CN1225620A - 作为基质金属蛋白酶抑制剂的取代的4-芳基丁酸衍生物 - Google Patents
作为基质金属蛋白酶抑制剂的取代的4-芳基丁酸衍生物 Download PDFInfo
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- CN1225620A CN1225620A CN97196458A CN97196458A CN1225620A CN 1225620 A CN1225620 A CN 1225620A CN 97196458 A CN97196458 A CN 97196458A CN 97196458 A CN97196458 A CN 97196458A CN 1225620 A CN1225620 A CN 1225620A
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- phenyl
- oxo
- compound
- butyric acid
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Abstract
基质金属蛋白酶抑制剂,含有它们的药物组合物,和应用它们治疗多种生物疾病的方法。本发明的化合物具有通式(Ⅰ),其中R1表示C6-C12烷基;C5-C12烷氧基;C5-C12烷硫基;式R2O(C2H4)a-的聚醚,其中a是1或2而R2是C1-C5烷基,苯基,或苄基;和式R3(CH2)b-C≡C-的取代的炔基,其中b是1—10而R3是H-,HO-,或R4O-,其中R4是C1-C3烷基,苯基,或苄基。R1的烷基,苯基,和苄基部分可以带有至少一个药学上可接受的取代基。下标n是2—4。R5表示苯基;4—12个碳原子的亚氨基;(3H)-苯并-1,2,3-三嗪-4-酮-3-基;N-糖精基;(2H)-2,3-二氮杂萘-1-酮-3-基;2-苯并噁唑啉-2-酮-3-基;5,5-二甲基噁唑烷-2,4-二酮-3-基;和噻唑烷-2,4-二酮-3-基;R5的苯基和苯并部分可以带有至少一个药学上可接受的取代基。也包括这些化合物的药用盐。
Description
领域
本发明涉及酶抑制剂,更具体地,涉及用作基质金属蛋白酶抑制剂的取代的4-芳基丁酸衍生物。
背景
基质金属蛋白酶(也称为基质金属内切蛋白酶或MMP)是一类锌内切蛋白酶,包括,但不限于,间质胶原酶(也称为MMP-1),溶基质素(也称为粘蛋白酶,transin,或MMP-3),明胶酶A(也称为72kDa-明胶酶或MMP-2)和明胶酶B(也称为95kDa-明胶酶或MMP-9)。这些MMP由多种细胞包括成纤维细胞和软骨细胞分泌,与称为TIMP(金属蛋白酶的组织抑制剂)的天然蛋白酶抑制剂一起。
所有这些MMP都可以破坏关节软骨或基膜的多种连接性组织成分。各个MMP以非活性酶原被分泌,该酶原在其能够显示其蛋白水解活性之前,必须在后续步骤中裂解。除了基质破坏作用之外,这些MMP的某一些如MMP-3已经含有作为其它MMP如MMP-1和MMP-9的体内活化剂的意义(Ito,A.;Nagase,H.生物化学与生物物理文章(Arch.Biochem.Biophys.)267,211-6(1988);Ogata,Y.;Enghild,J.J.;Nagase,H.,生物化学杂志,
267,3581-4(1992))。因此,一系列蛋白水解活性可以由过量的MMP-3引发。这意味着特定的MMP-3抑制剂将限制那些不直接由这类抑制剂抑制的其它MMP的活性。
也已经报道,MMP-3可以裂解并因此使其它蛋白酶如弹性蛋白酶的内源性抑制剂失活(Winyard,P.G.;Zhang,Z.;Chidwick,K.;Blake,D.R.;Carrell,R.W.;Murphy,G.FEBS Lett.279,91-4(1991))。因此,MMP-3抑制剂可以通过改变其内源性抑制剂水平而影响其它破坏性蛋白酶的活性。
