CN1863810B - [2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)烷基]膦酸衍生物及其作为n-甲基-d-天冬氨酸(nmda)受体拮抗剂的应用 - Google Patents
[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)烷基]膦酸衍生物及其作为n-甲基-d-天冬氨酸(nmda)受体拮抗剂的应用 Download PDFInfo
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- CN1863810B CN1863810B CN200480009542XA CN200480009542A CN1863810B CN 1863810 B CN1863810 B CN 1863810B CN 200480009542X A CN200480009542X A CN 200480009542XA CN 200480009542 A CN200480009542 A CN 200480009542A CN 1863810 B CN1863810 B CN 1863810B
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- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
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Abstract
本发明提供了式(I)化合物或其可药用盐,其中R2或R3当中至少有一个不是氢。本发明化合物是N-甲基-D-天冬氨酸(NMDA)受体拮抗剂,并可用于治疗存在于哺乳动物中的能够从抑制NMDA受体中获益的各种疾病。
Description
发明背景
本发明涉及[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)烷基]膦酸衍生物及其应用方法。本发明化合物尤其用作N-甲基-D-天冬氨酸(NMDA)受体拮抗剂。
谷氨酸和天冬氨酸作为必须氨基酸并且作为主要兴奋性神经递质在中枢神经系统中起着双重作用。有至少四种类别的兴奋性氨基酸受体:NMDA、AMPA(2-氨基-3-(甲基-3-羟基异噁唑-4-基)丙酸)、红藻氨酸和促代谢受体。这些兴奋性氨基酸受体调整影响生理学脑功能的各种各样的信号事件。例如,NMDA受体的激活已被证明是在很多疾病中导致兴奋毒性和中枢神经死亡的,以及头部创伤、卒中后和心搏停止后造成缺氧和缺血的中枢事件。人们还知道,NMDA受体在构成很多高等认知功能例如记忆和学习的突触可塑性中,在某些创伤感受神经途径中,以及在疼痛感知中,起着主要作用。另外,NMDA受体的某些特性表明,它们可以参与脑中构成意识本身的信息处理。
NMDA受体遍及整个中枢神经系统。NMDA受体是配基闸门离子通道,其在被谷氨酸与甘氨酸共同激活时,调整钠、钾和钙离子的流动。在结构上,NMDA受体被认为是由含有被称为NR1和NR2的两个主要亚单元的异多亚基通道构成。这些亚单元含有甘氨酸组合位点、谷氨酸组合位点和多胺组合位点。对于NR1亚单元,多剪接变异体已经被确认,而对于NR2亚单元,四个单独的亚单元类型(NR2A、NR2B、NR2C、和NR2D)已经被确认。NMDA受体还含有位于NMDA受体/通道复合体的离子载体的孔内的、阻塞离子的流动Mg++组合位点。
很多临床前和临床证据表明,N-甲基-D-天冬氨酸(NMDA)受体抑制剂具有治疗许多病症的治疗潜力。据信,对NMDA受体的抑制敏感的病症包括脑血管病症例如脑缺血(例如卒中)或导致一系列疾病例如血栓栓塞性或出血性卒中、或脑血管痉挛的脑梗死;脑损伤;肌肉痉挛;和痉挛性疾病例如癫痫或癫痫持续状态。NMDA受体拮抗剂还可以被用于耐受对阿片制剂痛觉缺失的障碍或帮助控制成由瘾性药物退隐的症状。
近年来,化合物的筛选已经发现若干NMDA受体拮抗剂,所述NMDA受体拮抗剂已被用于动物和临床的人类研究,以证明用于治疗各种病症的概念是正确的。证明NMDA受体拮抗剂的临床效用的困难通常是,拮抗剂缺乏NMDA受体亚型选择性和/或在口服用药时缺乏生物学活性。因此,对亚型选择性和/或口服有效的NMDA受体拮抗剂研究在继续进行。
发明概述
在一个实施方案中,本发明提供了式(I)化合物或其可药用盐:
其中:
R1是氢、C1-C6烷基、C2-C7酰基、C1-C6链烷磺酰基或C6-C14芳酰基;
A是1-4个碳原子的亚烷基或2-4个碳原子的亚链烯基;
R2和R3独立地选自氢或
条件是R2和R3当中至少有一个不是氢;
R4和R5独立地选自氢、C1-C4烷基、C5-C7芳基、在芳环中具有5-7个碳原子的C6-C15烷基芳基、C2-C7链烯基或C2-C7炔基,或者R4和R5可以一起形成螺C3-C8碳环;
R6是C1-C12直链或支链烷基、C2-C7直链或支链链烯基或炔基、C5-C13芳基、在芳基部分具有5-13个碳原子的C6-C21烷基芳基;5-13元杂芳基、在杂芳基部分具有5-13个环单元的6-21元烷基杂芳基、C4-C8环烷基、在环烷基环中具有4-8个碳原子的C5-C16烷基环烷基;
R7和R8独立地选自氢、C1-C12直链或支链链烷基、C2-C7直链或支链链烯基或炔基、C5-C13芳基、在芳基部分具有5-13个碳原子的C6-C21烷基芳基、5-13元杂芳基、在杂芳基部分具有5-13个环单元的6-21元烷基杂芳基,或者R7和R8可以一起形成在环中具有4-8个碳原子和任选1-2个选自氮、氧或硫的原子的环烷基或杂环烷基;
其中具有芳基、杂芳基、环烷基或杂环烷基部分的任何R1-R8基团可以任选在芳基、杂芳基、环烷基或杂环烷基部分上被1-约5个独立地选自下列的取代基取代:卤素原子、氰基、硝基或羟基、C1-C6烷基或C1-C6烷氧基。
在另一个实施方案中,本发明提供了在哺乳动物中治疗一种或多种病症的方法,所述方法包括向需要治疗的哺乳动物给药治疗有效量的式(I)的化合物或其可药用盐。可按照本发明方法治疗的疾病的实例包括脑血管病症例如脑缺血或脑梗死;脑损伤;肌肉痉挛;痉挛性病症例如癫痫或癫痫持续状态;青光眼;疼痛;焦虑性障碍;心境障碍;精神分裂症;精神分裂症样障碍;分裂情感性障碍;认知损伤;慢性神经变性病症例如帕金森病、亨廷顿病、阿尔茨海默病、肌萎缩侧索硬化、或慢性痴呆;炎性病症;低血糖;糖尿病终器并发症;心搏停止;窒息缺氧症;脊髓损伤;纤维肌痛,源于带状疱疹(带状疱疹)的并发症例如预防疱疹后神经痛;预防对阿片制剂痛觉缺失的耐受;或成瘾性药物退隐的症状或它们的组合。
在本发明的另一个实施方案中,提供了包含至少一种式(I)的化合物和至少一种可药用载体的药物组合物。
在本发明的还另一个实施方案中,提供通过这样的方法制备的产物,所述方法包括将式(II)化合物
与至少一种选自下列的酯反应
并形成式(I)产物或其可药用盐,其中Y是离去基团。
发明详述
本发明提供式(I)化合物或其可药用盐:
其中:
R1是氢、C1-C6烷基、C2-C7酰基、C1-C6链烷磺酰基或C6-C14芳酰基;
A是1-4个碳原子的亚烷基或2-4个碳原子的亚链烯基;
R2和R3独立地选自氢或
条件是R2和R3当中至少有一个不是氢;
R4和R5独立地选自氢、C1-C4烷基、C5-C7芳基、在芳环中具有5-7个碳原子的C6-C15烷基芳基、C2-C7链烯基或C2-C7炔基,或者R4和R5可以一起形成螺C3-C8碳环;
R6是C1-C12直链或支链烷基、C2-C7直链或支链链烯基或炔基、C5-C13芳基、在芳基部分具有5-13个碳原子的C6-C21烷基芳基;5-13元杂芳基、在杂芳基部分具有5-13个环单元的6-21元烷基杂芳基、C4-C8环烷基、在环烷基环中具有4-8个碳原子的C5-C16烷基环烷基;
R7和R8独立地选自氢、C1-C12直链或支链链烷基、C2-C7直链或支链链烯基或炔基、C5-C13芳基、在芳基部分具有5-13个碳原子的C6-C21烷基芳基、5-13元杂芳基、在杂芳基部分具有5-13个环单元的6-21元烷基杂芳基,或者R7和R8可以一起形成在环中具有4-8个碳原子和任选1-2个选自氮、氧或硫的原子的环烷基或杂环烷基。
除非另有指明:
