TWI358294B - Tosylate salt of a therapeutic compound and pharma - Google Patents
Tosylate salt of a therapeutic compound and pharma Download PDFInfo
- Publication number
- TWI358294B TWI358294B TW097102227A TW97102227A TWI358294B TW I358294 B TWI358294 B TW I358294B TW 097102227 A TW097102227 A TW 097102227A TW 97102227 A TW97102227 A TW 97102227A TW I358294 B TWI358294 B TW I358294B
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- Taiwan
- Prior art keywords
- diffraction pattern
- ray diffraction
- copper
- release
- tosylate salt
- Prior art date
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- 210000003491 skin Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- ILJOYZVVZZFIKA-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;hydrate Chemical compound O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 ILJOYZVVZZFIKA-UHFFFAOYSA-M 0.000 description 1
- LUZSXLWAUXSKHK-UHFFFAOYSA-M sodium;4-octadecoxy-4-oxobutanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)CCC([O-])=O LUZSXLWAUXSKHK-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- OHOBJYLZBONBBA-UHFFFAOYSA-N strontium zinc Chemical compound [Zn+2].[Sr+2] OHOBJYLZBONBBA-UHFFFAOYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- 230000001720 vestibular Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
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- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Description
九、發明說明： 【發明所屬之技術領域】 本發明係關於一種如本文中所述之式1化合物之甲笨續 酸鹽、一種包含此鹽之醫藥組合物及治療可藉由使用該甲 苯磺酸鹽拮抗組織胺-3(H3)受體來治療之病症或病狀的方 法。 【先前技術】 組織胺為通常由組織胺拮抗劑或”抗組織胺"治療之過敏 性反應（例如過敏、枯草熱及哮喘）中之熟知介體。亦已確 定組織胺受體以至少兩種不同類型（稱作Hi&H2受體）存 在。 咸信第三組織胺受體（H3受體）在中柩神經系統之神經傳 遞中起作用，其中認為該Η;受體在突觸前位於組織胺能神 經末梢上(Nature, 302, S32- S37 (1983))。H3受體之存在已 由選擇性％受體促效劑及拮抗劑之發展得以證實(Nature· Hi 1 17-123 (1987))且隨後已展示調節神經傳遞素在中枢 神經系統與周邊器官（尤其肺、心血管系統及胃腸道）中之 釋放。 可由組織胺-3受體配位體來治療多種疾病或病狀，其中 該H3配位體可為结抗劑、促效劑或部分促效劑，參見： (Imamura等人’ Circ. Res·，(1996) 7^., 475-481) ； (Imamura 等人，Circ. Res.，(1996) 78., 863-869) ; (Lin 等人，Brain Res. (1990) 523, 325-330) ; (Monti等人，Neuropsychopharmacology (1996) 11，31 35) ; (Sakai等人，Life Sci. (1991) 48., 2397- 128029.doc 1358294 2404) ； (Mazurkiewicz-Kwilecki 和 Nsonwah， Can. J.
Physiol. Pharmacol. (1989) 67., 75-78) ; (Panula，P.等人， Neuroscience (1998) 44. 465-481) ; (Wada等人，Trends in Neuroscience (1991) 14, 415) ; (Monti 等人，Eur. J.
Pharmacol. (1991) 205. 283) ; (Haas 等人，Behav. Brain Res. (1995) 66., 41-44) ; (De Almeida和 Izquierdo，Arch. Int. Pharmacodvn. (1986) 283. 193-198) ; (Kamei 等人， Psychopharmacology (1990) 102, 312-318) ; (Kamei 和
Sakata, Japan. J. Pharmacol. (1991) 5 7. 437-482)； (Schwartz 等人 ， Psychopharmacoloev ; The Fourth Generation of Progress. Bloom和 Kupfer(編），Raven Press， New York，（1995) 397) ; (Shaywitz等人，Psychopharmacology (1984) 82., 73-77) ; (Dumery和 Blozovski，Exp. Brain Res. (1987) 67, 61-69) ; (Tedford等人，J. Pharmacol. Exp. Ther. (1995) 275. 598-604) ; (Tedford 等人，Soc. Neurosci.
