CN101065370B - 具有β-2-肾上腺素受体激动剂活性的5-羟基-苯并噻唑衍生物 - Google Patents
具有β-2-肾上腺素受体激动剂活性的5-羟基-苯并噻唑衍生物 Download PDFInfo
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- CN101065370B CN101065370B CN2005800406137A CN200580040613A CN101065370B CN 101065370 B CN101065370 B CN 101065370B CN 2005800406137 A CN2005800406137 A CN 2005800406137A CN 200580040613 A CN200580040613 A CN 200580040613A CN 101065370 B CN101065370 B CN 101065370B
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Abstract
游离或盐或溶剂化物形式的式I化合物，其中T具有如说明书所示的含义，可用于治疗可通过β2-肾上腺素受体活化被防止或减轻的病症。还描述了含有这些化合物的药物组合物和制备这些化合物的方法。
Description
本发明涉及有机化合物、它们的制备和作为药物的用途。
本发明在一方面提供了游离或盐或溶剂化物形式的式I化合物，
其中
T是氢，或者C1-C10-烷基，任选在一个、两个或三个位置被C1-C10-烷氧基、-NR1R2、含有至少一个选自氮、氧和硫的环杂原子的5-或6-元杂环或者被C3-C15-碳环基团取代，所述C3-C15-碳环基团任选在一个、两个或三个位置被如下取代基取代：卤代基、C1-C10-烷基、C3-C10-环烷基、卤代-C1-C10-烷基、-NR3R4、含有至少一个选自氮、氧和硫的环杂原子的5-或6-元杂环或者任选在一个、两个或三个位置被C6-C10-芳基取代的C1-C10-烷氧基；或者
T是C3-C15-碳环基团，任选在一个、两个或三个位置被如下取代基取代：卤代基、C1-C10-烷基、C3-C10-环烷基、卤代-C1-C10-烷基、-NR5R6、含有至少一个选自氮、氧和硫的环杂原子的5-或6-元杂环或者任选在一个、两个或三个位置被C1-C4-烷基或C6-C10-芳基取代的C1-C10-烷氧基；
R1、R2、R3、R4、R5和R6独立地是氢、C1-C10-烷基、C1-C10-烷氧基、C3-C10-环烷基或C6-C10-芳基。
用在本说明书中的术语具有下列含义：
本文所用的“任选在一个、两个或三个位置被取代”表示所提到的基团可以在一个、两个或三个位置被后面所列举的基团中的任意一个或任意组合所取代。
本文所用的“卤代基”或“卤素”表示属于元素周期表第17族(以前称第VII族)的元素，例如可以是氟、氯、溴或碘。优选卤代基或卤素是氯。
本文所用的“C1-C10-烷基”表示具有1至10个碳原子的直链或支链烷基。当T是C1-C10-烷基时，它优选是C1-C8-烷基，尤其是正丙基、异丙基、正丁基、仲丁基、-C(CH3)2C2H5、-CH(CH3)C3H7或-CH(CH3)CH2C(CH3)3。当T是在一个、两个或三个位置被C1-C8-烷基取代的C5-C10-碳环基团时，该C1-C10-烷基优选是C1-C4-烷基，尤其是乙基或仲丁基。当任意一个R1、R2、R3、R4、R5和R6是C1-C10-烷基时，它优选是C1-C4-烷基，尤其是甲基。
本文所用的“C1-C10-烷氧基”表示具有1至10个碳原子的直链或支链烷氧基。当T是在一个、两个或三个位置被在一个、两个或三个位置被C1-C10-烷氧基取代的C5-C15-碳环基团取代的C1-C10-烷基时，该C1-C10-烷氧基优选是C1-C4-烷氧基，尤其是甲氧基或正丁氧基。当T是在一个、两个或三个位置被C1-C10-烷氧基取代的C5-C15-碳环基团时，该C1-C10-烷氧基优选是C1-C4-烷氧基，尤其是乙氧基。当任意一个R1、R2、R3、R4、R5和R6是C1-C10-烷氧基时，它优选是C1-C4-烷氧基。
本文所用的“C3-C10-环烷基”表示具有3至10个环碳原子的环烷基，例如单环基团，例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者二环基团，例如二环庚基或二环辛基。优选C3-C10-环烷基是C3-C6-环烷基，尤其是环戊基或环己基。
本文所用的“卤代-C1-C10-烷基”表示被一个或多个卤素原子、优选一个、两个或三个卤素原子取代的如上所定义的C1-C10-烷基。优选卤代-C1-C10-烷基是氟代-C1-C4-烷基。
本文所用的“C6-C10-芳基”表示含有6至10个碳原子的一价碳环芳族基团，例如可以是单环基团，例如苯基，或者二环基团，例如萘基。优选C6-C10-芳基是C6-C8-芳基，尤其是苯基。
本文所用的“C3-C15-碳环基团”表示具有3至15个环碳原子的碳环基团，例如芳族或非芳族的单环基团，例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基或苯基，或者二环基团，例如二环辛基、二环壬基、二环癸基、二氢茚基或茚基。当T是在一个、两个或三个位置被C5-C15-碳环基团取代的C1-C10-烷基时，该C5-C15-碳环基团优选是C5-C10-碳环基团，尤其是单环基团，例如苯基或环己基。当T是C5-C15-碳环基团时，它优选是C5-C10-碳环基团，尤其是单环非芳族基团，例如环戊基，或者二环基团，例如二氢茚基。
本文所用的“含有至少一个选自氮、氧和硫的环杂原子的5-或6-元杂环”例如可以是吡咯、吡咯烷、吡唑、咪唑、三唑、四唑、呋喃、噻二唑、异噻唑、噻吩、噁二唑、吡啶、噁唑、异噁唑、吡嗪、哒嗪、嘧啶、哌嗪、吗啉代基、三嗪、噁嗪或噻唑。优选的5-或6-元杂环包括不饱和的环，例如吡啶、呋喃和噻吩。
本文所用的“溶剂化物”表示包含本发明化合物和一个或多个可药用溶剂分子如乙醇的分子配合物。当溶剂是水时，使用术语“水合物”。
在本说明书和随后的权利要求书全文中，除非上下文另有要求，措辞“包含”将被理解为隐含包括所述的整数或步骤或者整数或步骤的集合，但是不排除任意其它整数或步骤或者整数或步骤的集合。
