在高劑量時誘導血管 舒張°㈣在脂肪細胞上充當脂肪分解抑制劑且在二 上充當抗聚集劑。 腺芽作用藉由與屬於G蛋白偶聯受體家族之不同膜特里 性受體的相互作用而調節。生物化學及藥理學研究連同： 子生物學進展已允許確認至少四種亞型腺苦受體：A : 1M445.doc 1335329
Ah、八^及八3。…及、受體抑制而八^及八以受體刺激腺苦 酸環化酶之活性。腺苷類似物能作為拮抗劑與Αι、Α^、 及八3受體相互作用亦已得到確認。 A2a受體之選擇性拮抗劑因其降低加強之副作用的可处 性而具有藥理學價值。在中樞神經系統中，、拮抗射 具抗抑鬱性質且可刺激認知功能。此外，資料已顯示A。 受體在基底神經節中以高密度存在，&已知在運動控制中
很重要。因此，A2a拮抗劑可改良歸因於神經退化性疾病 (諸如，帕金森氏病症、如阿茲海默氏症中之老年癡呆 症’及精神病）之運動障礙。 在觸〇5/〇44245中，已揭示腺苷A2a受體#抗劑可用於 治療或預防錐體外徑症候群_)、崎力肖礙、腿不寧 症候群（RLS)或睡目民時之週期性肢體運動（pLMs)，且: W〇02/G55G83中，已揭示其可用於治療注意力^過動症 (ADHD)。
EPS為用於一系列與使用精神抑制藥相關之有害神經反 應的集體術語。存在六類不同的Eps相關神經综合症，其 中四類（肌張力障礙 '靜坐不能、類帕金森氏症（類帕金森 氏症候群）及遲發性運動不能）在關精神抑制藥物之患者 立中特別普遍。肌張力障礙為肌群之疼痛痙攀，尤其在頸 部、顆部、㈣、咽部及喉部肌群處。此在以精神抑制藥 …療之年輕男性中十分常見，但可亦與使用可卡因、三環 抗抑鬱劑、Μ及抗驚厥藥（諸如，苯妥英及痛痙寧）相關。 類帕金森氏症自身表現為運動不能(僵硬、強直及自主運 114445.doc 動遲緩、値僂、行走遲缕 ㈣Μ 此 ）及震顏且該等症狀在治療開始 數週或數月内逐步顯現出來療開始 -ta ^ 7上不此自身表現為強烈主 硯内心痛苦或不適之感受， ‘、、 又具特徵在於運動不寧。哕堂f 系示合症常被誤認為係興奮哎 ^ 嘗次焦慮所致’故往往對其診斷不 /、對治療之反應性極底。遲發性運動不能為與長期使 用鎮神劑相關之晚期综合症。其更頻繁地出現於老年串者 中且特徵在於面部、眼瞼、嘴、 〜 角古乎足及軀幹之僵化、 反覆、無意識、快速舞蹈病樣運動。 EPS在使用典型精神㈣财更普遍，但在使用非业型率 劑中亦有報I典型精神抑·包括洛沙平（1。卿ine)、氣 ，咬醇、氯丙噪、氣t秦及甲派硫丙硫葱。非典型精神抑制 樂包括氯氮平（clozapine)、奥氮平（〇lanzapine)、洛沙平、喹 平（quetiapine)、齊拉西酮（邱阳丨如此）、利培酮 (risperidone)及阿立哌唑（aripipraz〇le)。 靜坐不能亦為RLS及PLMS以及PLMD(週期性腿（或肢體） 運動病症）之特徵。RLS為一種常見病症’其使患者具無法 壓製且令人人不快之要移動其腿的慾望；其通常在不活動 階段期間及/或在夜間表現且可擾亂睡眠。不具有典型RLS 症狀但展現對睡眠產生不利影響之週期性腿運動的患者係 診斷為PLMS。用於rLS及PlmS之治療藥物包括左旋多巴/ 卡比多巴、左旋多巴/苄絲肼、多巴胺激動劑（諸如，普拉 克索（pramipexole)及羅匹尼洛（r〇piner〇ie))、苯并二氮呼、類 鸦片、抗驚厥藥及鐵劑（硫酸亞鐵）。RLS及PLMS在文獻中已 廣泛描述’例如，由 Saletu等人，Neuropsychobiology，41, 4 H4445.doc 1335329 (2000)，第 190-9頁描述。 已發現一些黃嘌呤相關化合物為A!受體選擇性拮抗劑， 且已發現黃嘌呤及非黃嘌呤化合物具高A2a親和力，同時 具可變程度之八“對A】選擇性。先前已揭示三唾并-喷咬腺 苷A2a受體拮抗劑，例如在w〇 95/013 56、US 5，565,460、
WO 97/05 138、WO 98/52568、US 6,630,475、US 6,653,3 15、US 6,897,217 及 2005 年 4 月 19 曰申請之 PCT/US05/013454 中。 本發明為優於1^ 6,897,217之選擇發明。 【發明内容】 本發明係關於具結構式I之化合物
或其醫藥學上可接受之鹽。 本發明之另一態樣為一種醫藥組合物，其包含在醫 上可接受之載劑中之治療有效量之之化/合物3。 其包含在醫藥學
114445.doc c S ) 1335329 如’抑繫症、令風及精神病，該方法包含將式k化合物 投予需要該治療之哺乳動物。 特定言之，本發明係關於治療運動障礙（諸如，帕金森 氏病症、原發性震顫或亨丁頓氏舞蹈症)之方法，該方法 包含將式I之化合物投予需要該治療之哺乳動物。