许多疾病都被认为是由过量或不恰当的基质-破坏性金属蛋白酶活性,或由MMP与TIMP的比例不平衡介导的。这些疾病包括:a)骨关节炎(Woessner,J.F.,Jr.;Selzer,M.G.,生物化学杂志,259,3633-8(1984)和Phadke,K.J.Rheumatol.10,852-60(1983)),b)类风湿性关节炎(Mullins,D.E.;Rohrlich,S.T.Biochim.biophys.Acta 695,117-214(1983),Woolley,D.E.;Crossley,M.J.;Evanson,M.J.ArthritisRheum.20,1231-9(1977),和Gravallese,E.M.;Darling,J.M.;Ladd,A.L.;Katz,J.N.;Glimcher,L.H.Arthritis Rheum.34,1076-84(1991),c)脓毒性关节炎(Williams,R.J.,III;Smith,R.L.;Schurman,D.J.Arthritis Rheum.33,533-41(1990)),d)肿瘤转移(Reich,R.;Thompson,E.W.;Iwamoto,Y.;Martin,G.R.;Deason,J.R;Fuller,G.C.;Miskin,R.Cancer Res.48,3307-12(1988)和Matrisian,L.M.;et al Proc.Natl.Acad.Sci.U.S.A.83,9413-7(1986)),e)牙周疾病(Overall,C.M.等,牙周研究(Periontal Res.)22,81-8(1987)),f)角膜溃疡(Burns,E.R.等,眼科学研究(Invest.Ophthalmol.Vis.Sci.)30,1569-75(1989)),g)蛋白尿(Baricos,W.H.等,生物化学杂志(Biochem.J.)254,609-12(1988)),h)动脉粥样硬化斑破裂引起的冠状血栓形成(Davies,M.J.等,美国国家科学院刊(Proc.Natl.Acad.Sci.U.S.A.)88,8154-8(1991)),i)动脉瘤主动脉疾病(Vine,N.等,Clin.Sci.81,233-9(1991)),j)生育控制(Woessner,J.F.,Jr.等,Steroids 54,491-9(1989)),k)营养不良表皮松解大疱(Kronberger,A.等,J.Invest.Dermatol.79,208-11(1982)),和l)外伤型关节损伤引起的变性性软骨损失,引起发炎反应的病症,由MMP活性介导的骨质减少,颞下颌关节疾病,神经系统的脱髓鞘疾病,等等(Chantry,A.等,J.Neurochem.50,688-94(1988))。
在关节疾病的情况下,新治疗的需要尤其重要。骨关节炎(OA),类风湿性关节炎(AR)和脓毒性关节炎的主要伤残作用是关节软骨和其附近正常关节功能的进行性损失。市面上没有药物能够预防或减缓这一软骨损失,虽然非甾类消炎药(NSAID)能控制疼痛和肿胀。这些疾病的最终结果是关节功能的彻底丧失,这只能由关节置换手术治疗。预期MMP抑制剂能停止或逆转软骨损失的过程避免或延缓外科干扰。
蛋白酶在转移的癌症的过程中在几个阶段是关键元素。在此方法中,结构蛋白质在基膜中的蛋白水解降解引起在第一位点的肿瘤的扩散,从该位点离开并返回,并在远离的第二位点发病。而且,肿瘤诱导的血管生成对于肿瘤生长是需要的,并依赖于蛋白水解组织改造。各种类型的蛋白酶的转染实验已经显示,基质金属蛋白酶,尤其是,明胶酶A和B(分别为MMP-2和MMP-9)在这些过程中扮演重要的角色。这些领域的概况参见Mullins,D.E等,Biochim.Biophys.Acta 695,177-214(1983),Ray,J.M.等,Eur.Respir.J.7,2062-72(1994)和Birkedal-Hansen,H等,Crit.Rev.Oral.Biol.Med.4,197-250(1993)。
