TW201139375A

TW201139375A - Hydrochloride salt of biphenyl-2-yl-carbamic acid 1-{9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl}-piperidin-4-yl ester

Info

Publication number: TW201139375A
Application number: TW100100201A
Authority: TW
Inventors: Kim James
Original assignee: Pfizer Ltd
Priority date: 2010-01-07
Filing date: 2011-01-04
Publication date: 2011-11-16
Also published as: AR079835A1; WO2011083387A1; JP2011153136A

Abstract

This invention relates to the hydrochloride salt of biphenyl-2-yl-carbamic acid 1-{9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl}-piperidin-4-yl ester and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, said compound. The invention also relates to the hydrates, solvates and polymorphs of the hydrochloride salt of Biphenyl-2-yl-carbamic acid 1-{9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl}-piperidin-4-yl ester.

Description

201139375 六、發明說明：【發明所屬之技術領域】本發明關於聯苯-2-基-胺甲酸1-{9-〔（3 -氟-4-羥基-苯甲醯基）-甲基-胺基〕-壬基}-哌啶-4-基酯氫氯化物鹽 ’並關於用於製備含有該化合物之組成物之中間產物的製備方法及該化合物之用途。本發明亦關於聯苯-2-基-胺甲酸（3-氟-4-羥基-苯甲醯基）-甲基-胺基〕-壬基 }-哌啶-4-基酯氫氯化物鹽之水合物、溶劑化物和多晶型物。【先前技術】膽鹼能毒蕈鹼受體爲G-蛋白耦合受體超家族之一員並且被進一步被劃分爲5種亞型，Μι至M5。毒覃鹼受體亞型廣泛且差別表現在體內。所有5種亞型之基因均已被選殖且其中M1、M2和M3受體已被廣泛地以藥理學方式表徵於動物和人體組織內。Μ!受體表現在大腦（皮質和海馬區）、腺體及交感神經和副交感神經之神經節中。Μ2 受體表現於心臟、後腦、平滑肌和自主神經系統之突觸中。Μ3受體表現在大腦、腺體和平滑肌中。在呼吸道中，刺激Μ3受體會引起呼吸道平滑肌收縮而導致支氣管收縮，而在唾腺中，刺激Μ3受體會增加流體和黏液分泌，從而增加唾液分泌。據了解，表現在平滑肌上之Μ2受體會促進收縮而突觸前Μ2受體會調控副交感神經釋出乙醯膽鹼。刺激表現在心臟之Μ2受體會使心動過緩。 -5- 201139375 短效和長效毒蕈鹼受體拮抗劑係用於管理哮喘和 COPD;這些包括短效劑愛全#®(Atrovent®)(異丙托溴銨）和歐西文® ( Oxivent® )(氧托溴銨），以及長效劑思力華® ( Spiriva® )(噻托溴銨）。這些化合物在經由吸入性投服後可使支氣管擴張。除了改善肺功能數値外，抗膽鹼能在慢性阻塞性肺病（COPD )中之用途係與改善健康狀態和生活質量評分有關。由於毒蕈鹼受體廣泛分佈在體內，因此顯著的全身暴露於毒蕈鹼掊抗劑與諸如口乾、便秘、瞳孔散大、尿滯留（其均主要經由阻斷M3受體介導）及心動過速（經由阻斷1^2受體介導）之影#有關。吸入性投服目前臨床上使用之非選擇性毒蕈鹼受體拮抗劑之治療劑量後常被報導之一種副作用爲口乾，雖然據報導此強度僅算輕微，但其確實限制了給予之吸入劑的劑量。因此，仍需要具有適當之藥理變化形廓（例如：就效力而言爲藥物動力學或作用期間）之改良的M3受體拮抗劑且此種拮抗劑將特別適合藉由吸入途徑投服。【發明內容】在這種情況下，本發明關於新穎之M3受體拮抗劑，其爲下式所示之聯苯-2-基-胺甲酸1-{9-〔（3-氟_4-羥基-苯甲醯基）-甲基·胺基〕-壬基}-哌啶-4-基酯氫氯化物鹽 -6 - 201139375201139375 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to biphenyl-2-yl-aminecarboxylic acid 1-{9-[(3-fluoro-4-hydroxy-benzomethyl)-methyl-amine And the use of the compound for the preparation of an intermediate product for the preparation of a composition containing the compound. The present invention also relates to (3-fluoro-4-hydroxy-benzylidene)-methyl-amino]-indolyl}-piperidin-4-yl ester hydrochloride salt of biphenyl-2-yl-aminecarboxylic acid Hydrates, solvates and polymorphs. [Prior Art] The cholinergic muscarinic receptor is a member of the G-protein coupled receptor superfamily and is further classified into five subtypes, Μι to M5. The muscarinic receptor subtypes are widely and differentially expressed in the body. All five subtypes of genes have been cloned and the M1, M2 and M3 receptors have been extensively pharmacologically characterized in animal and human tissues. Μ! Receptors are expressed in the brain (cortex and hippocampus), glands, and sympathetic and parasympathetic ganglia. The Μ2 receptor is expressed in the synapse of the heart, hindbrain, smooth muscle, and autonomic nervous system. The Μ3 receptor is expressed in the brain, glands, and smooth muscle. In the respiratory tract, stimulation of the Μ3 receptor causes contraction of the airway smooth muscle and causes bronchoconstriction. In the salivary gland, stimulation of the Μ3 receptor increases fluid and mucus secretion, thereby increasing salivation. It is known that the Μ2 receptor expressed on smooth muscle promotes contraction and the presynaptic Μ2 receptor regulates the release of acetylcholine from the parasympathetic nerve. Stimulation in the heart of the 2 receptors will cause bradycardia. -5- 201139375 Short-acting and long-acting muscarinic receptor antagonists are used to manage asthma and COPD; these include the short-acting agents Astrovent® (Isotropium bromide) and Oxivent® (Oxivent) ® ) (oxytropium bromide) and the long-acting agent Spiriva® (Tiotropium bromide). These compounds can cause bronchiectasis after administration by inhalation. In addition to improving lung function, the use of anticholinergic in chronic obstructive pulmonary disease (COPD) is associated with improved health status and quality of life scores. Since muscarinic receptors are widely distributed in the body, significant systemic exposure to muscarinic antagonists such as dry mouth, constipation, dilated pupils, and urinary retention (both mainly through blocking M3 receptors) and The tachycardia (mediated by blocking the 1^2 receptor) is related to the shadow #. One side effect often reported after inhaled administration of a therapeutic dose of a non-selective muscarinic receptor antagonist currently used clinically is dry mouth, although it has been reported to be only mild, but it does limit the inhalation administered. Dosage of the agent. Thus, there is still a need for improved M3 receptor antagonists having an appropriate pharmacological profile (e.g., during pharmacokinetics or duration of action) and such antagonists will be particularly suitable for administration by the inhalation route. SUMMARY OF THE INVENTION In this case, the present invention relates to a novel M3 receptor antagonist which is a biphenyl-2-yl-aminecarboxylic acid 1-{9-[(3-fluoro-4-) represented by the following formula Hydroxy-benzimidyl)-methyl-amino]-mercapto}-piperidin-4-yl ester hydrochloride salt-6 - 201139375

較佳地，本發明關於一種實質上呈結晶之聯胺甲酸（3-氟_4_羥基-苯甲醯基）-甲基壬基丨-哌啶-4-基酯氫氯化物鹽。較佳地，當使用Cu Κ α !放射線（波長 =1 測量時，本發明之氫氯化物鹽藉由以2-0角（± )表示之下列4個獨特X射線繞射圖案峰之X 圖案來表徵：苯-2-基- -胺基〕- .5406Α ) 0.1° 20 射線繞射Preferably, the present invention relates to a substantially crystalline hydrazide (3-fluoro-4-hydroxy-benzhydryl)-methylindolyl-piperidin-4-yl ester hydrochloride salt. Preferably, the hydrogen chloride salt of the present invention is represented by the X pattern of the following four unique X-ray diffraction pattern peaks at a 2-0 angle (±) when measured using Cu Κ α ! radiation (wavelength = 1). Characterization: Benzene-2-yl--amino]-.5406Α) 0.1° 20 ray diffraction

當使用C u Κ α 1放射線（波長 =1 . 5 4 0 6 A ) 本發明之氫氯化物鹽具有之x射線繞射圖案亦言 0角（±0.1° 2β)表示之下列7個獨特X射線峰來表徵：測量時， I由以2-繞射圖案 201139375When using C u Κ α 1 radiation (wavelength = 1.54 6 A), the x-ray diffraction pattern of the present invention has the following seven unique Xs represented by the 0-angle (±0.1° 2β) Ray peaks to characterize: When measuring, I consist of 2-diffraction pattern 201139375

或者’當使用CuKcm放射線（波長=ι.5406Α)測量時’進一步藉由以2-0角（±〇·ι。20)表示之下列10 個獨特之X射線繞射圖案峰來表徵：Or 'when measured using CuKcm radiation (wavelength = ι. 5406 Α)' further characterized by the following 10 unique X-ray diffraction pattern peaks expressed at 2-0 (±〇·ι.20):