Abstr. (1996) 22., 22) ; (Yokoyama等人，Eur. J. Pharmacol. (1993) 234,129) ; (Yokoyama和 linuma，CNS Drugs (1996) 5., 321) ; (Onodera 等人，Prog. Neurobiol. (1994) 42. 685) ; (Leurs 和 Timmerman，Prog. Drug Res. (1992) 39.127) ; (The Histamine H3 Receptor. Leurs 和
Timmerman(編），Elsevier Science, Amsterdam (1998) i (Leurs等人，Trends in Pharm. Sci. (1998) \9_, 177-183)； (Phillips 等人，Annual Reports in Medicinal Chemistry (1998) 33_, 31-40) ; (Matsubara 等人，Eur. J. Pharmacol. 128029.doc < S ) 1358294
(1992) 224. 145) ; (Rouleau等人，J. Pharmacol. Exp. Ther. (1997) 28J_, 1085) ； (A. Szelag, "Role of Histamine H3-receptors in the proliferation of neoplastic cells in vitro", Med. Sci. Monit.. 4.(5):747-755, (1998)) ； (C. Fitzsimons, H. Duran, F. Labombarda, B. Molinari 和 E. Rivera, "Histamine Receptors signalling in epidermal tumor cell lines with H-ras gene alterations", Inflammation Res.. 12(增刊 1): S50-S51，（1998)) ; (R. Leurs，R.C. Vollinga和 H. Timmerman, "The medicinal chemistry and therapeutic potentials of ligand of the Histamine H3 receptor", Progress in Drug Research 45: 170，（ 1995)) ; (R. Levi 和 N.C.E. Smith, "Histamine H3-receptors: A new frontier in myocardial ischemia", J. Pharm. Exp. Ther.. 292: 825-830, (2000)) ; (Hatta，E·，K Yasuda和 R. Levi, "Activation of
Histamine H3 receptors inhibits carrier-mediated
norepinephrine release in a human model of protracted myocardial ischemia", J. Pharm. Exp. Ther.. 283: 494-500, (1997)) ; (H. Yokoyama 和 K. linuma，"Histamine and
Seizures: Implications for the treatment of epilepsy", CNS Drugs, 5.(5) ； 321-330, (1995)) ； (K. Hurukami, H. Yokoyama, K. Onodera，K. linuma和 T. Watanabe, AQ-0 145，"A newly developed Histamine H3 antagonist, decreased seizure susceptibility of electrically induced convulsions in mice", Meth. Find. Exp. Clin. Pharmacol.. 17(C): 70-73，（ 1995)); 128029.doc 1358294 (Delaunois A.，Gustin P.，Garbarg Μ.和 Ansay Μ” "Modulation of acetylcholine, capsaicin and substance P effects by Histamine H3 receptors in isolated perfused rabbit lungs", European Journal of Pharmacology 277(2-3):243-50，（1995));及（Dimitriadou 等人，"Functional relationship between mast cells and C-sensitive nerve fibres evidenced by Histamine H3-receptor modulation in rat lung
and spleen", Clinical Science 87Γ2^: 1 5 1-61T (1994))。該等 疾病或病狀包括心血管病症，諸如急性心肌梗塞；記憶過 程、癡呆症及認知病症，諸如阿茲海默氏病及注意力不足 過動症’神經系統病症’諸如帕金森氏病（parkins〇n，s disease)、精神分裂症、抑鬱症、癲癇症及抽搐或痙攣；
癌症，諸如皮膚癌、髓質性甲狀腺癌及黑素瘤；呼吸道病 症，諸如哮喘；睡眠失調，諸如嗜睡症；前庭功能障礙， 諸如梅尼爾氏病（Meniere's disease);胃腸道病症、炎症、 偏頭痛、動暈症、肥胖症、疼痛及敗血性休克。 Η;受體拮抗劑先前亦已描述於（例如）w〇 〇3/〇5⑼ wo们/嶋加、wo 〇2/12224及美國專利公開案 2〇〇5/0171181 A1號中。組織胺％受體(h3r)調節組織胺/ 其他钟經傳遞素（包括血清素及乙醯膽驗）之釋放eH3Rj 相對神經元特異性且抑制某些單胺（諸如組織胺）之釋放 ^受體^雜#抗作㈣高顺織胺含量 :物㈣之難，㈣最錢料㈣料料。== 括抗劑增加職織胺及其他單胺之合成及釋放。由此槽 128029.doc 1358294 制’其誘發延長之覺醒狀態、改良之認知功能、食物攝入 減少及則庭反射之正常化《因此’儘管決不限制此說明内 容，但該受體為以下疾病令之新穎治療劑之重要目標：阿 茲海默氏病、情緒及注意力調節（包括注意力不足過動症 (ADHD))、認知功能缺乏、肥胖症、頭暈、精神分裂症、 癲癎症、睡眠失調、嗜睡症及動暈症及各種形式之焦慮 症0 例如，如W0 96/38142中所述，迄今為止大多數組織胺 %受體拮抗劑與組織胺的相似之處在於其均具有可經取代 之咪唑環。非咪唑神經活性化合物（諸如p組織胺）（Arrang,