优选的本发明化合物包括如下定义的游离或盐或溶剂化物形式的式I化合物，其中
T是C1-C10-烷基，任选在一个、两个或三个位置被-NR1R2或C5-C15-碳环基团取代，所述C5-C15-碳环基团任选在一个、两个或三个位置被卤代基、-NR3R4或C1-C10-烷氧基取代；或者
T是C5-C15-碳环基团，任选在一个、两个或三个位置被C1-C10-烷基、C3-C10-环烷基、-NR5R6或者被任选在一个、两个或三个位置被C6-C10-芳基取代的C1-C10-烷氧基所取代；
R1、R2、R3、R4、R5和R6独立地是C1-C10-烷基或C6-C10-芳基。
尤其优选的本发明化合物包括如下定义的式I化合物，其中
T是C1-C8-烷基，任选在一个位置被-NR1R2或C5-C10-碳环基团取代，所述C5-C10-碳环基团任选在一个或两个位置被卤代基、-NR3R4或C1-C4-烷氧基取代；或者
T是C5-C10-碳环基团，任选在一个或两个位置被C1-C8-烷基、C3-C10-环烷基、-NR5R6或者被任选在一个位置被C6-C8-芳基、尤其是苯基取代的C1-C4-烷氧基取代；
R1、R2、R3、R4、R5和R6独立地是C1-C4-烷基或C6-C8-芳基，尤其是苯基。
式I化合物能够生成酸加成盐，特别是可药用酸加成盐。式I化合物的可药用酸加成盐包括无机酸和有机酸的盐，无机酸例如有氢卤酸(如氢氟酸、氢氯酸、氢溴酸或氢碘酸)、硝酸、硫酸、磷酸；有机酸例如有脂族一元羧酸，如甲酸、乙酸、三氟乙酸、丙酸和丁酸；脂族羟基酸，如乳酸、柠檬酸、酒石酸或苹果酸；二元羧酸，如马来酸或琥珀酸；芳族羧酸，如苯甲酸、对-氯苯甲酸、二苯基乙酸、对-联苯基苯甲酸或三苯基乙酸；芳族羟基酸，如邻-羟基苯甲酸、对-羟基苯甲酸、1-羟基萘-2-甲酸或3-羟基萘-2-甲酸；肉桂酸类，如3-(2-萘基)丙烯酸、对-甲氧基肉桂酸或对-甲基肉桂酸；和磺酸，如甲磺酸或苯磺酸。这些盐可通过已知的成盐工艺从式I化合物制备。
式I化合物可以以未溶剂化或溶剂化物的形式存在。可药用溶剂化物包括水合物和其中结晶溶剂可以被同位素取代的溶剂如D2O、d6-丙酮或d6-DMSO的溶剂化物。
式I化合物包括至少一个不对称的碳原子，因而它们可以以单一的旋光活性异构形式或其混合物、例如外消旋或非对映异构混合物的形式存在。本发明涵盖单一的旋光活性R与S异构体及其混合物，例如外消旋或非对映异构混合物。这些异构体可通过常规技术如分步结晶或柱色谱法分离。具体的尤其优选的本发明化合物是下文实施例所述的那些。
本发明还提供了制备游离或盐或溶剂化物形式的式I化合物的方法。它们可通过如下的方法制备，该方法包括：
(i)(A)使式II化合物
其中Ra和Rb是保护基，且Rc是C1-C4-烷基或C6-C10-芳基，
与其中T如上文定义的式III化合物反应；
H2N-T III，或者
(B)使其中Ra和Rb是保护基的式IIA化合物与其中T如上文定义的式III化合物反应；
(ii)除去保护基；和
(iii)以游离或盐或溶剂化物的形式回收所得的式I化合物。
方法变体A可以利用已知使磺酸酯与胺反应的工艺或者类似于下文实施例所述来进行。Rc优选是C1-C4-烷基，但尤其是甲基。反应方便地在有机溶剂如甲苯中进行。反应温度方便地为0℃至200℃，优选70℃至100℃，尤其是80℃至90℃。通过常规加热或微波照射可以达到该温度。
方法变体B可以利用已知使环氧化物与胺反应的工艺或者类似于下文实施例所述来进行。反应方便地在有机溶剂如甲苯中进行。反应温度方便地为0℃至200℃，优选70℃至100℃，尤其是80℃至90℃。通过常规加热或微波照射可以达到该温度。
保护基Ra和Rb可以根据官能团的属性来选择，例如如ProtectiveGroups in Organic Synthesis，T.W.Greene和P.G.M.Wuts，John Wiley&Sons Inc，第3版，1999中所述，该文献还描述了适宜于用氢代替保护基的工艺。Ra优选是C1-C4-烷基，尤其是异丙基。Rb优选是C1-C4-烷基，尤其是叔丁基。
保护基可以利用任意常规工艺引入和除去。例如，当羟基被苄基保护时，后者可利用常规工艺、在披钯炭的存在下进行催化氢化而除去，如下文实施例所用的那些。
式I化合物的游离形式可以按照常规方式转化为盐形式，反之亦然。化合物的游离或盐形式可以以水合物或含有结晶溶剂的溶剂化物的形式获得。式I化合物可以按照常规方式从反应混合物中回收和纯化。按照常规方式可以得到异构体、例如对映异构体，例如通过分步结晶或者由相应的不对称取代的、例如具有旋光活性的原料进行不对称合成而获得。
式II化合物是新的，可如下制备：使式IV化合物
其中Ra和Rb是保护基，
与磺酰氯如甲磺酰氯反应，该反应利用已知的选择性单磺酰化反应工艺，如Zhou等人，J.Organic Letters(2002)，4(1)，第43-46页所述，或者类似于下文实施例所述来进行。与(R)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-乙烷-1，2-二醇反应得到R-对映异构体，而与(S)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-乙烷-1，2-二醇反应得到S-对映异构体。反应方便地在有机溶剂如吡啶中进行。反应温度方便地为-20℃至30℃，但是优选约0℃。
式IIA化合物是新的，可以利用已知制备环氧乙烷基-取代的杂环化合物的方法来制备，例如国际专利申请WO 01/016601所述。例如，式IIA化合物可通过在室温至150℃、但优选50至100℃、在碱的存在下、在溶剂如甲苯、四氢呋喃或二氯乙烷中加热式II化合物来制备。式IIA化合物还可以在上述式II化合物与式III化合物反应生成式I化合物的反应期间作为中间体生成。
式III化合物是已知的或者可以利用已知或类似于下文实施例所述的工艺制备。
式IV化合物可如下制备：使式V化合物
其中Ra和Rb是保护基，