本發明之再-態樣為-種用式以化合物與一或多種可 用於治療帕金森氏病症之藥劑（例如，多巴胺、l_d〇pa、 多巴胺性激動劑、B型單胺氧化酶（MA〇 B)之抑制劑、 DOPA脫㈣抑㈣（DCI)或兒茶龄f基轉移酶（c〇mt) 抑制劑）的组合治療帕金森氏病症之方法。本發明亦請求一 種醫藥組合物，其包含在醫藥學上可接受之載劑令之式^ 之化合物及-❹種已知可用於治療帕金森氏症之藥劑。
本發明亦係關於治療或預防Eps(例如，肌張力障礙、靜 坐不此、類帕金森氏症及遲發性運動不能），其包含將式工 之化合物投予需要該治療之哺乳動物。特定言之，該方法 係用於在已用具誘導EPS副作用之精神抑制劑治療的患者 :化療或預防EPS。式I之化合物可在Eps症狀表現後投 藥或式I之化合物可在開始才曼予精神抑制劑時投藥以預 EPS發生。因此，本發明亦包括一種治療或預防由精神 抑制劑誘導之EPS之方& ’其包含將精神抑制劑與式！之化 合物的組合投予有此需要之患者。 本發明亦係關於台療原發性（自们生）肌張力障礙，且亦 係關於在由於用三環抗抑鬱劑m驚厥藥治療而展現 肌張力障礙或使料卡因之患者中治療或預防肌張力障
C 114445.doc -10. 1335329 礙’其包含將治療有效量之式j之化合物投予有此需要之 患者。當肌張力障礙係由用三環抗抑鬱劑、鋰或抗驚厥藥 . 治療引起時，式1之化合物可在肌張力障礙之症狀已表現 後投藥’或式1之化合物可在開始投予三環抗抑鬱劑、鋰 - 或抗驚厥藥時投藥以預防肌張力障礙發生。因此，本發明 亦包括一種治療或預防由三環抗抑鬱劑、鋰或抗驚厥藥誘 導之肌張力障礙之方法，其包含將式j之化合物與三環抗 φ 抑鬱劑、鋰或抗驚厥藥的組合投予有此需要之患者。 本發明進一步係關於治療諸如RLS或PLMs之異常運動 障礙，其包含將治療有效量之式I之化合物投予有此需要 之患者。本發明亦包含一種治療RLS或pLMS之方法，其 包含將式I之化合物與另一可用於治之藥劑 (諸如，左旋多巴/卡比多巴、左旋多巴/节絲肼、多巴胺激 動劑、苯并二氮平、類鸦片、抗驚厥藥或鐵劑）的組合投 予有此需要之患者。 又 • 本發明亦係關於治療注意力相關病症（諸如，注意力缺 乏症（ADD)及ADHD)以及認知障礙及精神分裂症之負性症 狀’其包含投予治療有效量之式I之化合物。 ； 在另-態樣中’本發明係關於一套組，其在單一包裝内 之獨立谷益中包含醫藥組合物，該等醫藥組合物用於組合 以治療帕金森氏病症’纟中一容器包含—種醫藥組合物： 該醫藥組合物包含在醫藥學上可接受之載劑中之有=旦， 式!之化合物’且其中一獨立容器包含一種醫藥組=之 邊醫樂組合物包含有效量之可用於治療帕金森氏病症之藥 lH445.doc 1335329
在另一態樣中，本發明係關於一套組，其在單一包裝内 之獨立容器中包含醫藥組合物，該等醫藥組合物用於組合 以治療或預防由用精神抑制劑治療引起之EPS，其中一容 器包含一種醫藥組合物，該醫藥組合物包含在醫藥學上可 接受之載劑中之有效量之式I之化合物，且其中一獨立容
器包含一種醫藥組合物’該醫藥組合物包含有效量之精神 抑制劑。 在另一態樣中，本發明係關於一套組，其在單一包裝内 之獨立容器中包含醫藥組合物，料醫藥組合物用於組合 以治療或預防由用三環抗抑鬱劑、鋰或抗驚厥藥治療引起 之肌張力障礙’其中一容器包含一種醫藥組合物，該醫藥 組合物包含在醫藥學上可接受之載劑中之有效量之以 化合物’且其中一獨立容器包含一種醫藥組合物，該醫藥
組合物包含有效量之三環抗抑鬱劑、鋰或抗驚厥藥。 在另-態樣中，本發明係關於—套組，其在單—包裝内 =立Μ中包含醫樂組合物，該等醫藥組合物用於組合 以治療RLS或PLMS，其中一究哭白人 4…… 〃、中今益包含-種醫藥組合物， 且合物含在醫藥學上可接受之載劑中之有效量之式 醫:二，且其中—獨立容器包含-種醫藥組合物，該 :樂二物包含有效劑量之左旋多巴/卡比多巴、左旋多 厥藥或鐵劑。 本开-氮呼、類鸦片、抗驚 本發明亦係關於式1之化合物之用#，係用以製備用於 114445.doc 12 1335329 早獨或與上述其他藥劑組合來治療或預防帕金森氏病症、 EPS、肌張力障礙、RLS、pLMS、原發性震顫、亨丁頓氏 舞蹈症、認知障礙或精神分裂症負性症狀之藥物。 【實施方式】 如本文所用之術語"組合物”係欲涵蓋一種包含指定董之 指定成份的產品，以及涵蓋直接或間接由指定量之指定成 份組合產生的任何產品。 本發明之化合物之前藥及溶劑合物亦涵蓋於本文中。如 本文所採用之術語"前藥"表示一種係藥物前驅體之化合 物’該藥物前驅體在投予患者後藉由代謝或化學過程經歷 化學轉化以產生式I之化合物或其鹽及/或溶劑合物。前藥 之論述在 T· Higuchi 及 V. Stella 之 Pro-drugs as Novel Delivery Systems (1987)，A.C.S. Symposium Series之第 14 卷中’及在 Bioreversible Carriers in Drug Design，（15*87)