而且,可以显示,由天然基质金属蛋白酶抑制剂TIMP-2(一种蛋白质)的胞外基质的降解抑制阻止癌症生长(De Clerck,Y.A等,癌症研究,52,701-8(1992)),并且,TIMP-2在实验系统中抑制肿瘤-诱导的血管生成(Moses,M.A等,科学,248,1408-10(1990))。综述参见De Clerck,Y等,Ann.N.Y.Acad.Sci.732,222-32(1994)。也已证明,当腹膜内给药时,合成的基质金属蛋白酶抑制剂batimastat抑制人结肠肿瘤生长,并在裸鼠体内在正位模型中传布(Wang,X等,癌症研究,54,4726-8(1994))并延长带有人卵巢癌外移植物大鼠的存活(Davies,B等,癌症研究,53,2087-91(1993))。这和相关化合物的应用已经在WO-A-9321942中描述。
有几份专利和专利申请公开了用于阻滞转移的癌症,促进肿瘤退化,抑制癌细胞增生,延缓或预防与骨关节炎相关的软骨损失,或用于治疗上面指出的其它疾病的金属蛋白酶抑制剂(例如WO-A-9519965,WO-A-9519956,WO-A-9519957,WO-A-9519961,WO-A-9321942,WO-A-9421625,USP-4599361;USP-5190937;EP-0574758A1,1993,12月22公开;1988年8月3日公开的EP-026436A1;和1992年12月30日公开的EP-0520573A1)。这些专利的优选的化合物具有在一端带有锌配位基(异羟肟酸,硫醇,羧酸或次膦酸)的肽骨架和许多侧链,既有在天然氨基酸发现的也有带有更新的官能团的。这类小肽常常不易吸收,显示低的口服生物利用率。它们也进行快速蛋白水解代谢,具有很短的半寿期。作为例子,batimastat,在WO-A-9321942中描述的化合物,只能腹膜内给药。
需要相对于现有技术的以肽为基础的化合物具有改进的生物利用率和生物稳定性,并可以使其最佳化,用于抗特定的靶MMP的有效MMP抑制剂。这类化合物是本申请的主题。
提要
其中
R1表示独立地选自如下组成的取代基
C6-C12烷基;
C5-C12烷氧基;
C5-C12烷硫基;
式R2O(C2H4O)a-的聚醚;其中
a是1或2;和
R2是C1-C5烷基,苯基,或苄基;和
式R3(CH2)b-C≡C-取代的炔基;其中
b是1-10;和
r3是H-,HO-,或R4O-,其中
R4是C1-C3烷基,苯基,或苄基;
R1的烷基,苯基,和苄基部分可以带有至少一个药学上可接受的取代基;
下标n是2-4;
R5表示独立地选自如下组成的基团
苯基;
4-12个碳原子的亚氨基;
(3H)-苯并-1,2,3-三嗪-4-酮-3-基
N-糖精基;
(2H)-2,3-二氮杂萘-1-酮-3-基;
2-苯并噁唑啉-2-酮-3-基;
5,5-二甲基唑烷-2,4-二酮-3-基;和
噻唑烷-2,4-二酮-3-基;
R5苯基和苯并部分可以带有至少一个药学上可接受的取代基;
和其药用盐。
除上述化合物外,本发明也涉及具有基质金属蛋白酶抑制活性的药物组合物,该组合物包含上述,更详细地在下面的详细说明中说明的本发明化合物,和药学上可接受的载体。
本发明也涉及在哺乳动物体内治疗基质金属蛋白酶-介导的病症以达到效果的方法,包括对哺乳动物施用能有效治疗病症的量的如上所述并在下面的详述中更详细说明的本发明化合物。
详述
本发明的基质金属蛋白酶-抑制化合物包括具有如上所示的通式(I)的4-苯基丁酸衍生物。