与二羟基化试剂如四氧化锇反应，该反应在有或无催化剂(如(DHQD)2PHAL(1，4-双(二氢奎尼丁基)酞嗪))和再氧化剂(re-oxidant)(如K3Fe(CN)6)的存在下进行，或者与预混合的二羟基化试剂如AD-mix-α或AD-mix-β反应，利用有关不对称二羟基化烯烃的已知工艺或者类似于下文实施例所述来进行。反应方便地在有机溶剂如叔丁醇/水中用四氧化锇进行，优选在催化剂如(DHQD)2PHAL的存在下并以K3Fe(CN)6作为再氧化剂来进行。反应温度方便地为-10℃至10℃，但是优选约0℃。
式V化合物可如下制备：使式VI化合物进行烯化反应，
其中Ra和Rb是保护基，该反应利用已知用于由醛反应生成烯的工艺如Wittig反应或者类似于下文实施例所述来进行。反应方便地在有机溶剂如THF或DCM中进行。反应温度方便地为10℃至40℃，但是优选室温。
式VI化合物可如下制备：使式VII化合物
其中Ra和Rb是保护基，X是卤代基，优选氟，
与强碱如叔丁基锂反应，加入亲电子试剂如二甲基甲酰胺淬灭中间体阴离子，该反应利用Stanetty等人，J.Org.Chem.1996，61，5130-5133所述工艺或者类似于下文实施例所述来进行。反应方便地在有机溶剂如THF中进行。反应温度方便地为-90℃至20℃，但是优选在约-78℃至约-10℃之间。
式VII化合物可如下制备：使式VIII化合物
其中Rb是保护基，X是卤代基，
与式IX化合物反应，其中Ra是保护基，
HO-Ra IX
该反应利用已知使异硫氰酸酯与醇反应生成硫代氨基甲酸酯的工艺或者类似于下文实施例所述来进行。R1优选是C1-C4-烷基，尤其是异丙基。反应方便地优选在碱如三乙胺的存在下进行。反应温度方便地为0℃至120℃，但是优选约60℃。
式VIII化合物可通过已知用于苯胺向异硫氰酸酯转化的工艺制备，例如如下制备：使式X化合物
其中Rb是保护基，X是卤代基，
与硫光气(二氯硫化碳)反应，该反应利用已知用于转化胺为异硫氰酸酯的工艺或者类似于下文实施例所述来进行。反应方便地在有机溶剂如氯仿中进行，优选在碱如碳酸钾的存在下进行。反应温度方便地为-20℃至20℃，但是优选约0℃。
式IX化合物是已知的或者可以利用已知或类似于下文实施例所述的工艺制备。
游离、盐或溶剂化物形式的式I化合物可用作药物。因此，本发明还提供了用作药物的游离、盐或溶剂化物形式的式I化合物。游离、盐或溶剂化物形式的式I化合物(下文还称为“本发明的物质”)具有良好的β2-肾上腺素受体激动剂活性。按照R.A.Coleman和A.T.Nials，J.Pharmacol.Methods 1989，21，71中的工艺，可以利用豚鼠气管条体外测定法测试本发明的物质的β2激动剂活性、作用起效和作用持续时间。按照CurrentProtocols in Pharmacology(S.J.Enna(主编)等人，John Wiley&Son，Inc，1998)的工艺通过经典的过滤结合测定法，或者按照B.January等人，Brit.J.Pharmacol.1998，123，701的工艺通过在表达β2-或β1-肾上腺素受体的细胞中测定cAMP，可以测定相对于β1-肾上腺素受体而言对β2-肾上腺素受体的结合效力和选择性。
本发明的物质普遍具有起效迅速，并且对β2-肾上腺素受体具有延长了的刺激作用，下文实施例的化合物具有0.1至1000nM级别的Ki(β2)值，具有1至大于12小时级别的作用持续时间。很多化合物具有1.5至500的β2-肾上腺素受体相对于β1-肾上腺素受体的结合选择性。通过经典的过滤结合测定法测量实施例2、4、9、14和17化合物的β2结合效力，以Ki值表示，分别为0.061、0.027、0.016、0.056和0.002μM。
在豚鼠气管条测定法中，实施例1和18的化合物在100nM浓度下具有＞672的T(50％)时间(以分钟计)，在10nM浓度下为595，其中T(50％)是抑制收缩至其最大值衰减达50％的时间。
考虑到它们的β2激动剂活性，本发明的物质适宜用于治疗任意可通过β2-肾上腺素受体活化被防止或减轻的病症。鉴于它们的长效选择性β2激动剂活性，本发明的物质可用于松弛支气管平滑肌和缓解支气管收缩。支气管收缩的缓解可以在模型中测量，例如Chong等人，J.Pharmacol.Toxicol.Methods 1998，39，163，Hammelmann等人，Am.J.Respir.Crit.Care Med.，1997，156，766的体内体积描记模型和类似模型。
本发明的物质因此可用于治疗阻塞性或炎性气道疾病。鉴于它们的作用时间长，有可能在治疗这类疾病时每天一次给予本发明的物质。另一方面，本发明的物质普遍表现出表明有较低的β2激动剂普遍所具有的副作用(例如心动过速、震颤和不安静)的发生率的特征，这类成分因此适宜用在阻塞性或炎性气道疾病的即时需要(援救)治疗以及预防性治疗中。
本发明的疾病治疗可以是对症或预防性治疗。本发明适用的炎性或阻塞性气道疾病包括任何类型或起因的哮喘，包括内源性(非变应性)哮喘和外源性(变应性)哮喘。哮喘的治疗也应理解为包括例如4或5岁以下的表现出喘鸣症状的受治疗者的治疗，所述受治疗者被诊断或可诊断为“喘鸣婴幼儿(wheezy infant)”，这是一种已确定的在医学上引起重视的患者类别，现在经常被确定为初期或早期哮喘患者。(为方便起见，这种特定的哮喘病症通常被称为“婴幼儿喘鸣综合征(wheezy infant syndrome)”)
哮喘治疗中的预防功效将通过症状性发作、例如急性哮喘或支气管收缩发作的频率或严重性减小、肺功能改善或气道反应性过高改善而被证明。还可以通过对其它症状性治疗、即在其发生时用于或旨在限制或中止症状性发作的治疗需求的减少来证明，例如对抗炎(例如皮质类固醇)或支气管扩张治疗的需求减少。哮喘的预防性益处可能在有“晨降(morningdipping)”倾向的个体中特别明显。“晨降”是一种公认的哮喘综合征，常见于大部分哮喘患者，以例如清晨约4至6之间的哮喘发作为特征，即发作时间通常距离任意以前所给予的症状性哮喘治疗的时间较远。
本发明适用的其它炎性或阻塞性气道疾病和病症包括成人/急性呼吸窘迫综合征(ARDS)，慢性阻塞性肺部或气道疾病(COPD或COAD)，包括慢性支气管炎或与之有关的呼吸困难，肺气肿，以及其它药物疗法、特别是其它吸入药物疗法引起的气道反应性过高的恶化。本发明还适用于治疗任何类型或起因的支气管炎，包括例如急性支气管炎、花生仁吸入性支气管炎、卡他性支气管炎、格鲁布性支气管炎、慢性支气管炎或结核性支气管炎。本发明适用的其它炎性或阻塞性气道疾病包括任何类型或起因的尘肺(一种炎性、普遍为职业性的肺疾病，无论慢性或急性，经常伴有气道阻塞，由反复吸入粉尘引起)，包括例如矾土肺、炭肺、石棉肺、石末肺、驼鸟毛尘肺、铁尘肺、矽肺、烟尘肺和棉尘肺。