Edward B. Roche編，American Pharmaceutical Association and Pergamon Press中提供’其兩者皆以引用至此的方式 併入本文中。 ”溶劑合物"意謂本發明之化合物與一或多個溶劑分子之 物理性締合。該物理性締合涉及可變程度之離子鍵及丘價 鍵（包括氫鍵）。在某些實例中，溶劑合物能分離，例如當 一或多個溶劑分子併入結晶固體之晶格中時。”溶劑合物" 包含溶液相及可分離溶劑合物兩者。合適溶劑合物之非限 制實例包括乙醇化物、甲醇化物及其類似物。"水合物•，為 一種溶劑合物，其中該溶劑分子為H2〇。 114445.doc •13· 1335329 式i之化合物及式i之化合物 晶型物係欲包括在本發明中。 ”有效量”或"治療有效量"意 枯抗劑且因此在合適患者中產 化合物或組合物的量。 患者包括人與動物兩者。 ”哺乳動物π意謂人及其他哺乳類動物。
之鹽、溶劑合物及前藥之多 謂描述有效用作腺苷AZa受體 生所要治療效果之本發明之 式I之化合物形成鹽，今女gg , Θ寺鹽亦在本發明之範疇内。—廡 瞭解本文對式I之化合物之引用包括對其鹽之引用，除: 另有說明4本文㈣用之術語”鹽’’表示與無機及/或 酸形成之酸性鹽’以及與無機及/或有機鹼形成之鹼性 鹽。此夕卜，當式！之化合物包含驗性部分（諸如，但不限於 °比咬或蛛唾)及酸性部分(諸如，但不限㈣酸)時，可形成 兩性離子（”内鹽，，）且其包括在如本文所用之術語，，鹽，，内。 儘管其他鹽亦可用，然醫藥學上可接受(亦即，非毒性、 生理學上可接又）之鹽較佳。式工之化合物之鹽可（例如）藉 由在介質(諸如’在其中鹽可沉澱之介質)中或在水性介質 中將式I之化合物盥—佘旦l ,, 疋里（诸如，相當量）之酸或鹼反應接 著凍乾而形成。 例不I·生酉夂加成鹽包括乙酸鹽、己二酸鹽、海藻酸鹽、抗 壞血S夂鹽、天門冬胺酸鹽、#甲酸鹽、苯磺酸鹽、硫酸氫 1爛I鹽了酸鹽、檸檬酸鹽、樟腦酸鹽、樟腦磺酸 鹽、環戊丙酸鹽、二 酸鹽、反丁烯二酸鹽 葡萄糖酸鹽、十二烷基硫酸鹽、乙磺 、葡糖庚酸鹽、甘油磷酸鹽、半硫酸 114445.doc 14 1335329 鹽、庚酸鹽、己酸鹽、鹽酸鹽 羥基乙磺酸鹽、乳酸鹽、順丁 磺酸鹽、煙鹼酸鹽、硝酸鹽、 酸鹽、3-笨基丙酸鹽、磷酸鹽 、氫溴酸鹽、氫峨酸鹽、2-烯二酸鹽、甲磺酸鹽、2-萘 乙二酸鹽、果膠酸鹽、過硫 、苦味酸鹽、特戊酸鹽、丙 酸鹽、水楊酸鹽、琥珀酸鹽、硫酸鹽、磺酸鹽(諸如本文 中彼等所提及者）、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽 (toluenesulfonate，tosylate)、十一烷酸鹽及其類似物。此
外，通常認為適於自鹼性醫藥化合物形成醫藥學上可用之 鹽的酸係為吾人所知曉。 例示性鹼性鹽包括銨鹽、鹼金屬鹽（諸如，鈉、鋰及鉀 鹽）、鹼土金屬鹽（諸如，鈣及鎂鹽）、與諸如N，N，_雙苄基 乙二胺、二環己胺、海卓胺（以沭沁雙（脫氫松香基）乙二胺 形成）、N-曱基葡糖胺、Ν·甲基葡糖醯胺、第三丁 胺之有機鹼（例如，有機胺）形成之鹽，及與諸如精胺酸、 離胺酸及其類似物之胺基酸形成之鹽。鹼性含氮基團可用
諸如低碳烷基函化物（例如，甲基、乙基、丙基及丁基氣 化物、溴化物及碘化物）、硫酸二烷酯（例如，硫酸二甲 酯、二乙酯、二丁酯及二戊酯）、長鏈鹵化物（例如，癸 基、十二烷基、十四烷基及十八烷基氣化物、溴化物及碘 化物）、芳烷基齒化物（例如，苄基及苯乙基溴化物）及其他 試劑之試劑來四級化。 所以省等酸性鹽及鹼性鹽係欲作為在本發明之範疇内的 面藥子上可接文之鹽，且認為所有酸性鹽及鹼性鹽相當於 用於本發明之目的之相應化合物的游離形態。 114445.doc 15 1335329 體二:之化合物及其鹽、溶劑合物及前藥可以其互變異構 /，作為醯胺或亞胺基驗）存在。所有該等互變異構 體作為本發明之部分涵蓋於本文中。 本化口物之所有立體異構體(例如’幾何異構體、光學 異構體及其類似物)(包括該化合物之鹽、溶劑合物及前藥 以及亦包括前藥之鹽及溶劑合物之彼等者)涵蓋於本發明 之範脅内’諸如可歸因於在多種取代基上之不對稱碳而存 ^的彼等者’包括對映異構體（其甚至可在不存在不對稱 石厌下存在）、旋轉異構體、滯轉異構體及非對映異構體。 本發明之化合物的個別立體異構體可（例如）大體上不含其 他異構體，或可（例如）混雜為外消旋體或與所有其他或其 他選定立體異構體混雜。本發明之對掌性中心可具如= IUPAC 1974標準所定義之s或R構型。術語„鹽，·、·，溶劑合 物、則藥'’及其類似者之使用係欲同樣適用於本發明化 合物之對映異構物、立體異構體、旋轉異構體、互變異構 體、外消旋體或前藥之鹽、溶劑合物及前藥。 