如本文所用,烷基或亚烷基是指具有1-12个碳原子的脂族烃链,并且包括但不限于直链或支链,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基和异己基。低级烷基是指具有1-3个碳原子的烷基。在本发明的某些实施方案中,烷基优选为C1-C8,更优选C1-C6。
链烯基或亚链烯基是指具有2-7个碳原子并且可含有1-3个双键的脂族直链或支链烃链。作为A的亚链烯基的实例是直链或支链的一、二或不饱和基团例如乙烯基、丙-1-烯基、烯丙基、甲代烯丙基、丁-1-烯基、丁-2-烯基或丁-3-烯基。
炔基是指具有2-7个碳原子并且可含有1-3个三键的脂族直链或支链烃链。
如本文所用,酰基是指基团R-C(=O)-,其中R是1-6个碳原子的烷基。例如,C2-C7酰基是指其中R是1-6个碳原子的烷基的基团R-C(=O)-。
如本文所用,链烷磺酰基是指基团R-S(O)2-,其中R是1-6个碳原子的烷基。
如本文所用,芳基是指芳族的5-13元单或双碳环例如苯基或萘基。优选地,含有芳基部分的基团是在环中具有5-7个碳原子的单环。杂芳基是指具有1-5个杂原子的芳族5-13元含碳单或双环,所述杂原子可独立地为氮、氧或硫。优选地,含有杂芳基部分的基团是在环中具有5-7个环单元的单环,其中1-2个环单元独立地选自氮、氧或硫。含有芳基或杂芳基部分的基团可以任选如下面所定义被取代,或未取代。
如本文所用,芳酰基是指基团Ar-C(=O)-,其中Ar是如上面所定义的芳基。例如,C6-C14芳酰基部分是基团Ar-C(=O)-,其中Ar是芳族5-13元碳环。
如本文所用,烷基芳基是指基团-R-Ar,其中Ar是如上面所定义的芳基,且R是具有1-8个、优选1-6个、更优选1-4个碳原子的烷基部分。烷基芳基的实例包括苄基、苯乙基、3-苯基丙基和4-苯基丙基。如本文所用,烷基杂芳基是指基团-R-hetAr,其中hetAr是如上面所定义的杂芳基,且R是具有1-8个、优选1-6个、更优选1-4个碳原子的烷基部分。
如本文所用,环烷基是指具有3-8个碳原子的单碳环,例如环丙基、环丁基、环戊基和环己基。杂环烷基是指含有碳的单环,所述单环具有3-8环单元,其中1-2个环单元独立地选自氮、氧或硫。含有环烷基或杂环烷基部分的基团可以任选如下面所定义被取代,或未取代。
如本文所用,烷基环烷基是指基团-R-cycloalk,其中cycloalk是如上面所定义的环烷基,且R是具有1-8个、优选1-6个、更优选1-4个碳原子的烷基部分。
卤素是指氟、氯、溴或碘。
如本文所用,取代的,是指部分,例如芳基、杂芳基、环烷基或杂环烷基部分具有1-约5个取代基,更优选1-约3个取代基,所述取代基独立地选自卤素原子、氰基、硝基或羟基、C1-C6烷基、或C1-C6烷氧基。优选的取代基是卤素原子、羟基或C1-C6烷基。
在上面式(I)中,在本发明的一个实施方案中,R1优选是H或C-C4烷基,更优选是H。在本发明的另一个实施方案中,A优选是亚烷基-(CH2)n-,其中n是1-3,更优选1-2,最优选2。
在另一个实施方案中,R2和R3优选独立地选自H或:
条件是R2和R3当中至少有一个不是H。当R2和R3都不是氢时,优选它们是相同的。R4和R5优选选自H或C1-C4烷基,更优选H或甲基。R6优选选自C3-C10直链或支链烷基、C5-C7芳基、5-7元杂芳基或在环中具有5-7个碳原子的环烷基。在优选的实施方案中,R6是C5-C7芳基。
在另一个优选的本发明实施方案中,式(I)的R2和R3是H或部分(B)或(D),
更优选H或部分(B),最优选两者都是部分(B),其中R4、R5和R6如上面所定义。
在本发明的另一个优选的实施方案中,R1是H或C1-C4烷基;A是具有式-(CH2)n-的亚烷基,其中n是1-3;R2和R3独立地选自H或:
条件是R2和R3当中至少有一个不是H;R4和R5独立地选自H或C1-C4烷基;且R6选自C3-C10直链或支链烷基、C5-C7芳基、5-7元杂芳基或在环中具有5-7个碳原子的环烷基。
在另一个优选的实施方案中,R6选自苯基、正庚-4-基、环己基、异丙基和叔丁基。在还另一个实施方案中,R7和R8都是甲基。
本发明化合物的具体实例包括下列化合物:
苯甲酸3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-7-苯基-2,4,6-三氧杂-3-磷杂庚-1-基酯;
2-丙基戊酸3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-8-丙基-2,4,6-三氧杂-3-磷杂十一烷-1-基酯;
2,2-二甲基-丙酸(2,2-二甲基-丙酰基氧基甲氧基)-[2-(8,9-二氧代-2,6-二氮杂-二环[5.2.0]壬-1(7)-烯-2-基)-乙基]-膦酰基氧基甲基酯;
环己烷甲酸7-环己基-3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-1,5-二甲基-3-氧化-7-氧代-2,4,6-三氧杂-3-磷杂庚-1-基酯;
环己烷甲酸7-环己基-3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-2,4,6-三氧杂-3-磷杂庚-1-基酯;
[2-(8,9-二氧代-2,6-二氮杂-二环[5.2.0]壬-1-(7)-烯-2-基)-乙基]-膦酸二异丙氧基羰基氧基甲基酯;
[2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基]-膦酸双[1-(苯甲酰基氧基)乙基]酯;
苯甲酸[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)-乙基]-羟基-膦酰基氧基甲基酯;或
[2-(8,9-二氧代-2,6-二氮杂-二环[5.2.0]壬-1(7)-烯-2-基)-乙基]-膦酸二-二甲基氨基甲酰基氧基甲基酯;
或其可药用盐。
本发明化合物可以含有不对称碳原子和/或磷原子,因此可以产生旋光异构体和非对映体。尽管式(I)中没有显示立体化学,但本发明包括这样的旋光异构体和非对映体;以及外消旋和拆分的、对映体纯的R和S立体异构体;以及其它R和S立体异构体的混合物和它们的可药用盐。
当对映体是优选的时,在某些实施方案中,可以提供基本上没有相应对映体的对映体。因此,基本上没有相应对映体的对映体是指经由分离技术离分或分离的化合物,或制备的没有相应对映体的化合物。如本文所用,“基本上没有”意指化合物绝大部分是由一种对映体构成的。在优选的实施方案中,化合物是由至少约90%重量的优选对映体构成。在本发明的其它实施方案中,化合物是由至少约99%重量的优选对映体构成。通过任何为本领域的技术人员已知的方法,包括高效液相色谱法(HPLC)和手性盐的形成和结晶,可以将优选的对映体从外消旋混合物中分离出来,或者通过本文描述的方法制备优选的对映体。参见,例如,Jacques等人,Enantiomers.Racemates andResolutions(Wiley Interscience,New York,1981);Wilen,S.H.等人,Tetrahedron 33:2725(1977);Eliel,E.L. Stereochemistry ofCarbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables ofResolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)。
本领域技术人员还将认识到,式(I)的互变异构体的存在是可能的。尽管没有显示于式(I),本发明包括所有这样的互变异构体。
用于本发明的化合物也包括式(I)化合物的可药用盐。所谓“可药用盐”,意指通过加入可药用碱和式(I)化合物以形成相应的盐而形成的任何化合物。所谓“可药用”,意指从毒理学角度看可以适用于药物学应用并且不与活性组分产生有害相互作用的物质。优选地,可药用盐是式(I)化合物的碱金属(钠、钾、锂)或碱土金属(钙、镁)盐,或者式(I)化合物与衍生自氨或碱性胺的阳离子的盐。后者的实例包括但不限于铵,一、二、或三甲基铵,一、二、或三乙基铵,一、二、或三丙基铵(异或正),乙基二甲基铵,苄基二甲基铵,环己基铵,苄基铵,二苄基-铵,哌啶鎓,吗啉鎓,吡咯烷鎓,哌嗪鎓,1-甲基哌啶鎓,1-异丙基吡咯烷鎓,1,4-二甲基哌嗪鎓,1-正丁基哌啶鎓,2-甲基哌啶鎓,1-乙基-2-甲基哌啶鎓,单、二或三乙醇铵,三-(羟基甲基)甲基铵,或苯基单乙醇铵。优选地,当R2或R3当中有一个是氢时,可以形成盐。