根據另一體系’本發明之氫氯化物鹽亦可藉由具有以下主要碳化學位移（其係對.照Η. 5 ppm之固相金剛烷外部標準）之固態l3C核磁共振來表徵： 201139375 π化學位移 [ppm ± 0.2 ppml 140.0 124.5 49.1 — 309 根據另一體系，本發明之氫氯化物鹽亦可藉由具有以下主要氟化學位移（其係對照-76.54ppm之三氟醋酸水溶液（50%體積/體積）外部標準）之固態19F核磁共振來表徵： 19F化學位移 [ppm ± 0.4 ppm] -133.5 現已發現，本發明之氫氯化物鹽爲一種M3受體拮抗劑，這對治療由M3介導之疾病和/或病況特別有用，且其顯示出良好之效力。再者，本發明之氫氯化物鹽實質上呈結晶，從而展現出包括固態穩定性及與某些藥品賦形劑（諸如，例如：乳糖，尤其是α-乳糖單水合物）相容之性質，這使其優於其相對應之非結晶型游離鹼。因此，本發明之氫氯化物鹽特別適合經由吸入途徑（例如：使用乾粉吸入器）投服。爲免生疑問，根據本發明，“實質上呈結晶”意指本發明之氫氯化物鹽至少7 0 %呈結晶，較佳地，至少8 0 % 呈結晶，更佳地，至少85%呈結晶，再更佳地，至少90 %呈結晶且甚至更佳地，至少9 5 %呈結晶。 -9- 201139375 本發明之氫氯化物鹽可根據用於製備鹽類之習知方法，諸如 “Handbook of Pharmaceutical Salts, Properties, Selection and Use.由 Wiley-VCH 出版，2002.由 P. Heinrich Stahl, Camille G Wermutli 編輯。ISBN 3-906390-26-8”中所揭示者，從聯苯-2-基-胺甲酸1- { 9-〔（ 3-氟-4-羥基·苯甲醯基）-甲基-胺基〕·壬基}-哌啶-4-基酯製備。舉例而言，本發明之氫氯化物鹽可經由將氫氯酸水溶液加入在合適溶劑中之爲游離鹼形式之聯苯-2-基-胺甲酸1-{9-〔（3-氟- 4-羥基-苯甲醯基）-甲基·胺基〕-壬基}-哌啶-4-基酯中來製備》由此取得之聯苯-2-基-胺甲酸1-{9-〔（3-氟-4-羥基- 苯甲醯基）-甲基-胺基〕-壬基}-哌啶-4-基酯氫氯化物鹽可進一步從其他溶劑，諸如，例如：丙酮中再結晶以產生具有較高結晶度之物質。根據本發明之聯苯-2 -基-胺甲酸1 - { 9 _〔（ 3 -氟-4 -羥基-苯甲醯基）-甲基-胺基〕-壬基}-哌啶_4_基酯氫氯化物鹽可同時以未溶劑化和溶劑化二種形式存在。此處所使用之’溶劑化物'一詞係描述包含本發明之氫氯化物鹽及化學計算量之一或多種藥學上可接受之溶劑分子（例如：乙醇 )的分子複合物。當該溶劑爲水時則使用、水合物· 一詞。這些未溶劑化/未水合及溶劑化/水合之形式係包含在本發明之範圍內。複合物亦包括在本發明之範園內，諸如包合物、藥物-主體內包複合物，其中，相對於上述之溶劑化物，藥 -10- 201139375 物和主體係以化學計算量或非化學計算量存在。本發明之範圍亦包括含有二或多種有機和/或無機成分之藥物複合物’該有機和/或無機成分可能以化學計算量或非化學計算量存在。所產生之複合物可爲經離子化、經部分離子化或非經離子化。審閱這類複合物可見J Pharm Sci，64 (8)， 1 269- 1 288 by Haleblian (August 1 975)。本發明之氫氯化物鹽的多晶型及結晶形態/習性亦包括在本發明之範圍內。 “本發明之氫氯化物鹽”一詞包括聯苯-2-基-胺甲酸 1-{9-〔（3-氟-4-羥基-苯甲醯基）-甲基-胺基〕-壬基}-哌啶-4-基酯氫氯化物鹽以及其溶劑化物和/或多晶型物。本發明之氫氯化物鹽爲一種寶貴之藥學上活性化合物 ’其適合用於其中涉及M3毒蕈鹼受體或其中此受體之拮抗作用可能帶來助益之多種病症的療法和預防。本發明之氫氯化物鹽具有與M3受體交互作用之能力，由於該氫氯化物鹽在所有哺乳動物之生理學中具有重要作用，因而具有如下文中進一步說明之廣泛的治療應用範圍。爲避免疑問，此處提及之“治療”包括治癒性、緩和及預防性治療之相關資料。因此，本發明之氫氯化物鹽在過敏性和非過敏性呼吸道疾病（如哮喘、COPD...)之療法和預防中特別有用，亦可用於治療其他疾病，諸如發炎性腸病、大腸激躁症、大腸憩室病、暈車、胃潰瘍、腸道放射性檢查、BPH之對症治療（良性前列腺增生）、由NSAID誘導之胃潰瘍、 -11 - 201139375 尿失禁（包括尿急、尿頻、尿失禁、膀腕過動症、夜尿及下尿路症狀）、睫狀肌麻痺、擴瞳及帕金森病。根據本發明之較佳觀點，本發明之氫氯化物鹽適合用於治療其中涉及m3受體之疾病、病症和病況。更具體地說，本發明亦關於本發明之氫氯化物鹽於冶療選自下列群組之疾病、病症和病況上的用途： •慢性或急性支氣管收縮、慢性支氣管炎、小呼吸道阻塞及肺氣腫； •阻塞性或發炎性呼吸道疾病，尤其是慢性嗜酸性粒細胞肺炎、慢性阻塞性肺病（COPD )、包括慢性支氣管炎、肺氣腫之COPD或與COPD相關或不相關之呼吸困難、特徵爲不可逆轉、進行性呼吸道阻塞之COPD、成人呼吸窘迫症候群（ARDS)、其他藥物治療後所產生之呼吸道過度反應惡化以及與肺動脈高血壓有關之呼吸道疾病； •支氣管炎，尤其是急性支氣管炎、急性喉氣管支氣管炎、花生仁吸入性支氣管炎、卡他性支氣管炎、格魯布性‘支氣管炎（croupus bronchitis )、乾燥支氣管炎、傳染性哮喘性支氣管炎、增生性支氣管炎、葡萄球菌或鏈球菌支氣管炎及肺泡性支氣管炎； •哮喘，尤其是異位性哮喘、非畢位性哮喘、過敏性哮喘、由IgE介導之異位性支氣管哮喘、支氣管哮喘、特發性哮喘、真性哮喘、因病理生理性紊亂引起之內因性哮喘、因環境因素引起之外因性哮喘、 -12- 201139375 不明或不明顯原因之特發性哮喘、非異位性哮喘、支氣管性哮喘、肺氣腫性哮喘、因運動引起之哮喘、因過敏原引起之哮喘、因冷空氣引起之哮喘、職業性哮喘、因細菌、真菌、原蟲或病毒感染引起的感染性哮喘、非過敏性哮喘、早期哮喘、喘息嬰兒症候群及細支氣管炎； •急性肺損傷； •支氣管擴張症，尤其是柱狀支氣管擴張症、囊狀支氣管擴張症、梭形支氣管擴張症、細支氣管擴張症、囊性支氣管擴張症、乾燥支氣管擴張症和濾泡性支氣管擴張症。更具體地說，本發明亦關於用於治療選自下列群組之疾病、病症和病況的本發明之氫氯化物鹽：慢性或急性支氣管收縮、肺氣腫、慢性阻塞性肺病（COPD )、成人呼吸窘迫症候群（ARDS )、支氣管炎、哮喘、急性肺損傷和支氣管擴張症。本發明之另一觀點亦關於本發明之氫氯化物鹽於製備具有M3拮抗活性之藥物上的用途。特別是，本發明關於本發明之氫氯化物鹽於製備用於治療由M3受體介導之疾病和/或病況，特別是上列疾病和/或病況之藥物的用途。因此，本發明提供以有效量之本發明的氫氯化物鹽治療哺乳動物（包括人類）之特別令人關注的方法。更確切地說，本發明提供用於治療哺乳動物（包括人類）中由 M3受體介導之疾病和/或病況（尤其是上列疾病和/或病況 -13- 201139375 )之特別令人關注的方法，其包含投予該哺乳動物有效量之本發明的氫氯化物鹽。本發明之氫氯化物鹽可以用於治療和/或預防之藥物形式根據本發明投予動物（宜爲哺乳動物，尤其是人類）。其可本身彼此混合投服，或爲含有有效劑量之本發明氫氯化物鹽與常用之藥學上無害的賦形劑和/或添加劑的活性成分以製劑形式投服。本發明之氫氯化物鹽可經冷凍乾燥、噴霧乾燥或蒸發乾燥以提供結晶型或非結晶型物質之固態栓劑、粉末或薄膜。微波或射頻乾燥可用於此目的中。本發明之氫氯化物鹽可單獨或與其他藥物一起投服，且一般係與一或多種藥學上可接受的賦形劑結合以調製劑之形式投服。此處所使用之“賦形劑”一詞係描述本發明之氫氯化物鹽以外之任何成分。賦形劑之選擇將主要取決於投藥之特定模式。本發明之氫氯化物鹽可直接投入血液、肌肉或到內部器官中。用於腸胃道外投服之合適方式，包括靜脈內、動脈內、腹腔內、鞘內、腦室內、尿道內、胸骨內、顱內、肌肉內和皮下注射。用於胃腸道外投藥之合適裝置包括有針（包括微針）注射器、無針注射器和輸液技術。腸胃道外調製劑通常爲可能含有賦形劑之水溶液，該賦形劑爲’諸如鹽、碳水化合物及緩衝劑（pH値宜爲3 至9) ’但是’在某些應用方面’其可能更適合調製成無菌非水性溶液或與合適之載劑（諸如無菌、無致熱原之水 -14 - 201139375 )一起使用之乾燥形式。在無菌條件下製備腸胃道外調製劑（例：如經由凍乾製備）可使用熟習本技藝之人士所周知之標準製藥技術很容易地完成。用於腸胃道外投服之調製劑可調製成用於立即和/或調控釋出。調控釋出之調製劑包括延時、持續、脈衝、經控制、針對性及設定釋出。因此，本發明之氫氯化物鹽可調製成用於提供經調控釋出之活性化合物的固態、半固態或觸變液體，以植入劑（implant depot )形式投服。這類調製劑之實例包括經藥物塗覆之支架及PGLA聚^/-乳酸-乙醇酸共聚物（PGLA )微球。本發明之氫氯化物鹽亦可局部投予皮膚或黏膜，亦即經皮或透皮投藥。用於此目的之典型調製劑包括凝膠、水凝膠、乳劑、溶液、乳膏、油膏、撒粉、敷料、泡沫、膜、皮膚貼片、圓片、植入劑、海綿、纖維、繃帶和微乳劑。亦可使用脂質體。典型之載體包括乙醇、水、礦物油、液態凡士林、白色凡士林、甘油、聚乙二醇及丙二醇。可納入之透皮增強劑-見，例如：J Pharm Sci，88 (10)，95 5 -958 by Finnin and Morgan (October 1 999) ° 其他局部投藥之方法包括藉由電穿孔、離子導入、聲泳法（phonophoresis)、超聲導入（sonophoresis)及微針或無針（如：P〇wderjectTM、BiojectTM，等）注射。用於局部投藥之調製劑外可調製成用於立即和/或調控釋出。調控釋出調製劑包括延時、持續、脈衝、控制、 -15- 201139375 針對性及設定釋出。本發明之氫氯化物鹽亦可經由直腸或陰道投服，例如 :以栓劑、子宮托或灌腸劑形式投服。可可脂爲一種傳統的栓劑基質，但可依適當情況使用各種替代品。用於直腸/陰道投服之調製劑可調製成用於立即和/或調控釋出。調控釋出之調製劑包括延時、持續、脈衝、控制、針對性及設定釋出。本發明之氫氯化物鹽亦可直接投予眼睛或耳朵，其通常爲在等張、pH値經調整之無菌生理鹽水中的微米化懸浮液之滴劑形式。其他適合用於眼部及耳朵投服之調製劑包括油讶、可生物降解（如：可吸收之凝膠海綿、膠原蛋白）及不可生物降解（如矽膠）之植入劑、圓片、鏡片和顆粒或水泡系統，諸如囊泡或脂質體。聚合物，諸如交聯聚丙烯酸、聚乙烯醇、透明質酸、纖維素聚合物（例如：羥丙基甲基纖維素、羥乙基纖維素或甲基纖維素）或雜多醣聚合物（例如：結冷膠）可與防腐劑（如：苯扎氯）一同倂入。這類調製劑亦可藉由離子導入投遞。用於眼部/耳朵投服之調製劑可調製成用於立即和/或調控釋出。調控釋出調製劑包括延時、持續、脈衝、控制、針對性或設定釋出。本發明之氫氯化物鹽可與可溶性大分子實體（諸如環糊精及其合適之衍生物或含有聚乙二醇之聚合物）合倂以改良其用於任何上述之投服模式的溶解度、溶解速度、口味掩蔽、生物利用性和/或穩定性。 -16- 201139375 例如：已發現藥物-環糊精複合物可普遍用於大部分齊!I型及投藥途徑。包合物及非包合物二者均可使用。該環糊精可作爲輔助添加劑（即，作爲載體、稀釋劑或助溶劑 )來替代與藥物直接複合。最常用於這些目的爲《-、和I r -環糊精，其實例可在國際專利申請案編號 wo 91/11172、WO 94/02518 及 WO 98/55148 中找到。最後，本發明之氫氯化物鹽亦可經由鼻內或吸入投服 ’其通常以乾燥粉末形式從乾燥粉末吸入器投遞（其可單獨以混合物形式投遞，例如：與乳糖，宜爲α-乳糖單水合物之乾燥混合物，或以混合之成分顆粒形式投遞，例如：與磷脂，諸如卵磷脂混合）或係從使用或未使用合適之推進劑（諸如1，1，1，2-四氟乙烷或1,1，1，2,3,3,3-七氟丙烷）的加壓容器、幫浦、噴霧、霧化器（宜爲使用電動水力來產生細霧之霧化器）或噴霧器中出來之氣溶膠噴霧形式投遞。在鼻內使用方面，該粉末可包含生物黏附劑，例如：殼聚醣或環糊精。該加壓容器 '幫浦、噴霧、霧化器或噴霧器含有本發明化合物之溶液或懸浮液，該溶液或懸浮液包含，例如：用於分散、助溶或延長活性物質釋出的乙醇、乙醇水溶液或合適之替代劑、推進劑作爲溶劑及可選擇之表面活性劑，諸如山梨醇酐三油酸酯、油酸或低聚乳酸。在以乾燥粉末或懸浮液調製劑使用前，將該藥品先微粒化至適合經由吸入投遞之大小（通常小於5微米）。此可能藉由任何形成奈米粒之適當的粉碎方法（諸如，例如 -17- 201139375 螺旋氣流硏磨、流體化床氣流硏磨、超臨界流體處理）、高壓均質化或噴霧乾燥達成。用於吸入器或吹入器之膠囊（從，例如：明膠或羥丙基甲基纖維素製成）、塑料罩和藥筒匣可調製成含有本發明之氫氯化物鹽、合適之粉末基質（諸如乳糖或澱粉）及性能改質劑（諸如/-亮胺酸、甘露醇或硬脂酸鎂）的粉末混合物。乳糖可爲無水的或爲單水合物之形式，宜爲後者。其他合適之賦形劑包括右旋糖酐、葡萄糖、麥芽糖、山梨醇、木糖醇、果糖、蔗糖及海藻糖。用於吸入/鼻內投藥之本發明的調製劑中可添加合適之味道，諸如薄荷醇及左旋薄荷腦，或甜味劑，諸如糖精或糖精鈉。用於吸入/鼻內投藥之調製劑可利用，例如：PGLA調製成用於立即和/或調控釋出。調控釋出之調製劑包括延時、持續 '脈衝、控制、針對性及設定釋出。爲了投予人類患者，當然，本發明之氫氯化物鹽的每日總劑量根據投服模式通常在0.001毫克至5 000毫克之範圍內。因此，本發明亦關於包含0.001毫克至5000毫克之本發明之氫氯化物鹽與一或多種藥學上可接受之賦形劑的醫藥組成物。可選擇地，這些醫藥組成物可進一步包含一或多種其他治療劑。例如：每日靜脈內注射劑量僅需要0.001毫克至40 毫克。該每日總劑量可以單一或分割之劑量投服，並可由翳師酌情決定，以在此處給定之典型範圍外的劑量投服。 -18- 201139375 用於使用電動水力來產生細霧之霧化器中的合適溶液調製劑中可在每次驅動釋出之體積中包含1微克至20毫克之本發明的氫氯化物鹽且驅動體積可在1微升至100微升之間變化。典型之調製劑可包含本發明之氫氯化物鹽、丙二醇、無菌水、乙醇及氯化鈉。可用於替代丙二醇之替代溶劑包括甘油及聚乙二醇。在乾燥粉末吸入器和氣溶膠之情況中，該劑量單位係由預先塡充之膠囊、塑料罩或貯存袋決定或係由使用重量測定式進料之給藥室的系統决定。根據本發明之單位通常被安排投予含有0.001毫克至10毫克之本發明之氫氯化物鹽的計量劑量或“吹氣”。每日總劑量通常係在0.001 毫克至40毫克之範圍內，此劑量可在一天中以單一劑量投服，或者，更常以分割劑量投服。本發明之氫氯化物鹽特別適合經由吸入投服。尤其是，本發明之氫氯化物鹽適合與乳糖（宜爲乳糖單水合物）一起調製成乾燥粉末形式，從而可使用乾燥粉末吸入器（如：W0 2005/002654中所描述之乾燥粉末吸入器）投服。因此，本發明亦關於包含與乳糖單水合物混合之0.00 1毫克至40毫克之聯苯-2-基-胺甲酸1-{ 9-〔（3-氟-4-羥基-苯甲醯基）-甲基-胺基〕-壬基}-哌啶-4-基酯氫氯化物鹽的藥學乾燥粉末。可選擇地，這些藥學調製劑可進一步包含一或多種其他治療劑。這些劑量係根據重量約65至70公斤之一般人。醫生將可輕易地決定體重超出此範圍之受試者（諸如嬰兒和老 -19- 201139375 人）的劑s。根據本發明之另一體系，本發明之氫氯化物鹽或其組成物亦可與一或多種欲共同投予患者之其他治療劑組合使用’以取得某些特別需要之治療最終結果，諸如治療病理生理相關的疾病過程，包括，但不限於：（i)支氣管收縮、UO炎症、（iii)過敏、（iv)組織損壞、（v)徵兆和症狀，諸如呼吸困難、咳嗽。本文中所使用之關於本發明之氫氯化物鹽和一或多種其他治療劑的“共同投服”，“經共同投予”及“組合” 等詞係欲指，且確實係指並包括以下內容： •本發明之氫氯化物鹽與治療劑之這類組合同步投予需要治療之患者，此係當這類成分被一起調製在單一劑型中，而該單一劑型係在大致相同之時間將該成分釋予該患者， •本發明之氫氯化物鹽與治療劑之這類組合大致上同時投予需要治療之患者，此係當這類成分彼此分別被調製在分開之劑型中，而該患者係在大致相同之時間投服這些分開之劑型，該成分隨之在大致相同之時間釋入該患者體內， •依序投予需要治療之患者本發明之氫氯化物鹽與治療劑之這類組合，此係當這類成分彼此分別被調製在分開之劑型中，而該患者在連續之時間投服各分開之劑型，每次投服之間有明顯之間隔期，該成分隨之在大致上不同之時間釋入該患者體內；及 -20- 201139375 •依序投予需要治療之患者本發明之氫氯化物鹽與治療劑之這類組合，此係當這類成分一起被調製成單一劑型時，該患者在相同和/或不同時間同時、連續及/或重疊投服該劑型時，該成分隨之以經控制之方式釋出，其中各部分可經由相同或不同路徑投服。可與本發明之氫氯化物鹽一起使用之其他治療劑的合適實例，包括，但絕不侷限於： (a) 5-脂氧合酶（5-LO )抑制劑或5-脂氧合酶激活蛋白（FLAP)拮抗劑； (b )白三烯拮抗劑（LTRAs )，其包括LTB4、LTC4 、LTD4及LTE4拮抗劑； (c )組織胺受體拮抗劑，其包括Η1和H3拮抗劑； (d )用於解充血劑之α , •及α 2-腎上腺素受體激動劑血管收縮類交感神經劑； (e) PDE抑制劑，其包括PDE3、PDE4及PDE5抑制劑； (f) yS 2受體激動劑； (g) 茶鹼； (h )色甘酸鈉； (i ) COX抑制劑，其包括非選擇性及選擇性COX-1 或 CΟX-2 抑制齊[((NSAIDs )； (j )前列腺素受體拮抗劑和前列腺素合成酶抑制劑 -21 - 201139375 (k ) 口服及吸入性糖皮質類固醇； (1 )解離之皮質激素受體激動劑（DAGR)； (m)主動對抗內源性炎症實體之單株抗體； (η)抗腫瘤壞死因子（抗-TNF- α )作用劑； (〇 )黏附分子抑制劑，其包括VLA-4拮抗劑； (Ρ)激肽^^及Β2-受體拮抗劑； (q )免疫遏制劑，其包括IgE途徑及環孢素之抑制劑； (Ο基質金屬蛋白酶（MMPs)抑制劑； (s )速激肽NK,、NK2和NK3受體拮抗劑； (t )蛋白酶抑制劑，諸如彈性酶抑制劑； (u )腺苷A2a受體激動劑和A2b拮抗劑； (v )尿激酶抑制劑； (w )作用在多巴胺受體之化合物，諸如D2激動劑 » (X ) NF /c点途徑之調控劑，諸如IKK抑制劑； (y)細胞因子傳訊途徑調控劑，諸如p3 8 MAP激酶、ΡΠ激酶：JAK激酶、syk激酶、EGFR或MK-2; (z )可被歸類爲痰液溶解劑或鎭咳劑之作用劑； (aa )增進對吸入性皮質類固醇之反應的作用劑； (bb)有效對抗可集落於呼吸道之微生物的抗生素和抗病毒劑； (cc ) HDAC 抑制齊U ; (dd) CXCR2 拮抗劑； -22- 201139375 (ee)整合素拮抗劑； (f f )趨化因子； (gg )上皮鈉通道（ENaC )阻斷劑或上皮鈉通道（ ENaC)抑制劑； (hh) P2Y2激動劑及其他核苷酸受體激動劑； (i i)血栓烷抑制劑； (jj) PGD2 合成及 PGD2 受體（DPI 及 DP2/CRTH2 ) 抑制劑； (kk)菸鹼酸；及 (11)黏附因子，其包括VLAM、ICAM及ELAM。根據本發明，包含本發明之氫氯化物鹽與H3拮抗劑、β2激動劑（包括長效β2激動劑）、PDE4抑制劑、類固醇（包括吸入性糖皮質類固醇）、腺苷A2a受體激動劑、細胞因子信號途徑之調控子（包括P3 8 MAP激酶或syk激酶）和/或白三烯拮抗劑（LTRAs )(包括LTB4 ' LTC4、 LTD4及LTE4拮抗劑）之醫藥組成物爲較佳者。根據本發明，包含本發明之氫氯化物鹽與糖皮質類固醇’尤其是具有減少之全身副作用的吸入性糖皮質類固醇和/或Θ 2激動劑之醫藥組成物爲更佳者。合適之糖皮質類固醇的實例包括，但不限於：強的松 (prednisone)、強的松龍（prednisolone)、氟尼縮松（ flunisolide)、曲安奈德（triamcinolone acetonide)、倍氯米松（beclomethasone)、布地奈德（budesonide)、氟替卡松（fluticasone)、環索奈德（ciclesonide)、莫 -23- 201139375 米松（mometasone)及彼等之鹽類。合適之Θ 2激動劑的實例包括，但不限於：沙丁胺醇 (salbutamol )、特布他林（terbutaline)、班布特羅（ bambuterol )、非諾特羅（feηoterο 1 )、沙美特羅（ salmeterol )、福莫特羅（formoterol)、妥洛特羅（ tulobuterol )及彼等之鹽類。根據另一較佳觀點，本發明之醫藥組成物包含本發明之氫氯化物鹽與糖皮質類固醇（例如··上文中所列者）及冷2激動劑（例如：上文中所列者），從而與一或多種藥學上可接受之賦形劑形成一種“三重組合”。根據其他較佳觀點，本發明之醫藥組成物包括包含本發明之氫氯化物鹽、糖皮質類固醇及；δ2激動劑（包括長效沒2激動劑）與乳糖單水合物之乾燥粉末》由於投服活性化合物之組合來，例如：治療特定疾病或病況可能較令人滿意，本發明之範圍包括將二或多種醫藥組成物（其中至少一種包含本發明之氫氯化物鹽）方便地合倂在適合用於共同投服該組成物之試劑盒形式中。因此，本發明之試劑盒包含二或多種分開之醫藥組成物（其中至少一種包含根據本發明之本發明的氫氯化物鹽 )以及用於分別保留該組成物之工具，諸如容器、分隔之瓶子或分隔之鋁箔袋。這類試劑盒之一種實例爲用於包裝片劑、膠缀，等之爲人熟悉的罩板包裝。本發明之試劑盒特別適合用於投服不同劑型，例如：用於在不同給藥期間經由腸胃道外投服分開之組成物，或 -24- 201139375 用於分開之組成物彼此滴定。爲了協助合規，該試劑盒通常包含投服指示且可能與所謂的記憶輔助一起提供。下列實驗細節具體說明如何製備本發明之氫氯化物鹽【實施方式】製備方法1 : 9-甲胺基-壬-1-醇According to another system, the hydrochloride salt of the present invention can also be characterized by solid-state l3C nuclear magnetic resonance having the following major carbon chemical shifts (which is the external standard of solid phase adamantane of 5 ppm): 201139375 π Chemical shift [ppm ± 0.2 ppml 140.0 124.5 49.1 - 309 According to another system, the hydrochloride salt of the present invention may also have the following main fluorine chemical shift (which is a control - 76.54 ppm aqueous solution of trifluoroacetic acid (50% by volume) /F) external standard) solid state 19F NMR to characterize: 19F chemical shift [ppm ± 0.4 ppm] -133.5 It has been found that the hydrochloride salt of the present invention is an M3 receptor antagonist, which is treated by M3 The disease and/or condition is particularly useful and it shows good efficacy. Further, the hydrochloride salt of the present invention is substantially crystalline, thereby exhibiting properties including solid state stability and compatibility with certain pharmaceutical excipients such as, for example, lactose, especially α-lactose monohydrate. This makes it superior to its corresponding amorphous free base. Accordingly, the hydrochloride salt of the present invention is particularly suitable for administration via an inhalation route (e.g., using a dry powder inhaler). For the avoidance of doubt, in accordance with the present invention, "substantially crystalline" means that at least 70% of the hydrochloride salt of the present invention is crystalline, preferably at least 80% is crystalline, more preferably at least 85%. Crystallization, even more preferably, at least 90% is crystalline and even more preferably at least 915% is crystalline. -9- 201139375 The hydrochloride salt of the present invention can be used according to conventional methods for preparing salts, such as "Handbook of Pharmaceutical Salts, Properties, Selection and Use. Published by Wiley-VCH, 2002. by P. Heinrich Stahl, Edited by Camille G Wermutli. ISBN 1-906390-26-8", from biphenyl-2-yl-carbamic acid 1-{9-[(3-fluoro-4-hydroxybenzoyl)- Preparation of methyl-amino]-mercapto}-piperidin-4-yl ester. For example, the hydrochloride salt of the present invention can be added to a suitable base in the form of a free base of biphenyl-2-yl-aminocarboxylic acid 1-{9-[(3-fluoro-4). -Hydroxy-benzylidenyl)-methylamino-]-indenyl}-piperidin-4-yl ester. Preparation of biphenyl-2-yl-aminecarboxylic acid 1-{9-[ (3-Fluoro-4-hydroxy-benzylidenyl)-methyl-amino]-indenyl}-piperidin-4-yl ester hydrochloride can be further purified from other solvents such as, for example, acetone. Crystallization to produce a substance having a higher degree of crystallinity. Biphenyl-2-yl-carbamic acid 1 - { 9 _[( 3 -fluoro-4-hydroxy-benzhydryl)-methyl-amino]-indenyl}-piperidine _4_ according to the present invention The base ester hydrochloride salt can be present in both unsolvated and solvated forms. The term 'solvate' as used herein is used to describe a molecular complex comprising a hydrochloride salt of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used. These unsolvated/unhydrated and solvated/hydrated forms are included within the scope of the invention. Complexes are also included in the scope of the invention, such as clathrates, drug-host inclusion complexes, wherein the drug -10-201139375 and the host system are stoichiometric or non-chemical relative to the solvate described above. The amount of calculation exists. Also included within the scope of the invention are pharmaceutical complexes containing two or more organic and/or inorganic components. The organic and/or inorganic components may be present in stoichiometric or non-stoichiometric amounts. The resulting composite can be ionized, partially ionized, or non-ionized. A review of such complexes can be found in J Pharm Sci, 64 (8), 1 269- 1 288 by Haleblian (August 1 975). The polymorphic forms and crystal forms/habits of the hydrochloride salts of the present invention are also included in the scope of the present invention. The term "hydrochloride salt of the present invention" includes 1-{9-[(3-fluoro-4-hydroxy-benzomethyl)-methyl-amino]-oxime of biphenyl-2-yl-aminecarboxylic acid. a 5-piperidin-4-yl ester hydrochloride salt and solvates and/or polymorphs thereof. The hydrochloride salt of the present invention is a valuable pharmaceutically active compound which is suitable for use in the therapy and prevention of a variety of conditions in which the M3 muscarinic receptor or the antagonism of the receptor may be beneficial. The hydrochloride salt of the present invention has the ability to interact with the M3 receptor, and since the hydrochloride salt plays an important role in the physiology of all mammals, it has a wide range of therapeutic applications as further explained below. For the avoidance of doubt, the term “treatment” as used herein includes information on curative, palliative and prophylactic treatment. Therefore, the hydrochloride salt of the present invention is particularly useful in the treatment and prevention of allergic and non-allergic respiratory diseases (such as asthma, COPD...), and can also be used for the treatment of other diseases such as inflammatory bowel disease, large intestine. Hysteria, large bowel diverticulosis, motion sickness, gastric ulcer, intestinal radioactivity check, symptomatic treatment of BPH (benign prostatic hyperplasia), gastric ulcer induced by NSAID, -11 - 201139375 urinary incontinence (including urgency, frequent urination, urinary incontinence, bladder wrist) Hyperactivity, nocturia and lower urinary tract symptoms), ciliary muscle paralysis, dilatation and Parkinson's disease. In accordance with a preferred aspect of the invention, the hydrochloride salt of the invention is suitable for use in the treatment of diseases, disorders and conditions in which the m3 receptor is involved. More specifically, the present invention also relates to the use of the hydrochloride salt of the present invention in the treatment of diseases, disorders and conditions selected from the group consisting of: chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction and lung Emphysema; • Obstructive or inflammatory respiratory diseases, especially chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, emphysema, or dyspnea associated with or unrelated to COPD, Features are irreversible, COPD in progressive airway obstruction, adult respiratory distress syndrome (ARDS), worsening of respiratory hyperreactivity after other medications, and respiratory diseases associated with pulmonary hypertension; • Bronchitis, especially acute bronchitis , acute laryngotracheal bronchitis, peanut inhalation bronchitis, catarrhal bronchitis, grub's bronchitis (broupus bronchitis), dry bronchitis, infectious asthma bronchitis, proliferative bronchitis, staphylococcus Or streptococcal bronchitis and alveolar bronchitis; • asthma, especially Is atopic asthma, non-aberitive asthma, allergic asthma, IgE-mediated ectopic bronchial asthma, bronchial asthma, idiopathic asthma, true asthma, endogenous asthma due to pathophysiological disorders, Environmental factors cause exogenous asthma, -12- 201139375 Unexplained or inconspicuous idiopathic asthma, non-atopic asthma, bronchial asthma, emphysema asthma, asthma caused by exercise, caused by allergens Asthma, asthma caused by cold air, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, non-allergic asthma, early asthma, wheezing infant syndrome and bronchiolitis; • acute lung injury; • Bronchiectasis, especially columnar bronchiectasis, cystic bronchiectasis, fusiform bronchiectasis, bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis. More particularly, the present invention relates to a hydrochloride salt of the present invention for use in the treatment of diseases, disorders and conditions selected from the group consisting of chronic or acute bronchoconstriction, emphysema, chronic obstructive pulmonary disease (COPD), Adult respiratory distress syndrome (ARDS), bronchitis, asthma, acute lung injury, and bronchiectasis. Another aspect of the present invention also relates to the use of the hydrochloride salt of the present invention for the preparation of a medicament having M3 antagonistic activity. In particular, the invention relates to the use of the hydrochloride salt of the invention for the manufacture of a medicament for the treatment of a disease and/or condition mediated by the M3 receptor, in particular the diseases and/or conditions listed above. Accordingly, the present invention provides a particularly interesting method of treating mammals, including humans, in an effective amount of the hydrochloride salt of the present invention. More specifically, the present invention provides particular concern for the treatment of diseases and/or conditions mediated by M3 receptors in mammals, including humans, particularly the above listed diseases and/or conditions-13-201139375. A method comprising administering to the mammal an effective amount of a hydrochloride salt of the invention. The hydrochloride salt of the present invention can be administered to an animal (preferably a mammal, especially a human) according to the present invention in a pharmaceutical form which can be used for the treatment and/or prevention. They may be administered in admixture with each other or in the form of a formulation containing an effective amount of the hydrochloride salt of the present invention and a conventional pharmaceutically non-toxic excipient and/or additive. The hydrochloride salt of the present invention can be freeze-dried, spray-dried or evaporated to provide a solid suppository, powder or film of a crystalline or amorphous material. Microwave or radio frequency drying can be used for this purpose. The hydrochloride salts of the present invention may be administered alone or in combination with other drugs, and are generally administered in combination with one or more pharmaceutically acceptable excipients in the form of a modulator. The term "excipient" as used herein is used to describe any component other than the hydrochloride salt of the present invention. The choice of excipient will depend primarily on the particular mode of administration. The hydrochloride salt of the present invention can be directly administered into blood, muscle or into internal organs. Suitable means for parenteral administration include intravenous, intravascular, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous injections. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free injectors, and infusion techniques. The parenteral preparation is usually an aqueous solution which may contain excipients such as salts, carbohydrates and buffers (pH is preferably from 3 to 9) but may be more suitable in certain applications. A dry form for use as a sterile non-aqueous solution or with a suitable carrier such as sterile, pyrogen-free water-14 - 201139375. The preparation of parenteral formulations under sterile conditions (e.g., via lyophilization) can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art. Modulators for parenteral administration can be made for immediate and/or controlled release. Modulators that regulate release include delay, duration, pulse, controlled, targeted, and set release. Thus, the hydrochloride salt of the present invention can be formulated into a solid, semi-solid or thixotropic liquid for providing a controlled release of the active compound, in the form of an implant depot. Examples of such modulators include drug coated stents and PGLA poly-/-lactic acid-glycolic acid copolymer (PGLA) microspheres. The hydrochloride salt of the present invention may also be administered topically to the skin or mucosa, i.e., transdermally or transdermally. Typical preparations for this purpose include gels, hydrogels, emulsions, solutions, creams, ointments, dusting, dressings, foams, films, dermal patches, wafers, implants, sponges, fibers, Bandages and microemulsions. Liposomes can also be used. Typical carriers include ethanol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Transdermal enhancers that can be included - see, for example: J Pharm Sci, 88 (10), 95 5 -958 by Finnin and Morgan (October 1 999) ° Other methods of topical administration include electroporation, iontophoresis, sound Injection by phonophoresis, sonophoresis, and microneedle or needleless (eg, P〇wderjectTM, BiojectTM, etc.). Modulators for topical administration are externally adjustable for immediate and/or controlled release. Regulatory release modulators include delay, duration, pulse, control, -15-201139375 pertinence and set release. The hydrochloride salt of the present invention may also be administered rectally or vaginally, for example, in the form of a suppository, pessary or enemas. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate. Modulators for rectal/vaginal administration can be made for immediate and/or controlled release. Modulators that regulate release include delay, duration, pulse, control, targeting, and set release. The hydrochloride salts of the present invention may also be administered directly to the eye or ear, typically in the form of drops of micronized suspension in isotonic, pH adjusted sterile saline. Other modulating agents suitable for eye and ear administration include oily, biodegradable (eg, absorbable gel sponge, collagen) and non-biodegradable (eg silicone) implants, wafers, lenses And granule or vesicular systems such as vesicles or liposomes. a polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer (for example: hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose) or a heteropolysaccharide polymer (for example) : Gellan gum) can be infused with a preservative (eg, benzalkonium chloride). Such modulators can also be delivered by iontophoresis. Modulators for eye/ear delivery can be made for immediate and/or controlled release. Regulating the release of the modulator includes delay, duration, pulse, control, targeting or set release. The hydrochloride salt of the present invention can be combined with a soluble macromolecular entity such as a cyclodextrin and a suitable derivative thereof or a polyethylene glycol-containing polymer to improve its solubility for any of the above-described modes of administration, Dissolution speed, taste masking, bioavailability and/or stability. -16- 201139375 For example, drug-cyclodextrin complexes have been found to be commonly used in most of the types I and the route of administration. Both clathrates and non-inclusions can be used. The cyclodextrin can be used as an auxiliary additive (i.e., as a carrier, diluent or co-solvent) instead of directly complexing with the drug. The most commonly used for these purposes are "-, and Ir-cyclodextrin, examples of which can be found in International Patent Application Nos. WO 91/11172, WO 94/02518 and WO 98/55148. Finally, the hydrochloride salt of the invention may also be administered by intranasal or inhalation 'which is usually delivered as a dry powder from a dry powder inhaler (which may be delivered as a mixture alone, for example: with lactose, preferably alpha-lactose a dry mixture of monohydrates, or in the form of mixed component granules, for example: mixed with phospholipids, such as lecithin, or with or without a suitable propellant (such as 1,1,1,2-tetrafluoroethane) a pressurized container of alkane or 1,1,1,2,3,3,3-heptafluoropropane), a pump, a spray, an atomizer (preferably an atomizer using electric hydraulics to produce a fine mist) or a sprayer The aerosol spray is delivered in the form of a spray. In terms of intranasal use, the powder may comprise a bioadhesive, such as: chitosan or cyclodextrin. The pressurized container 'pump, spray, atomizer or sprayer contains a solution or suspension of a compound of the invention, for example: ethanol, ethanol for dispersing, solubilizing or prolonging the release of the active substance An aqueous solution or suitable substitute, propellant as solvent and optionally a surfactant such as sorbitan trioleate, oleic acid or oligomeric lactic acid. Prior to use in a dry powder or suspension formulation, the drug is first micronized to a size suitable for delivery via inhalation (typically less than 5 microns). This may be achieved by any suitable comminuting method for forming the nanoparticles, such as, for example, -17-201139375 spiral air honing, fluidized bed air honing, supercritical fluid processing, high pressure homogenization, or spray drying. Capsules for use in an inhaler or insufflator (made, for example, from gelatin or hydroxypropyl methylcellulose), plastic covers and cartridges can be adjusted to contain a hydrochloride salt of the invention, a suitable powder matrix A powder mix (such as lactose or starch) and a performance modifying agent such as /-leucine, mannitol or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, dextrose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. A suitable taste such as menthol and levomenthol, or a sweetener such as saccharin or sodium saccharin may be added to the preparation of the present invention for inhalation/intranasal administration. Modulators for inhaled/intranasal administration may be utilized, for example, PGLA formulated for immediate and/or controlled release. Modulators that regulate release include delayed, continuous 'pulsing, controlled, targeted, and set release. For administration to human patients, of course, the total daily dose of the hydrochloride salt of the present invention is usually in the range of 0.001 mg to 5,000 mg depending on the mode of administration. Accordingly, the present invention is also directed to pharmaceutical compositions comprising from 0.001 mg to 5000 mg of the hydrochloride salt of the present invention and one or more pharmaceutically acceptable excipients. Alternatively, these pharmaceutical compositions may further comprise one or more additional therapeutic agents. For example, a daily intravenous dose of only 0.001 mg to 40 mg is required. The total daily dose may be administered in a single or divided dose and may be decided at the discretion of the individual to be administered at a dose outside the typical range given herein. -18- 201139375 A suitable solution preparation for use in an atomizer using electric hydraulic power to produce a fine mist may contain 1 μg to 20 mg of the hydrochloride salt of the present invention in a volume per actuation release and drive The volume can vary from 1 microliter to 100 microliters. Typical modulating agents may comprise the hydrochloride salts, propylene glycol, sterile water, ethanol, and sodium chloride of the present invention. Alternative solvents that can be used in place of propylene glycol include glycerin and polyethylene glycol. In the case of dry powder inhalers and aerosols, the dosage unit is determined by a pre-filled capsule, plastic cover or storage bag or by a system using a dosing chamber for weight measurement. Units according to the present invention are typically arranged to administer a metered dose or "blowing" containing from 0.001 mg to 10 mg of the hydrochloride salt of the present invention. The total daily dose is usually in the range of 0.001 mg to 40 mg, which can be administered in a single dose throughout the day, or more often in divided doses. The hydrochloride salts of the invention are particularly suitable for administration via inhalation. In particular, the hydrochloride salt of the present invention is suitably formulated with a lactose (preferably lactose monohydrate) in the form of a dry powder such that a dry powder inhaler (e.g., a dry powder inhaler as described in WO 2005/002654) can be used. ) to commit. Accordingly, the present invention also relates to 1-{9-[(3-fluoro-4-hydroxy-benzoguanidino)-containing biphenyl-2-yl-aminocarboxylic acid of 0.001 mg to 40 mg mixed with lactose monohydrate. A pharmaceutically dry powder of a methyl-amino]-mercapto}-piperidin-4-yl ester hydrochloride salt. Alternatively, these pharmaceutical modulators may further comprise one or more additional therapeutic agents. These dosages are based on the average weight of about 65 to 70 kg. The physician will be able to easily determine the dose of the subject (such as infants and old -19-201139375 people) whose body weight is outside this range. According to another system of the present invention, the hydrochloride salt of the present invention or a composition thereof may also be used in combination with one or more other therapeutic agents to be co-administered to a patient to achieve a particular desired therapeutic end result, such as treatment. Pathophysiological-related disease processes, including, but not limited to, (i) bronchoconstriction, UO inflammation, (iii) allergies, (iv) tissue damage, (v) signs and symptoms, such as difficulty breathing, coughing. As used herein, the terms "co-administered", "co-administered" and "combined" with respect to the hydrochloride salt of the present invention and one or more other therapeutic agents are intended to mean, and do, refer to and include the following Content: • The combination of the hydrochloride salt of the present invention and the therapeutic agent is administered to a patient in need of treatment, when such components are formulated together in a single dosage form, and the single dosage form will be at substantially the same time The component is administered to the patient, and the combination of the hydrochloride salt of the present invention and the therapeutic agent is administered to the patient in need of treatment substantially simultaneously, wherein the components are separately formulated in separate dosage forms, and The patient administers the separate dosage forms at approximately the same time, and the component is subsequently released into the patient at approximately the same time. • The patient in need of treatment is sequentially administered to the patient of the present invention as the hydrochloride salt and the therapeutic agent. Combination of classes, when such components are separately formulated in separate dosage forms, and the patient administers separate dosage forms for a continuous period of time, with a distinct interval between each administration, The composition is then released into the patient at substantially different times; and -20-201139375 • The combination of the hydrochloride salt of the present invention and the therapeutic agent is administered sequentially to a patient in need of treatment, as such a component When formulated together into a single dosage form, the patient will be released in a controlled manner while the dosage form is administered simultaneously, continuously, and/or over the same and/or at different times, wherein the portions may be the same or different Path to persuade. Suitable examples of other therapeutic agents which may be used with the hydrochloride salt of the invention include, but are in no way limited to: (a) 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase Activator protein (FLAP) antagonists; (b) leukotriene antagonists (LTRAs) comprising LTB4, LTC4, LTD4 and LTE4 antagonists; (c) histamine receptor antagonists comprising guanidine 1 and H3 antagonists; (d) vasoconstrictor sympathetic agents for α, • and α2-adrenoreceptor agonists for decongestants; (e) PDE inhibitors, including PDE3, PDE4 and PDE5 inhibitors; (f) yS 2 receptor agonists; (g) theophylline; (h) sodium cromoglycate; (i) COX inhibitors, including non-selective and selective COX-1 or CΟX-2 inhibitions [(NSAIDs); j) prostaglandin receptor antagonist and prostaglandin synthetase inhibitor-21 - 201139375 (k) oral and inhaled corticosteroids; (1) dissociated corticosteroid receptor agonist (DAGR); (m) active confrontation Individual antibodies to endogenous inflammatory entities; (η) anti-tumor necrosis factor (anti-TNF-α) agents; (〇) adhesion molecule inhibitors, including VLA-4 antagonists (Ρ) kinin and Β2-receptor antagonists; (q) immunosuppressive agents, including IgE pathway and cyclosporine inhibitors; (Ο matrix metalloproteinases (MMPs) inhibitors; (s) Kinin NK, NK2 and NK3 receptor antagonists; (t) protease inhibitors, such as elastase inhibitors; (u) adenosine A2a receptor agonists and A2b antagonists; (v) urokinase inhibitors; w) compounds acting on dopamine receptors, such as D2 agonists » (X) NF / c point pathway modulators, such as IKK inhibitors; (y) cytokine signaling pathway modulators, such as p3 8 MAP kinase, lumbrokinase : JAK kinase, syk kinase, EGFR or MK-2; (z) an agent that can be classified as a sputum lysing or coughing agent; (aa) an agent that enhances the response to inhaled corticosteroids; Antibiotics and antiviral agents effective against microorganisms that can colonize the respiratory tract; (cc) HDAC inhibitors; (dd) CXCR2 antagonists; -22- 201139375 (ee) integrin antagonists; (ff) chemokines; (gg) epithelial sodium channel (ENaC) blocker or epithelial sodium channel (ENaC) inhibitor; (hh) P2Y2 agonist and other nucleotides (ii) thromboxane inhibitor; (jj) PGD2 synthesis and PGD2 receptor (DPI and DP2/CRTH2) inhibitors; (kk) nicotinic acid; and (11) adhesion factors, including VLAM, ICAM and ELAM. According to the present invention, a hydrochloride salt of the present invention and an H3 antagonist, a β2 agonist (including a long-acting β2 agonist), a PDE4 inhibitor, a steroid (including an inhaled glucocorticosteroid), and an adenosine A2a receptor agonist are included. Preferred are pharmaceutical compositions of cytokine signaling pathway regulators (including P3 8 MAP kinase or syk kinase) and/or leukotriene antagonists (LTRAs), including LTB4 'LTC4, LTD4 and LTE4 antagonists. According to the present invention, a pharmaceutical composition comprising the hydrochloride salt of the present invention and a glucocorticosteroid, especially an inhaled glucocorticosteroid and/or a quinone agonist having reduced systemic side effects, is more preferred. Examples of suitable glucocorticosteroids include, but are not limited to, prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone , budesonide, fluticasone, ciclesonide, mo-23-201139375 mometasone and their salts. Examples of suitable Θ 2 agonists include, but are not limited to, salbutamol, terbutaline, bambuterol, feñoterο 1 , salmeterol , formoterol, tulobuterol and their salts. According to another preferred aspect, the pharmaceutical composition of the present invention comprises a hydrochloride salt of the present invention and a glucocorticosteroid (for example, as listed above) and a cold 2 agonist (for example, those listed above). Thereby forming a "triple combination" with one or more pharmaceutically acceptable excipients. According to other preferred embodiments, the pharmaceutical composition of the present invention comprises a dry powder comprising the hydrochloride salt of the present invention, a glucocorticosteroid, and a δ2 agonist (including a long-acting agonist) and lactose monohydrate. Combinations of active compounds, for example, treatment of a particular disease or condition may be desirable, and the scope of the invention includes conveniently combining two or more pharmaceutical compositions, at least one of which comprises a hydrochloride salt of the invention It is suitable for use in a kit form for co-administration of the composition. Accordingly, the kit of the present invention comprises two or more separate pharmaceutical compositions (at least one of which comprises the hydrochloride salt of the present invention according to the present invention) and a means for separately retaining the composition, such as a container, a separate bottle Or separate foil bags. An example of such a kit is a blister pack for packaging tablets, glues, and the like. The kit of the present invention is particularly suitable for administration to different dosage forms, for example: for separate compositions by parenteral administration during different administration periods, or -24-201139375 for separate compositions to be titrated with one another. To aid compliance, the kit typically includes a perfusion indication and may be provided with so-called memory assistance. The following experimental details specify how to prepare the hydrochloride salt of the present invention. [Embodiment] Preparation Method 1: 9-Methylamino-inden-1-ol