Em·. J. Pharm. 1985, 11 1:72-84)顯示一些組織胺比受體活 性’但具有不良效能。EP 978512及EP 0982300A2揭示作 為組織胺受體拮抗劑之非咪°坐烧基胺。W0 02/12224 (Ortho McNeil Pharmaceuticals)描述作為組織胺h3受體配 位體之非咪唑雙環衍生物。其他受體拮抗劑已描述於w〇 02/32893及 W0 02/06233 中。 在2006年10月13曰申請之u.S.第1 1/549175號中提及作為 組織胺-3受體拮抗劑之化合物，其包括反_N_乙基_3_氟_3_ [3-氟-4-(吡咯啶_1_基甲基）苯基]環丁烷甲醯胺及其鹽酸鹽 及其他相關化合物。前述申請案（與本申請案歸屬一樣且 係以引用的方式全部併入本文中）一般敍述本文中所提及 化合物之醫藥學上可接受之酸加成鹽。 【發明内容】 本發明係關於式1化合物之曱苯續酸鹽： 128029.doc 1358294 反-N-乙基-3-氟- 3-[3 -氟-4-(。比 甲醯胺之先前已知之鹽。 洛啶-1-基曱基）苯基]·環丁烷
本發明化合物(亦即式1}可以在完全非晶形至完全晶態 範圍内呈固態連續體形式存在。術語"非晶形"係指其中物 質在分子層級上缺乏長程有序性且視溫度而定可呈現固體 或液體之物理特性之-種狀態。通常，該等物質不產生特 殊X射線繞射圖案，且雖然呈現固體特性，但更正式應稱 為液體。加熱後’固體特性轉變為液體特性，其特徵^狀 態變化（通常為二級狀態變化（"玻璃轉移”））。術語”晶雄"係 指其中物質在分子級別上具有有序内部結構且產生具有特 定波峰之獨特X射線繞射圖案之一種固相。該等物質經充 分加熱後亦將呈現液體特性，但固體轉變為液體之特徵為 相變（通常為一級相變（"熔點。 本發明化合物（亦即式^亦可以非溶劑化形式及溶劑化 形式存在。術語"溶劑合物”在本文中係用於描述包含本發
明化合物與一個或多個醫藥學上可接受之溶劑分子（例 如’乙醇）之分子複合物。當該溶劑為水時，使用術語"水 合物π。 目前公認之有機水合物分類系統為一種界定隔離點、通 道或金屬離子配位水合物之系統，參見K R M〇rds之 Polymorphism in Pharmaceutical Solids rw 〇 ^ · ~ Brittain編，
Marcel Dekker，1995)。隔離點水合物為藉由插入有機分子 而使水分子彼此不直接接觸之水合物。在通道水合物^， 水分子處於晶格通道中，在該等晶格通道中其與其他水分 I28029.doc -13- 1358294 水分子與金屬離子鍵 子緊鄰。在金屬離子配位水合物中 結0 右溶劑或水緊密結合’則該複合物將具有與濕度&關之 明確化學計量。然而’若溶劑或水微弱結合（如在通道容 劑合物及吸濕性化合物中），則水/溶劑含量將視渴度及乾 燥條件而定。在此等情況下’將以非化學計量為標準計 量 ° • 多組份複合物（除鹽及溶劑合物之外）亦包括於本發明之 範嘴内，其令藥物及至少-種其他組份係以化學計量或非 化學計量存在。此類型複合物包括籠形物（藥物_主體包人 複合物)及共晶體。後者通常定義為經由非共價相互作用 •、结合在—起之中性分子成份之結晶複合物，但亦可為中性 分子與鹽之複合物。可藉由熔融結晶、自溶劑再結晶或將 組份物理研磨在-起來製備共晶體，參見〇. Ah㈣〇n及 M. J. Zaworotko^Chem. Commun., n, 1S89-1896 (2004) 〇 i W於多組份複合物之—般概述，參見制咖扣之了抑随·
Sci.’ M(8)，1269-1288 (1975年 8月）。 本發明化合物（亦即式1}在經受適合條件時亦可以介晶 態(介晶相或液晶)存在。介晶態為介於真正結晶狀態與真曰 正液體狀態（熔體或溶液）之間的中間態。由於溫度變化而 出現之介晶現象經描述為，’熱致性”，且由於添加第二組份 ^諸如水或另一溶劑)而產生之介晶現象經描述為"向液性"。 八有形成向液性介晶相趨勢之化合物經描述為"兩親媒性,， 且由具有離子（諸如_C〇〇-Na+、_c〇〇.K%t Ua+)極性 】28029.doc 14 頭基或非離子（諸如-N-N+(CH3)3)極性頭基之分子組成。關 於更多資訊，參見 N. H. Hartshorne 及 A. Stuart 之 Crystals —Polarizing Microscope，第 4 版（Edward Arnold， 1970)〇 下文中所有提及式丨化合物皆包括提及其鹽、溶劑合 物、多組份複合物及液晶，以及其鹽之溶劑合物、多組份 複合物及液晶。 本發明之曱苯續酸鹽由如表I及圖1中所呈現且如本文中 所述之如由銅輻射所量測之以2Θ表示的主要X射線繞射圖 案峰（在所示誤差範圍内）進一步表徵。 使用動力學蒸氣吸附技術來評估吸濕性，其中使精確稱 重之樣品經受逐漸改變之水蒸氣壓力，同時記錄重量變 化。在25。(：下等溫進行實驗。 本發明之另一實施例係關於一種醫藥組合物，其包含式 1化合物之甲苯磺酸鹽及醫藥學上可接受之載劑或賦形 劑，該醫藥組合物尤其適用於治療抑鬱症、情感障礙、精 神分裂症、焦慮症、認知病症、阿茲海默氏病、注意力缺 乏症（ADD)、注意力不足過動症（ADHD)、精神病、睡眠失 調、肥胖症、帛暈、癲癇症、動暈症、呼吸道疾病、過 敏、過敏誘發之氣管反應、過敏性鼻炎、鼻充血、過敏性 充血、充血、低血壓、心血管疾病、胃腸道疾病、胃腸道 之蠕動過度或過低及酸分泌。 本發明此外係關於-種治療以下病症之方法：抑營症、 情感障礙、精神分裂症、焦慮症、認知病症、阿兹海默氏 128029.doc -15- 1358294 . 病、注意力缺乏症（ADD)、注意力不足過動症（ADHD)、精 .. 神病、睡眠失調、肥胖症、頭暈、癲癎症、動暈症、呼吸 道疾病、過敏、過敏誘發之氣管反應、過敏性鼻炎、鼻充 血、過敏性充血、充血、低血壓、心血管疾病、胃腸道疾 病、胃腸道之蠕動過度或過低及酸分泌，其包含向需要此 治療之哺乳動物投與式1化合物之鹽。 本發明亦係關於一種製備式1化合物之甲苯磺酸鹽的方 法，其包含以下步驟： (1)使溶解於適合溶劑中之式1化合物與對甲苯磺酸（通 常稱作對曱基苯磺酸）接觸；及 (Π)收集所形成之晶體。 本發明亦係關於根據本發明之方法製備之反_N_乙基·3· 氟-3-[3-氟_4-(吼咯啶d•基曱基）笨基]環丁烷甲醯胺（1)的 甲苯磺酸鹽。 【實施方式】 • 式1化合物為組織胺-3(Η3)受體之拮抗劑，且可用於治療 多種CNS疾病、病症及病狀。可根據2〇〇6年1〇月13日申請 之U.S.第1 1/549175號中提出之方法來製備該化合物之游離 鹼及其鹽酸鹽（亦參見"Histamine-3 Receptor Antag〇nists"， W〇2007/049123 ’其全部揭示内容係如完全列出一樣以引 用的方式併入本文中）。可在多種不同條件下製備曱苯磺 酸鹽。在本發明之一實施例中’使式i化合物之游離鹼較 佳溶解於適合溶劑中，直至完全溶解，隨後將對甲苯磺酸 添加至由此製備之溶液中以產生本發明之甲苯磺酸鹽加成 128029.doc -16- < S ) 1358294 鹽。適合溶劑包括 醇、乙醇、正丙醇 及甲基第三丁基醚 乙酸乙醋、乙酸甲g旨 、異丙醇、第三丁醇 :較佳為乙酸乙醋或 、乙酸異丙酯、甲 、乙醚、二異丙醚 甲醇。在該方法之