考虑到它们的β2激动剂活性，本发明的物质还可用于治疗需要松弛子宫或脉管系统的平滑肌的病症。它们因而可用于预防或减轻妊娠中的早产疼痛。它们还可用于治疗慢性与急性荨麻疹、银屑病、变应性结膜炎、痤疮疹、枯草热和肥大细胞病。
本发明的物质还可用作共用治疗剂与其它药物联合使用，例如抗炎药、支气管扩张药、抗组胺药或止咳药物，特别是在阻塞性或炎性气道疾病的治疗中，例如上文提到的那些，例如作为这类药物治疗活性的增效剂或者作为减少这类药物的所需剂量或潜在副作用的手段。本发明的物质可以与其它药物混合在固定的药物组合物中，或者它可以与其它药物分开、之前、同时或之后给药。因此，本发明包括上述本发明的物质与抗炎药、支气管扩张药、抗组胺药或止咳药物的组合，所述本发明的物质和所述药物处于相同或不同的药物组合物中。
适宜的抗炎药包括类固醇类，特别是糖皮质激素类，例如布地奈德、二丙酸倍氯米松、丙酸氟替卡松、环索奈德或糠酸莫米松，或者如下文献所述的类固醇类：WO 02/88167、WO 02/12266、WO 02/100879、WO02/00679(尤其是实施例3、11、14、17、19、26、34、37、39、51、60、67、72、73、90、99和101的那些)、WO 03/35668、WO 03/48181、WO03/62259、WO 03/64445、WO 03/72592、WO 04/39827和WO 04/66920；非类固醇类糖皮质激素受体激动剂，例如如下文献所述的那些：DE10261874、WO 00/00531、WO 02/10143、WO 03/82280、WO 03/82787、WO 03/86294、WO 03/104195、WO 03/101932、WO 04/05229、WO04/18429、WO 04/19935和WO 04/26248；LTB4拮抗剂，例如BIIL 284、CP-195543、DPC11870、LTB4乙醇酰胺、LY 293111、LY 255283、CGS025019C、CP-195543、ONO-4057、SB 209247、SC-53228和US5451700所述的那些；LTD4拮抗剂，例如包括孟鲁司特、普仑司特、扎鲁司特、安可来、SR2640、Wy-48,252、ICI 198615、MK-571、LY-171883、Ro 24-5913和L-648051；PDE4抑制剂，例如西洛司特(
GlaxoSmithKline)、罗氟司特(Byk Gulden)、V-11294A(Napp)、BAY19-8004(Bayer)、SCH-351591(Schering-Plough)、阿罗茶碱(AlmirauProdesfarma)、PD189659/PD168787(Parke-Davis)、AWD-12-281(AstaMedica)、CDC-801(Celgene)、SelCIDTM CC-10004(Celgene)、VM554/UM565(Vernalis)、T-440(Tahabe)、KW-4490(Kyowa HakkoKogyo)和如下文献中公开的那些：WO 92/19594、WO 93/19749、WO93/19750、WO 93/19751、WO 98/18796、WO 99/16766、WO 01/13953、WO 03/104204、WO 03/104205、WO 03/39544、WO 04/000814、WO04/000839、WO 04/005258、WO 04/018450、WO 04/018451、WO 04/018457、WO 04/018465、WO 04/018431、WO 04/018449、WO 04/018450、WO04/018451、WO 04/018457、WO 04/018465、WO 04/019944、WO 04/019945、WO 04/045607和WO 04/037805；A2A激动剂，例如EP 1052264、EP1241176、EP 409595A2、WO 94/17090、WO 96/02543、WO 96/02553、WO 98/28319、WO 99/24449、WO 99/24450、WO 99/24451、WO 99/38877、WO 99/41267、WO 99/67263、WO 99/67264、WO 99/67265、WO 99/67266、WO 00/23457、WO 00/77018、WO 00/78774、WO 01/23399、WO 01/27130、WO 01/27131、WO 01/60835、WO 01/94368、WO 02/00676、WO 02/22630、WO 02/96462和WO 03/086408所述的那些；和A2B拮抗剂，例如WO02/42298所述的那些。
适宜的支气管扩张药包括抗胆碱能或抗毒蕈碱剂，特别是异丙托溴铵、氧托溴铵、噻托铵盐和CHF 4226(Chiesi)，和格隆铵，以及如下文献所述的那些：EP 424021、US 3714357、US 5171744、WO 01/04118、WO02/00652、WO 02/51841、WO 02/53564、WO 03/00840、WO 03/33495、WO 03/53966、WO 03/87094、WO 04/018422和WO 04/05285。
适宜的双重作用的支气管扩张药包括双重β-2肾上腺素受体激动剂/毒蕈碱拮抗剂，例如公开在如下文献中的那些：US 2004/0167167、WO04/74246和WO 04/74812。
适宜的抗组胺药物包括盐酸西替利嗪、对乙酰氨基酚、富马酸氯马斯汀、异丙嗪、氯雷他定(loratidine)、地氯雷他定、苯海拉明、盐酸非索非那定、activastine、阿司咪唑、氮
斯汀、依巴斯汀、依匹斯汀、咪唑斯汀和特非那定(tefenadine)，以及公开在JP 2004107299、WO 03/099807和WO 04/026841中的那些。