在9-溴壬醇（25克）中加入甲胺（在乙醇中之33% 溶液’ 200毫升）並將溶液在室溫，氮氣下攬拌1 8小時。在真空下去除溶劑，將由此產生之無色固體溶解於二氯甲院（200毫升）中，以氫氧化鈉水溶液（2M，100毫升）、水（100毫升）清洗之，並在真空中乾燥（硫酸鈉）後濃縮以產生在靜置時固化之黃色油的標題化合物，14.95 克。將該化合物以此狀態用於製備方法2中。製備方法2 : ( 9-羥基-壬基）-甲基-胺甲酸第三-丁酯Methylamine (33% solution in ethanol '200 ml) was added to 9-bromofurfuryl alcohol (25 g) and the solution was stirred at room temperature under nitrogen for 18 hours. The solvent was removed under vacuum, and the thus obtained colorless solid was dissolved in methylene chloride (200 ml), washed with aqueous sodium hydroxide (2M, 100 ml), water (100 ml) and dried in vacuo ( The title compound was obtained after aq. This compound was used in the production method 2 in this state. Preparation 2 : (9-Hydroxy-indenyl)-methyl-aminecarboxylic acid tert-butyl ester

將9-甲胺基-壬-卜醇（製備方法1，14.95克）懸浮在二氯甲烷（250毫升）與三乙胺（17.6克）之混合物中並在冰浴中冷卻並一邊攪拌。在5分鐘內將Boc酐（1 8.8克 )—部分一部分加入其中並將反應物在冰浴中攪拌1小時 -25- 201139375 ，然後在室溫下攪拌4小時。以水（1 5 0毫升）、1 0 %檸檬酸水溶液（50毫升）及飽和鹽水（50毫升）清洗反應物，再在真空中乾燥（硫酸鈉）後濃縮之以產生爲黃色液體之標題化合物，22.95克，97%。 'Η NMR (400MHz, CDC13) δ = 1.20- 1.3 8 (m, 10H), 1.47 (s，9H), 1.47-1.60 (m, 4H), 2.80 (s, 3H), 3.10-3.22 (t，2H)，3.78-3.83 (t, 2H) ppm o 製備方法3:甲磺酸9-(第三-丁氧羰基-甲基-胺基 )-壬酯9-Methylamino-indole-propanol (Production Method 1, 14.95 g) was suspended in a mixture of dichloromethane (250 ml) and triethylamine (17.6 g) and cooled in an ice bath and stirred. Boc anhydride (18.8 g) - part of it was added thereto over 5 minutes and the reaction was stirred in an ice bath for 1 hour -25 - 201139375 and then stirred at room temperature for 4 hours. The reaction was washed with EtOAc (EtOAc) (EtOAc (EtOAc) , 22.95 grams, 97%. 'Η NMR (400MHz, CDC13) δ = 1.20- 1.3 8 (m, 10H), 1.47 (s, 9H), 1.47-1.60 (m, 4H), 2.80 (s, 3H), 3.10-3.22 (t, 2H ), 3.78-3.83 (t, 2H) ppm o Preparation 3: 9-(T-butoxycarbonyl-methyl-amino)-decyl methanesulfonate