本发明化合物可以这样制得:合成式(II)化合物,其中A和R1如式(I)所定义
所述合成按照描述于U.S.专利5,168,103、5,240,946、5,990,307和6,011,168中的方法来进行,此中将其内容全部引用作为参考。优选的合成途径描述于U.S.专利5,990,307和6,011,168的实施例5中。
然后将获得的式(II)化合物溶解于适宜的溶剂例如二甲基甲酰胺中。所谓“适宜的溶剂”意指式(II)化合物可以在其中溶解而不与其反应的溶剂。优选地,将酸清除剂(以与酰卤反应副产物反应)例如胺在优选室温下加到反应混合物中。所述胺优选是空间位阻的仲或叔胺,更优选叔胺例如二异丙基乙胺。将下式所示适当取代的酯:
其中R4、R5和R6如式(I)所定义,且Y是离去基团,加到反应混合物中。如本文所用,术语“离去基团”是指在化学反应过程中,例如通过亲核取代或消除,可以被另一部分选择性地置换的部分。通常,离去基团包括当通过亲核取代或消除被除去时以阴离子形式较稳定的部分。离去基团在本领域是众所周知的,并且包括例如卤化物(例如氯化物、溴化物和碘化物)和烷基以及芳基磺酸酯例如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、萘磺酸酯(nosylate)、三氟甲磺酸酯等。在优选的实施方案中,Y是卤素原子。
将反应混合物在约50℃至约80℃,优选约65℃至75℃加热足够长的时间,以便卤代酯与式(II)化合物反应形成式(I)化合物。通常,对于优选的产率,所述反应时间为约20小时至约40小时,更优选约25小时至约35小时。反应完成后,优选将反应混合物冷却至室温,并用本领域技术人员所知的标准技术将式(I)化合物分离。优选的分离方法是,将反应混合物在弱碱例如碳酸氢钠水溶液与有机溶剂例如乙酸乙酯之间分配。优选将水相用有机溶剂重复萃取几次,然后把合并的有机层再用弱碱洗涤。然后,将有机层干燥,例如用盐水洗涤并且用硫酸镁干燥,过滤并蒸发。然后,用分离化合物的标准技术,优选通过快速硅胶色谱来分离残余物。
当给药于哺乳动物时,本发明化合物是NMDA拮抗剂,因此用于治疗从抑制哺乳动物中的NMDA受体获益的各种病症。如本文所用,所谓“治疗”意指部分或完全减轻、抑制、预防、改善和/或缓解病症。例如,如本文所用,“治疗”包括部分或完全减轻、抑制或缓解所述病症。如本文所用,“哺乳动物”是指温血脊椎动物,例如人。
因此,本发明提供了在哺乳动物中治疗能够从抑制NMDA受体获益的疾病的方法,所述方法包括向需要治疗的哺乳动物给药治疗有效量的至少一种式(I)化合物。
尽管不会以任何方式意图束缚于理论,但是据信本发明化合物在给药进入哺乳动物后,形成相应的膦酸(即在式(I)中的R2和/或R3是氢的情况下)。令人惊奇地发现,当口服给药于哺乳动物时,本发明化合物较之式(II)化合物具有改进的生物利用度。另外,本发明化合物,在给药进入哺乳动物后,对于NMDA受体上的组合位点具有独特的亲合性和选择性。这种独特的亲合性和选择性相信能够在较低的剂量下提供有效治疗和/或在提供期望的治疗下引起较轻的副作用。这种情况在被治疗的疾病是疼痛时尤其明显。
在一个实施方案中,本发明提供了治疗与谷氨酸异常有关的疾病的方法,所述方法包括向需要这种治疗的哺乳动物给药治疗有效量的至少一种式(I)化合物。如本文所用,“有关的”是指直接或间接由谷氨酸异常引起的疾病。“谷氨酸异常”是指由这样的疾病或病症引起的疾病,在所述疾病或病症中,谷氨酸-通常是处于量的升高状态,作为促进因素而与该疾病或病症有牵连。被认为与谷氨酸异常有关的疾病包括,但不限于,脑血管病症例如脑缺血(例如卒中)或脑梗死,其引起一系列疾病例如栓塞性或出血性卒中,或脑血管痉挛;脑损伤;肌肉痉挛;痉挛性疾病例如癫痫或癫痫持续状态;青光眼;疼痛;焦虑性障碍例如惊恐发作,广场恐慌症,恐慌症,特定恐慌症,社交恐慌症,强迫症,创伤后应激障碍,急性应激障碍,广泛性焦虑障碍,分离焦虑障碍,或物质诱发的焦虑障碍;心境障碍例如双相障碍(例如双相I型障碍、双相II型障碍、和环性气质障碍),抑郁症(例如重症抑郁障碍、心境恶劣障碍、或物质诱发的心境障碍),心境发作(例如重症抑郁发作、躁狂发作、混合发作、和轻躁狂发作);精神分裂症;精神分裂症样障碍;分裂情感性障碍;认知损伤例如记忆丧失;和慢性神经变性病症例如帕金森病,亨廷顿病,阿尔茨海默病,肌萎缩侧索硬化,或涉及例如卢伊体病、阿尔茨海默病、额颞、或AIDS的慢性痴呆。就上面所列心理障碍例如精神分裂症、心境障碍和焦虑性障碍而论,参考Diagnostic and Statistical Manual of Mental Disorders,4thedition,Washington,DC,American Psychiatric Association(1994)以获取每一种心理障碍的完整的描述。据信与谷氨酸异常有关的另外的疾病包括炎性疾病;低血糖;糖尿病终器并发症;心搏停止;窒息性缺氧,例如源于近乎淹溺、肺部外科手术和脑损伤;和脊髓损伤。本发明化合物可以被用于治疗纤维肌痛、和源于带状疱疹(带状疱疹)的并发症例如预防带状疱疹后的神经痛。因此,本发明提供治疗任何一种前面所述疾病或这些疾病组合的方法,所述方法包括向需要这种治疗的哺乳动物给药治疗有效量的至少一种式(I)化合物。
在一个优选的实施方案中,本发明化合物被用于治疗疼痛。所述疼痛可以是,但不限于,急性疼痛(短时间持续)或者慢性疼痛(周期性反复发生或持久发生)。所述疼痛还可以是集于中心的或周围的。
可以按照本发明方法治疗的剂型或慢性疼痛包括炎性疼痛,肌骨骼疼痛,骨性疼痛,腰骶疼痛,颈或上背疼痛,内脏疼痛,躯体疼痛,神经病性疼痛,癌痛,由损伤或外科手术引起的疼痛例如灼伤疼痛或牙痛,或者头痛例如偏头痛或紧张性头痛,或者这些疼痛的组合。本领域技术人员将会认识到这些疼痛可以相互重叠。例如由炎症引起的疼痛就其本质也可以是内脏或肌骨骼性的。
在本发明的一个优选的实施方案中,将用于本发明的化合物给药于哺乳动物,以便治疗慢性疼痛例如神经病性疼痛,例如与损伤或周围或中枢神经系统中的病理变化有关的神经病性疼痛;癌痛;与例如腹部、骨盆、和/或会阴部位或胰腺炎有关的内脏疼痛;与例如下或上背、脊柱、纤维肌痛、颞下颌关节或肌筋膜痛综合征有关的肌骨骼疼痛;与例如骨或关节退化病症例如骨关节炎、风湿性关节炎、或椎管狭窄有关的骨性疼痛;头痛例如偏头痛或紧张性头痛;或与感染例如HIV、带状疱疹(带状疱疹)、镰状细胞贫血、自身免疫病、多发性硬化、或炎症例如骨关节炎或风湿性关节炎有关的疼痛。
在更优选的实施方案中,按照本文所描述的方法,将用于本发明的化合物用于治疗慢性疼痛,所述慢性疼痛是神经病性疼痛,内脏疼痛,肌骨骼疼痛,骨性疼痛,癌痛或炎性疼痛或它们的组合。炎性疼痛可以与各种内科疾病例如骨关节炎,风湿性关节炎,外科手术,或损伤有关。神经病性疼痛可以与例如糖尿病性神经病,周围神经病,带状疱疹后神经痛,三叉神经痛,腰或颈神经根病,纤维肌痛,舌咽神经痛,反射交感营养不良,casualgia,丘脑综合征,神经根撕裂,或由导致周围和/或中心致敏作用的损伤引起的神经损害,例如幻肢痛、反射交感营养不良或血栓形成后疼痛、癌、化学损伤、毒素、营养缺乏、或病毒或细菌感染例如带状疱疹或HIV、或它们的组合。本发明化合物的使用方法还包括神经性疼痛的治疗,其中所述神经性疼痛是从属于与丘脑疾病有关的转移性侵润、痛性肥胖、灼伤或中心疼痛的疾病。
如前面所述,本发明方法可以被用于治疗在本质上是躯体和/或内脏的疼痛。例如,可以按照本发明方法治疗的躯体疼痛包括在外科手术、牙齿手术、灼伤或创伤性身体损伤过程中经受的与结构性或软组织损伤有关的疼痛。可以按照本发明方法治疗的内脏疼痛包括涉及或起因于内部器官疾病的那些类型的疼痛,所述内部器官疾病例如溃疡性结肠炎,肠易激综合征,刺激性膀胱,克罗恩病,风湿病(关节痛),肿瘤,胃炎,胰腺炎,器官感染,或胆管病,或它们的组合。本领域的技术人员将会认识到,按照本发明方法治疗的疼痛也可以涉及痛觉过敏、异常性疼痛、或此两者的疾病。另外,慢性疼痛可以具有或不具有周围或中枢致敏作用。
用于本发明的化合物也可以被用于治疗与女性疾病有关的急性和/或慢性疼痛,所述疼痛也被称作女性特有疼痛。这样类型的疼痛包括单独或主要由女性遭遇的那些疼痛,包括与下列疾病有关的疼痛:月经,排卵,妊娠或分娩,流产,异位妊娠,逆行月经,卵泡破裂或黄体囊肿,骨盆内腔刺激,子宫纤维瘤,子宫内膜异位,子宫内膜异位,感染和发炎,骨盆器官缺血,梗阻,腹内粘连,骨盆内腔解剖扭曲,卵巢脓肿,骨盆支撑丧失,肿瘤,骨盆充血,或源于非妇产科学原因的有关疼痛。