另一實施例中’完成式丨化合物與對甲苯續酸之溶液或對 甲苯磺酸之固體在溶液相中之接觸。 接觸步驟較佳係在介於!小時與24小時之間、更佳介於 10小時與20小時之間的時期内進行，且包含㈣或混合所 得混合物。該方法之—較佳實施例為其中該方法之步驟⑴ 在介於周圍溫度與溶劑之回流溫度之間；更佳介於周圍溫 度與約8(TC之間的溫度下進行；該方法最佳在介於抑與 6代之間的溫度下進行。較佳適合溶劑為乙酸乙酿或甲 醇。心佳地’在對甲苯續酸添加完成後使反應混合物冷卻 至周圍溫度且允許在反應時期之剩餘時 佳實施例中，請參見實例】之方案。㈣在較
式1化合物之甲笨磺酸鹽僅具有輕微吸濕性且具有高水 溶性。該等特性及㈣醫藥調配物巾利之常見賦形劑之 相對惰性使其非常適於醫藥調配物用途。 物理表徵 1(a)·結晶度 於石夕油中製備-樣品且將其在正交偏振光下觀測。該樣 品呈晶態且含有具有_些聚集體之高度雙折射不規則棱柱 形粒子。在樣品中未觀測到非晶形物質。 1 (b).粉末X射線繞射圖案 使用裝備有一鋼輻射源、固定狹縫（發散丨〇 、防散 128029.doc •17· 1358294 射1 ·0 mm及接收0.6 mm)及一 Solex固態積測器之Bruker D5000繞射儀（Madison, Wisconsin)來收集本發明之曱苯確 酸鹽之粉末X射線繞射圖案。使用0.040度之步長及1秒之 步時在銅波長Και = 1.5405 6且Ka2= 1.54439(相對強度0.5)下 自3.0度至40.0度（2Θ)自一平板樣品固持器以2Θ(2Θ)Θ測角儀 組態來收集資料。X射線管電壓及安培數（amperage)分別 設定為40 kV及30 mA。 收集資料且使用Bruker DIFFRAC Plus軟體進行分析。 藉由將其置於一石英固持器中來製備樣品。（應注意Bruker D5000繞射儀在操作上類似於Siemans D5000型。）結果概 述於表1中，其提供所有反射（線）之2Θ值及相對強度，使用 0.30之反射寬度及4.0之臨限值，該等反射（線）具有大於或 等於7%之相對強度。 表I.甲苯磺酸鹽之粉末X射線繞射反射
角 相對強度# 2Θ ± 0_2〇 % 8.959 32.8 13.816 9.5 15.515 29.3 17.991 100 18.523 15.9 19.406 15.4 19.741 9.0 20.250 14.6 21.054 24.4 21.995 10.1 128029.doc -18- 1358294
該相對強度可視粒度及形狀而改變
本發明包括式1化合物之甲苯磺酸鹽’其中如由銅如丨= 1.54056，Κα2=1.54439)輻射所量測之以2Θ表示之主要又射 線繞射圖案峰包括表I中之峰與圖丨中所示峰之任何組合。 舉例而言，本發明包括式丨化合物之〒苯磺酸鹽，其中以 2Θ(土〇.2)表示之主要X射線繞射圖案峰包括（例如）8 ; 13.816 ； 15.515 ； 17.991 ； 18.523 ； 19.406 ； 19.741 ； 20.250 ； 21.054 ； 21.995 ； 22.590 ； 24.409 ； 25.327 ； 26.328 ;錢州或其任何子集或其個別峰（例—起或個 別之8.959;13.816;15.515;及17 991)。所測試物質經測 定為完全結晶。 2.熱分析 差示掃描熱量測定鑑別出單—吸熱事件，其中開始溫度 為約161°(：(ΔΗ=1〇〇.4 J/g)，接著為一開始於約175<)(：之放 熱事件（參見圖2)4與在高溫載台賴顯微鏡下觀測到之 物質之熔融及分解一致。 高溫載台炼解顯微鏡係在不具有石夕油之情況下進行操 作’且使用- Linkam可變溫載台（Linkam加缝T，咖⑽ g )在加熱至225 C之情況下在正交偏振光下觀測粒子。 128029.doc •19· 1358294 ·. 稜柱粒子之熔融發生在約165°C下，且到168^時炼融完 .. 成。隨著載片冷卻至室溫，未偵測到其他事件且未觀測到 結晶 ° 3·吸濕性 在初始乾燥週期（25°c ’ 1% RH)中，觀測到小於〇 1%重 畺損失’其與無水非吸濕性形式一致。當樣品在2 5下暴 露於5%至90%之相對濕度時，由DVS分析偵測到約〇 〇6% • 重量增加。當相對濕度降至5%時，解吸附相類似於吸附 相（參見圖3)。另外，在吸濕性測試後樣品之粉末χ射線繞 射圖案與在彼測試之前樣品之圖案相匹配。 4·水溶性 以下資訊係關於水溶性進行測定。本發明之甲苯磺酸鹽 在0·1 Μ磷酸鹽緩衝鹽水（最終ρΗ值為65)中具有大於l〇mg/mL 之溶解度；在具有0.5重量百分比之牛磺膽酸鈉/磷脂醯基 膽鹼鹽之〇_1 Μ磷酸鹽緩衝鹽水（最終pH值為6.5)中具有大 魯 於11 mg/mL之溶解度；且在未經缓衝之水（最終值為 3.8)中具有23.6 mg/mL之溶解度。該等值表示在藥物培養 基混合物經受溫度循環程式（在4(rCT8小時，在15艽下5 小時，且在25°C下12小時）後經由RP_HPLC分析測定之結 ' 晶化合物之溶解度。 本發明之甲苯磺酸鹽可由諸如沈澱、結晶、冷凍乾燥、 噴霧乾燥或蒸發乾燥之方法以（例如）固體栓塞、粉末或薄 膜形式提供。就此目的而言，可使用微波或射頻乾燥。 甲苯磺酸鹽可單獨投與或與一或多種本發明之其他化合 128029.doc •20· 1358294 物’且σ或肖或夕種其他藥物(或以其任何組合形式)組合 奴與。-般而言’其將以與一或多種醫藥學上可接受之賦 形劑結合之調配物的形式來投與。術語"賦形劑"在本文中 用於描述除本㈣化合物以外之任何成份。賦形劑之選擇 將在很大程度上視諸如以下之因素而定：特定投藥模式、 賦形劑對溶解度及穩定性之影響及劑型特性。
熟習此項技術者將易於認識到適用於傳遞本發明化合物 之醫藥組合物及其製備方法。該等組合物及其製備方法可 見於（例如Sciences，第 19版 (Mack Publishing Company, 1995)中。 本發明之鹽可經口投與。經口投藥可包括吞咽，以使化 口物進入月腸道中；及/或經頻、經舌或經舌下投藥，化 合物藉此由口直接進入血流中。 ▲適於經口投藥之調配物包括固體、半固體及液體系統， 諸如錠劑；含有多微粒或奈米微粒、液體或粉末之軟或硬 膠囊；口含劑（包括填充液體）；口嚼旋；凝膠劑；快速分 散劑型；薄膜；卵狀體；喷霧劑；及頻/黏膜黏附貼片。 液體調配物包括詩液、溶液、糖漿及_。該等調配 物可用作軟膠嚢或硬膠囊（例如由明膠或經丙基曱基纖維 素製成)中之填充物且通常包含載劑(例如水、乙醇、聚乙 二醇、丙二醇、甲基纖維素或適合油）及—或多種乳化劑 及/或懸洋劑。液體調配物亦可藉由固體之復水（例如）自藥 快速崩解之劑型（諸如在 本發明之鹽亦可以快速溶解 128029.doc -21 - 1358294