在5 °C下’將甲磺醯氯（7.2毫升）一滴滴地加入在二氯甲烷（230毫升）和三乙胺（18毫升）中之（9 -羥基-壬基）-甲基-胺甲酸第三·丁酯（製備方法2, 22.95克）的溶液中並將該黏性混濁溶液在室溫下攪拌1小時。以水、飽和碳酸氫鈉水溶液清洗該混合物並將該有機層在真空中乾燥（硫酸鎂）後蒸發以產生該爲淡黃色油之標題化合物，29.30 克。 'H NMR (400MHz, CDC13) δ = 1.20- 1.45 (m, 1 OH), 1.44 (s, 9H), 1.44- 1.52 (m, 2H), 1.70- 1.79 (m, 2H), 2.82 (s, 3H), 2.98 (s, 3H), 3.14-3.24 (m, 2H), 4.20-4.4.24 (t, 2H) ppm。 -26- 201139375 製備方法4 :聯苯·2-基-胺甲酸1-[9-(第三-丁氧羰基-甲基-胺基）-壬基]-六氫吡啶-4-基酯(9-Hydroxy-indenyl)-methyl-amine was added dropwise to methanesulfonium chloride (7.2 ml) in dichloromethane (230 ml) and triethylamine (18 ml) at 5 °C. A solution of the third butyl formate (Preparation Method 2, 22.95 g) was added and the viscous turbid solution was stirred at room temperature for 1 hour. The mixture was washed with EtOAc (EtOAc m.) 'H NMR (400MHz, CDC13) δ = 1.20- 1.45 (m, 1 OH), 1.44 (s, 9H), 1.44- 1.52 (m, 2H), 1.70- 1.79 (m, 2H), 2.82 (s, 3H ), 2.98 (s, 3H), 3.14-3.24 (m, 2H), 4.20-4.4.24 (t, 2H) ppm. -26-201139375 Preparation 4: Biphenyl-2-yl-carbamic acid 1-[9-(tris-butoxycarbonyl-methyl-amino)-indenyl]-hexahydropyridin-4-yl ester

將4-哌啶基-N- ( 2-聯苯基）胺基甲酸酯氫氯化物（ US 2006/2 05 779，29.3克）與碳酸鉀（46克）在二甲基甲醯胺（250毫升）中攪拌〇.5小時。然後，加入甲磺酸9_ (第三-丁氧羰基-甲基-胺基）-壬酯（製備方法3，27.7 克）和碘化鉀（277毫克）。將反應混合物在65 °C攪拌24 小時，然後加入額外之二甲基甲醯胺（1 〇〇毫升）以協助在65 °C另外攪拌24小時。在真空中去除溶劑並將殘質分佈在水和醋酸乙酯（各5 00毫升）之間。將水層分開並以另外之醋酸乙酯（ 200毫升）萃取之。以飽和鹽水清洗合倂之有機層，在真空中乾燥（硫酸鈉）並濃縮之。利用正相矽膠柱層析法，使用醋酸乙酯：庚烷：880氨（ 80:20:0.5，體積比）作爲洗提液將粗殘質（46.46克）純化，以產生爲無色油之標題化合物，其在靜置時會結晶化，30 克，65%。 'H NMR (400MHz, CDC13) δ = 1.22- 1.3 8 (m, 12H), 1.44 (s, 9H), 1.44- 1.56 (m, 2H), 1.61-1.73 (m, 2H), 1.88- 1.97 (m, 2H), 2.12-2.24 (t, 2H), 2.23-2.30 (t, 2H), 2.64- 2.72 (m, 2H), 2.82 (s, 3H), 3.16-3.24 (m, 2H), 4.63- 4.78 -27- 201139375 (m, 1H)，6.60 (s，1H)，7.08-7.56 (m，8H)，8.03-8.15 (d， 1 H) p p m。製備方法5:聯苯-2-基-胺甲酸1-(9-甲胺基-壬基）-六氫吡啶-4-基酯；二氫氯化物鹽4-piperidinyl-N-(2-biphenyl)carbamate hydrochloride (US 2006/2 05 779, 29.3 g) and potassium carbonate (46 g) in dimethylformamide ( Stir in a 250 ml) for 5 hours. Then, 9-(tris-butoxycarbonyl-methyl-amino)-decyl methanesulfonate (Preparation Method 3, 27.7 g) and potassium iodide (277 mg) were added. The reaction mixture was stirred at 65 °C for 24 hours, then additional dimethylformamide (1 mL) was added to assist for additional stirring at 65 °C for 24 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate (500 mL). The aqueous layer was separated and extracted with additional ethyl acetate (200 mL). The organic layer was washed with saturated brine, dried (MgSO4) The crude residue (46.46 g) was purified by normal phase tannin column chromatography using ethyl acetate: heptane: 880 ammonia (80:20:0.5, by volume) as eluent to give the title of colorless oil. A compound which crystallizes upon standing, 30 g, 65%. 'H NMR (400MHz, CDC13) δ = 1.22- 1.3 8 (m, 12H), 1.44 (s, 9H), 1.44- 1.56 (m, 2H), 1.61-1.73 (m, 2H), 1.88- 1.97 (m , 2H), 2.12-2.24 (t, 2H), 2.23-2.30 (t, 2H), 2.64- 2.72 (m, 2H), 2.82 (s, 3H), 3.16-3.24 (m, 2H), 4.63- 4.78 -27- 201139375 (m, 1H), 6.60 (s, 1H), 7.08-7.56 (m, 8H), 8.03-8.15 (d, 1 H) ppm. Preparation 5: Biphenyl-2-yl-aminecarboxylic acid 1-(9-methylamino-indenyl)-hexahydropyridin-4-yl ester; dihydrochloride salt

在室溫下，將聯苯-2-基-胺甲酸1-〔 9-(第三-丁氧羰基-甲基-胺基）-壬基〕-哌啶-4-基酯（製備方法4，18.5 克）在二噁烷中氫氯酸溶液（85毫升，4M)中攪拌18小時。在真空中去除溶劑和過量酸並將殘質與二氯甲烷（ 100毫升）共沸兩次，以產生爲白色固體之標題化合物， 18.0 克。 'H NMR (400MHz, CDC13) δ = 1.22- 1.3 8 (m, 1 OH), 1.54-2.10 (m, 8H), 2.78-2.97 (m, 4H), 3.29-3.42 (m, 2H), 3.5 3 -3.65 (m, 2H), 3.57 (s, 3H), 4.5 7- 4.67 (m, 1H), 4.74 (bs, 1H), 7.3 0-7.45 (m, 8H), 8.80-8.90 (m, 3H) 10.71- 10.87 (m, 1H) ppm。製備方法6:聯苯-2-基-胺甲酸l-{9-[(3-氟-4-羥基-苯甲醯）-甲基·胺基]-壬基}-六氫吡啶-4-基酯 -28- 2011393751-[9-(Thr-Butoxycarbonyl-methyl-amino)-indolyl]-piperidin-4-ylbiphenyl-2-yl-carbamic acid at room temperature (Preparation method 4 , 18.5 g) was stirred in dioxane in a solution of hydrochloric acid (85 mL, 4M) for 18 hours. The solvent and excess acid were removed in vacuo and EtOAc (EtOAc m. 'H NMR (400MHz, CDC13) δ = 1.22- 1.3 8 (m, 1 OH), 1.54-2.10 (m, 8H), 2.78-2.97 (m, 4H), 3.29-3.42 (m, 2H), 3.5 3 -3.65 (m, 2H), 3.57 (s, 3H), 4.5 7- 4.67 (m, 1H), 4.74 (bs, 1H), 7.3 0-7.45 (m, 8H), 8.80-8.90 (m, 3H) 10.71- 10.87 (m, 1H) ppm. Preparation Method 6: Biphenyl-2-yl-aminocarboxylic acid 1-{9-[(3-fluoro-4-hydroxy-benzoguanidine)-methyl-amino]-indenyl}-hexahydropyridine-4- Carbamate-28- 201139375