本发明化合物也可以被用于预防对阿片制剂痛觉缺失的耐受,或者帮助控制成瘾性药物的退瘾综合征。
可以通过为本领域技术人员所知的任何方法给药本发明化合物,包括例如,通过口服或肠胃外给药例如通过肌内,腹膜内,硬膜外,鞘内,静脉内,皮下,粘膜内例如舌下或鼻内,阴道,直肠或经皮给药。在本发明优选的实施方案中,将本发明化合物口服、粘膜内或静脉内给药。关于鼻内给药,参考2003年4月提交的第60/461,571号未决临时申请以及与本申请同时提交的,发明名称为“[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)烷基]膦酸和衍生物的用于鼻内给药的药物组合物及其使用方法”的尚未转让的U.S.申请Ser.No.,特此将其公开全文引用作为参考。
以治疗有效量向需要治疗的哺乳动物给药本发明化合物。如本文所用,“治疗有效量”是治疗哺乳动物的所述疾病的至少最小量的化合物或其可药用盐形式。治疗有效量将取决于这样的变数例如所使用的特定条件,给药途径,被治疗的特定患者。为了确定被给药化合物的有效量,医师可以,例如,通过逐渐增加剂量直至达到期望的症状缓解为止,对所给药的式(I)化合物在患者中的效果进行评价。对持续给药方法加以调整以便达到期望的结果。例如,在口服给药的情况下,优选将本发明化合物在患者中以3mg/kg-1000mg/kg的量逐渐增加,直至达到症状缓解的水平为止。然后对持续给药方法加以调整以取得期望的结果,口服剂量范围优选为约20mg/天-约900mg/天。按照类似的方法,以生物利用度数据为基础,确定其它给药途径例如静脉内或肌内途径的有效剂量范围。
在本发明的另一个实施方案中,可以将本发明化合物与一种或多种其它药物活性剂,例如治疗存在于哺乳动物中的任何其它内科疾病的药剂,一起给药于哺乳动物。这样的药物活性剂的实例包括疼痛减轻剂、抗血管形成剂、抗肿瘤剂、抗糖尿病剂、抗感染剂或胃肠治疗剂(gastrointestinal agents)或它们的组合。
可以将一种或多种其它药物活性剂同时(例如在同一时间分别,或共同存在于药物组合物中)和/或与本发明的一种或多种化合物顺序给药。
其它药物活性剂的给药方法可以与本发明化合物所用的给药途径相同或不同。例如,可以将其它药物活性剂通过口服或肠胃外给药,例如通过肌内,腹膜内,硬膜外,鞘内,静脉内,粘膜内例如通过鼻内或舌下,皮下或经皮给药。优选的给药途径将取决于所选择的特定特定药物活性剂及其为本领域技术人员所知的推荐给药途径。
药物活性剂的更为全面的说明可见之于Physicians′DeskReference,2001年,第55版,由Medical Economics Co.,Inc.,Montvale,NJ出版。可以将这些药剂的每一种按照本领域已知的治疗有效剂量给药,例如在Physicians′Desk Reference,55 Edition,2001,Medical Economics Co.,Inc.,Montvale,NJ出版,中对所该产品所做的描述。
在本发明的优选实施方案中,可以将本发明化合物与一种或多种在哺乳动物中治疗疼痛的其它疼痛减轻药剂一起给药。所谓“疼痛减轻药剂”是指直接或间接治疗疼痛症状的任何其它药剂。间接疼痛减轻药剂的实例包括例如消炎药剂,例如抗风湿药剂。
可以将一种或多种其它疼痛减轻药剂同时(例如在同一时间分别,或共同存在于药物组合物中)和/或相续与本发明化合物一起给药。优选地,将本发明化合物和一种或多种疼痛减轻药剂以使两者都能够在哺乳动物体内存在治疗疼痛的一定时间的方式给药。
其它疼痛减轻药剂的给药方法可以与本发明化合物所用的给药途径相同或不同。例如,阿片样物质优选通过口服、静脉内、或肌内途径给药。
本领域技术人员将会认识到,给药于哺乳动物的其它疼痛减轻药剂的剂量将取决于所述特定疼痛减轻药剂和意欲的给药途径。因此,可以按照本领域专业人员已知的途径给药其它疼痛减轻剂,例如公开于参考文献中的给药途径,例如Physicians′Desk Reference,2001年,第55版,Medical EconomicsCo.,Inc.,Montvale,NJ出版。
可以与本发明化合物一起给药的疼痛减轻药剂的实例包括镇痛药例如非麻醉镇痛药剂或麻醉镇痛药剂;消炎药例如非甾体消炎药剂(NSAID)、甾族化合物或抗风湿药剂;偏头痛制剂例如β肾上腺能阻滞药剂、麦角衍生物、或异美汀;三环类抑郁药例如阿米替林、地昔帕明、或丙米嗪;抗癫痫药例如加巴喷丁、卡马西平、托吡酯、丙戊酸钠或苯妥英;α2激动剂;或选择性5-羟色胺重摄取抑制药/-选择性去甲肾上腺素重摄取抑制药、或它们的组合。本领域技术人员将会认识到,下文描述的某些药剂能够起减轻多种疾病例如疼痛和炎症的作用,而其它药剂可以只减轻一种症状例如疼痛。具有多种特性的药剂的具体实例是阿司匹林,其中当高剂量给药时阿司匹林是消炎药,但在低剂量下只是一种止痛药。疼痛减轻剂可以包括任何上述药剂的组合,例如疼痛减轻剂可以是与麻醉性止痛药组合的非麻醉性止痛药。
用于本发明的非麻醉性止痛药包括,例如,水杨酸酯例如阿司匹林、布洛芬( )、酮洛芬()、萘普生()、扑热息痛、消炎痛或它们的组合。可以与环丁烯衍生物组合使用的麻醉性止痛剂的实例包括阿片类止痛药例如fentenyl、舒芬太尼、吗啡、氢吗啡酮、可待因、羟考酮、丁丙诺啡或其可药用盐或它们的组合。可以与环丁烯衍生物组合使用的消炎药的实例包括但不限于阿司匹林;布洛芬;酮洛芬;萘普生;依托度酸();COX-2抑制剂例如塞来考昔()、罗非考昔()、伐他考昔()、帕瑞考昔、etoricoxib(MK663)、deracoxib、2-(4-乙氧基-苯基)-3-(4-甲磺酰基-苯基)-吡唑并[1,5-b]哒嗪、4-(2-氧代-3-苯基-2,3-二氢噁唑-4-基)苯磺酰胺、达布非酮、氟舒胺、4-(4-环己基-2-甲基-5-噁唑基)-2-氟苯磺酰胺、美洛昔康、尼美舒利、1-甲磺酰基-4-(1,1-二甲基-4-(4-氟苯基)环戊-2,4-二烯-3-基)苯、4-(1,5-二氢-6-氟-7-甲氧基-3-(三氟甲基)-(2)-苯并噻喃并(4,3-c)吡唑-1-基)苯磺酰胺、4,4-二甲基-2-苯基-3-(4-甲磺酰基)苯基)环丁烯酮、4-氨基-N-(4-(2-氟-5-三氟甲基)-噻唑-2-基)-苯磺酰胺、1-(7-叔丁基-2,3-二氢-3,3-二甲基-5-苯并呋喃基)-4-环丙基丁-1-酮或其可药用盐、酯或溶剂合物;舒林酸();双氯芬酸();吡罗昔康()、二氟尼柳()、萘丁美酮()、噁丙嗪()、吲哚美辛();或甾族化合物例如醋酸钠泼尼松龙口服液、注射用琥钠甲泼尼龙、牌泼尼松龙糖浆剂。
优选用于治疗类风湿性关节炎的消炎剂的其它实例包括可以购自Roche Labs的形式的缓释片剂、 和片剂和悬浮液,牌塞勒科西片剂,牌罗非考昔,牌倍他米松,牌青霉胺胶囊,牌可滴定青霉胺片剂,DEPO-MEDROL牌醋酸甲泼尼龙可注射悬浮液,ARAVATM来氟米特片剂,AZULFIDIINE牌柳氮磺吡啶缓释片剂,牌吡罗昔康胶囊,双氯芬酸钾片剂,二氯芬钠缓释片剂,-XR二氯芬钠长效释放片剂,或依那西普产品。
用于治疗炎症特别是风湿性关节炎的其它药剂包括免疫依制剂例如GENGRATM牌环胞菌素,牌环胞菌素胶囊或口服溶液,或牌硫唑嘌呤片剂或IV注射剂;牌吲哚美辛胶囊,口服悬浮液或栓剂;牌硫酸羟氯喹;或注射用英夫利昔单抗重组体;或金化合物例如金诺芬或硫代苹果酸金钠注射剂。
在本发明优选的实施方案中,将至少一种本发明化合物与至少一种阿片类镇痛药,按照本文前面所述方法一起给药。已经证明,本发明化合物,当与至少一种阿片类镇痛药例如吗啡一起给药时,具有这样的有利效果如协同地减轻疼痛感觉,增长疼痛减轻的持续时间,和/或减少有害的副作用。
给药的本发明化合物可以是纯净的(即原样)或者存在于含有至少一种可药用载体的药物组合物中。因此,本发明还提供含有药物有效量的至少一种式(I)化合物或其可药用盐和至少一种可药用载体的药物组合物。存在于本发明药物组合物中的优选化合物包括前面作为优选描述的式(I)的那些化合物。可药用载体是与制剂中的其它组分相容且生物学可接受的载体。如本文前面所述,可以将药物组合物给药于哺乳动物以治疗可以获益于抑制NMDA受体的各种疾病。