R1可以是6-12个碳原子,优选7-11个碳原子的直链或支链,或环状烷基,并任选地带有一个或多个药学上可接受的取代基,这些取代基在下面充分讨论。任何分支或取代优选地在R1基与苯环连接的点相隔至少3个链原子的位置上。
R1也可以是含有5-12个碳原子,优选地6-10个碳原子的直链,支链或环状烷基的烷氧基或烷硫基。这些烷基任选地可以带有一个或多个药学上可接受的取代基,这些取代基在下面充分讨论。任何分支或取代优选地在R1基与苯环连接的点相隔至少3个链原子的位置上。
R1也可以是式R2O(C2H4O)a-的多醚,其中下标“a”是1或2,而R2是1-5个碳原子,优选1-3个碳原子的直链,支链或环状烷基,或苯基,或苄基。R2任选地带有一个或多个药学上可接受的取代基,这些取代基在下面充分讨论。任何分支或取代优选地在R1多醚基与苯环连接的点相隔至少3个链原子的位置上。
R1也可以是下式取代的炔基
R3(CH2)b-C≡C-,
其中下标“b”是1-10,和基团R3是H-,HO-,或R4O-,优选地是HO-基。R4可以是1-3个碳原子的烷基,或苯基,或苄基。R3任选地带有一个或多个药学上可接受的取代基,这些取代基在下面充分讨论。
在式(1)中下标n表示在带有取代基R5的链中亚甲基单位的数量,并且是2-4,但优选地是2-3。
基团R5可以是:
苯基,
4-12个碳原子的亚氨基
下式的N-糖精基
优选地,R5是如上所示的苯二甲酰亚氨基或(3H)-苯并1,2,3-三嗪-4-酮-3-基。在取代基R5中,苯基或苯并环可以任选地带有一个或多个药学上可接受的取代基,这些取代基在下面充分讨论。
可能的取代基包括如下:卤素,低级烷基,卤代烷基,-CN,-NO2,-CO2R6,-OCOR6,CH2OR6,-CONR6R7,-COR6,和-OR8。在这些式中,R6表示H或低级烷基;R7表示H或低级烷基;或R6和R7与它们所连接的氮原子一起形成吗啉环;R8表示H,低级烷基或卤代烷基。术语低级烷基被定义为1-4个碳原子的直链或支链烷基。卤代烷基被定义为被1-3个相同或不同的卤原子取代的低级烷基。
除了上面讨论的式(I)化合物之外,本发明也包括这些物质的类似物,包括4-或5-员环结构(没有在式(I)中显示),该环含有母体丁酸的第2和3个碳原子,并可以包括带有基团R5的一些或所有的亚烷基链。这些含环的化合物示于下面图(I’)中,
其中m是2-3;q是0-2,R1和R5如上定义。
本专业熟练的技术人员将认识到,许多本发明化合物存在对映体或非对映体形式,而且在本领域知道,这类立体异构形式通常在生物体系中显示不同的活性。本发明包括对MMP具有抑制活性的所有可能的立体异构体,与其立体异构设计无关,以及其中至少一个具有抑制活性的立体异构体的混合物。
本发明最优选的化合物在下面指出并命名:
4-(4-(3-羟基丙-1-炔基)苯基)-4-氧代-2-(3-苯基丙基)丁酸
4-(4-(己-1-炔基)苯基)-4-氧代-2-(3-苯基丙基)丁酸
4-(4-(6-羟基己-1-炔基)苯基)-4-氧代-2-(3-苯基丙基)丁酸
4-(4-(己-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
4-(4-(6-羟基己-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
4-(4-(3-羟基丙-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
4-(4-己基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
4-(4-(癸-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
4-(4-(3-苯氧基丙-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