本发明的物质还可用作共用治疗剂与其它β-2肾上腺素受体激动剂联合使用，例如作为援救药物治疗。适宜的β-2肾上腺素受体激动剂包括阿布特罗(沙丁胺醇)、奥西那林、特布他林、沙美特罗、非诺特罗、卡莫特罗(carmoterol)、丙卡特罗，尤其是福莫特罗及其可药用盐，和WO 00/75114的式I化合物(游离或盐或溶剂化物形式)，该文献引入本文作为参考，优选其实施例化合物，尤其是下式化合物及其可药用盐，
以及WO 04/16601的式I化合物(游离或盐或溶剂化物形式)，还有如下文献的化合物：EP 1440966、JP 05025045、WO 93/18007、WO 99/64035、US 2002/0055651、WO 01/42193、WO 01/83462、WO 02/66422、WO 02/70490、WO 02/76933、WO 03/24439、WO 03/42160、WO 03/42164、WO03/72539、WO 03/91204、WO 03/99764、WO 04/16578、WO 04/22547、WO 04/32921、WO 04/33412、WO 04/37768、WO 04/37773、WO 04/37807、WO 04/39762、WO 04/39766、WO 04/45618 WO 04/46083、WO04/80964、EP1460064、WO 04/087142、WO 04/089892、EP 01477167、US 2004/0242622、US 2004/0229904、WO 04/108675、WO 04/108676、WO 05/033121、WO 05/040103和WO 05/044787。
本发明的物质与抗炎药的其它有用组合是与趋化因子受体拮抗剂的组合，例如CCR-1、CCR-2、CCR-3、CCR-4、CCR-5、CCR-6、CCR-7、CCR-8、CCR-9和CCR10、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5拮抗剂，特别是CCR-5拮抗剂，例如Schering-Plough拮抗剂SC-351125、SCH-55700和SCH-D，Takeda拮抗剂，例如N-[[4-[[[6，7-二氢-2-(4-甲基苯基)-5H-苯并-环庚烯-8-基]羰基]氨基]苯基]-甲基]四氢-N，N-二甲基-2H-吡喃-4-铵氯化物(TAK-770)，和如下文献所述的CCR-5拮抗剂：US6166037(特别是权利要求18和19)、WO 00/66558(特别是权利要求8)、WO 00/66559(特别是权利要求9)、WO 04/018425和WO 04/026873。
本发明的物质与类固醇类、PDE4抑制剂、A2A激动剂、A2B激动剂或LTD4拮抗剂的组合可以用于例如治疗COPD或者特别是哮喘。本发明的物质与抗胆碱能或抗毒蕈碱剂、PDE4抑制剂、A2A激动剂、A2B激动剂、多巴胺受体激动剂或LTB4拮抗剂的组合可以用于例如治疗哮喘或者特别是COPD。
按照上述，本发明还提供了治疗阻塞性或炎性气道疾病的方法，该方法包括对有需要的受治疗者、特别是人类受治疗者给予上述式I化合物或其可药用盐或溶剂化物。另一方面，本发明提供了用于制备药物的式I化合物或其可药用盐或溶剂化物，所述药物用于治疗阻塞性或炎性气道疾病。
本发明的物质可通过任意适当的途径给药，例如经口服施用，例如以片剂或胶囊形式；胃肠道外施用，例如静脉内给药；局部施用于皮肤，例如在银屑病的治疗中；鼻内施用，例如在枯草热的治疗中；或者优选通过吸入施用，特别是在阻塞性或炎性气道疾病的治疗中。
在进一步的方面，本发明还提供了药物组合物，包含游离形式或其可药用盐或溶剂化物形式的式I化合物以及任选的可药用稀释剂或载体。这类组合物可以利用常规稀释剂或赋形剂和盖仑领域已知的技术加以制备。因而，口服剂型可以包括片剂和胶囊。局部给药制剂可以采取霜剂、软膏、凝胶或透皮递送系统，例如贴剂。吸入组合物可以包含气雾剂或其它可雾化的制剂或干粉制剂。
当组合物构成气雾剂时，它优选含有例如氢氟烷烃(HFA)抛射剂，例如HFA134a或HFA227或者它们的混合物，并且可以含有一种或多种本领域已知的助溶剂(例如乙醇，至多20重量％)和/或一种或多种表面活性剂(例如油酸或脱水山梨醇三油酸酯)和/或一种或多种填充剂(例如乳糖)。当组合物构成干粉制剂时，它优选含有例如粒径至多10微米的式I化合物以及任选的具有所需粒径分布的稀释剂或载体(例如乳糖)和帮助保护产品性能不因水分而被破坏的化合物，例如硬脂酸镁，例如0.01至1.5％。当组合物构成雾化制剂时，它优选含有例如溶解或悬浮在载体中的式I化合物，所述载体含有水、助溶剂(例如乙醇或丙二醇)和稳定剂(它可以是表面活性剂)。
本发明包括(A)可吸入形式的游离或者可药用盐或溶剂化物形式的如上所述的式I化合物；(B)可吸入的药剂，包含可吸入形式的该式I化合物以及可吸入形式的可药用载体；(C)药物产品，包含可吸入形式的该式I化合物以及吸入装置；和(D)吸入装置，含有可吸入形式的该式I化合物。
用于实施本发明的式I化合物的剂量当然将因例如所治疗的具体病症、所需效果和给药方式而异。一般而言，适宜于吸入给药的日剂量为1至5000μg的级别。
下列实施例阐述本发明。
实施例
尤其优选的式I化合物还是式XI化合物
其中T如下表所示，下文描述了其制备方法。所有化合物为盐或者游离形式。1H NMR光谱在400MHz下、在CDCl3中记录，另有注解除外。质谱在电雾化电离条件下获得，其LC梯度洗脱为5％至95％乙腈-水，在0.1％甲酸的存在下。
中间体的制备
所用缩写如下：DCM是二氯甲烷，DMF是二甲基甲酰胺，DMSO是二甲基亚砜，THF是四氢呋喃。
1-溴-3-叔丁氧基-5-氟苯
将叔丁醇(28.2g)溶于二甲基乙酰胺(200ml)。历经15分钟加入NaH(15.6g，60％油分散液)。将反应混合物在室温下搅拌2小时。历经30分钟滴加3，5-二氟溴苯(50g)。将反应混合物在室温下搅拌，直至HPLC显示反应完全。加入水(10ml)淬灭反应混合物，用水洗涤(1x)，经MgSO4干燥，过滤，真空除去溶剂，得到标题化合物。1H nmr(CDCl3，400MHz)；7.00(ddd，1H)，6.95(dd，1H)，6.68(ddd，1H)，1.4(s，9H).