Liang及 Chen之 Expert Opinion in Therapeutic Patents，11 (6)，981-986，（2001)中所述之劑型）的形式使用。 對於錠劑劑型而言，視劑量而定，藥物可佔劑型之i重 量％至80重量％，更通常佔劑型之5重量％至6〇重量％。除 藥物外，錠劑通常含有崩解劑。崩解劑之實例包括乙醇酸 澱粉鈉、羧甲基纖維素鈉、羧曱基纖維素鈣、交聯羧曱纖 維素納、父聯聚乙稀β比η各酿|、聚乙稀。比洛咬酮、甲基纖維 素、微晶纖維素、經低碳烷基取代之羥丙基纖維素、澱 粉、預膠凝化澱粉及海藻酸鈉。一般而言，崩解劑將佔劑 型之1重量。/〇至25重量％、較佳5重量％至2〇重量％。 通常使用黏合劑以賦予錠劑調配物内聚品質。適合黏合 劑包括微晶纖維素、明膠、糖、聚乙二醇、天然膠及合成 膠、聚乙烯吡咯啶酮、預膠凝化澱粉、羥丙基纖維素及羥 丙基甲基纖維素。錠劑亦可含有稀釋劑，諸如乳糖（單水 合物、經喷霧乾燥之單水合物、無水物及其類似物）、甘 露糖醇、木糖醇、右旋糖、蔗糖、山梨糖醇、微晶纖維 素、澱粉及二水合鱗酸氫二約。 錠劑亦可視情況包含表面活性劑（諸如月桂基硫酸鈉及 聚山梨醇酯80)及助流劑（諸如二氧化矽及滑石粉）。若存 在’則表面活性劑可佔錠劑之〇·2重量％至5重量％，且助 流劑可佔旋劑之0.2重量％至1重量％。 錠劑通常亦含有潤滑劑，諸如硬脂酸鎂、硬脂酸鈣、硬 月曰鲅鋅、硬脂醯基反丁烯二酸鈉及硬脂酸鎂與月桂基硫酸 鈉之混合物。潤滑劑通常佔錠劑之0.25重量％至10重量 128029.doc •22· 1358294 較佳0·5重量％至3重量％。 其他可能之成份包括抗氧化劑 劑及掩味劑。 例不性錠劑含有至多約8〇%藥物 ' 約1〇重量％至賴重 量％黏合劑、約0重量％至約85重量％稀釋劑、約2重量％至 約重量。/。崩解劑及約〇.25重量％至約1〇重量％潤滑劑。 可將錠劑摻合物直接壓縮或藉由滾筒壓縮以形成錠劑。
、著色劑、芳香劑、防腐 或者，錠劑摻合物或摻合物之部分可在製鍵前經濕式造 粒、乾式造粒或㈣造粒、熔融凝結或擠麗。最終調配物 可包含一或多個層且可經塗佈或未經塗佈；其甚至可經囊 封。 錠劑調配物論述於Η. Lieberman及L. Lachman之 且Tabiets ,第 ι 卷（Marcel
Dekker，New York, 1980)中。 用於人類或獸醫用途之可消耗經口薄膜通常為柔韌、水 溶性或水溶脹性薄臈劑型，其可快速溶解或具黏膜黏附性 且通常包含式I化合物、成膜聚合物、黏合劑、溶劑、濕 潤劑、增塑劑、穩定劑或乳化劑、黏度調節劑及溶劑。調 配物之一些組份可執行一種以上功能。 式I化合物可具水溶性或不溶性。水溶性化合物通常佔 溶質之1重量％至80重量％、更通常20重量％至5〇重量％。 冷解性較小之化合物可佔組合物之較大比例，通常佔溶質 之至多88重量％。或者，式I化合物可呈多微粒珠粒形式。 成膜聚合物可選自天然多糖、蛋白質或合成水膠體，且 128029.doc -23 · 通常係以在0.0丨重量％至9 9重量％之範圍内 重至80重量％之範圍内的量存在。 、其他可能之成份包括抗氧化劑、著色劑、芳香劑及香味 增強劑、Ρ方腐劑、唾液刺激劑、冷卻劑、共溶劑(包括 油)、潤膚劑、膨化劑、消泡劑、界面活性劑及掩味劑。 根據本發明之薄膜通常係藉由將塗佈於可剥型背概支標 物或紙上之水性薄膜蒸發乾燥而製備。此可在乾燥烘箱：
通道（通常為組合式塗佈機乾燥器）中進行，或藉由冷康乾 燥或真空乾燥進行。 可將用於經口投藥之固體調配物調配為立即釋放型及/ 或改良釋放型。改良釋放型調配物包括延遲釋放、持續釋 放脈衝釋放、受控釋放、乾向釋放及程式化釋放。 就本發明之目的而言，適合改良釋放型調配物描述於美 國專利第6，106,864號中。其他適合釋放技術（諸如高能分 散及渗透及塗佈粒子）之細節見於Verma等人之
、更通常在3〇 25(2)，1-14 (2001)中。 口嚼膠用於達成受控釋放之用途描述於冒〇〇〇/35298中。 亦可將本發明之甲苯磺酸鹽直接投予血流、肌肉或内臟 中。適合非經腸投藥方式包括靜脈内、動脈内、腹膜内、 鞘内〜至内、尿道内、胸骨内、顧内、肌肉内、滑液内 及皮下投藥。用於非經腸投藥之適合裝置包括針（包括微 針）注射器、無針注射器及輸液技術。 非經腸調配物通常為水溶液，其可含有諸如鹽、碳水化 合物及緩衝劑（較佳達3至9之pH值）之賦形劑，但對於一些 I28029.doc •24- ⑺ 8294 應用而言，可將其更適宜地調配為無菌非水性溶液或乾燥 形式，以與適合媒劑（諸如無菌無熱原質水）結合使用。 舉例而言，使用熟習此項技術者所熟知之標準醫藥技術 可易於實現在無菌條件下藉由来乾製備非經腸調配物。1 可藉由使用適當調配技術（諸如併入溶解度增強劑）來增 用於製備非經腸溶液之甲苯項酸鹽之溶解度。 可將用於非經腸投藥之調配物調配為立即釋放型及/或 改良釋放型。改良釋放型調配物包括延遲釋放、持續釋 放、脈衝釋放、受控釋放、乾向釋放及程式化釋放。因 此，本發明化合物可經調配為懸浮液或固體、半固體或觸 隻性液體以供作為提供活性化合物改良釋放之植人式健槽 而投藥。該等調配物之實例包含經藥物塗佈之血管支架及 包含經藥物裝載之聚（w_乳酸-共乙醇酸）(PGLA)微球體的 半固體及懸浮液。 本發明之f苯磺酸鹽亦可經局部、經皮（内）或經皮投予 1膚或黏膜。用於此目的之典型調配物包括凝膠劑、水凝 膝畜1 /先劑、溶液、乳膏、軟膏、粉劑、敷料、發泡體、
薄膜、皮膚貼片、糯米紙囊劑、植入劑、海綿、纖維、繃 帶及微乳液。亦可使用脂質體。典型載劑包括醇、水、礦 物油、液態石蠟脂、白石蠟脂、甘油、聚乙二醇及丙二 户 了併入’參透增強劑’例如參見Finnin及Morgan之J
Pharrn Sci’ 处（10)，95 5-958 (1999年 10月）。 其他局部投藥方式包括藉由電穿孔、離子導入療法、超 曰藥物透入療法、超音電滲法及微針或無針（例如 128029.doc •25· 1358294
Powderjectm、Bi〇jectTlv^)注射來傳遞。 可將用於局部投藥之調配物調配為立即釋放型及/或改 良釋放型。改良釋放型調配物包括延遲釋放、持續釋放、 脈衝釋放、文控釋放、靶向釋放及程式化釋放。 本發明之曱苯磺酸鹽亦可經鼻内或藉由吸入投與，其通 导為來自乾燥粉末吸入器之乾燥粉末（單獨，或作為混合 物（例如與乳糖之乾燥摻合物，或作為混合組份粒子，= 如與諸如磷脂醯基膽鹼之磷脂混合）之形式，為在使用或 不使用適合推進劑（諸如丨山丨，^四氟乙烷或u山2,3,3> 七氟丙烷)之情況下之來自加壓容器、泵、噴射器、霧化 器（較佳為使用電流體動力以產生精細薄霧之霧化器）或嘴 霧器之氣溶膠喷霧形式，或為滴鼻劑形式^對於鼻内使用 而言，粉末可包含生物黏著劑’例如聚葡萄胺糖或環糊 精0 該加壓容器、系、噴射器、霧化器或喷霧器含有本發明