其他已知可用於治療帕金森氏病症且可與式〗之化合物 組合投藥之藥劑包括：L_D0PA ;多巴胺性激動劑，諸 如，喹吡羅（quinpirole)、羅匹尼洛、普拉克索、培高利特 (pergolide)及溴麥角環肽；MAO-B抑制劑，諸如，鹽酸司 來吉蘭（deprenyl)及司來吉蘭（seleginne) ; d〇PA脫敌酶抑 制劑，諸如’卡比多巴及苄絲肼；及COMT抑制劑，諸 如’托卡朋（tolcapone)及恩他卡朋（entacapone)。 引起由腺苷A〗a受體拮抗劑治療之EPS且用於與腺皆A2a 114445.doc • 16- 1335329 受體拮抗劑組合之精神抑制劑包括典型及非典型精神抑制 劑。典型精神抑制藥包括洛沙平、氟哌啶醇、氣=嗓、「氣 。比嗪及甲哌硫丙硫蒽。非典型精神抑制藥包括氣氮平、奥 氮平、洛沙平、啥硫平、齊拉西酮、利培酮及阿立旅唾。 引起由腺苷AZa受體拮抗劑治療之肌張力障礙的三環抗抑 鬱劑包括羥哌氣丙嗪、阿密曲替林（amitriptyline)、地昔帕明 (desipramine)、多慮平（doxepin)、曲米帕明（tdmipramine)及 普羅替林（protriptyline)。可引起肌張力障礙但亦可用於治 療ERLS或PLMS之抗驚厥藥包括二苯乙内醯脲、痛痙甯及 加巴噴丁（gabapentin)。 可用於治療RLS及PLMS之多巴胺激動劑包括培高利 特、普拉克索、羅匹尼洛、非諾多泮（fen〇ld〇pam)及卡麥 角林（cabergoline)。 可用於治療PRLS及PLMS之類鴉片包括可待因 (codeine)、氫可酮（hydrocodone)、羥可酮（oxyc〇d〇ne)、丙 氧吩及曲馬多（tramadol)。 可用於治療PRLS及PLMS之苯并二氮呼包括氯硝西泮 (clonazepam)、三唑侖及羥基安定。 精神抑制劑、三環抗抑鬱劑、抗驚厥藥、多巴胺激動 劑、類鴉片及苯并二氮呼可購得且已在文獻中進行描述， 例如在 The Physicians’ Desk Reference (Montvale: Medical Economics Co.，Inc.，2001)中。 儘管將式I之化合物與一種其他藥劑組合來投藥對各病 症而言較佳，然涵蓋可將式I之化合物與一或多種其他藥 114445.doc 17 劑（例如，精神抑制 胺激動劑'類鸦片：苯t抑營劑4驚厥藥、多巴 ,τ 次本开二氮呼）組合來投藥。儘管投予 :之化。物及其他藥劑之獨立劑型較佳，然亦涵蓋可將 /樂劑卜或多種）在單—劑型中與幻之化合物組合好 療或預防帕金森氏病症、EPS、職力障礙、RLS或 MS ’亦涵盍可將式!之化合物與另一腺苷‘拮抗劑组 來投藥。 式I之化口物可藉由已知方法自該項技術中已知之起始 物質或自藉由該項技術中已知之方法製備者來製備；參^ (例如）US 6,897,217。 在本說明書中使用之縮寫如下所示：Ac (乙醯基）；Me (甲基）；Et (乙基）；Ph (苯基）；DMF (二甲基甲醯胺）； DIPEA (二異丙基乙胺）；RT (室溫）。 實例1
hno3( h2so4 0-1 o°c Π 4445.doc -18- 1335329
DIPEA, Kl, DMF, 110°C, 48h
步驟1 :將4-氟-2-羥基苯乙酮1 (50 g, 324 mmol)、胲鹽酸 鹽（45 g，648 mmol)及乙酸納（40 g，488 mmol)在無水 MeOH (1 L)中之混合物回流2小時。在冷卻至RT後，將反應混合 物缓慢傾倒於冰上且授拌3 0分鐘。因而獲得之白色沉激物 藉由抽吸過濾且然後將其溶解於CH2C12，乾燥（MgS04)， 過濾且濃縮以提供一種呈白色固體之2 (50 g，91%產率）， 其未經進一步純化而用於下一步驟中。
步驟2 :向肪2 (50 g，296 mmol)在DMF (800 ml)中之溶液 中添加乙酸納（55 g，670 mmol)，接著添加乙酸肝（65 ml, 689 mmol)。將反應混合物回流3-4小時，在該階段所有起 始物質之消耗如由TLC (在己烷中之10% EtOAc)所示。在 冷卻至RT後，將反應混合物傾倒入水中且用醚萃取數次。 混合有機溶離份用鹽水洗滌，乾燥（Na2S04)，過濾且濃縮 以提供呈淺褐色固體之3 (42 g，94%產率）。 步驟3 :經由加料漏斗向3 (42 g，278 mmol)在濃H2S04 (300 ml)中之冰冷溶液中逐滴添加濃硝酸（70 ml)。在添加完成 後，將反應混合物溫熱至RT且攪拌2-3小時。在起始物質 消耗（如由TLC (在己烧中之1 0% EtOAc)所示）後，在恆速 114445.doc -19- 1335329 震蘯下將反應混合物緩慢傾倒於冰上。過濾所得固體，將 其溶解於CHAh中且用飽和NaHC03水溶液及鹽水洗滌。 混合有機溶離份經MgS04乾燥，過濾且濃縮以提供呈黃色 . 固體之4 (47 g，86%產率）。 . 