4-(4-庚氧基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
4-(4-己氧基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
4-(4-癸氧基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
4-(4-(2-苄氧基乙氧基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
一般制备方法:
本发明的化合物可以容易地通过用已知的化学反应和工艺制备。不过,下列一般制备方法用于帮助读者合成该抑制剂,在下面描述工作实施例的实验部分有更详细具体的实施例。
如果没有在下面特别指出,这些方法的所有可变基团都如一般性说明中所述。对于各种方法,可变下标n独立地定义。当带有给出的符号的可变基团(即R9)在给出的结构中多次应用时,应该理解,这些基团的各个可以独立地在对于该符号定义的范围内变化。
一般方法A-其中R1基团是烷基,烷氧基,烷硫基,或多醚的式(I)化合物通过如在方法A中所示的反应程序方便地制备。因此,可以购买或容易制备的取代的苯II在Friedel-Crafts条件下与卤代乙酰卤反应产生中间体III(合适的溶剂和催化剂见E.Berliner,Org.React.,5,229(1949)或H.Heaney,Comp.Org.Synth.,2,733(1991))。另外,II可以首先与乙酰卤反应形成IV,它然后用,例如,溴卤化产生结构III的中间体。一些结构III的化合物,如2-溴-4-十四烷氧基苯乙酮(III其中R1=C14H29而X=Br),可以购买到。
丙二酸二烷基酯V(R9=乙基,甲基,烯丙基,2-(三甲基甲硅烷基)或叔丁基)用结构VI的取代的烷基卤化物一-烷基化产生结构VII的中间体,然后用III烷基化形成化合物VIII(方法A-1)。另外,反应程序可以变为先用III一-烷基化,然后用VI烷基化产生VIII(方法A-2)。
丙二酸二酯VIII然后转化为二酸IX,然后加热产生本发明化合物I-A。VIII向IX的转化可以由几种途径实现,取决于在R1和R5中所含的官能团对碱或强酸处理的灵敏度。当R5,例如,含有对碱敏感的苯二甲酰亚氨基团时,R9方便地是烯丙基,并通过用反式-二氯二(三苯膦)钯酸/吡咯烷处理而脱除。另外,R9可以是叔丁基,它通过用HCl在诸如二噁烷的溶剂中回流处理而脱除,直接形成本发明化合物。当中间体VIII不含对碱敏感的基团时,如R5是苯基,R9可以通过用氢氧化钠或氢氧化钾水溶液处理而脱除,接着用酸处理产生IX。
在醚或硫醚原料II或IV不能购买的情况下,它们通过苯酚,硫代苯酚或4’-羟基苯乙酮(IV其中R1是OH)与烷基或芳基或芳烷基卤化物在碳酸钾存在下,在溶剂如THF或DMF中反应而制备。另外,苯酚,或4’-羟基苯乙酮可以用Mitsunobu条件以本专业熟练的技术人员公知的工艺,与醇反应(参见O.Mitsunobu,Synthesis,1(1981))。
方法A
一般方法B-其中R1是炔基或取代的炔基的本发明化合物根据一般方法B制备。中间体X根据方法A从可购买到的III(R1=Br)开始制备。X与取代的乙炔XI在Cu(I)/钯试剂存在下反应给出本发明化合物I-B-1。如果需要,这些物质可以在标准条件下氢化产生其中式I的R1是取代的烷基的本发明化合物I-B-2。在某些情况下,R3可以是保护为三烷基甲硅烷基的醇。在这类情况下,甲硅烷基可以通过用酸如三氟乙酸或HF-吡啶试剂处理而脱除。