化合物之溶液或懸浮液，其包含（例如）乙醇、乙醇水溶液 或用於分散、增溶或延期釋放活性物質之適合替代性試 劑:作為溶劑之推進劑及可選界面活性劑（諸如脫水山梨 糖醇三油酸酯、油酸或寡聚乳酸）。 在用於乾粉或懸浮液調配物中之前，將藥物產物微粉化 至適於猎由吸入而傳遞之大小(通常小於5微米卜此可藉由 任何適當粉碎方法達成’諸如螺旋喷射研磨、流化床喷射 =、用以形成奈米粒子之超臨界流體處理、高麼均質化 或喷霧乾燥。 128029.doc • 26 - 1358294 ·· 在吸入器或吹入器中使用之膠囊(例如由明膠或羥丙基 .甲基纖維素製成）、發泡包及卡管可經調配以含有本發明 化合物之粉末混合物、合適之粉末基質(諸如乳糖或澱粉) 及效月b改質劑(諸如/_白胺酸、甘露糖醇或硬脂酸鎂”乳 • 料為無水物或呈單水合物形式，較佳為後者。其他合適 • 賦形劑包括葡聚糖、葡萄糖、麥芽糖、山梨糖醇、木糖 醇、果糖、蔗糖及海藻糖。 φ 在使用電流體動力學以產生精細薄霧之霧化器中使用之 合適溶液調配物每次致動可含有！叫至2〇 mg本發明化合 物且致動體積可在1 μ1至i ^之間變化。典型調配物 可包含式1化合物、丙二醇、無菌水、乙醇及氯化鈉。可 替代丙二醇使用之替代性溶劑包括甘油及聚乙二醇。 可將合適芳香劑（諸如薄荷醇及左薄荷醇（lev〇menth〇1)) 或甜味劑（諸如糖精或糖精鈉）添加至預期用於吸入/鼻内投 藥之本發明調配物中。 φ 可使用（例如）PGLA調配用於吸入/鼻内投藥之調配物成 為立即釋放型及/或改良釋放型。改良釋放型調配物包括 延遲釋放、持續釋放、脈衝釋放、受控釋放、靶向釋放及 程式化釋放。 ' 若為乾粉吸入器及氣霧劑時，藉由傳遞計量量之閥門來 確定劑量單位。根據本發明之單位通常經配置以投與含有 1 Kg至20 mg式I化合物之計量劑量或"喷出劑量"。總每曰 劑量通常將在1 mg至200 mg之範圍内，其可以投與單一劑 量’或（更通常）在一整天内以分次劑量投與。 128029.doc •27· 1358294 本發明之曱苯續酸鹽可（例如）以栓劑、子宮托或灌腸劑 形式經直腸或經陰道投與。可可脂為傳統栓劑基質，但適 當時可使用各種替代物。 可將用於經直腸/經陰道投藥之調配物調配為立即釋放 型及/或改良釋放型。改良釋玫型調配物包括延遲釋放、 持續釋放、脈衝釋放、受控釋放、靶向釋放及程式化釋 放。
本發明之甲苯磺酸鹽亦可通常以於等張、pH值經調節之 無菌生理鹽水中之微粉化懸浮液或溶液滴劑的形式直接投 予眼睛或耳朵。適於經眼及經耳投與之其他調配物包括= 膏、凝膠、可生物降解（例如可吸收凝膠海綿、膠原蛋白） 植入物及不可生物降解（例如聚矽氧）植入物、糯米紙囊 劑、透鏡體及微粒或囊狀系統（諸如非離子體（ni〇s〇me)或 脂質體）。可將聚合物(諸如交聯聚丙稀酸、聚乙稀醇、玻 糖駿酸、纖維質聚合物（例如經丙基甲基纖維素、m乙基
纖維素或甲基纖維素）或異多酶聚合物（例如膠質膠狀物;) 與防腐劑（諸如氯节院銨）-起併入。該等調配物亦可藉由 離子導入療法傳遞。 可將用於經眼/經耳投與之調配物調配為立即釋放型及/ 或改良釋放型。改良釋放型調配包括延遲釋放、持續釋 放、脈衝釋放、受控釋放、杂a 枰双靶向釋放或程式化釋放。 可將本發明之曱苯碏酸鹽盥 '、1興可溶性大分子實體（諸如環 糊精及其適合衍生物或含聚 一岬之聚合物）組合，以改 良其溶解度、溶解速率、掩 释味11、生物可用性及/或穩定 128029.doc -28- < S ) 性以用於任何前述投藥模式中。 舉例而言，吾人發現藥物_環糊精複合物通常可用於大 多數劑型及投藥途徑。包合複合物與非包合複合物均可使 用。作為與藥物直接複合之替代性方法，可使用環糊精作 為辅助添加劑’亦即作為載劑、稀釋劑或增溶劑。就該等 目的而S ，最常使用者為^環糊精、Ρ_環糊精及丫_環糊 精’其之實例可見於國際專利中請案第wo 91/11172號、 第 W0 94/02518號及第 W〇 98/55148號中。 由於（例如）就治療特定疾病或病狀之目的而言，可需要 投與活性化合物之組合’因此可便利地將兩種或兩種以上 醫藥組合物（其中至少一者含有根據本發明之化合物）以適 於組〇物共投藥之套組形式加以組合，此在本發明之範疇 内0 因此，本發明之套組包含兩種或兩種以上單獨醫藥組合 物（其中至少一者含有根據本發明之甲苯磺酸鹽）及用於分 別保持該等組合物之構件(諸如容器、分隔瓶或分隔式羯 封包）。此套組之一實例為用於封裝錠劑、膠囊及其類似 物之常見發泡包裝。 本發明之套組尤其適於投與不同劑型，例如經口及非經 腸劑型，適於以不同給藥時間間隔投與個別組合物，或適 於彼此相對滴定個別組合物為有助於順應性，該套組通 常包含投藥說明書且可具備所謂記憶輔助物。 本發明之曱苯續酸鹽可經由經口、經皮（例如經由使用 貼片）、經鼻内、經舌下、經直腸、非經腸或經局部途徑 < S ) 128029.doc -29· 1358294 •- 扠與。較佳為經皮及經口投藥。最希望將活性鹽以在每天 .· 約0.001叫心至約5〇 mg/kg、較佳每天約〇〇1 mg/kg至約 mg/kg之範圍内之劑量以單次給藥或分次給藥形式投 與，但視待治療個體之體重及狀況及所選特定投藥途徑而 定，將有必要發生改變。然而，最希望使用在每天每公斤 • 體重约〇.01 至約mg之範圍内之劑量水平。然而，視 待治療患者之體重及狀況及其對該藥物之個別反應以及所 • 選醫藥調配物類型及此投藥進行之時期及時間間隔而定， 可發生改變。在一些情況下，低於前述範圍下限之劑量水 平可足夠多，而在其他情況下，可使用更大劑量而不造成 有害副作用，其限制條件為該等更大劑量首先經分為若干 小劑量以在一整天内投與。在本實施方式及隨附申請專利 範圍中所提出之劑量量可用於（例如）具有約6〇 kg至約7〇 kg體重之一般人類個體。熟練執業者將能夠容易地根據個 體之病史來確定體重處於約60 kg至約7〇 kg範圍外之個體 ·(諸如嬰兒及老年人）所需之劑量量的任何改變。可以每天 夕達6人、較佳每天1至3次（諸如每天兩次或每天一次）之方 案來投與醫藥組合。 為避免疑義，本文中對"治療"之提及包括對治癒性治 療、緩解性治療及預防性治療之提及。 以下實例說明本發明之方法及化合物。然而，應瞭解本 發明並不限於此特定實例。 實例1 實例1-反-N-乙基-3-氟-3-[3-氟-4-(吡咯啶-I基甲基）苯基】 128029.doc •30- 1358294 環丁烷甲醯胺之曱苯磺酸鹽 經20分鐘將對曱苯續酸（2.50 g，13.14 mmol)於乙酸乙醋 (70 mL)中之溶液添加至反乙基-3-氟-3-[3-氟-4-(吡嘻 咬-1-基曱基）苯基]-環丁烷甲醯胺（4.18 g，12.97 mmol)於 乙酸乙酯（35 mL)中之攪拌溶液中。將所得混合物再擾拌1 小時。將白色沈澱物過濾，用EtOAc沖洗且風乾，得到 6_32 g甲苯磺酸鹽。將此物質溶解於甲醇中且過濾以移除 微粒且再濃縮《在緩慢加熱下將所得固體溶解於約12_14 mL曱醇中。經2〇分鐘添加乙酸乙酯（75 mL)且隨後在室溫 下將混合物攪拌1小時。將固體過濾，用乙酸乙酯沖洗且 風乾，得到5.59 g呈白色結晶粉末狀之（反）_3_氟_3_[3_氟_ 4-("比咯啶-1-基曱基）苯基]環丁烷甲酸乙基醯胺甲笨磺酸 鹽。 !H NMR (CDC13) δ 7.71 (d, J = 8.3 Hz, 2H), 7.65 (t, J = 7.9 Hz, 1H), 7.28-7.22 (m, 2H), 7.15 (d, J = 7.9 Hz, 2H), 6.52 (br s，1H)，4.28 (d，J = 5.4 Hz, 2H)，3.68-3.37 (m, 2H)， 3.33-3.18 (m, 3H), 2.97-2.88 (m, 2H), 2.84-2.57 (m, 4H), 2.32 (s, 3H), 2.27-1.96 (m, 4H), 1.07 (t, J = 7.3 Hz, 3H) 〇 13C NMR (CDCI3) δ 173.8, 161.3 (d, JC-f = 248.7 Hz), 147.4 (dd，JC_F = 24.1，7.5 Hz)，142.4，140.4，133.5，129.1， 126.0, 121.7 (d, JC.F = 6.0 Hz), 116.4 (d, JC-F = 14.3 Hz), 112.6 (dd, JC.F = 23.3, 9.0 Hz), 96.7 (d, JC-f = 197.6 Hz), 53.4, 50.4, 39.0, 38.7, 34.7, 32.6, 23.0, 21.52, 14.9。 