步驟4 :將4 (47 g，240 mmol)在 AcOH (800 ml)中之溶液溫 熱至40°C且將向該溫熱溶液中添加SnCl2*H20 (150 g5 665 mmol)在濃HC1 (400 ml)中之溶液。將反應混合物回流2小 φ 時且然後冷卻至RT。小心用NaOH水溶液將pH調至5-6以沉 殿大部分錫鹽且接著在恆速攪拌下添加乙醚至混合物。在 傾析液體後’分離有機層且其後水層用乙醚反萃取數次。 混合有機溶離份用鹽水洗滌，乾燥（Na2S〇4)，過濾且濃縮 以提供一種褐色油。藉由管柱層析法（在己烷中之1〇_2〇% EtOAc)進行之純化提供呈黃色固體之5(22g，55%產率）。 步驟 5 .用 2 M HC1/ 乙喊（9_6 ml，19 mmol)處理 5 (3.2 g，19 mmol)在CH2Cl2 (100 ml)中之溶液且在減壓下移除溶劑。 • 在氯苯（8〇 中獲得白色固體且用雙（氣乙基）-胺（3.8 g, 21 mmol)處理。將反應混合物回流以小時’在該階段消耗大 部分起始物質。在減壓下移除大部分溶劑且將殘餘物溶解 於熱MeOH (200 ml)中。將黑色不可溶殘餘物渡除且藉由 管柱層析法（在C^Cl2中之2·5% 7 N NH3_Me〇H)純化遽液 以提供6 (2.6 g，57%產率）。 步驟6 :將6 (2.6 g，u mm〇1)、7 (3 2 g，i2 mm〇i)、幻 μ g，12 麵〇1)及 DIPEA (2.3 叫 13.3 _〇1)在 DMF (3〇 叫中 之混合物在11 〇。〇下加孰48 W、η主 刀…48小時。在冷部至汉丁後，添加水 114445.doc -20· 1335329 且過遽所得固體。將固體殘餘物溶解於H)% MeOH_CH2Cl2 中，無水負載於石夕朦管柱上且純化（在咖12中之2% MeOH)以提供2·7 g (52%產率）標題化合物。[⑽：仍 (M+H)，純度= ι〇〇〇/0。 本發明之化合物因其腺苦、受體拮抗劑活性而可用於 治療中㈣㈣統疾病，心，帕金森氏病症、錐體外徑 症=群、腿不寧症候群、原發性震顏、亨丁頓氏舞蹈症、
注意力不足過動症、認知障礙、精神分裂症之負性症狀、 抑營症、中風或精神病。特定言<，本發明之化合物可改 良歸因於神經退化性疾病（諸>，帕金森氏病症）之運動障 礙。 本發明之化合物之藥理學活性可藉由下列用以量測Ah 受體活性的活體外及活體内檢定來測定。 人腺苷入^及Ai受體競爭性結合檢定方案 膜來源：
A2a ••人A2a腺苷受體膜，目錄#rbHA2AM，Perkin Elmer Life Sciences’ Shelton CT。在膜稀釋緩衝液中稀釋至17 pg/100 μΐ (見下）。 檢定緩衝液： 膜稀釋緩衝液：杜貝卡氏（Dulbecco’s)鱗酸鹽緩衝生理 食鹽水（Gibco/BRL)+10 mM MgCl2。 化合物稀釋緩衝液：杜貝卡氏磷酸鹽緩衝生理食鹽水 (Gibco/BRL)+10 mM MgCl〕，補充以 1.6 mg/ml 甲基纖維素 及16% DMSΟ。每日新鮮製備。 114445.doc 1335329 配位體： A2a : [3H]-SCH 58261，委託合成 ’ AmershamPharmacia Biotech，Piscataway, NJ。在膜稀釋缓衝液中製備1 nM儲備 液。最終檢定濃度為0.5 nM。
Ai ： [3H]-DPCPX, AmershamPharmacia Biotech, Piscataway, NJ。在膜稀釋缓衝液中製備2 nM儲備液。最終檢定濃度為 1 nM。 非特異性結合：
A2a :為測定非特異性結合，添加100 nM CGS 15923 (RBI，Natick，ΜΑ)。在化合物稀釋緩衝液中製備400 nM工 作儲備液。 A,:為測定非特異性結合，添加100 μΜ NECA (RBI， Natick, ΜΑ)。在化合物稀釋緩衝液中製備400 μΜ工作儲 備液。 化合物稀釋： 在100% DMSO中製備化合物之1 mM儲備溶液。在化合 物稀釋缓衝液中稀釋。在自3 μΜ至3 0 pM之範圍中的10個 濃度下測試。在化合物稀釋緩衝液中製備4X終濃度之工作 溶液。 檢定程序. 在深孔之9 6孔板中執行檢定。總檢定體積為2 0 0 μ 1。添 加50 μΐ化合物稀釋緩衝液（總配位體結合）或50 μΐ CGS 1 5923工作溶液（A2a非特異性結合）或50 μΐ NECA工作溶液 (Α,非特異性結合）或50 μΐ藥物工作溶液。添加50 μΐ配位體 f： s) I14445.doc -22- 1335329 儲備液（A2a: [3H]-SCH 58261，A1: [3H]-DPCPX)。添加 loo 有適當文體之稀釋膜，混合。在室溫下培養9〇分鐘。 . 使用Bnndel細胞收集器收集於Packard GF/B滤板上。