將3-氟-4-羥基丁酸（1.85克，11.9毫莫耳）、三乙胺（2.07毫升’ 14_8毫莫耳）、N，N-二甲胺基吡啶（484 毫克，3.96毫莫耳）及（3-(二甲胺基）丙基）乙基碳二醯亞胺氫氯化物（2.66克，13.9毫莫耳）加入在四氫呋喃 (150毫升）中之聯苯-2-基-胺甲酸1-(9-甲胺基-壬基）-哌啶-4-基酯二氫氯化物鹽（製備方法5，4.47克，9.90毫莫耳）之溶液中。將該混合物在室溫下攪拌15分鐘，然後在60 °C攪拌18小時。加入額外之3-氟-4·羥基苯甲酸（ 308毫克，2.0毫莫耳）並將反應物在60 °C下另外加熱18 小時。在真空中去除溶劑並將殘質分佈在醋酸乙酯（200 毫升）和水（150毫升）之間。以醋酸乙酯（200毫升）進一步萃取水層並將合倂之有機層在硫酸鎂上乾燥並在真空中濃縮。將殘質溶解於甲醇/水（1 15毫升/23毫升）中 ’以碳酸鉀（12.9克，93.2毫莫耳）處理之並在50 °C加熱 1 8小時。在真空中去除溶劑並將殘質分佈在二氯甲烷（ 200毫升）和水（200毫升）之間。以鹽水（100毫升）清洗有機層並在真空中濃縮。在矽膠上，以二氯甲烷：甲醇 :880氨（100:0:0至95:5:0.5，體積比）作爲洗提液，藉由管柱層析法將殘質純化，以提供爲油性泡沬之標題化合物，產量52%，3.01克。 LCMS ： APCI ESI m/z 590 [M + H] + -29- 201139375 NMR (400 MHz，甲醇-d4) δ = 1.12-1.40 (m，10H)， 1.4 5 - 1.54 (m, 2H), 1.5 6- 1.68 (m, 4H), 1.81-1.91 (m, 2H), 2.29-2.40 (m, 4H), 2.64-2.75 (m, 2H), 3.01 (s, 3H), 3.34-3.53 (m, 2H), 4.58-4.65 (m, 1H), 6.92-6.96 (m, 1H), 7.05 (d, 1H), 7.12 (d, 1H), 7.23 -7.44 (m, 8H), 7.55 (d, 1H) ppm o 實例1 :聯苯-2-基-胺甲酸l-{9-[(3-氟-4-羥基-苯甲醯 )-甲基-胺基）-壬基）-六氫吡啶-4-基酯之氫氯化物鹽3-Fluoro-4-hydroxybutyric acid (1.85 g, 11.9 mmol), triethylamine (2.07 mL '14_8 mmol), N,N-dimethylaminopyridine (484 mg, 3.96 mmol) And (3-(dimethylamino)propyl)ethylcarbodiimide hydrochloride (2.66 g, 13.9 mmol) added to biphenyl-2-yl-amine in tetrahydrofuran (150 ml) A solution of 1-(9-methylamino-indenyl)-piperidin-4-yl dihydrochloride salt (manufacture method 5, 4.47 g, 9.90 mmol). The mixture was stirred at room temperature for 15 minutes and then stirred at 60 ° C for 18 hours. Additional 3-fluoro-4-hydroxybenzoic acid (308 mg, 2.0 mmol) was added and the reaction was heated at 60 °C for additional 18 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (150 mL). The aqueous layer was further extracted with ethyl acetate (200 mL) and organic layer dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in methanol / water (1 15 mL / 23 mL). The solvent was removed in vacuo and the residue was partitioned between dichloromethane (200 mL) and water (200 mL). The organic layer was washed with brine (100 mL) and concentrated in vacuo. The residue was purified by column chromatography using dichloromethane:methanol: 880 ammonia (100:0:0 to 95:5:0.5 by volume) as an eluent to provide oily The title compound of the saponin, yield 52%, 3.01 g. LCMS : APCI ESI m/z 590 [M + H] + -29- 978 355 NMR (400 MHz, methanol-d4) δ = 1.12-1.40 (m, 10H), 1.4 5 - 1.54 (m, 2H), 1.5 6 - 1.68 (m, 4H), 1.81-1.91 (m, 2H), 2.29-2.40 (m, 4H), 2.64-2.75 (m, 2H), 3.01 (s, 3H), 3.34-3.53 (m, 2H) , 4.58-4.65 (m, 1H), 6.92-6.96 (m, 1H), 7.05 (d, 1H), 7.12 (d, 1H), 7.23 -7.44 (m, 8H), 7.55 (d, 1H) ppm o Example 1: Biphenyl-2-yl-carbamic acid 1-{9-[(3-fluoro-4-hydroxy-benzoguanidine)-methyl-amino)-indenyl)-hexahydropyridin-4-yl Ester hydrochloride salt