一般方法C-在某些情况下,如当R5是(3H)-苯并-1,2,3-三嗪-4-酮-3-基,N-糖精基,(2H)-2,3-二氮杂萘-1-酮-2-基,2-苯并噁唑啉-2-酮-3-基,5,5-二甲基噁唑烷-2,4-二酮-3-基,或噻唑烷-2,4-二酮-3-基时,中间体VI不能购买到,但根据方法C制备。可以购买的杂环化合物XII在Mitsunobu条件下与溴代烷醇XIII反应产生所需的中间体VI-C。
一般方法D-含有取代的5-员环的式(I’)化合物最方便由方法D制备。在此方法中,酸XIV(R=H)用在Tetrahedron,Vol.37,Suppl.,411(1981)中所述的原始记录制备。该酸通过用偶合剂如1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐和本专业熟练的技术人员公知的工艺保护为酯(R=苄基或2-(三甲基甲硅烷基)乙基)。取代的溴代苯基XV用镁处理转化为其Grignard试剂,然后与XIV反应产生醇XVI。通过用本专业熟练的技术人员公知的条件,用碱处理其甲磺酸酯,将醇进行消除产生烯烃XVII。另外,XV通过先用正丁基锂在低温(典型地-78℃)将溴化物金属化,接着用氯代三甲基锡处理转化为三甲基锡中间体,而XIV通过与2-[N,N-二(三氟甲磺酰基)氨基]-5-氯吡啶在强非质子酸存在下反应而转化为烯醇三氟甲磺酸酯。锡和烯醇三氟甲磺酸酯中间体然后在Pd0催化剂,CuI和AsPh3存在下偶合,直接产生中间体XVII。XVII臭氧解(用二甲硫处理)产生醛XVIII。另外,用OsO4处理接着用HIO4处理将XVII转化为XVIII。
关键的中间体XVIII向式(I’)化合物I-D的转化分几步完成,取决于侧链官能团R5的同一性。XVIII与Wittig试剂反应,接着氢化产生其中R5是芳烷基的产物。醛XVIII用LAH还原产生醇I-D(R5=OH)。通过用合适的杂环和如方法C中所示的Mitsunobu条件和本专业熟练的技术人员公知的条件转化为苯基酯或N-杂环衍生物;参见O.Mitsunobu,Synthesis,1(1981)。另外,I-D的醇(R5=OH)通过本专业熟练的技术人员公知的条件转化为离去基如甲苯磺酸酯(R5=OTs)或溴化物(R5=Br),然后离去基用硫或叠氮化物亲核试剂置换产生R5=硫醚或叠氮化物的产物,然后还原并酰化产生酰胺(R5=NHAcyl)。醇I-D(R5=OH)直接酰化产生其中R5=OACyl的化合物,而醇与各种烷基卤化物在碱存在下反应产生烷基醚(R5=OR2)。在各种情况下,最后的步骤都是用取决于R和R5稳定性的条件除去酸封端基R产生酸(R=H),但在所有本专业熟练的技术人员周知的各种的条件下,如通过碱水解除去苄基,或通过用氟化四丁基铵处理除去2-(三甲基甲硅烷基)乙基。
方法D
一般方法E-含有四员环的式(I’)化合物根据一般方法E制备。取代的四员环原料酐XXI在如马来酸酐XIX和乙酸烯丙基酯XX之间所示的光化学2+2反应中形成。在产生XXII的系列Friedel-Crafts反应之后,乙酸酯可以通过碱性水解而除去,羧基通过转化为2-(三甲基甲硅烷基)乙基酯而保护。产生的中间体XXIII可以用在一般方法D中所述的工艺转化为带有其它R5基团的式(I’)化合物。
方法E
本发明化合物的合适的药用盐包括与有机或无机碱形成的加成盐。从这类碱衍生的成盐离子可以是金属离子,例如,铝,碱金属离子,如钠或钾,碱土金属离子如钙或镁,或胺盐离子,其中许多是已知用于此目的的。例子包括铵盐,芳基烷基胺如二苄基胺和N,N-二苄基乙二胺,低级烷基胺如甲基胺,叔丁基胺,普鲁卡因,低级烷基哌啶如N-乙基哌啶,环烷基胺如环己基胺或二环己基胺,1-金刚烷基胺,benzathine,或从氨基酸如精氨酸,赖氨酸等衍生的盐。生理上可接受的盐如钠盐或钾盐和氨基酸盐可以如下所述在医药上应用,并且是优选的。