添加 ； 45 μ1 Mlcrosclnt 20 (Packard)，且使用 Packard T〇pC〇unUt .閃爍計數器進行計數。藉由使用迭代曲線擬合程式㈣叫 擬σ取代曲線來測疋ICm值。使用cheng_prusoff方程式測 定K;值。 Φ 大鼠中氟哌啶醇誘導之全身僵硬症 使用重 175-200 g 之雄性 Sprague_Dawley 大鼠（Ch訂ies River，Calco’ Italyp在用垂直網格測試動物前9〇分鐘，藉 由皮下投予多巴胺受體拮抗劑氟哌啶醇（1 mg/kg，皮下）來 誘導全身僵硬症狀態。在該測試中，將大鼠置放於與牆台 成約70度角置放之25 M3譜萊玻璃籠的金屬絲網蓋上。將 大鼠置放於網格上，使其所有四腿外展且伸長（"青蛙姿 勢）。對於该用於全身僵硬症之測試的特異性而言有必要 • 使用該非自然姿勢。量測自爪置放至首次完全移動一爪之 間的時間間隔（降下時間），最長歷時12〇秒。 在評定動物之前1小時及4小時，將評估下之選擇性A。 腺苷拮抗劑以在0.03 mg/kg與3 mg/kg之間的範圍之劑量經 口投藥。 在各獨立實驗中，測定參考化合物L_D〇PA (25 mg/kg、 50 mg/kg及100 mg/kg，腹膜内）之抗全身僵硬症效果。 大鼠中之中間前腦束之6_〇HD A損傷 在所有實驗中使用重275_300 g的成年雄性帅以纠卜 114445.doc -23· 1335329
Dowley 大鼠（Charles River，Calco, Como, Italy)。在受控溫 度及12小時光/暗循環之條件下使大鼠以每籠四隻成群居 住’使其自由獲取食物及水^在手術前一天，將大氣禁食 過夜，但任其隨意飲用水。
根據由Ungerstedt等人所述之方法（Brain Research，1971， 6-OHDA and Cathecolamine Neurons, North Holland, Amsterdam，101-127)，藉由稍作改變來執行中間前腦束之 單侧6-羥基多巴胺（6-OHDA)損傷。簡言之，在注射6_ OHDA前30分鐘用水合氣酸（4〇〇 mg/kg，腹膜内）麻醉動 物，且以地昔帕明（1 〇 mpk，腹膜内）處理，以便由產生去 曱腎上腺素末端來阻斷毒素之攝取。然後，將動物置放於 立體定向儀（stereotaxic frame)中。根據pellegrino等人 (Pellegrino L.J., Pellegrino A.S. and Cushman A.J., A
Stereotaxic Atlas of the Rat Brain，1979，New York : Plenum
Press)之圖譜’反照頭骨上之皮膚且獲取立體定向座標（前 固後（AP)-2.2、前囪側（ML)+1.5、硬腦脊膜腹面（dv) 7·8)。接著在損傷位點上方之頭骨中鑽孔，且將附接至
Hamilton注射器之針降低放至左MFB中。接著將8 pg 6- OHDA-HCl溶解於4 μΐ具有0·05ο/〇抗壞血酸作抗氧化劑之鹽 水中，且使用灌輸泵以1 μΐ/ΐ min之恆定流速灌輸。在另 外5分鐘後取出針且縫合手術創口，且讓動物恢復2週。 在損傷後兩週，向大鼠投予L-DOPA (50 mg/kg，腹膜 内）加节絲肼（25 mg/kg ’腹膜内）且藉由自動轉子流量計根 據在2小時測試期間内量化之完全對側轉動圈數來選擇大 < S ) H4445.doc • 24· 1335329 鼠（致敏測試）。任何未顯示至少200整圈/2小時之大氣不包 括在本研究中。 在致敏測試（最大多巴胺受體超過敏性）後3天使選定大 鼠接受測試藥物。在不同時間點（亦即，1小時、6小時、 12小時）經口投予在〇 1爪““與3 mg/kg之間的範圍内之劑 1水平之新AZa受體拮抗劑，之後注射亞臨限劑量之L DOPA (4 mpk，腹膜内）加苄絲肼（4 mpk，腹膜内）且進行 轉動行為之評定。 EPS檢定 下列程序描述使用腺苷八；^拮抗劑以減弱在對巴胺D2受 體拮抗劑氟旅咬醇敏感之卷尾（cebus apella)猴中顯示之錐 體外徑症候群（EPS)。 當急劇投予氟。底咬醇（0.3 mg/kg，口服）時，先前對氣。底 啶醇之慢性效杲敏感之卷尾猴群展現EPS。測試化合物係 以0.3-30 mg/kg之範圍之劑量結合氟哌啶醇經口（口服）投 藥。使用受檢者内設計進行研究，使得各猴在交又平衡設 計中皆接受所有處理（媒劑及一定劑量之測試化合物）。測 定最高EPS評分之減少’以及在EPS發作時之劑量依賴性 延遲。
用於治療RLS及PLMS之臨床指引已建立：參見a L
Chesson 等人 ’ Sleep，22，7 (1999)，第 961-8 頁。在治療 RLS及PLMS中腺苷AZa拮抗劑之功效可藉由—種方法測 定’該方法類似於由Weimerskirch等人（Annais 〇^.