3-叔丁氧基-5-氟-苯基胺
将1-溴-3-叔丁氧基-5-氟苯(56.1g)、二苯酮(50.9g)、NaOMe(50.5g)和2，2′-双-二苯基膦基-[1，1′]联萘(17.5g)溶于甲苯(500ml)。将反应混合物用氩冲洗，加入Pd2(dba)3(5.4g)，将反应混合物加热至80℃达40小时。用水淬灭反应混合物。分离有机层，经MgSO4干燥，过滤，真空除去溶剂。经过快速柱色谱法处理(二氧化硅，洗脱剂为二氯甲烷)得到中间体。然后将所得产物溶于MeOH(1L)。加入NaOAc(46.1g)、盐酸羟胺(29.1g)，将反应混合物在室温下搅拌2.5小时。将反应混合物用0.1M NaOH淬灭，用DCM萃取(2x)，经MgSO4干燥，过滤，真空除去溶剂，得到标题化合物。1H nmr(CDCl3，400MHz)；6.20(m，3H)，3.75(br s，2H)，1.4(s，9H).
1-叔丁氧基-3-氟-5-异氰硫基苯
在0℃下，将硫光气(33.6g)的CHCl3(250ml)溶液和K2CO3(64.7g)的H2O(450ml)溶液单独和同时滴加到3-叔丁氧基-5-氟-苯基-胺(42.9g)的CHCl3(350ml)溶液中。使反应混合物升温至室温过夜。分离有机层，用水(3x)、盐水(1x)洗涤，经MgSO4干燥，过滤，真空除去溶剂。经过快速柱色谱法处理(二氧化硅，洗脱剂为二氯甲烷/异己烷1∶3)得到标题化合物。1Hnmr(CDCl3，400MHz)；6.70(m，3H)，1.40(s，9H).
(3-叔丁氧基-5-氟-苯基)-硫代氨基甲酸O-异丙基酯
将1-叔丁氧基-3-氟-5-异氰硫基-苯(24.0g)和三乙胺(10.9g)溶于异丙醇(150ml)。使反应混合物回流18小时，真空除去溶剂。将粗产物溶于己烷∶二乙醚(19∶1)。真空除去二乙醚，将溶液冷却至0℃达3小时。过滤溶液，得到标题化合物。1H nmr(CDCl3，400MHz)；8.10(br s，1H)，6.65(br s，2H)，6.45(ddd，1H)5.60(七重峰，1H)，1.35(d，6H)，1.30(s，9H).
5-叔丁氧基-2-异丙氧基-苯并噻唑-7-甲醛
将(3-叔丁氧基-5-氟-苯基)-硫代氨基甲酸O-异丙基酯(2.2g)溶于无水四氢呋喃(20ml)。将反应混合物冷却至-78℃，历经20分钟加入叔丁基锂(15.2ml，1.5M溶液)。然后使反应混合物升温至-10℃达75分钟。然后将反应混合物重新冷却至-78℃，加入N，N-二甲基甲酰胺(1.5g)，使反应混合物缓慢升温至室温，然后在-10℃下搅拌1小时。用HCl(aq)(5ml，2M溶液)淬灭反应混合物，在乙酸乙酯/水之间分离有机层，真空除去。经过快速柱色谱法处理(二氧化硅，洗脱剂为乙酸乙酯/异己烷1∶9)得到标题化合物。MS(ES+)m/e 294(MH+)LCT50865
5-叔丁氧基-2-异丙氧基-7-乙烯基苯并噻唑
在氩下，将Ph3PMe.Br(5.0g)溶于无水四氢呋喃(100ml)。在室温下历经10分钟加入正丁基锂(8.8ml，1.6M溶液)，将反应混合物搅拌另外30分钟。向反应混合物滴加5-叔丁氧基-2-异丙氧基-苯并噻唑-7-甲醛(1.25g)的二氯甲烷(40ml)溶液，将反应混合物在室温下搅拌4.5小时。真空除去溶剂，重新溶于乙酸乙酯，用水(3x)、盐水(1x)洗涤，经MgSO4干燥，过滤，真空除去溶剂。经过快速柱色谱法处理(二氧化硅，洗脱剂为乙酸乙酯/异己烷1∶9)得到标题化合物。MS(ES+)m/e 292(MH+)LCT55980
(R)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-乙烷-1，2-二醇
在氩下，将K3Fe(CN)6(1.2g)、K2CO3(0.5g)、(DHQD)2PHAL(19mg)溶于叔丁醇/水(15ml，1∶1混合物)，搅拌15分钟。将反应混合物冷却至0℃，加入OsO4(3.1mg)，然后加入5-叔丁氧基-2-异丙氧基-7-乙烯基-苯并噻唑(0.35g)。将反应混合物在室温下搅拌过夜。将反应混合物用焦亚硫酸钠(1g)淬灭，搅拌1.5小时。加入乙酸乙酯，分离有机层，用水(2x)、盐水(1x)洗涤，经MgSO4干燥，过滤，真空除去溶剂。经过快速柱色谱法处理(二氧化硅，洗脱剂为乙酸乙酯/异己烷2∶5)得到标题化合物。MS(ES+)m/e 326(MH+)LCT56091
甲磺酸(R)-2-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-2-羟基-乙基酯
在0℃下，将甲磺酰氯(35mg)加入到(R)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-乙烷-1，2-二醇(100mg)的吡啶(2ml)溶液中。然后将反应混合物在0℃下搅拌3.5小时。真空除去溶剂。使所得残余物在HCl(aq)(2M)与乙醚之间分配。将有机层用水(1x)、盐水(1x)洗涤，经MgSO4干燥，过滤，真空除去溶剂，得到标题化合物。1H nmr(CDCl3，400MHz)；7.20(d，1H)，6.80(d，1H)，5.30(七重峰，1H)，5.10(t，1H)，4.30(d，2H)，3.00(s，3H)，1.40(d，6H)，1.30(s，9H).