元素分析’關於c18h24f2n2oc7h8o3s之計算值：c < S ) 128029.doc •31 - 1358294 60.71，Η 6·52, N 5.66, F 7.68, S 6·48。實驗值：C 60.55 (60.52, 60.57)，Η 6·40 (6.35, 6.44)，N 5·58 (5.56, 5.59)，F 7‘67(7.78,7.55)，8 6.68;分子量為 494.61公克/莫耳，其 與無水單甲苯磺酸鹽一致。 【圖式簡單說明】 圖1為反-N-乙基-3-氟-3-[3-氟-4-(吡咯啶-1-基甲基）苯基] 環丁垸甲醯胺之甲苯磺酸鹽之所觀測X射線粉末繞射圖案 (y轴為每秒線性計數；X，以2Θ度計），其中操作條件為： 2Th/Th鎖定，開始於3.000度，結束於40.000度，步長為 〇-〇40度。步時為1 s，在室溫（25°C )下。 圖2提供1.5220 mg反-N-乙基-3-氟-3-[3-氟-4-(吡咯啶·ι_ 基曱基）苯基]環丁烷甲醯胺之曱苯磺酸鹽樣品之差示掃描 熱量測定迹線[以熱流動（W/g)對溫度繪圖，放熱向上]，其 以5.0(rC/min之速率自3(rc至“(^進行’其中存在兩個主 要事件，第一者在161.27。〇下，1〇〇·4 J/g。熱流動之導數 展示為下部迹線。 圖3提供反-N-乙基_3_氟_3_[3_氟_4_(吡咯啶基曱基）苯 基]環丁烷甲醯胺之甲苯磺酸鹽之水分吸附等溫線，其中 使用動力學流經彳法繪製重量百分比變化隨相㈣度的變 化，吸附為（♦)曲線且解吸附為（)曲線（8丨mg樣品，Μ 。⑺。 128029.doc -32·
Claims (1)
1358294 -—~ 第097102227號專利申請案 公告本 ' 中文申請專利範圍替換本(Ιοσ__年τ月）〜 ； 十、申請專利範圍： .-種反-N·乙基-3-氟·3-[3-氣·4·(料咬小基曱基）苯基] 環丁烷甲醯胺之甲苯磺酸鹽。 2. —種式1化合物之甲苯磺酸鹽
3.如請求項1或2之曱苯續酸鹽，右 /、兴有之X射線繞射圖案 特徵大體上在於採用銅= 射在8.959土0.2之2Θ下量測到之χ射線繞射圖案波峰。 4·如請求項！或2之甲苯續酸鹽，其具有之χ射線繞射圖案 特徵大體上在於採用銅（Kai=L54056，Κα2=1 54439)輻 射在17.991±0.2之2Θ下量測到之χ射線繞射圖案波峰。 5. 如請求項丨或2之甲苯磺酸鹽，其具有之χ射線繞射圖案 特徵大體上在於採用銅（Και = ι·54056，Κα2=1·54439)輻 射在21.054±0.2之2Θ下量測到之χ射線繞射圖案波峰。 6. 如請求項1或2中任一項之甲苯磺酸鹽，其具有之χ射線 繞射圖案特徵大體上在於採用銅（Και = 1 54〇56，Κα2= 1.54439) 輻射在22·590±0·2之2Θ下量測到之χ射線繞射圖 案波峰。 7. 如請求項1或2中任一項之甲苯磺酸鹽，其具有之χ射線 繞射圖案特徵大體上在於採用銅（και=1 54〇56，Κα2= 1.54439) 輻射在28·050±0.2之2Θ下量測到之\射線繞射圖 128029-1000408.doc 1358294
案波峰。. 8·如請求項1或2之甲苯磺酸鹽，其具有之χ射線繞射圖案 特徵大體上在於採用銅（Και = 1·54056，Κα2=1.54439)輻 射在15.51 5(± 0.2)之2Θ下量測到之X射線繞射圖案波峰。 9.如吻求項1或2之曱苯磺酸鹽，其具有之χ射線繞射圖案 特徵大體上在於採用銅（Και = 1.54056，Kci2 = 1.54439)賴 射在 8.959 ; 15.515 ; 17.991 ; 21.054 ; 22.590 ;及 28.050 之2Θ(± 0.2)下量測到之χ射線繞射圖案波岭。
10·如請求項1或2之甲苯磺酸鹽，其中該鹽為無水鹽。 Π· —種醫藥組合物，其包含如請求項1至1〇中任一項之曱 苯磺酸鹽及醫藥學上可接受之載劑。
12. 一種如請求項1或2之甲苯磺酸鹽之用途，其係用於製造 供治療哺乳動物之以下病症用之藥物：抑鬱症、情感障 礙、精神分裂症、焦慮症、認知病症、阿茲海默氏病 (Alzheimer's disease)、注意力缺乏症（ADD) '注意力不 足過動症（ADHD) '精神病、睡眠失調、肥胖症、頭 暈、癲痛症、動暈症、呼吸道疾病、過敏、過敏誘發之 氣管反應、過敏性鼻炎、鼻充血、過敏性充灰、充血、 低血壓、心血管疾病、胃腸道疾病、胃腸道之罐動過度 或過低及酸分泌。 128029-1000408.doc 1358294 第097102227號專利申請案 ~7-—- 中文說明書替換頁(100年4月） （碎Y月茨曰修(更)正替換頁 七、指定代表圖·· ---- (一) 本案指定代表圖為：第（1 )圖。 (二) 本代表圖之元件符號簡單說明： (無元件符號說明） 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：
128029-1000408.doc
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| ES (1) | ES2395744T3 (zh) |
| IL (1) | IL199587A (zh) |
| MX (1) | MX2009007782A (zh) |
| NZ (1) | NZ577951A (zh) |
| PE (1) | PE20081690A1 (zh) |
| PL (1) | PL2124933T3 (zh) |
| PT (1) | PT2124933E (zh) |
| RU (1) | RU2430099C2 (zh) |
| SI (1) | SI2124933T1 (zh) |
| TW (1) | TWI358294B (zh) |
| UY (1) | UY30878A1 (zh) |
| WO (1) | WO2008090429A1 (zh) |
| ZA (1) | ZA200905827B (zh) |
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| JP2015529239A (ja) | 2012-09-20 | 2015-10-05 | ファイザー・インク | アルキル置換ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物 |
| UA110688C2 (uk) | 2012-09-21 | 2016-01-25 | Пфайзер Інк. | Біциклічні піридинони |