Pharmacotherapy，35, 5 (2001)，第 627-30 頁）在有關普拉克 114445.doc -25- 1335329 索及羅匹尼洛之文獻中所述之臨床方法。 使用上述測試方法，對本發明之化合物雅 \侍下列結果。 對本發明之化合物之結合檢定結果展示a v ， A2a K：i 值為 〇·43 ηΜ。 選擇性係藉由Α丨受體之Kj除以A〗a受體之&來长出。本 發明之化合物的選擇性大於2500倍。 在6-OHDA損傷測試中，經投予式j之化合物與亞臨限量 鲁之L-DOPA之組合的測試動物顯示顯著更高之對侧轉動： L-DOPA: 171±47 圈 0.1 mpk: 218±142 圈 0.3 mpk: 406±167 圈 1 mpk: 360±178圈 3 mpk: 403±125圈 在氟哌啶醇誘導大鼠之全身僵硬症檢定4小時時，％抑 制如下所示： _ 〇·3 mpk :全身僵硬症之28%抑制 1 mpk .全身僵硬症之ο%抑制 3 mpk :全身僵硬症之53%抑制 在EPS檢疋中四隻氟°底咬醇致敏之猶經共同投予在香 蕉中之式I之化合物（30 mg/kg)及氟哌啶醇（〇3 mg/kg)。採 用種《平刀系統以5平疋經6小時之觀察階段之各症狀之嚴 私度在6】時之觀察階段期間，式〗之化合物完全阻斷 3隻受試狼中的氟娘咬醇誘導之咖且在第四隻受試狼中， 車乂之單獨服用氟哌啶醇之猴中所觀察者，Eps發作時間延 < S ) H4445.doc -26 - 1335329 遲且嚴重程度下降。 用以顯示受體佔有之持續時間的活體外結合研究： 使大鼠服用1 mg/kg式I之化合物及式π之化合物（在us 6,897,217中一般揭示者），
II
在4小時、8小時、12小時及16小時之後將其宰殺且移除 腦。剖開富含AZa受體之紋狀體核且使其在緩衝溶液中均 質。以A2a拮抗劑放射性配位體3H-SCH 58261 (參見W〇 96/38728)培養紋狀體勻漿，之後藉由過濾分離來受缚放射 能與游離放射能。乾燥在過濾器上之受缚放射性配位體， 用閃爍流體浸泡且對其計數。自用相同實驗條件處理之經 媒劑處理大鼠的紋狀體獲得之勻漿定義在無測試化合物下 受缚放射性配位體之量。 對兩種化合物而言，在4小時時測試化合物佔有受體， 此藉由3H-SCH 58261結合之下降（42%及47%)證實。然 而，在自服用式II之大鼠獲得之紋狀體勻漿中，8小時時放 射性配位體結合恢復至接近媒劑處理程度，表明測試化合 物在彼時不再競爭Ah受體。在整個12小時中，式I之化合 物展現放射性配位體之持續不變的取代（放射性標記之4〇〇/0 取代）。 對自本發明之化合物製備醫藥組合物而言，惰性、醫藥 114445.doc -27- 學上可接受之载體可係固體抑或液體。固態製劑包括粉 =、錠劑、分散性顆粒、膠囊'爲囊劑及栓劑。粉劑及錠 背J可L 3約5 /。至約70%之活性成份。合適之固體載體在該 項技術中已知，例如，碳酸鎂、硬脂酸鎂、滑石粉、糖、 乳糖錠劑、粉劑、扁囊劑及膠囊可用作適於口服投藥之 固體劑型。 對製備栓劑而言，首先熔融低熔點蠟（諸如，脂肪酸甘 油酯之混合物或可可油），且將活性成份均勻分散於其中 (如藉由攪拌）。然後將熔融均質混合物傾倒入便利大小之 模具中’使其冷卻且藉此來固化。 液態製劑包括溶液、懸浮液及乳液。用於非經腸注射之 水或水_丙二醇溶液可作為實例提及。 液態製劑亦可包括用於鼻内投藥之溶液。 適於吸入之氣溶膠製劑可包括溶液及呈粉末狀之固體， 該等氣溶膠製劑可組合醫藥學上可接受之載劑，諸如，惰 性壓縮氣體。 亦包括欲在使用前不久轉變成用於口服抑或非經腸投藥 之液態製劑的固態製劑。該等液體形態包括溶液、懸浮液 及乳液。 本發明之化合物亦可為經皮可傳遞。經皮組合物可表現 為乳膏、洗劑 '氣溶膠及/或乳液之形態且可包括在用於 該目的之在該項技術中習知之基質型或储藥型的經皮貼片 中。 較佳為化合物係經口投藥。 114445.doc •28- 1335329 較佳地’醫藥製劑係以單位劑型存在。在該劑型中，製 劑再分為含有適當量之活性組份的單位劑量，例如，用以 達成所要目的之有效量。 根據特定應用，在單位劑量製劑中的式j之活性化合物 之量可自約0.1 mg至1〇〇〇 mg改變或調節，更佳自約i 至3 0 0 rn g改變或調節。
使用之實際劑量可視患者之需求及待治療病症之嚴重程 度而改變。確定用於㈣狀況之正4劑量係在該項技術之 技能内。通常用小於化合物之最適宜劑量較小劑量開始治 療。其後，以小增量來增加劑量直至達至該等情形下之最 i且效果為便利起見’若需要則總每日劑量在該天期間 了刀成右干部分且以若干部分投藥。
本發明之化合物及其醫藥學上可接受之鹽之投藥量及頻 率將«慮及諸如患者年齡 '病症及體形以及待治療之症 嚴重私度之因素的主治臨床醫師的判斷而調節。式I 之化合物之典型推薦給藥方案為將自1〇毫克/天至2〇〇〇毫 克/天、較佳1〇毫克/天至_毫克/天之劑量分2次至4次口 服投藥以提供對中樞神經系統疾病（諸如，帕金森氏病症） 或其他上列疾病或病症之減輕。 八他用於。式I之化合物组合之藥劑（亦即，怕金森氏病 症藥劑、精神抑制齊卜三環抗抑營劑、抗驚厥藥' 多巴胺 激動劑、苯并二氮呼、類殖ΰ 頰鴉片、鋰或鐵劑）的劑量及給藥 方案將由主治臨床醫師馨於藥品說明書中的經認 及給藥方案且慮及患者年齡、 汪别及病症及疾病之嚴重程 H4445.doc -29- 1335329 度而確定。當組合投筚 , 時式1之化合物及其他藥劑可同
時或順序投藥。此當_ & A 田忒組合之組份較佳以不同 給時特別有用，例如，糸碍备供 ,r , 、 種組份母日投藥，且其他組份每 6小時投藥，或當較佳盤溢4 佳醫糸組合物不同時特別有用，例 如，-種較佳為錠劑且一種為膠囊。因此在—套组中提供 式1之化合物及其他藥劑係有利的，該套組在單一包裝内、 之獨立容器中包含用於組合幻台療或預防帕金森氏病症、
EPS、肌張力障礙、RLLtpLMS之醫藥組合物，其中一容 接 器包έ種醫藥組合物，該醫藥組合物包含在醫藥學上可 文載劑中之有效量之式I之化合物’且其中一獨立容器
包含一種醫藥組合物，該醫藥組合物包含有效量之另一適 於治療所示病症之藥劑。 熟習此項技術者將瞭解到可改變該組合中之組份中之— 者的劑型以含有式I之化合物及另一藥劑兩者，例如，式工 之化合物與精神抑制劑或式I之化合物與多巴胺激動劑。 儘管本發明已結合上面陳述之特定實施例進行描述，然 一般熟習此項技術者將易瞭解眾許多對其之替代、修改及 變更。所有該等替代、修改及變更係欲落至本發明之精神 及範脅内。 114445.doc 30-
Claims (1)
1335329 mnrrtr- 第095134895號專利申請案 年月曰修正本 中文申請專利範圍替換本(99年4月）- 十、申請專利範圍： 1. 一種具以下結構式之化合物，