(S)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-乙烷-1，2-二醇
在氩下，将K3Fe(CN)6(3.4g)、K2CO3(1.4g)、(DHQ)2PHAL(53mg)在叔丁醇/水(40ml，1∶1混合物)中搅拌20分钟。将反应混合物冷却至0℃，加入OsO4(8.6mg)，然后加入5-叔丁氧基-2-异丙氧基-7-乙烯基-苯并噻唑(1.0g)。将反应混合物在室温下搅拌过夜。将反应混合物用焦亚硫酸钠(1.2g)淬灭，搅拌1.5小时。加入乙酸乙酯，分离有机层，用水(2x)、盐水(1x)洗涤，经MgSO4干燥，过滤，真空除去溶剂。经过快速柱色谱法处理(二氧化硅，洗脱剂为乙酸乙酯/异己烷1∶3)得到标题化合物。MS(ES+)m/e 326.12LCT60289
甲磺酸(S)-2-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-2-羟基-乙基酯
在0℃下，将甲磺酰氯(112mg)加入到(S)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-乙烷-1，2-二醇(289mg)的吡啶(2ml)溶液中。然后将反应混合物在0℃下搅拌3小时。真空除去溶剂。使所得残余物在HCl(aq)(2M)与乙醚之间分配。将有机层用水(2x)、盐水(1x)洗涤，经MgSO4干燥，过滤，真空除去溶剂，得到标题化合物。1H nmr(CDCl3，400MHz)；7.20(d，1H)，6.80(d，1H)，5.30(七重峰，1H)，5.10(t，1H)，4.30(d，2H)，3.00(s，3H)，1.40(d，6H)，1.30(s，9H).
2-(4-丁氧基-苯基)-1，1-二甲基-乙基胺
按照国际专利申请WO 01/83462所述工艺制备该化合物。MS(ES+)m/e 222.20(MH+)20％LCT59933
[4-(2-氨基-2-甲基-丙基)-苯基]-二甲基-胺
按照国际专利申请WO 01/83462所述工艺制备该化合物。MS(ES+)m/e 193(MH+)2％LCT59932
(S)-5-异丁基-二氢茚-2-基胺
(a)(S)-5-溴-二氢茚-2-基胺：
按照国际专利申请WO 96/23760所述工艺制备该化合物。
(b)(S)-(5-异丁基-二氢茚-2-基)-氨基甲酸苄基酯：
将混悬在二氯甲烷(10ml)中的(S)-5-溴-二氢茚-2-基胺(1.0g)冷却至0℃，滴加氯甲酸苄基酯(0.74ml)，将反应混合物搅拌0.5小时。过滤溶液，得到(S)-(5-溴-二氢茚-2-基)-氨基甲酸苄基酯。将PdCl2(dppf)2(59mg)置于氩下的干燥烧瓶中，加入异丁基溴化锌(50ml，0.5M THF溶液)。将(5-溴-二氢茚-2-基)-氨基甲酸苄基酯(2.50g)溶于无水THF(2ml)，向反应混合物加入该溶液。将反应混合物在50℃下搅拌18小时，然后用HCl(aq)(2M)淬灭，在乙酸乙酯与水之间分配。将有机层经MgSO4干燥，过滤，真空除去溶剂。经过快速柱色谱法处理(二氧化硅，洗脱剂为乙酸乙酯/异己烷1∶4)得到标题化合物。1H nmr(CDCl3，400MHz)；7.35(m，5H)，7.10(d，1H)，7.00(s，1H)，6.90(d，1H)，5.1(s，2H)，4.55(m，1H)，3.30(m，2H)，2.75(dt，2H)，2.45(d，2H)，1.80(m，1H)，0.90(d，6H).
(c)(S)-5-异丁基-二氢茚-2-基胺：
将(S)-(5-异丁基-二氢茚-2-基)-氨基甲酸苄基酯()溶于甲醇(100ml)，加入10％Pd-C(200mg)，用H2(g)(0.35bar)净化烧瓶。将反应混合物搅拌18小时，滤出催化剂。真空除去溶剂，得到标题化合物。1H nmr(CDCl3，400MHz)；7.10(d，1H)，7.00(s，1H)，6.90(d，1H)，3.85(m，1H)，3.15(dd，2H)，2.65(dt，2H)，2.45(d，2H)，1.80(br m，3H)，0.90(d，6H).
5，6-二乙基-二氢茚-2-基胺
按照国际专利申请WO 03/76387所述工艺制备该化合物。
(R，R)-二环戊基-2-基胺
按照S.Hartmann等人，Eur.J.Med.Chem.(2000)，35，377-392的工艺从二环戊基-2-酮制备该化合物。MS(ES+)m/e 154.23(MH+)LCT59419
实施例1
(R)-7-[2-(1，1-二甲基-2-苯基-乙基氨基)-1-羟基-乙基]-5-羟基-3H-苯并噻唑
-2-酮
a)(R)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-2-(1，1-二甲基-2-苯基-乙 基氨基)-乙醇
将甲磺酸(R)-2-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-2-羟基-乙基酯(122mg)和芬特明(165mg)溶于甲苯(2ml)。将反应混合物加热至90℃达20小时。真空除去溶剂，通过采用Jones Flashmaster PersonalTM快速色谱系统(ISOLUTE FLASH C18，梯度洗脱AcCN/水0至60％)的反相柱色谱法得到(R)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-2-(1，1-二甲基-2-苯基-乙基氨基)-乙醇。MS(ES+)m/e 457.32(MH+)LCT56716
b)(R)-7-[2-(1，1-二甲基-2-苯基-乙基氨基)-1-羟基-乙基]-5-羟基-3H-苯并 噻唑-2-酮
将(R)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-2-(1，1-二甲基-2-苯基-乙基氨基)-乙醇(40mg)在甲酸(2ml)中搅拌72小时。真空除去甲酸，通过采用Jones Flashmaster PersonalTM快速色谱系统(ISOLUTE FLASH C18，梯度洗脱AcCN/水0至50％)的反相柱色谱法得到标题化合物。MS(ES+)m/e 359.26(MH+)LCT57144
实施例2至17
利用类似于实施例1所用的工艺制备实施例2至17的化合物。
实施例18
(S)-7-{2-[2-(4-二甲基氨基-苯基)-1，1-二甲基-乙基氨基]-1-羟基-乙基}-5-羟
基-3H-苯并噻唑-2-酮
a)(S)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-2-[2-(4-二甲基氨基-苯 基)-1，1-二甲基-乙基氨基]-乙醇
将[4-(2-氨基-2-甲基-丙基)-苯基]-二甲基-胺(210mg)和甲磺酸(S)-2-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-2-羟基-乙基酯(120mg)溶于甲苯(2ml)。将反应混合物加热至80℃达20小时。真空除去溶剂，得到(S)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-2-[2-(4-二甲基氨基-苯基)-1，1-二甲基-乙基氨基]-乙醇。MS(ES+)m/e.500