这些和其它不必要是生理上可接受的盐在分离或纯化在下述目的中可接受的产物时是有用的。例如,在通常被称为“经典拆分”的方法中,可购买的对映体纯的胺如(+)-辛可宁在合适的溶剂中可以产生本发明化合物的单个对映体盐晶体,在溶液中留下相反的对映体。因为一个给定的本发明化合物的对映体在生理作用上比其对映体大得多,所以此活性异构体可以以晶体或液相被纯化。该盐通过化合物的酸形式与等当量的,在介质中提供碱性离子的碱反应而生产,其中该盐沉淀或在含水介质中,然后冻干。游离的酸形式可以从盐提供普通中和技术,例如,用硫酸氢钾,盐酸等等获得。
本发明的化合物已经被发现抑制基质金属蛋白酶MMP-3,MMP-9,和MMP-2,因此可以用于治疗或预防与其相关的病症。由于没有在上面列出的其它MMP与上面列出的具有很高程度的同源性,尤其是在催化位点上,因此,可以认为本发明的化合物应该也在不同程度上抑制这类其它MMP。改变分子中芳基部分上的取代基,以及所要求的化合物的丁酸链的取代基,已经证明能影响所列出的MMP的相对抑制。因此,此一般类型的化合物可以通过选择特定的取代基而“调节”,从而使与特定病理状况有关的特定的MMP的抑制被加强,而使不包括的MMP少受影响。
本发明的抑制剂被期望用于人和兽医。因此,本发明涉及通过施用有效量的本发明化合物治疗患有基质金属蛋白酶介导的,如前述的病症的哺乳动物受试者的方法(包括人和/或宠物,肉用动物,竞技动物,或皮毛工业用动物,或观赏动物,例如,小鼠,大鼠,马,牛,羊,狗,猫,等等)。在此治疗方法中,哺乳动物优选地是人。可以实现的效果有:减轻骨关节炎,风湿性关节炎,脓毒性关节炎,牙周疾病,角膜溃疡,蛋白尿,动脉瘤的主动脉疾病,营养不良表皮松解疱,导致炎症反应的病症,由MMP活性介导的骨质减少,颞下领骨关节疾病,或神经系统的脱髓鞘疾病;肿瘤转移的阻滞或创伤型关节损伤引起的变性的软骨损失;降低由动脉粥样硬化斑破裂引起的冠状动脉血栓形成;或改进的生育控制。在此治疗方法中,抑制剂化合物的量是有效抑制至少一种基质金属蛋白酶活性,导致实现所需效果的量。
本发明化合物被用于药物组合物中,该药物组合物含有活性成分加一种或多种药学上可接受的载体,稀释剂,填充剂,粘合剂,和其它赋形剂,取决于期望的给药方式和剂型。
抑制剂的给药可以是本专业人员已知的任何合适的方式。合适的肠胃外给药包括静脉内,关节内,皮下和肌内途径。静脉内给药可以被用于获得药物的峰血浆浓度的急性调节。改进的半寿期和药物对关节腔的靶向瞄准可以通过将药物捕集在脂质体内而加强。通过将配位体掺入结合在滑液特异性大分子上的脂质体的外围,可以改善脂质体向关节腔靶向瞄准的选择性。另外,在有或没有药物胶囊化的情况下,肌内,关节内或皮下贮存注射到可降解的微球,例如,包含聚(DL-丙交酯-co-乙交酯)的微球,可被用于获得药物缓释。由于剂量形式改善的便利,可以用i.p.植入的贮器和间隔如从Pharmacia得到的Percuseal系统。改善的便利和患者的依从也可以通过用注射笔(例如Novo Pin或Q-pen)或无针喷射注射器(例如从Bioject或Becton Dickinson得到的)实现。延缓的零-阶或其它精确的控制释放如脉动释放也可以根据需要,用可植入的泵,将药物通过套管输送到滑液空间而实现。其例子包括皮下植入从ALZA得到的渗透泵,如ALZET渗透泵。
鼻腔输送可以通过将药物掺入生物粘性的颗粒载体(<200μm)如包含纤维素,聚丙烯酸酯或polycarbophil的载体,与合适的吸收增强剂如磷脂或酰基肉碱结合而实现。可购买的系统包括DanBiosys和Scios Nova开发的那些。
口服输送可以通过将药物掺入片剂,包衣片剂,糖衣丸,硬或软胶囊,溶液,乳化液或悬浮液中而实现。口服输送也可以通过将药物掺入设计为将药物释放到消化蛋白酶活性很低的结肠中的肠衣胶囊内而实现。其例子包括分别从ALZA和Scherer Drug Delivery Systems得到的OROS-CT/OsmetTM和PULSINCAPTM系统。其它系统使用通过结肠特殊细菌偶氮还原酶降解的偶氮-交联聚合物,或pH敏感的,通过升高结肠内pH而活化的聚丙烯酸酯聚合物。上述系统可以与广泛可得到的吸收增强剂联合使用。