或其醫藥學上可接受之鹽。 2. 一種醫藥組合物，其包含在醫藥學上可接受載劑中之治 療有效量之如請求項丨之化合物。 3. 一種如請求項1之化合物之用途，其係用以製造用於治 療中樞神經系統疾病之藥劑。 4. 如請求項3之用途，其中該藥劑係用於治療帕金森氏病 症錐體外控症候群（Extra-Pyramidal Syndrome)、腿不 寧症候群、原發性震顫（essential tremor)、亨丁頓氏舞蹈 症、注意力不足過動症、認知障礙、精神分裂症之負性 症狀、抑鬱症、中風或精神病。 5. 如請求項4之用途，其中該藥劑係用於治療帕金森氏病 症、錐體外徑症候群、腿不寧症候群或注意力不足過動 症0 6· —種醫藥組合物，其包含在醫藥學上可接受载劑中之治 療有效量的如請求項1之化合物與一至三種其他可用於 /〇療帕金森氏病症之藥劑之組合。 7·如凊求項3至5項中任一項之用途，其中該藥劑係用以治 療帕金森氏病症，該藥劑係與一至三種其他可用於治療 114445-990413.doc 1335329 帕金森氏病症之藥劑組合使用或進一步包含該其它藥 劑。 8.如請求項7之用途，其中該等其他藥劑係選自由L-DOPA、多巴胺性激動劑、MAO-B抑制劑、DOPA脫羧酶 抑制劑及COMT抑制劑組成之群。 114445-990413.doc
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|---|---|---|---|---|
| SE462170B (sv) | 1987-10-27 | 1990-05-14 | Aahlstrom Corp | Avlaegsnande av loesta och kolloidala makromolekylaera organiska aemnen ur effluenter |
| IT1264901B1 (it) | 1993-06-29 | 1996-10-17 | Schering Plough S P A | Analoghi eterociclici di 1,2,4-triazolo(15-c)pirimidine ad attivita' antagonista per il recettore a2 dell'adenosina |
| WO1995003806A1 (en) | 1993-07-27 | 1995-02-09 | Kyowa Hakko Kogyo Co., Ltd. | Remedy for parkinson's disease |
| IT1275420B (it) | 1995-06-02 | 1997-08-05 | Schering Plough S P A | Metodo per misurare l'affinita' di legame al recettore a2a dell'adenosina di componenti di interesse farmacologico mediante l'uso del ligando triziato (3h)-sch 58261 |
| IT1277392B1 (it) | 1995-07-28 | 1997-11-10 | Schering Plough S P A | Analoghi eterociclici di 1,2,4-triazolo(1,5-c]pirimidine ad attivita' antagonista per il recettore a2a dell'adenosina |
| DE19604919A1 (de) * | 1996-02-01 | 1997-08-07 | Schering Ag | Neue 2,3-Benzodiazepinderivate, deren Herstellung und Verwendung als Arzneimittel |
| IT1291372B1 (it) | 1997-05-21 | 1999-01-07 | Schering Plough S P A | Uso di analoghi eterociclici di 1,2,4-triazolo (1,5-c) pirimidine per la preparazione di medicamenti utili per il trattamento delle malattie |
| IL152726A0 (en) | 2000-05-26 | 2003-06-24 | Schering Corp | Adenosine a2a receptor antagonists |
| GB0100624D0 (en) | 2001-01-10 | 2001-02-21 | Vernalis Res Ltd | Chemical compounds VII |
| AR037243A1 (es) | 2001-10-15 | 2004-11-03 | Schering Corp | Antagonistas del receptor de adenosina a2a,a5-amino-imidazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pirimidina, composiciones farmaceuticas y el uso de dichos compuestos para la preparacion de un medicamento |
| EP2295047A3 (en) | 2002-12-19 | 2011-05-18 | Schering Corporation | Use of adenosine A2a receptor antagonists for the treatment of restless leg syndrome and other movement disorders |
| PT1622912E (pt) * | 2003-04-23 | 2009-08-17 | Schering Corp | Antagonistas 2-alcinil- e 2-alcenilpirazolo-[4,3-b]-1,2,4- triazolo-[1,5-c]-pirimidina do receptor a2a da adenosina |
| ATE461932T1 (de) | 2004-04-21 | 2010-04-15 | Schering Corp | Pyrazoloä4,3-eü-1,2,4-triazoloä1,5-cüpyrimidine als antagonisten des adenosin-a2a-rezeptors |
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