b)(S)-7-{2-[2-(4-二甲基氨基-苯基)-1，1-二甲基-乙基氨基]-1-羟基-乙 基}-5-羟基-3H-苯并噻唑-2-酮
将(S)-1-(5-叔丁氧基-2-异丙氧基-苯并噻唑-7-基)-2-(1，1-二甲基-2-苯基-乙基氨基)-乙醇(40mg)在甲酸(2ml)中搅拌72小时。真空除去甲酸，通过采用Jones Flashmaster PersonalTM快速色谱系统(ISOLUTE FLASH C18，梯度洗脱AcCN/水0至50％)的反相柱色谱法得到标题化合物。MS(ES+)m/e.402.15
Claims (9)
1.游离或盐形式的式I化合物，
其中
T是氢，或者C1-C10-烷基，任选在一个、两个或三个位置被C1-C10-烷氧基、-NR1R2、含有至少一个选自氮、氧和硫的环杂原子的5-或6-元杂环或者被C3-C15-碳环基团取代，所述C3-C15-碳环基团任选在一个、两个或三个位置被如下取代基取代：卤代基、C1-C10-烷基、C3-C10-环烷基、卤代-C1-C10-烷基、-NR3R4、含有至少一个选自氮、氧和硫的环杂原子的5-或6-元杂环或者任选在一个、两个或三个位置被C6-C10-芳基取代的C1-C10-烷氧基；或者
T是C3-C15-碳环基团，任选在一个、两个或三个位置被如下取代基取代：卤代基、C1-C10-烷基、C3-C10-环烷基、卤代-C1-C10-烷基、-NR5R6、含有至少一个选自氮、氧和硫的环杂原子的5-或6-元杂环或者任选在一个、两个或三个位置被C1-C4-烷基或C6-C10-芳基取代的C1-C10-烷氧基；
R1、R2、R3、R4、R5和R6独立地是氢、C1-C10-烷基、C1-C10-烷氧基、C3-C10-环烷基或C6-C10-芳基。
2.根据权利要求1的化合物，其中
T是C1-C10-烷基，任选在一个、两个或三个位置被-NR1R2或C5-C15-碳环基团取代，所述C5-C15-碳环基团任选在一个、两个或三个位置被卤代基、-NR3R4或C1-C10-烷氧基取代；或者
T是C5-C15-碳环基团，任选在一个、两个或三个位置被C1-C10-烷基、C3-C10-环烷基、-NR5R6或者被任选在一个、两个或三个位置被C6-C10-芳基取代的C1-C10-烷氧基所取代；
R1、R2、R3、R4、R5和R6独立地是C1-C10-烷基或C6-C10-芳基。
3.根据权利要求1的化合物，其中
T是C1-C8-烷基，任选在一个位置被-NR1R2或C5-C10-碳环基团取代，所述C5-C10-碳环基团任选在一个或两个位置被卤代基、-NR3R4或C1-C4-烷氧基取代；或者
T是C5-C10-碳环基团，任选在一个或两个位置被C1-C8-烷基、C3-C10-环烷基、-NR5R6或者被任选在一个位置被C6-C8-芳基取代的C1-C4-烷氧基取代；
R1、R2、R3、R4、R5和R6独立地是C1-C4-烷基或C6-C8-芳基。
4.根据权利要求3的化合物，其中T和R1、R2、R3、R4、R5和R6定义中的C6-C8-芳基独立地是苯基。
5.根据前述权利要求任一项的化合物，它还是式Ⅺ化合物
其中T如下表所示，
6.药物组合物，包含根据前述权利要求任一项的化合物以及可药用载体。
7.根据权利要求1至5任一项的化合物在制备用于治疗通过β2-肾上腺素受体活化被防止或减轻的病症的药物中的用途。
8.根据权利要求7的化合物的用途，其中所述病症是阻塞性或炎性气道，病。
9.制备如权利要求1所要求的游离或盐形式的式I化合物的方法，该方法包括：
(i)(A)使式II化合物
其中Ra和Rb是保护基，且Rc是C1-C4-烷基或C6-C10-芳基，
与其中T如权利要求1定义的式III化合物反应；
H2N-T III，或者
(B)使其中Ra和Rb是保护基的式IIA化合物与其中T如权利要求1定义式III化合物反应；
(ii)除去保护基；和
(iii)以游离或盐形式回收所得的式I化合物。
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Also Published As
| Publication number | Publication date |
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| JP4648950B2 (ja) | 2011-03-09 |
| WO2006056471A1 (en) | 2006-06-01 |
| CA2586443C (en) | 2014-09-02 |
| CA2586443A1 (en) | 2006-06-01 |
| AU2005308909A1 (en) | 2006-06-01 |
| PT1819686E (pt) | 2011-10-11 |
| MX2007006374A (es) | 2007-06-20 |
| KR20070067733A (ko) | 2007-06-28 |
| DK1819686T3 (da) | 2011-12-05 |
| US20080096940A1 (en) | 2008-04-24 |
| AU2005308909B2 (en) | 2009-08-27 |
| EP1819686B1 (en) | 2011-08-17 |
| CN101065370A (zh) | 2007-10-31 |
| US20120041041A1 (en) | 2012-02-16 |
| GB0426164D0 (en) | 2004-12-29 |
| PL1819686T3 (pl) | 2012-01-31 |
| EP2305659A1 (en) | 2011-04-06 |
| ATE520676T1 (de) | 2011-09-15 |
| RU2007124329A (ru) | 2009-01-10 |
| EP1819686A1 (en) | 2007-08-22 |
| JP2008520618A (ja) | 2008-06-19 |
| RU2402540C2 (ru) | 2010-10-27 |
| CY1112237T1 (el) | 2015-12-09 |
| US8076489B2 (en) | 2011-12-13 |
| KR100891415B1 (ko) | 2009-04-02 |
| SI1819686T1 (sl) | 2011-12-30 |
| ES2370833T3 (es) | 2011-12-23 |
| BRPI0517894A (pt) | 2008-10-21 |
| AU2005308909C1 (en) | 2014-11-27 |
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