將氫氯酸水溶液（0.1毫升，2M濃度，0.2毫莫耳）加入在乙醇（1毫升）中之聯苯-2-基-胺甲酸1-{9-〔（ 3-氟-4-羥基-苯甲醯基）-甲基-胺基〕-壬基}-哌啶-4-基酯（製備方法6，118毫克，0.2毫莫耳）的溶液中，令該溶液蒸發至低體積一整夜。將第三丁基甲基醚（4毫升）加入殘質中並將混合物在先前製備之晶種的存在下，在室溫中攪拌。將由此產生之無色結晶固體過濾並在真空中乾燥以提供該標題化合物，產量55%，65毫克。 'H NMR (DMSO-d6) δ =1.0-2.05 (m, 18H), 2.74-3.00 (m, 4H), 2.84 (s, 3H), 3.21-3.43 (m, 4H), 4.56-4.68 (m), 4.70-4.74 (m) (1H，旋轉異構物），6.94-7.04 (111，214)，7.10-7.20 (d，1H)，7.25-7.44 (m，9H)，8.74 (s)，8.82 (s) (1H， 201139375 旋轉異構物），10.〇5-1〇·3〇 (m，1H)，10.27 (s, 依下述製備晶種：將在乙醇（〇·1毫升）和氫氯酸水溶液（ 2M濃度，0.024毫莫耳）中之富馬酸（1.5 毫莫耳）溶液加入在乙醇（0·5毫升）中之聯酸1- { 9-〔（ 3-氟-4-徑基-苯甲醯基）-甲基 }-哌陡-4-基酯游離驗（製備方法6，15毫克耳）的溶液中，令該溶液暴露於空氣中使其成膠。以甲基第三丁基醚（1毫升）處理此置6週。出現一個晶體且當以調和刀處理時 2小時之間結晶化，過濾之並在真空中乾燥晶種，60%產量，9毫克。 DSC數據採用TA儀器Q1000差示掃描量熱儀，量熱法（D S C )測定實例1中所得之物質的本在標準鋁鍋中以20°C/分鐘之速度從10°C 。第1圖中顯示所得之DSC熱譜圖形，其線及對應於該熔點之尖銳的吸熱峰。由起始 °C之強烈吸熱可表明實例1中所得之2.0 7 2 點。 CHN數據 1 H) ppm。 0.012毫升，毫克，0.0 1 2 5 苯-2-基-胺甲 -胺基〕-壬基，0.025毫莫在室溫下蒸發膠，並將其靜，剩餘之膠在以產生所需之藉由差示掃描熔點。將該樣力口熱到2 50 °C 具有平坦之基溫度在1Π-2 毫克物質的熔 -31 - 201139375 分析 C35H45N304FC1 : C 67.13，Η 7.24，N 6.71。結果發現：C 66.79，Η 7.23，N 6.62。粉末X射線繞射數據使用配合自動採樣更換器、0 - 0測角儀幾何圖形、自動光束發散狹縫（Divergence Slit)及PSD Vantec-Ι探測器之Bruker-AXS有限公司D4 ENDEAVOR粉末X射線繞射儀測定實例1之粉末X射線繞射樣式。將樣品安裝在具有一個0.5毫米空腔之低背景矽晶片標本架上以準備進行分析。當以在35kV/40mA操作之X光管的銅ΚαιΧ光 (波長= 1.5406埃）照射時一邊旋轉標本。分析係在室溫下，以連續模式進行，其設定爲在2°至55°之兩個0範圍內，每0.018°步距計算0.2秒來取得數據。在Bruker-AXS 所釋出之EVA軟體內，採用分別設定爲1和0.3之閾限和寬度參數來搜索峰値。使用剛玉參考標準（NIST : SRM 1 976XRD平板X射線繞射強度標準）驗證該儀器之校準。測量之樣式顯示於第2圖中。所得之粉末X射線繞射圖案的強度和波峰位置（角度2 0誤差爲+/-〇.1度）顯示於表1中： -32- 201139375 表1 :相對強度截止之1 5 %之實例1的特色繞射峰(±0.1°2 0 角度（°2叫強度％ 8.2 22.3 10.5 16.4 12.2 15.7 13.6 21.4 14.0 15.5 14.8 39.3 16.4 23.4 17.1 55.7 18.2 20.8 18.6 42.4 19.2 91.5 19.5 100.0 20.1 49.0 20.8 27.6 21.1 20.2 22.3 64.7 22.6 23.2 23.6 44.2 24.5 65.5 25.3 24.1 26.1 33.2 27.3 40.1 27.7 21.3 28.1 22.0 實例2 :實例1之化合物從丙酮中再結晶將聯苯-2-基-胺甲酸（3-氟-4-羥基-苯甲醯 )-甲基-胺基〕-壬基}-哌啶-4_基酯之氫氯化物鹽（實例 1，100毫克）在回流下溶解於乾丙酮中（約1毫升）。令溶液冷卻一整夜’藉由過濾將結晶產品分離出並在真空中乾燥以產生具有較高結晶度之聯苯·2-基·胺甲酸1- { 9-〔 (3·氣-4-經基-本甲酿）-甲基-0女基〕-壬基}-峨卩疋-4-基酯之氫氯化物鹽，產量60 %，60毫克。 DSC數據 -33- 201139375 依實例1中所描述者之相同方法測定2.027毫 2中所取得之物質的熔點，此可由起始溫度在11 強烈吸熱表明。所取得之DSC熱譜圖形顯示於第 ’其具有平坦之基線及對應於該熔點之尖銳的吸熱粉末X射線繞射數據當使用實例1中所描述之相同方法藉由PXRD 徵時，以實例2之物質可取得相同之無水多晶型。固態NMR數據將依上述實例2中描述之相同方式取得的2克本（藉由PXRD決定特徵時該樣本具有相同之形式度）中的約80毫克緊緊擠壓在一個4毫米Zr02轉在周圍溫度和壓力下，在置入寬口徑Bruker-Biosp 500 ΜΗζ^Η 頻率）NMR 光譜儀之 Bruker-Biosp BL CPMAS探針上收集光譜。將包裝之轉子指向魔 15.0kHz旋轉。利用質子去耦交叉極化魔角旋轉（ )收集l3C固相光譜。將交叉極化接觸時間設定爲秒。施用約85kHz之質子去耦場。收集4096次掃循環延遲爲8 · 5秒。碳譜係參考結晶型金剛烷外部將其高磁場共振設爲2 9.5 ppm。利用質子去耦魔角驗（MAS)收集氟固相光譜。施用約85kHz之質子。收集8次掃描，再循環延遲爲420秒。氟譜係參醋酸外部標準（50%體積/體積，在水中），將其克實例 8 _ 1 。。之 2圖中峰。決定特物質樣和結晶子中。 in DSX in 4 mm 角並在 CPMAS 2.0毫描，再標準，旋轉實去耦場考三氟共振設 -34- 201139375 爲- 76·54ρρηι 觀察到之碳化學位移如下 13c化學位移 fppm + 0.2 DDmla 強度b 168.8 2.5 155.3 1.9 155.0 1.6 148.3 1 3.8 140.0 4.0 135.8 3.6 135.2 Π 2.4 129.9 9.1 129.6 8.2 128.5 7.0 128.2 8.2 127.9 8.6 127.3 7.2 124.5 8.4 123.8 4.0 118.1 2.4 115.4 3.1 70.7 5.7 57.2 4.1 54.0 4.2 49.1 6.0 38.8 5.6 34.7 5.1 30.9 12.0 30.5 6.8 29.9 7.2 29.1 6.7 27.3 5.3 26.2 4.4 a對照29.5 ppm之固相金剛院外部樣本。 b定義爲峰高。強度可根據CPMAS實驗參數之確實設置及樣本之熱歷史而有不同。CPMAS強度不一定爲定量性的。觀察到之4個獨特的碳化學位移如下： -35- 201139375 化學位移 fppm ± 0.2 ppml3 強度b 140.0 4.0 124.5 8.4 ~ 49.1 6.0 30.9 12.0 ~ 對應之碳CPMAS譜說明於第3圖中。觀察到之氟化學位移如下： 1SF化學位移 [ppm ± 0.4 ppm]a 強度b -133.5 12.0 a對照-76.54PPm之三氟醋酸外部標準（50%體積/體積，在水中）。 b定義爲峰高。對應之氟MAS譜說明於第4圖中。實例3 :在人類重組Μ3毒覃鹼受體評估結合親和力膜製備方法將來自經重組表現人毒蕈鹼Μ3受體之CH〇(中國倉鼠卵巢）細胞的細胞小九在20mM HEPES ( pH値7.4 )中均化並在4 °C，4 8 0 0 0 X g離心2 0分鐘。將小九再懸浮於緩衝液中並重複均化及離心步驟。將所產生之小九以每1毫升原始擠壓之細胞體積重新懸浮於1毫升緩衝液中並重複均化步驟。在懸浮液上估計蛋白質並將約1毫克/毫升之1 毫升等份懸浮液冷凍在-8(TC。 hM3競爭結合分析議定計劃 -36- 201139375 在RT (室溫）下，將膜（5微克/槽）與3H-NMS (濃度5χΚρ)加/減測試化合物在1毫升聚苯乙烯96-槽深槽塊中培育24小時。最後之分析體積爲200微升，其包含 :2〇微升加/減測試化合物；20微升3H-NMS ( Perkin Elmer NEN 636 )及160微升膜溶液。以0.1 %二甲基亞颯定義總結合；以1 μΜ阿托品定義非特異性結合。分析緩衝液爲20mm HEPES ( pH値7.4 )。一旦加入所有分析成分，將盤覆蓋，在室溫下培育24小時並一邊搖動。使用惠普filtermate收集器，經由快速通過預先浸泡過0.5% 聚乙烯亞胺之GF/B Uni filter盤來終止分析，再以3x1毫升之4°C分析緩衝液清洗過濾盤。將該過濾盤在45 °C乾燥 1小時。將過濾盤之底部密封，並加入50微升/槽之 Microscint'O'，以Topseal密封盤之頂部。90分鐘之後，在NXT Topcount上讀取該盤之數値（每槽之讀取時間爲 1分鐘）。由此產生之數據以特異性結合之百分比表示（特異性結合=總結合-非特異性結合）。使用內部數據分析程序繪製％特異性結合對測試化合物濃度之圖形，以從S型曲線測定IC5Q。應用Cheng-Prussoff程式將IC5Q値修正爲Ki 値·· IC5〇 = _ 1 + [L]/Kd 其中IC5〇爲可抑制50%之特異性放射配體結合的未經標示藥物之濃度。〔L〕爲游離放射配體之濃度且KD及 -37- 201139375Aqueous hydrochloric acid solution (0.1 ml, 2M concentration, 0.2 mmol) was added to 1-{9-[(3-fluoro-4-hydroxy-)-biphenyl-2-yl-aminecarboxylic acid in ethanol (1 mL) a solution of benzhydryl)-methyl-amino]-mercapto}-piperidin-4-yl ester (Preparation Method 6, 118 mg, 0.2 mmol), allowing the solution to evaporate to a low volume night. Tributyl methyl ether (4 ml) was added to the residue and the mixture was stirred at room temperature in the presence of a previously prepared seed crystal. The colorless crystalline solid thus obtained was filtered and dried in vacuo to give the title compound. 'H NMR (DMSO-d6) δ =1.0-2.05 (m, 18H), 2.74-3.00 (m, 4H), 2.84 (s, 3H), 3.21-3.43 (m, 4H), 4.56-4.68 (m) , 4.70-4.74 (m) (1H, rotamer), 6.94-7.04 (111,214), 7.10-7.20 (d,1H), 7.25-7.44 (m,9H),8.74 (s),8.82 ( s) (1H, 201139375 rotamer), 10.〇5-1〇·3〇(m,1H), 10.27 (s, seed crystals prepared as follows: will be in ethanol (〇·1 ml) and hydrogen A solution of fumaric acid (1.5 mM) in aqueous chloric acid (2M concentration, 0.024 mmol) was added to the acid 1-(9-[(3-fluoro-4-) in ethanol (0.5 ml) In the solution of the thiol-benzylidene-methyl}-piperidin-4-yl ester free test (preparation method 6, 15 mg of ear), the solution was exposed to air to form a gel. The third butyl ether (1 ml) was treated for 6 weeks. A crystal appeared and crystallized between 2 hours when treated with a blending knife, filtered and dried in vacuo, 60% yield, 9 mg. The data was measured in a standard aluminum pan using the TA Instruments Q1000 Differential Scanning Calorimeter and the calorimetric method (DSC) for the material obtained in Example 1. The speed of 20 ° C / min from 10 ° C. Figure 1 shows the resulting DSC thermogram, its line and the sharp endothermic peak corresponding to the melting point. The strong endotherm from the initial °C can be shown in Example 1. The resulting 2.0 7 2 points. CHN data 1 H) ppm. 0.012 ml, mg, 0.0 1 2 5 phenyl-2-yl-amine methyl-amino]-fluorenyl, 0.025 mmol was evaporated at room temperature and allowed to stand, and the remaining gum was used to produce the desired The melting point is scanned by differential. Heat the sample to 2 50 °C with a flat base. The temperature is between 1 and 2 mg. Melting -31 - 201139375 Analysis C35H45N304FC1: C 67.13, Η 7.24, N 6.71. The results were found to be C 66.79, Η 7.23, N 6.62. Powder X-ray diffraction data using an automatic sampling changer, 0-0 goniometer geometry, automatic beam divergence slit (Divergence Slit) and PSD Vantec-Ι detector Bruker-AXS Ltd. D4 ENDEAVOR powder X-ray winding The powder X-ray diffraction pattern of Example 1 was measured by a radiograph. The sample was mounted on a low background crucible specimen holder with a 0.5 mm cavity to prepare for analysis. The specimen was rotated while being irradiated with a copper ΚαιΧ light (wavelength = 1.5406 angstrom) of an X-ray tube operated at 35 kV/40 mA. The analysis was carried out in a continuous mode at room temperature, which was set to be in the range of two 0 from 2 to 55, and the data was calculated by calculating 0.2 seconds per 0.018 step. In the EVA soft body released by Bruker-AXS, the threshold and width parameters set to 1 and 0.3, respectively, were used to search for peaks. The calibration of the instrument was verified using a corundum reference standard (NIST: SRM 1 976XRD flat X-ray diffraction intensity standard). The measurement pattern is shown in Figure 2. The intensity and peak position of the resulting powder X-ray diffraction pattern (angle 20 error is +/- 〇.1 degree) are shown in Table 1: -32- 201139375 Table 1: Relative Strength Cutoff 1 5 % Example 1 Characteristic diffraction peak (±0.1°2 0 angle (°2 is called intensity% 8.2 22.3 10.5 16.4 12.2 15.7 13.6 21.4 14.0 15.5 14.8 39.3 16.4 23.4 17.1 55.7 18.2 20.8 18.6 42.4 19.2 91.5 19.5 100.0 20.1 49.0 20.8 27.6 21.1 20.2 22.3 64.7 22.6 23.2 23.6 44.2 24.5 65.5 25.3 24.1 26.1 33.2 27.3 40.1 27.7 21.3 28.1 22.0 Example 2: Recrystallization of the compound of Example 1 from acetone to biphenyl-2-yl-aminocarboxylic acid (3-fluoro-4-hydroxy-benzamide) Hydrochloride salt of methyl-amino]-mercapto}-piperidin-4-yl ester (Example 1, 100 mg) was dissolved in dry acetone (about 1 ml) under reflux. Throughout the night, the crystalline product is separated by filtration and dried in a vacuum to produce a biphenyl·2-yl-carbamic acid having a higher degree of crystallinity 1-{9-[(3·气-4- 经基-本酿))-Methyl-0-female]-mercapto}-indol-4-yl ester hydrochloride, yield 60%, 60 DSC Data-33-201139375 The melting point of the material obtained in 2.027 mil was determined by the same method as described in Example 1, which can be indicated by a strong endotherm at a starting temperature of 11. The obtained DSC thermogram is shown in The first 'has a flat baseline and sharp endothermic powder X-ray diffraction data corresponding to the melting point. When the PXRD is used in the same manner as described in Example 1, the same anhydrous polycrystal can be obtained with the material of Example 2. The solid state NMR data will be squeezed in a 4 gram Zr02 rpm in a 2 gram of the same method as described in Example 2 above (the sample has the same form factor when PXRD determines the characteristics). Spectra were collected on a Bruker-Biosp BL CPMAS probe placed on a wide-bore Bruker-Biosp 500 ΜΗζ Η Η NMR spectrometer at ambient temperature and pressure. The packaged rotor was rotated at 15.0 kHz. Proton decoupled crossover The polarization magic angle rotation ( ) collects the l3C solid phase spectrum. The cross polarization contact time is set to seconds. A proton decoupling field of about 85 kHz is applied. The 4096 sweep cycle delay is 8.5 seconds. The carbon spectrum is referenced to the outside of the crystalline adamantane, and its high magnetic field resonance is set to 2 9.5 ppm. Fluorine solid phase spectra were collected using Proton Decoupled Magical Angle (MAS). A proton of about 85 kHz is applied. Eight scans were collected with a recirculation delay of 420 seconds. The fluorine spectrum is based on the external standard of acetic acid (50% v/v in water) and the gram is 8 _ 1 . . In the figure 2, the peak. Determining specific substances and crystals. In DSX in 4 mm angle and in CPMAS 2.0 mA, re-standard, rotating real decoupling field test trifluoro resonance set -34- 201139375 for - 76·54ρρηι observed carbon chemical shifts as follows 13c chemical shift fppm + 0.2 DDmla intensity b 168.8 2.5 155.3 1.9 155.0 1.6 148.3 1 3.8 140.0 4.0 135.8 3.6 135.2 Π 2.4 129.9 9.1 129.6 8.2 128.5 7.0 128.2 8.2 127.9 8.6 127.3 7.2 124.5 8.4 123.8 4.0 118.1 2.4 115.4 3.1 70.7 5.7 57.2 4.1 54.0 4.2 49.1 6.0 38.8 5.6 34.7 5.1 30.9 12.0 30.5 6.8 29.9 7.2 29.1 6.7 27.3 5.3 26.2 4.4 a Control external sample of 29.5 ppm solid phase diamond plant. b is defined as the peak height. The intensity can vary depending on the actual settings of the CPMAS experimental parameters and the thermal history of the sample. The CPMAS intensity is not necessarily quantitative. The four unique carbon chemical shifts observed are as follows: -35- 201139375 Chemical shift fppm ± 0.2 ppml3 Strength b 140.0 4.0 124.5 8.4 ~ 49.1 6.0 30.9 12.0 ~ The corresponding carbon CPMAS spectrum is illustrated in Figure 3. The chemical shifts observed were as follows: 1 SF chemical shift [ppm ± 0.4 ppm] a Strength b - 133.5 12.0 a Control - 76.54 ppm of trifluoroacetic acid external standard (50% v/v in water). b is defined as the peak height. The corresponding fluorine MAS spectrum is illustrated in Figure 4. Example 3: Evaluation of Human Recombinant Μ3 Muscarinic Receptor Binding Affinity Membrane Preparation Method Cells from CH〇 (Chinese hamster ovary) cells recombinantly expressing the human muscarinic Μ3 receptor were small in a 20 mM HEPES (pH 値 7.4 The medium was homogenized and centrifuged at 4 ° C, 4 800 0 g for 20 minutes. Resuspend the small nine in the buffer and repeat the homogenization and centrifugation steps. The resulting small nine was resuspended in 1 ml of buffer per 1 ml of the original extruded cell volume and the homogenization step was repeated. Estimate the protein on the suspension and freeze the aliquot of about 1 mg/ml in aliquots at -8 (TC. hM3 competition binding assay protocol -36- 201139375 at RT (room temperature), membrane (5 micrograms) /well) and 3H-NMS (concentration 5 χΚρ) plus / minus test compound in a 1 ml polystyrene 96-well deep trough block for 24 hours. The final analysis volume is 200 microliters, which contains: 2 〇 microliters plus /minus test compound; 20 microliters of 3H-NMS (Perkin Elmer NEN 636) and 160 microliters of membrane solution. Total binding was defined as 0.1% dimethyl hydrazine; non-specific binding was defined as 1 μ Μ atropine. 20mm HEPES (pH 値 7.4). Once all the analytical components have been added, cover the plate, incubate for 24 hours at room temperature and shake while using a HP filtermate collector, by rapidly passing GF/ pre-soaked with 0.5% polyethyleneimine. B Uni filter disc was used to terminate the analysis, and the filter disc was washed with 3 x 1 ml of 4 ° C analysis buffer. The filter disc was dried at 45 ° C for 1 hour. The bottom of the filter disc was sealed and 50 μl/well was added. Microscint'O', topped with Topseal sealing disc. 90 points After that, the number of disks was read on the NXT Topcount (the reading time per slot was 1 minute). The resulting data is expressed as a percentage of specific binding (specific binding = total binding - non-specific binding) Use the internal data analysis program to plot the % specific binding to the concentration of the test compound to determine IC5Q from the S-curve. Use the Cheng-Prussoff program to correct IC5Q値 to Ki 値·· IC5〇= _ 1 + [L]/ Kd where IC5〇 is the concentration of an unlabeled drug that inhibits 50% of specific radioligand binding. [L] is the concentration of free radioligand and KD and -37- 201139375