用于本发明的药物组合物可以是为本领域专业人员所知的任何形式,例如液体或固体形式。组分的比例将取决于这样的因素如式(I)化合物的溶解性和化学性质以及选自的给药路径。这样的组合物是按照可接受的制药方法制备的,例如在Remingtons PharmaceuticalSciences,17th版,ed.Alfonso R.Gennaro,Mack Publishing Company,Easton,PA(1985)中描述的制药方法。
药物组合物,除了含有治疗有效量的一种多种本发明化合物和可药用载体外,还可以包含本领域专业人员所知的用于形成药物组合物的一种或多种其它组分。这样的组分包括例如调味剂、滑润剂、增溶剂、悬浮剂、填料、助流剂、压缩助剂、结合剂、片剂崩解剂、形成胶囊的材料、乳化剂、缓冲剂、防腐剂、甜味剂、增稠剂、着色剂、粘性调节剂、稳定剂或渗透调节剂或它们的组合。
固体药物组合物优选含有一种或多种固体载体,并且任选哟扎或多种其它添加剂例如调味剂、滑润剂、增溶剂、悬浮剂、填料、助流剂、压缩助剂、粘合剂、片剂崩解剂、形成胶囊的材料。适宜的固体载体包括例如磷酸钙、硬脂酸镁、滑石粉、糖、乳糖、糊精、淀粉、凝胶、纤维素、甲基纤维素、羧基甲基纤维素钠、聚乙烯基吡咯烷、低融蜡或离子交换树脂或它们的组合。在粉末药物组合物中,载体优选是与磨成细粉的活性组分混合的磨成细粉的固体。在片剂中,以适当的比例将活性组分与具有必要压缩特性的载体混合,然后压制成要求的形状和大小。固体药物组合物,例如粉末和片剂,优选含有最高达99%的活性组分。
液体药物组合物优选含有一种或多种本发明化合物和一种或多种液体载体以形成例如溶液、悬浮液、乳化液、糖浆、酏剂、或加压组合物。可药用液体载体包括例如水,有机溶剂,可药用油或脂肪,或它们的组合。液体载体可以含有其它适宜的药物添加剂例如增溶剂、乳化剂、缓冲剂、防腐剂、甜味剂、调味剂、悬浮剂、增稠剂、染色剂、粘度调节剂、稳定剂或渗透调节剂或它们的组合。
适用于口服或肠胃外给药的液体载体的实例包括水(优选含有添加剂例如纤维素衍生物例如羧基甲基纤维素钠),醇或它们的衍生物(包括一元醇或多元醇例如乙二醇)或油(例如分馏的椰子油和花生油)。对于肠胃外给药,载体可以是油酯例如油酸乙酯和豆蔻酸异丙酯。用于加压组合物的液体载体可以是卤代烃或其它可药用推进剂。
无菌溶液或悬浮液的液体药物组合物可以经由例如肌内、腹膜内、硬膜上、鞘内、静脉内或皮下注射进行肠胃外给药。用于口服或经粘膜给药的药物组合物可以是液体或固体组合物形式。
本发明化合物可以常规的栓剂形式直肠或阴道给药。对于经由鼻内或支气管内吸入或吹入的给药,可以将本发明化合物制成水或部分水溶液,任何将其用于气雾剂形式中。也可以将本发明化合物通过使用含有活性化合物和载体的经皮贴片经皮给药,所述载体对于活性化合物是惰性的,对于皮肤是无毒的,并且使药剂的递送可以经由皮肤全身吸收到血流中。载体可以采用若干形式例如乳膏和软膏、糊、凝胶、和闭塞装置。乳膏和软膏可以是水包油或油包水类型的粘性液体或半固体乳胶液。散布于含有活性组分的石油或亲水石油中吸收性粉末也是适宜的。各种闭塞装置可以被用于将活性组分释放到血流中,例如覆盖含有有或没有载体的活性组分的贮器的半透膜,或含有活性组分的基体。其它闭塞装置在文献中是已知的。
在本发明的另一个实施方案中,如本文前面所述,药物组合物,除了含有本发明化合物以外,还可以含有治疗有效量的一种或多种疼痛减轻剂,和/或治疗有效量的一种或多种其它药物活性剂。因此,本发明还提供这样的药物组合物,所述药物组合物含有治疗有效量的至少至少一种或多种本发明化合物和治疗有效量的至少一种药物活性组分,例如如前面所述的疼痛减轻剂。例如药物组合物可以含有包括阿片类镇痛剂的一种或多种疼痛减轻剂。
优选地,药物组合是单位剂量形式,例如片剂或胶囊。在这样的形式中,组合物被再分在含有适当量活性剂组分的单位剂量中。单位剂量可以是包装的组合物,例如包装的粉末,小瓶,安瓿,含有液体的预先装填的注射器或小袋。单位剂型可以是,例如,胶囊或片剂本身,或者可以是适当数量的任何这样包装形式的组合物。
因此,本发明还提供在单位剂型中含有治疗有效量的至少一种本发明化合物的药物组合物。如本领域专业人员将会认识到的,优选的剂量将取决于给药方法和被治疗的疾病。例如,口服给药治疗疼痛的单位剂型优选为约20mg-约300mg本发明化合物。
本发明向被治疗的哺乳动物还提供散布本发明化合物的治疗包。优选地,治疗包含有一个或多个单位剂量的本发明化合物和容器,含有一个或多个单位剂量并标注指导用于在哺乳动物中治疗疾病例如疼痛的治疗包的使用。在优选的实施方案中,单位剂量是片剂或胶囊形式。在优选的实施方案中,每一单位剂量是用于治疗疼痛的治疗有效量。
实施例
制备本发明化合物并对其治疗疼痛的效能进行评价。在实施例1-10的合成中,原料[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸是按照U.S.专利5,990,307实施例5中描述的方法制备的。用于实施例的所有的其它化学药品和中间体是可以从市场上买到的,能够通过文献中现有的标准方法制备,或者被描述于实施例中。
实施例1-苯甲酸3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-
基]乙基}-3-氧化-7-氧代-7-苯基-2,4,6-三氧杂-3-磷杂庚-1-基酯
将[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸(20.16mmol,5.25g)在无水DMF(120mL)中的溶液用N,N-二异丙基乙胺(80.64mmol,14ml)在室温下处理0.5小时。在室温和排除湿气条件下加入苯甲酸氯甲酯(60.49mmol,10.32g,下面所述合成的)。把反应混合物在65℃加热20小时。然后将温度升高至72℃并在72℃搅拌16小时,之后反应完成。将混合物冷却至室温并在10%碳酸氢钠与乙酸乙酯之间分配。分离各层后,将水相再次用乙酸乙酯(6×)萃取直到水相中不再有产物为止(用TLC检测,7%2M氨在甲醇中的溶液和93%氯仿)。将合并的有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发至干。将残余物在400g硅凝胶上进行快速色谱纯化,用1%2M氨在甲醇中的溶液与99%氯仿的混合物洗脱。逐渐将氨在甲醇中的溶液的百分比增加至7%和93%氯仿。将溶剂在真空中蒸发,得到期望的产物(10.5g,99%;玻璃状材料)。MS(ES-):m/e 527(M-H)。
制备反应物苯甲酸氯甲酯:
将低聚甲醛(4.5g)与氯化锌(催化量)在0℃混合在一起。用1小时滴加苯甲酰氯(0.142摩尔,20g)。使反应升温至室温,然后在55℃加热10小时。反应之后进行TLC检测(硅胶,5/95,乙酸乙酯/己烷)。因为仍能看见原料,所以再加入1g低聚甲醛。将反应在55℃继续搅拌10小时,冷却,然后在500g硅胶上进行快速色谱纯化,用2%乙酸乙酯与98%己烷的溶剂混合物洗脱。将溶剂真空蒸发。由于产物具有低沸点,所以旋转蒸发仪的浴温不高于35℃。获得期望的产物11.82g(49%),为澄清油状物。MS(ES+):m/e 171(M+H)。
实施例2-2-丙基戊酸3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-
烯-2-基]乙基}-3-氧化-7-氧代-8-丙基-2,4,6-三氧杂-3-磷杂十一烷-1-基
酯
在室温和排除湿气的条件下,将原料[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸(26mmol,6.765g)在无水DMF(250mL)中的溶液用N,N-二异丙基乙胺(104mmol,13.442g)处理,然后用2-丙基戊酸氯甲酯(88mmol,17g,下面所述合成的)处理。在搅拌的同时将反应混合物加热至65℃,并于搅拌下在65℃保持16小时。通过真空蒸馏除去溶剂,并将残余物在水与乙醚之间分配(2×)。将有机相分离,用硫酸镁干燥,过滤,并蒸发至干,得到约16g粗产物,为稠的黄色油状物。将该油状物在350g硅胶上进行快速色谱纯化,用8%甲醇/乙酸乙酯洗脱,得到8.4g(56%)期望的产物,为无色固化的蜡状物。MS(ES+):m/e 573(M+H)。
制备反应物2-丙基戊酸氯甲酯:
在0℃将低聚甲醛(1g)与氯化锌(催化量)混合在一起。用1小时滴加2,2-二正丙基乙酰氯(30摩尔,4.88g)。将反应升温至室温,然后在50-55℃加热6小时。在室温把反应混合物继续搅拌16小时。将反应混合物置于二氯甲烷(5mL)中,并在150g硅胶上进行快速色谱纯化,用1-5%乙酸乙酯/己烷洗脱,得到3.3g(58%)期望的产物。
实施例3-2,2-二甲基丙酸(2,2-二甲基-丙酰基氧基甲氧基)-[2-(8,9-二
氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)-乙基-膦酰基氧基甲基酯
在室温和排除湿气条件下,将原料[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸(20mmol,5.2g)在无水DMF(60mL)中的溶液用N,N-二异丙基乙胺(80mmol,10.34g)处理,然后用市场上买到的新戊酸氯甲酯(66mmol,9.94g)处理。将反应混合物加热至65℃,并在搅拌下于65℃保持24小时以上。通过真空蒸馏除去溶剂,并将残余物在水与甲苯之间分配(2×)。把有机相分离,用硫酸镁干燥,过滤,并蒸发至干,得到约14g粗产物,为稠的琥珀色油状物。将该油状物在400g硅胶上进行快速色谱纯化,用6%甲醇/乙酸乙酯洗脱,得到5.88g(60.2%)期望的产物。MS(ES+):m/e 489(M+H)。
实施例4至5-环己烷甲酸7-环己基-3-{2-[8,9-二氧代-2,6-二氮杂二环
[5.2.0]壬-1(7)-烯-2-基]乙基}-1,5-二甲基-3-氧化-7-氧代-2,4,6-三氧杂-3-
磷杂庚-1-基酯的立体异构体
在室温和排除湿气条件下,将原料[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸(10mmol,2.6g)在无水DMF(30mL)中的溶液依次用N,N-二异丙基乙胺(33mmol,4.3g)和环己烷甲酸1-氯乙酯(33mmol,6.293g)处理。将反应混合物加热至65℃,并在搅拌下于65℃保持24小时以上。通过真空蒸馏除去溶剂,并将残余物在水与甲苯之间分配(2×)。将有机相分离,用硫酸镁干燥,过滤,并蒸发至干,得到约7g粗产物,为稠的油状物。将该油状物在250g硅胶上进行快速色谱纯化,用3%甲醇/乙酸乙酯洗脱,得到0.95g(17%)实施例4的产物。MS(ES-):m/e 567(M-H)。洗脱出环己烷甲酸7-环己基-3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-1,5-二甲基-3-氧化-7-氧代-2,4,6-三氧杂-3-磷杂庚-1-基酯的较低极性的立体异构体(实施例5),真空蒸发,获得0.35g(6%)实施例5的产物。MS(ES-):m/e 567(M-H)。
实施例6-环己烷甲酸7-环己基-3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]
壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-2,4,6-三氧杂-3-磷杂庚-1-基酯
将原料[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸(8.17mmol,2.1g)在无水DMF(50mL)中的溶液用N,N-二异丙基乙胺(33.34mmol,5.7mL)处理。室温下搅拌30钟后,在室温和除去湿气条件下加入环己烷甲酸氯甲酯(4.33g,8.17mmol)。将反应混合物加热至72℃,并在搅拌下于72℃保持36小时以上。将混合物冷却至室温后,加入碳酸氢钠水溶液(10%,50mL),并将产物用乙酸乙酯萃取(5×50mL)。将合并的有机层用盐水洗涤,用硫酸镁干燥,过滤,并真空蒸发。将获得的残余物在200g硅胶上进行快速色谱纯化,用1-5%甲醇/乙酸乙酯进行梯度洗脱,得到3.2g(73%)实施例6的产物。使所得产物从乙酸乙酯∶乙醚∶甲烷(70∶15∶15)中结晶,得到2.75g期望的产物,为在64-65℃熔化的灰白色微晶固体。MS(ES+):m/e 541(M+H)。
实施例7-[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1-(7)-烯-2-基)乙基]-
膦酸二异丙氧基羰基氧基甲基酯
将原料[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸(9.61mmol,2.5g)在无水DMF(40mL)中的溶液一次性用N,N-二异丙基乙胺(33.62mmol,5.86mL)处理。在室温下把混合物搅拌30分钟,然后加入碳酸氯甲酯异丙酯(28.82mmol,4.4g,下面所述合成的)。在搅拌下将混合物在70℃加热24小时。然后将混合物冷却至室温,加入柠檬酸(2%水溶液,40mL)。将产物用乙酸乙酯萃取(2×40mL),然后用氯仿萃取(2×40mL)。将合并的有机层用硫酸镁干燥,过滤,并将滤液蒸发至干。将残余物在硅胶上进行快速色谱纯化。用2-7%氨在氯仿中的溶液进行梯度洗脱,然后从乙酸乙酯/乙醚/己烷中结晶,得到2.1g(44.4%)产物,为在74-75℃熔化的灰白色固体。MS(ES+):m/e 493(M+H)。
制备反应物碳酸氯甲酯异丙酯
将2-丙醇(73.14mmol,5.6mL)加到氯甲酸氯甲酯(73.85mmol,6.5mL)在乙醚(100mL)内的溶液中。将反应混合物冷却至0℃,并在搅拌下滴加吡啶(74.18mmol,6mL)。然后,将反应混合物在室温下搅拌20小时。将形成的固体过滤,并将滤液用柠檬酸(1%水溶液)、碳酸氢钠水溶液(1%)和盐水洗涤。把有机层用硫酸镁干燥,过滤,并蒸发至干,得到10.26g(92%)无色油状物。MS(ES+):m/e 152(M+H)。
实施例8至9-[2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙
基]-膦酸二[1-(苯甲酰基氧基)乙基]酯的立体异构体
将原料[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸(19.22mmol,5g)在无水DMF(100mL)中的溶液用N,N-二异丙基乙胺(76.88mmol,13.39mL)处理。把反应混合物在室温下搅拌30分钟,然后加入苯甲酸-1-氯乙酯(57.66mmol,10.65g,下面所述合成的)。然后将混合物在70℃搅拌36小时,冷却至室温并用柠檬酸(2%水溶液,70mL)稀释。将产物用乙酸乙酯萃取(3×50mL),用碳酸氢钠(3%)和盐水洗涤。把有机层用硫酸镁干燥,过滤,并蒸发至干。将残余物在硅胶上进行快速色谱纯化。用2-8%甲醇在氯仿中的溶液进行梯度洗脱,获得1.66g(15.5%)[2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基]-膦酸二[1-(苯甲酰基氧基)乙基]酯的立体异构体(实施例8)[MS(ES+):m/e 557(M+H)]和0.73 g(6.8%)[2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基]-膦酸二[1-(苯甲酰基氧基)乙基]酯的较小极性的立体异构体(实施例9)[MS(ES+):m/e 557(M+H)]。
制备反应物苯甲酸-1-氯乙酯
将苯甲酰氯(177.85mmol,20.63mL)与氯化锌(0.2g)的混合物冷却至-20℃。滴加乙醛(178.88mmol,10mL),并将反应混合物在-20℃搅拌1小时,然后升温至室温并继续搅拌18小时。将全部混合物在硅胶上进行快速色谱纯化。用2-7%乙酸乙酯在己烷中的混合物进行梯度洗脱,得到22.43g(68%)产物,为无色油状物。MS(ES+):m/e 171(M+H)。
实施例10-苯甲酸[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-
基)-乙基]-羟基-膦酰基氧基甲基酯