| CN103113405B (zh) * | 2012-10-17 | 2016-03-02 | 上海日馨生物科技有限公司 | 苯磷硫胺多晶型体、制备方法及其应用 |
| EP2919788A4 (en) | 2012-11-14 | 2016-05-25 | Univ Johns Hopkins | METHOD AND COMPOSITIONS FOR TREATING SCHIZOPHRENIA |
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| JP2016507551A (ja) | 2013-02-13 | 2016-03-10 | ファイザー・インク | ヘテロアリール置換ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物 |
| US9233981B1 (en) | 2013-02-15 | 2016-01-12 | Pfizer Inc. | Substituted phenyl hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds |
| MD20150071A2 (ro) | 2013-02-19 | 2016-02-29 | Pfizer Inc. | Compuşi azabenzimidazolici ca inhibitori ai PDE4 izoenzimelor pentru tratamentul tulburărilor SNC şi altor afecţiuni |
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| HUE044040T2 (hu) | 2014-08-06 | 2019-09-30 | Pfizer | Imidazopiridazin vegyületek |
| EP3253755B1 (en) | 2015-02-03 | 2020-08-26 | Pfizer Inc | Novel cyclopropabenzofuranyl pyridopyrazinediones |
| TN2017000485A1 (en) | 2015-06-17 | 2019-04-12 | Pfizer | Tricyclic compounds and their use as phosphodiesterase inhibitors |
| KR102161364B1 (ko) | 2015-09-14 | 2020-09-29 | 화이자 인코포레이티드 | LRRK2 억제제로서 이미다조[4,5-c]퀴놀린 및 이미다조[4,5-c][1,5]나프티리딘 유도체 |
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| JP2018534251A (ja) | 2015-09-24 | 2018-11-22 | ファイザー・インク | Ｂａｃｅ阻害剤として有用なｎ−［２−（３−アミノ−２，５−ジメチル−１，１−ジオキシド−５，６−ジヒドロ−２ｈ−１，２，４−チアジアジン−５−イル）−１，３−チアゾール−４−イル］アミド |
| AU2017223132B2 (en) | 2016-02-23 | 2019-12-05 | Pfizer Inc. | 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide compounds |
| HUE054857T2 (hu) | 2016-07-01 | 2021-10-28 | Pfizer | 5,7-dihidro-pirrolo-piridinszármazékok neurológiai és neurodegeneratív betegségek kezelésére |
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| US11161844B2 (en) | 2017-03-10 | 2021-11-02 | Pfizer Inc. | Cyclic substituted imidazo[4,5-c]quinoline derivatives |
| WO2018226992A1 (en) | 2017-06-07 | 2018-12-13 | Adrx, Inc. | Tau aggregation inhibitors |
| US11198692B2 (en) | 2017-06-22 | 2021-12-14 | Pfizer Inc. | Dihydro-pyrrolo-pyridine derivatives |
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| WO2019183636A1 (en) | 2018-03-23 | 2019-09-26 | Pfizer Inc. | Piperazine azaspiro derivaves |
| US12144815B2 (en) | 2021-02-23 | 2024-11-19 | Hoth Therapeutics, Inc. | Use of aprepitant for treating Alzheimer's disease |
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| US6559140B2 (en) * | 2000-03-09 | 2003-05-06 | Abbott Laboratories | Cyclic and bicyclic diamino histamine-3 receptor antagonists |
| GB0308333D0 (en) * | 2003-04-10 | 2003-05-14 | Glaxo Group Ltd | Novel compounds |
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| US8158673B2 (en) * | 2005-10-27 | 2012-04-17 | Pfizer Inc. | Histamine-3 receptor antagonists |
| NZ585671A (en) | 2007-12-07 | 2012-06-29 | Pfizer | Tosylate salt of trans-n-isobutyl-3-fluoro-3- [3-fluoro-4- (pyrrolidin-1-yl-methyl) -phenyl] cyclobut anecarboxamide |
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