Ki分別爲放射配體和未經標示藥物之平衡解離常數。因此，亦已發現：已在上述分析中測試之聯苯-2-基· 胺甲酸1-{9-〔（3-氟-4-羥基-苯甲醯基）-甲基-胺基〕- 壬基}-哌啶-4-基酯之氫氯化物鹽顯示出〇.615nM之hM3 受體拮抗劑活性。實例4:天竺鼠氣管分析在提高之二氧化碳濃度下宰殺重3 50-450克之雄 Dunkin-Hartley天竺鼠，接著將腔靜脈放血。將氣管從喉部至胸腔入口點解剖出再將其放置在室溫下之新鮮、含氧之改良的 Krebs緩衝液中（含有 ΙΟμΜ普萘洛爾（ propranolol) 、ΙΟμΜ胍乙啶及3μΜ吲哚美辛之Krebs中 )。將氣管肌肉對面之軟骨切開，以打開氣管。切下約3-5個軟骨環寬之長條帶。將一條棉線連接該長條帶之一端的軟骨以連接力傳感器，另一端製成棉環以將組織固定在器官浴中。將長條帶安裝在充滿溫暖（37°C )經曝氣之改良Krebs的5毫升器官浴中。幫浦流速設定成1.0毫升/分鐘並連續清洗組織。將組織置於1000毫克之起始張力下。15和30分鐘後使組織重新拉緊，再令其進一步平衡 30-45分鐘。令組織.接受具下列參數之電場刺激（EFS ):每2分鐘訓練I 〇秒，〇. 1毫秒脈衝闊度，1 0Hz及I 0-30V。在規定範圍內每1 〇分鐘提高5 V電壓，直到在各組織中觀察到最大收縮反應。然後，在剩餘之全部實驗中使用此各組織 -38- 201139375 之正確最大電壓。對EFS平衡20分鐘後，停止幫浦，15 分鐘後，在8-10分鐘的期間內（4-5次反應）讀取控制讀數。然後，將在30xKi之化合物（在過濾結合分析中於表現在CHO細胞中之人類M3受體中測定）的注射劑量加入各組織中並培育2小時。然後，以改良之Krebs快速沖洗組織1分鐘以清洗該化合物，在剩餘之實驗中使水流回復到1毫升/分鐘。實驗結束時，以組織胺（1 μΜ )挑戰組織以測定存活力。使用Notocord®軟體自動收集在實驗期間採取之讀數。考量EFS反應受抑制之測量値將原始數據轉換成反應百分比。開始清洗後，記錄組織從經誘導之抑制作用恢復2 5 %所花費之時間，並以此作爲化合物作用期間之測量値。組織存活力將實驗期間限制在化合物沖洗掉後 1 6個小時。通常採n = 2至5測試化合物以估計作用持續時間。或者亦可使用下列天竺鼠氣管分析：從雄Dunkin-Hartley天竺鼠（重3 50-450克）移出氣管，再移除黏附之結締組織，通過氣管肌肉對面之軟骨製造切口並製備3-5個軟骨環寬之長條帶。將氣管帶懸浮在等距應變計（strain gauge )與固定之組織鉤之間，肌肉係在lg之起始張力下水平置於5毫升組織浴中並泡在含有 3μΜ吲哚美辛及ΙΟμΜ胍乙啶之溫暖（37°C )的經曝氣（ 95% 02 /5% C02)之Krebs溶液中。將組織置於平行鉑線電極（〜1公分溝隙）之間。使用懦動幫浦（Peristaltic -39- 201139375 pump )維持固定之1毫升/分鐘新鮮Krebs溶液（上述組成物之溶液）流過組織浴》在平衡期開始後1 5分鐘和3 0 分鐘令組織平衡1小時使張力回復到lg。在平衡結束時，以下列參數令組織接受電場刺激（EFS) : l〇v，10Hz 0.1 毫秒闊度，每2分鐘訓練1 0秒。在各組織中構建在】0v_ 30V之範圍內的電壓反應曲線（所有其他刺激參數保持不變），以測定正確之最大刺激。使用這些刺激參數，由 ΙμΜ河豚毒素或ΙμΜ阿托品造成之阻斷作用證實EFS反應爲100%神經介及100%膽鹼能導。然後，以2分鐘之間隔反復刺激組織，直到可複製該反應。在加入硏究化合物前20分鐘停止蠕動幫浦，記錄過去1〇分鐘之期間內之平均抽搐收縮作爲控制反應。將硏究化合物加入組織浴中，各組織接受單一濃度之化合物並令其平衡2小時。加入後2小時，記錄EFS反應之抑制情形，來自同一動物之氣管條上使用在一範圍內之化合物濃度以製作IC 5Q曲線。然後，迅速清洗組織並重新建立1毫升/分鐘之Krebs溶液灌注。進一步刺激組織1 6小時並記錄EFS反應之恢復情形。在1 6小時結束時，在組織浴中添加1 0 μ Μ組織胺以確認組織存活力。從1C 5()曲線鑑定拮抗劑之正確最大濃度（產生>70 %，但小於1 00 %抑制之反應的測試濃度）且在接受此濃度之組Ρ中計算該經誘導.之抑制作用恢復2 5 %的時間（Τ25 )。通常在η = 2至5測試化合物以估計作用持續時間。 -40- 201139375 【圖式簡單說明】第1圖：實例1和2之DSC熱譜。第2圖：實例1之PXRD樣式。第3圖：實例2之碳CPMAS譜。第4圖：實例2之氟MAS譜。 -41 -Ki is the equilibrium dissociation constant of radioligand and unlabeled drug, respectively. Therefore, it has also been found that 1-{9-[(3-fluoro-4-hydroxy-benzylcarboxylidene)-methyl-amino]-benz-2-yl-aminocarbamate has been tested in the above analysis. The hydrochloride salt of mercapto}-piperidin-4-yl ester showed an activity of hM3 receptor antagonist of 615.615 nM. Example 4: Gastrointestinal tracheal analysis The male Dunkin-Hartley guinea pig weighing 3 50-450 g was slaughtered at an elevated carbon dioxide concentration, followed by bronching the vena cava. Dissipate the trachea from the larynx to the chest entry point and place it in fresh, oxygenated modified Krebs buffer at room temperature (containing propranolol, ΙΟμΜ胍乙及 and 3 μΜ吲哚) In the Krebs of Mesin). Cut the cartilage opposite the tracheal muscle to open the trachea. Cut about 3-5 strips of cartilage ring width. A cotton thread is attached to the cartilage at one end of the strip to attach the force sensor, and the other end is made into a cotton loop to secure the tissue in the organ bath. The long strips were mounted in a 5 ml organ bath filled with warm (37 ° C) aerated modified Krebs. The pump flow rate was set to 1.0 ml/min and the tissue was continuously cleaned. Place the tissue under the initial tension of 1000 mg. After 15 and 30 minutes, the tissue was re-tensioned and allowed to equilibrate for another 30-45 minutes. Order the organization. Accept electric field stimulation (EFS) with the following parameters: 1 sec. per 2 minutes, 〇 1 ms pulse width, 10 Hz and I 0-30V. Increase the voltage by 5 V every 1 minute in the specified range until the maximum contraction response is observed in each tissue. Then, the correct maximum voltage for each of these organizations -38-201139375 was used in all remaining experiments. After 20 minutes of equilibration of EFS, the pump was stopped, and after 15 minutes, the control reading was read during the 8-10 minute period (4-5 reactions). Then, an injection dose of 30 x Ki of the compound (measured in the human M3 receptor in CHO cells in the filtration binding assay) was added to each tissue and incubated for 2 hours. The tissue was then quickly rinsed with modified Krebs for 1 minute to wash the compound and the water flow was returned to 1 ml/min in the remaining experiments. At the end of the experiment, tissue was challenged with histamine (1 μΜ) to determine viability. Use the Notocord® software to automatically collect the readings taken during the experiment. Consider the measurement of inhibition of the EFS reaction and convert the raw data to the percentage of reaction. After the start of the wash, the time taken for the tissue to recover from the induced inhibition of 25 % was recorded and used as a measure of the duration of the action of the compound. Tissue viability was limited to 16 hours after the compound was rinsed off during the experiment. Test compounds are usually taken at n = 2 to 5 to estimate the duration of action. Alternatively, the following guinea pig tracheal analysis can be used: Remove the trachea from the male Dunkin-Hartley guinea pig (weight 3 50-450 g), remove the adherent connective tissue, make an incision through the cartilage opposite the tracheal muscle and prepare 3-5 cartilage rings. Long strips wide. The tracheal band is suspended between an isometric strain gauge and a fixed tissue hook, and the muscle line is placed horizontally in a 5 ml tissue bath under the initial tension of lg and soaked in a mixture containing 3 μm of mexin and ΙΟμΜ胍. Azeitized (37 ° C) aerated (95% 02 /5% C02) Krebs solution. Place the tissue between parallel platinum wire electrodes (~1 cm gap). Maintain a fixed 1 ml/min fresh Krebs solution (solution of the above composition) through the tissue bath using a sway pump (Peristaltic -39- 201139375 pump). Balance the tissue at 15 minutes and 30 minutes after the start of the equilibration period. The tension was returned to lg for 1 hour. At the end of the balance, the tissue is subjected to electric field stimulation (EFS) with the following parameters: l〇v, 10 Hz 0.1 ms width, 10 hours per 2 minutes of training. A voltage response curve (with all other stimulation parameters remaining) in the range of 0v_30V was constructed in each tissue to determine the correct maximum stimulus. Using these stimulation parameters, the blocking effect by ΙμΜ tetrodotoxin or ΙμΜ atropine confirmed that the EFS response was 100% neurogenic and 100% cholinergic. Then, the tissue was repeatedly stimulated at intervals of 2 minutes until the reaction could be replicated. The peristaltic pump was stopped 20 minutes before the addition of the study compound, and the average twitch contraction during the past 1 minute period was recorded as a control response. The study compound was added to the tissue bath and each tissue received a single concentration of compound and allowed to equilibrate for 2 hours. Two hours after the addition, the inhibition of the EFS reaction was recorded, and the concentration of the compound in a range was used on the gas strip from the same animal to prepare an IC 5Q curve. Then, quickly clean the tissue and re-establish a 1 ml/min Krebs solution. The tissue was further stimulated for 16 hours and the recovery of the EFS response was recorded. At the end of 16 hours, 10 μM of histamine was added to the tissue bath to confirm tissue viability. The correct maximum concentration of the antagonist was determined from the 1C 5() curve (the test concentration yielding > 70%, but less than 100% inhibition) and the inhibition was calculated in the group receiving this concentration. 2 5 % of the time (Τ 25 ). Compounds are typically tested at η = 2 to 5 to estimate the duration of action. -40- 201139375 [Simple description of the diagram] Figure 1: DSC thermogram of Examples 1 and 2. Figure 2: PXRD style of Example 1. Figure 3: Carbon CPMAS spectrum of Example 2. Figure 4: Fluoride MAS spectrum of Example 2. -41 -

Claims

201139375 VII. Patent application scope: 1. A compound, which is a biphenyl-2-yl-aminecarboxylic acid represented by the following formula: { 9-[(3-fluoro-4-hydroxy-benzylidene). Alkyl-amino]hydrazinopiperidin-4-yl ester hydrochloride salt:

2. A compound as claimed in claim 1 which is characterized by its crystalline nature. 3. For the compound of claim 2, when using Cu anti-(1) radiation (wavelength = 1.5406A), the X-ray diffraction pattern is characterized by a 2-0 angle (±0.1). 2 β ) represents the following main X-ray diffraction pattern peaks:

4. The compound of the second application of the patent scope 'the solid state 13': NMR is characterized by the following main chemical shifts (±0.2 ppm) expressed in parts per million (ppm): 30.9, 49.1, 124.5 and I40 .0 ' This chemical shift is based on an external standard of 29.5 ppm solid phase adamantane. 5. For example, the compound of the second application of the patent scope 'the solid state 19? NMR is characterized by the following main chemical sites expressed in parts per million (ppm) -42 ~ 201139375 shift (± 〇.4ppm): -133.5 The chemical shift was compared to an external standard of 76.54 ppm aqueous trifluoroacetic acid solution (50% v/v). 6. A pharmaceutical composition comprising from 0.001 mg to 5000 mg of a compound according to any one of claims 1 to 5 and one or more pharmaceutically acceptable excipients. A pharmaceutical dry powder comprising 0.001 mg to 40 mg of a compound according to any one of claims 1 to 5 and a lactose monohydrate. 8. A compound according to any one of claims 1 to 5, which is a medicament. 9. A compound according to any one of claims 1 to 5 for use in the treatment of a disease, condition and condition selected from the group consisting of chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction, lung Emphysema' chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD containing chronic bronchitis, emphysema or dyspnea associated with or unrelated to COPD, COPD characterized by irreversible progressive airway obstruction, Adult respiratory distress syndrome (ARDS), worsening of respiratory hyperreactivity after treatment with other drugs, respiratory diseases associated with pulmonary hypertension, bronchitis, acute bronchitis, acute laryngotracheal bronchitis, peanut inhalation bronchitis, card Other bronchitis, croupus bronchitis, dry bronchitis, infectious asthma bronchitis, proliferative bronchitis, staphylococcus or streptococcal bronchitis, alveolar bronchitis, asthma, atopic Asthma, non-atopic asthma, allergic asthma, IgE-mediated atopic bronchial asthma, support Asthma, idiopathic asthma, true asthma, endogenous asthma caused by pathophysiological disorders-43-201139375, xeropathic asthma caused by environmental factors, idiopathic asthma with unknown or insignificant causes, non-ectopic Asthma, bronchial asthma, emphysema asthma, asthma caused by exercise, asthma caused by allergens, asthma caused by cold air, occupational asthma, infection caused by bacteria, fungi, protozoa or viral infections Asthma, non-allergic asthma, early asthma, wheezing infant syndrome, bronchiolitis, acute lung injury, bronchiectasis, cylindrical bronchiectasis, bronchial dilatation, fusiform bronchiectasis, bronchiectasis, conjugation Bronchiectasis, dry bronchiectasis, and follicular bronchiectasis. A composition of a compound according to any one of claims 1 to 5 and one or more therapeutic agents selected from the group consisting of: (a) 5-lipoxygenase (5-LO) Inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist; (b) leukotriene antagonist (LTRAs) comprising LTB4, LTC4, 1^04 and LTE4 antagonists; (c) histamine receptor Antagonists comprising Η 1 and H3 antagonists; (d) vasoconstrictor sympathetic agents for decongestants and α-adrenergic receptor agonists; (e) PDE inhibitors, including PDE3 , PDE4 and PDE5 inhibitors (Ο / 3 2 receptor agonists; (g) theophylline; (1 〇 cromolyn; (i) C Ο X inhibitors, including non-selective and selective C Ο X · 1 or -44· 201139375 CΟX-2 inhibitor (NSAID); (j) prostaglandin receptor antagonist and prostaglandin synthetase inhibitor (k) oral and inhaled corticosteroids; (l) dissociated corticosteroids Body agonist (DAGR); (m) a single antibody that actively fights against endogenous inflammatory entities; (η) anti-tumor necrosis factor (anti-TNF-α) agent; (〇) adhesion points a sub-inhibitor comprising a VLA-4 antagonist; (P) a kinin-B!- and a B2-receptor antagonist; (q) an immunosuppressive agent comprising an IgE pathway and an inhibitor of cyclosporine (r) Matrix metalloproteinase (MMP) inhibitor; (S) tachykinin NK〇, NKda NK3 receptor antagonist; (t) protease inhibitors, such as elastase inhibitors; (u) adenosine A2a receptor agonist and A2b Antagonist; (v) urokinase inhibitor; (w) a compound acting on a dopamine receptor, such as a D 2 agonist; (X) a modulator of the NFkP pathway, such as an IKK inhibitor; (y) regulation of cytokine signaling pathways Agents, such as p38 MAP kinase, PI3 kinase: JAK kinase, syk kinase, EGFR or MK-2; (z) can be classified as a lysate or cough inhibitor; (aa) promotes inhalation cortex An antibiotic and antiviral agent effective against colonies that can colonize the respiratory tract: -45- 201139375 (cc) HDAC inhibitor; (dd) CXCR2 antagonist; (ee) integrin antagonist (ff) Chemotaxis; (gg) epithelial sodium channel (ENaC) blocker or epithelial sodium channel (ENaC) Preparations; (hh) P2Y2 agonists and other nucleotide receptor agonists; (Π) thromboxane inhibitors; (jj) PGD2 synthesis and PGD2 receptor (DPI and DP2/CRTH2) inhibitors; (kk) nicotine Acid; and (11) adhesion factors, including VLAM, ICAM, and ELAM. -46 -