将苯甲酸3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-7-苯基-2,4,6-三氧杂-3-磷杂庚-1-基酯(实施例1,0.75mmol,397mg)在乙腈(15mL)中的溶液加到四硼酸钠十水合物(0.9mmol,344mg)、硼酸(3.6mmol,223mg)和氯化钠(210mg)在水(30mL)内的溶液中。将反应混合物在45℃搅拌10分钟。将反应混合物真空浓缩以除去乙腈。用稀释的(1∶10)的磷酸盐缓冲液把剩余相中和至pH7,然后用二氯甲烷(10mL,5mL,5mL)萃取三次。将水相真空浓缩至体积7mL,然后以分别1.2mL的等份试样施加到用Primesphere10 C18填充的制备HPLC柱,5×25cm上。用10%乙腈在10mM乙酸铵中的混合物进行等度洗脱。将乙腈从所收集的适当级份中蒸发,把水缓冲液冷冻干燥,获得140mg期望的产物,为白色粉末。MS(ES+):m/e 412(M+H)。
实施例11-[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]
膦酸二-二甲基氨基甲酰基氧基甲基酯
将[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸(10mmol,2.602g)在无水DMF(130mL)中的溶液在室温下用N,N-二异丙基乙胺(40mmol,5.17g)处理,并搅拌30分钟。在室温和排除湿气条件下将二甲基氨基甲酸氯甲酯(30mmol,4.14g)加入反应混合物中。将反应混合物加热至70℃,并在搅拌下于70℃保持26小时以上。通过真空蒸馏除去溶剂,并将残余物在水与乙醚之间分配(2×)。将有机相分离,用硫酸镁干燥,过滤,并蒸发至干。在200g硅胶上进行快速色谱纯化,用8%甲醇/氯仿洗脱,获得产物。
实施例12-本发明化合物在临床前模型中治疗疼痛的评价
评价本发明化合物治疗疼痛的效力。也对化合物[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸,式(II)化合物,进行试验并作为比较例1记录在表中。此中所用的试验方法已经被本领域技术人员用于评价化合物减轻疼痛的效力。参见例如Bennett GJ和Xie TK,A peripheral mononeuropathy in rat produces disorders ofpain sensation like those seen in man,Pain 33:87-107(1988);ChaplanSR,Bach RW,Pogrel JW,Chung JM和Yaksh TL,Quantitativeassessment of tactile allodynia in the rat paw,J.Neurosci.Methods 53:55-63(1994);和Mosconi T和Kruger L,Fixed-diameter polyethylenecuffs applied to the rat sciatic nerve induce a painful neuropathy:ultrastructural morphometric analysis of axonal alterations Pain 64:37-57(1996)。
受试个体
单独饲养Spraque-Dawley大鼠能够自由获取食物和水。实行12小时光亮/12小时黑暗循环(光照早晨6:00点-下午6:00)。动物饲养和研究按照National Institutes of Health Committee on LaboratoryAnimal Resources提供的指南进行。将这些受试个体用于下面的试验。
步骤-前列腺素E2诱发的热超敏感性
将尾巴末端10cm放入盛有加热至38、42、46、50或54℃的热水瓶中。大鼠将尾巴从水中移开的以秒计的潜伏期被用作伤害感受的测定结果。如果动物在20秒内没有将尾巴移开,实验者将动物尾巴移开并记录20秒的最大潜伏期。
基准热敏感性评估后,通过将50μL 0.1mg前列腺素E2(PGE2)注射入尾巴末端1cm处,来产生热超敏感性。在注射PGE2之前(基准)和之后30分钟形成温度-效应曲线。先前在其它种类动物中进行的研究(例如猴子;Brandt等人,J.Pharmacol.Exper.Ther.296:939,2001)和目前的研究证明PGE2产生与剂量和时间有关的热超敏感性,所述热超敏感性在15分钟达到峰值,2小时后消失。
用单一剂量时间进程方法,对化合物逆转PGE2诱发的热超敏感性的能力进行评价。在这种方法中,在注射PGE2之前10、30、100或300分钟,口服给药单一剂量的试验化合物。PGE2注射30分钟后,评价触觉敏感性。
数据分析
由温度-效应曲线来计算产生尾巴抽回潜伏期(即T10)的一半最大增加的温度。T10是这样确定的:在温度-效应曲线上,从10秒上面的点和10秒下面的点之间划出的线通过内插法确定。对于这些研究来说,热超敏感性被定义为在温度-效应曲线中的向左位移和T10值的减小。热超敏感性的逆转被定义为向温度-效应曲线和T10值的基准的回返,并且按照下列方程式计算:
其中T10 药物+PGE2是药物与PGE2合并后的T10,T10 PGE2是在仅有PEG2后的T10,T10 基准是在对照条件下的T10。%MPE值×100表示观察到的未注射PGE2的向基准热敏感性的完全回返。大于100%的值表示,试验化合物将热敏感性减至低于未注射PGE2的基准热敏感性的值。
结果:本发明化合物对于逆转PGE2诱发的热超敏感性是有效的(表1)。
表1:PGE2诱发的热超敏感性的逆转
化合物 | 10mg/k9%MPE(±1 SEM)<sup>*</sup> | 30mg/kg%MPE(±1 SEM) |
比较例1 | -4.7(10.6)<sup>**</sup> | 44(9.5) |
实施例1 | 57.2(4.7) | 81(3.4) |
实施例2 | 45.6(13.9) | 76.5(3.3) |
实施例3 | 87.6(3.3) | |
实施例4 | 78.9(5.8) | |
实施例5 | 55.9(9.8) | |
实施例6 | 16.8(6.8) | |
实施例7 | 47.0(12.6) | 77.5(6.7) |
*SEM是平均值标准误差。
**括号内的数字是来自报告的%MPE的误差。例如,对于实施例1,在10mg/kg的剂量下,%MPE是57.2±4.7。
Claims (21)
2.权利要求1的化合物,其中R4和R5独立地选自H或C1-C4烷基,且R6选自C3-C10直链或支链烷基、苯基或在环中具有5-7个碳原子的环烷基。
3.权利要求1或2的化合物,其中R2和R3独立地选自H或下式的部分:
条件是R2和R3当中至少有一个不是H。
4.权利要求1或2的化合物,其中R6是苯基。
5.权利要求1的化合物,其中式(I)化合物选自:
a)苯甲酸3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-7-苯基-2,4,6-三氧杂-3-磷杂庚-1-基酯;
b)2-丙基戊酸3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-8-丙基-2,4,6-三氧杂-3-磷杂十一烷-1-基酯;
c)2,2-二甲基-丙酸{(2,2-二甲基-丙酰基氧基甲氧基)-[2-(8,9-二氧代-2,6-二氮杂-二环[5.2.0]壬-1(7)-烯-2-基)-乙基]-膦酰基氧基}甲基酯;
d)环己烷甲酸7-环己基-3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-1,5-二甲基-3-氧化-7-氧代-2,4,6-三氧杂-3-磷杂庚-1-基酯;
e)环己烷甲酸7-环己基-3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-2,4,6-三氧杂-3-磷杂庚-1-基酯;
f)[2-(8,9-二氧代-2,6-二氮杂-二环[5.2.0]壬-1-(7)-烯-2-基)-乙基]-膦酸二异丙氧基羰基氧基甲基酯;
g)[2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基]-膦酸双[1-(苯甲酰基氧基)乙基]酯;或
h)苯甲酸[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)-乙基]-羟基-膦酰基氧基甲基酯;
或其可药用盐。
6.权利要求1的化合物,其中式(I)化合物选自:
a)苯甲酸3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-7-苯基-2,4,6-三氧杂-3-磷杂庚-1-基酯;
b)[2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基]-膦酸双[1-(苯甲酰基氧基)乙基]酯;或
c)苯甲酸[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)-乙基]-羟基-膦酰基氧基甲基酯;
或其可药用盐。
7.权利要求1-6任一项的式(I)化合物或其可药用盐在制备用于在哺乳动物中治疗至少一种选自下列的病症的药物中的应用:选自脑缺血、脑梗死或脑血管痉挛的脑血管病症;脑损伤;肌肉痉挛;选自癫痫或癫痫持续状态的痉挛性病症;青光眼;糖尿病终器综合征;低血糖;心搏停止;窒息性缺氧;或脊髓损伤。
8.权利要求1-6任一项的式(I)化合物或其可药用盐在制备用于在哺乳动物中治疗至少一种选自下列的病症的药物中的应用:焦虑性障碍;心境障碍;精神分裂症;精神分裂症样障碍;分裂情感性障碍;抑郁症;心境发作;或认知损伤。
9.权利要求8的应用,其中所述焦虑性障碍选自惊恐发作、恐慌症、强迫症、创伤后应激障碍、急性应激障碍、广泛性焦虑障碍、分离性焦虑障碍或物质诱发的焦虑障碍;或者心境障碍选自双相障碍,抑郁症选自重症抑郁障碍、心境恶劣障碍或物质诱发的心境障碍,或心境发作选自重症抑郁发作、躁狂发作、混合发作或轻躁狂发作。
10.权利要求9的应用,其中所述恐慌症选自广场恐慌症、特定恐慌症和社交恐慌症。
11.权利要求1-6任一项的式(I)化合物或其可药用盐在制备用于在哺乳动物中治疗至少一种选自下列的慢性神经病变性病症的药物中的应用:帕金森病、亨廷顿病、阿尔茨海默病、肌萎缩侧索硬化或慢性痴呆。
12.权利要求1-6任一项的式(I)化合物或其可药用盐在制备用于在哺乳动物中治疗至少一种选自下列的病症的药物中的应用:炎性疾病;纤维肌痛;源于带状疱疹的并发症;预防对阿片制剂痛觉丧失的耐受;或成瘾性药物退瘾症状。
13.权利要求1-6任一项的式(I)化合物或其可药用盐在制备用于在哺乳动物中治疗疼痛的药物中的应用。
14.权利要求13的应用,其中所述疼痛是选自下列的至少一种:神经病性疼痛;癌痛;与胰腺炎或腹部、骨盆或会阴部位有关的内脏疼痛;与下或上背、脊柱、纤维肌痛、颞下颌关节或肌筋膜痛综合征有关的肌骨骼疼痛;与骨或关节退化病症有关的骨性疼痛;头痛;或与感染、镰状细胞贫血、自身免疫病、多发性硬化、牙齿手术、灼伤或炎症有关的疼痛。
15.权利要求14的应用,其中所述疼痛包括神经性疼痛并且与下列疾病的至少一种有关:糖尿病性神经病、周围神经病、疱疹后神经痛、三叉神经痛、腰或颈神经根病、纤维肌痛、舌咽神经痛、反射交感营养不良、灼痛、丘脑综合征、神经根撕裂,或由选自幻肢痛、反射交感营养不良或血栓形成后疼痛、癌、化学损伤、毒素、营养缺乏、或病毒或细菌感染引起的神经损害。
16.权利要求7-15任一项的应用,其中哺乳动物是人。
17.药物组合物,所述组合物包含
a)治疗有效量的至少一种权利要求1-6任一项的式(I)化合物或其可药用盐,和
b)至少一种可药用载体。
19.权利要求17的组合物,其中式(I)化合物选自:
a)苯甲酸3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-7-苯基-2,4,6-三氧杂-3-磷杂庚-1-基酯;
b)2-丙基戊酸3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-8-丙基-2,4,6-三氧杂-3-磷杂十一烷-1-基酯;
c)2,2-二甲基-丙酸{(2,2-二甲基-丙酰基氧基甲氧基)-[2-(8,9-二氧代-2,6-二氮杂-二环[5.2.0]壬-1(7)-烯-2-基)-乙基]-膦酰基氧基}甲基酯;
d)环己烷甲酸7-环己基-3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-1,5-二甲基-3-氧化-7-氧代-2,4,6-三氧杂-3-磷杂庚-1-基酯;
e)环己烷甲酸7-环己基-3-{2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基}-3-氧化-7-氧代-2,4,6-三氧杂-3-磷杂庚-1-基酯;
f)[2-(8,9-二氧代-2,6-二氮杂-二环[5.2.0]壬-1-(7)-烯-2-基)-乙基]-膦酸二异丙氧基羰基氧基甲基酯;
g)[2-[8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基]乙基]-膦酸双[1-(苯甲酰基氧基)乙基]酯;或
h)苯甲酸[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)-乙基]-羟基-膦酰基氧基甲基酯;
或其可药用盐。
20.制备权利要求1的式(I)化合物的方法,所述方法包括将式(II)化合物
其中R1是氢;
A是-CH2-CH2-;
与至少一种选自下列的酯反应
其中Y是离去基团;
R4和R5独立地选自氢、C1-C4烷基、C2-C7链烯基或C2-C7炔基;且
R6是C1-C12直链或支链烷基、C2-C7直链或支链链烯基或炔基、苯基、C4-C8环烷基或在环烷基环中具有4-8个碳原子的C5-C16烷基环烷基。
21.权利要求1-6任一项的式I化合物在制备药物中的应用,其中所述药物用于:在哺乳动物中治疗至少一种选自下列的病症:选自脑缺血、脑梗死或脑血管痉挛的脑血管病症;脑损伤;肌肉痉挛;选自癫痫或癫痫持续状态的痉挛性病症;青光眼;糖尿病终器综合征;低血糖;心搏停止;窒息性缺氧;或脊髓损伤;或者在哺乳动物中治疗至少一种选自下列的病症:焦虑性障碍、心境障碍、精神分裂症、精神分裂症样障碍、分裂情感性障碍或认知损伤;或者在哺乳动物中治疗至少一种选自下列的病症:帕金森病、亨廷顿病、阿尔茨海默病、肌萎缩侧索硬化或慢性痴呆;或者在哺乳动物中治疗至少一种选自下列的病症:炎性疾病;纤维肌痛;源于带状疱疹的综合征;预防对阿片制剂痛觉丧失耐受;或成瘾性药物退瘾症状;或者在哺乳动物中治疗疼痛。
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TWI349674B (en) | 2011-10-01 |
DK1611144T3 (da) | 2010-11-22 |
JP4621659B2 (ja) | 2011-01-26 |
CN1863810A (zh) | 2006-11-15 |
US20070225257A1 (en) | 2007-09-27 |
DE602004029146D1 (de) | 2010-10-28 |
EP1611144A1 (en) | 2006-01-04 |
AU2004230895B2 (en) | 2010-09-09 |
TW200504085A (en) | 2005-02-01 |
PT1611144E (pt) | 2010-11-12 |
ATE481103T1 (de) | 2010-10-15 |
EP1611144B1 (en) | 2010-09-15 |
CA2521313A1 (en) | 2004-10-28 |
CL2004000769A1 (es) | 2005-02-04 |
AR044013A1 (es) | 2005-08-24 |
US7879825B2 (en) | 2011-02-01 |
JP2006523694A (ja) | 2006-10-19 |
BRPI0409255A (pt) | 2006-03-28 |
US7253153B2 (en) | 2007-08-07 |
CY1110863T1 (el) | 2015-06-10 |
WO2004092189A1 (en) | 2004-10-28 |
ES2350449T3 (es) | 2011-01-24 |
MXPA05010760A (es) | 2005-12-12 |
AU2004230895A1 (en) | 2004-10-28 |
PL1611144T3 (pl) | 2011-03-31 |
US20050004080A1 (en) | 2005-01-06 |
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