直肠输送可以通过将药物掺入栓剂而实现。
本发明化合物可以通过加入本专业技术人员已知的各种治疗惰性的无机或有机载体,制成上述制剂。这些例子包括,但不限于,乳糖,玉米淀粉或其衍生物,滑石,植物油,蜡,脂肪,多醇如聚乙二醇,水,蔗糖,醇类,甘油等等。各种防腐剂,乳化剂,分散剂,调味剂,湿润剂,抗氧化剂,甜味剂,着色剂,稳定剂,盐,缓冲剂等等也根据需要被加入,帮助稳定制剂,或帮助增加活性成分的生物利用率,产生在口服剂型情况下可接受味道或气味的制剂。
所应用的药物组合物的量将取决于接受者和被治疗的病症。所需的量不需要过度的实验,由本专业技术人员确定。另外,所需的量可以以测定必需被抑制而治疗病症的靶酶的量为基础进行计算。典型地,每天每千克体重约0.05mg至约150mg的剂量水平(每位成人受试者每天约4mg至约12mg)可以用于治疗上述疾病。但是,应该理解,对于任何特定的受试者,具体的剂量水平将取决于许多因素,包括受试者年龄,体重,总体健康状况,性别,和饮食,所用具体化合物的活性和预期的副作用程度,给药的时间和途径,排泄速率,以及药物联合和被治疗的具体病症的严重程度。
本发明的基质金属蛋白酶抑制剂不仅可以用于治疗上面讨论的病症,而且可以用于金属蛋白酶的纯化,基质金属蛋白酶活性的试验。这类活性试验既可以用天然或合成的酶制剂体外进行,也可以用,例如,其中异常破坏性酶水平被自然发现(用基因突变或转基因动物)或通过施用外源性药剂或通过破坏关节稳定性的手术而诱导的动物模型体内进行。
实验:本文中的Ph是苯基,Me是甲基,THF是四氢呋喃,Bu是丁基,
tBu是叔丁基,Et是乙基。
一般过程:
除非另外说明,所有的反应都在火焰-干燥或烘箱-干燥的玻璃仪器中,在氩气正压下,并在电磁搅拌下进行。敏感的液体和溶液通过注射器或导管转移,并通过橡胶隔膜导入反应器中。除非另外说明,反应产物溶液用Buchi蒸发器浓缩。
原料:
商品级的试剂和溶剂不经进一步纯化而使用,只有乙醚和四氢呋喃在氩气中用二苯酮羰游基常规蒸馏,二氯甲烷在氩气中用氢化钙蒸馏。许多特殊的有机或金属有机原料和试剂从Aldrich,1001 West Saint Paul Avenue,Milwaukee,WI 53233得到。溶剂通常如VWR Scientific分类的从EMScience得到。
色谱:
分析薄层色谱(TLC)在Whatman预涂的玻璃支载的硅胶60 A F-254μm板上进行。斑点的显色通过下列技术之一进行:(a)紫外光照,(b)暴露于碘蒸汽中,(c)将板浸入磷钼酸的10%乙醇溶液,然后加热,和(d)将板浸入含有0.5%浓硫酸的对-甲氧基苯甲醛的3%乙醇溶液,然后加热。
柱层析用230-400目EM Science硅胶进行。
分析性高效液相色谱(HPLC)在lmL min-1在4.6×250mm Microsorb柱上进行,在288nm监测,而半制备性HPLC在24mL min-1在21.4×250mmMicrosorb柱上进行,在288nm监测。
仪器:
熔点(mp)用Thomas-Hoover熔点仪测定,并且未经校正。
质子(1H)核磁共振(NMR)谱用General Electric GN-OMEGA 300(300MHz)光谱仪测量,碳13(13C)NMR谱用General Electric GN-OMEGA 300(75MHz)光谱仪测量。在下面实验中合成的大部分化合物通过nmr分析,并且在各种情况下,光谱与假设的结构一致。
质谱(MS)数据在Kratos Concept 1-H光谱仪上,用液体-铯二代离子(LCIMS),一个快速原子轰击(FAB)的版本,获得。在下面实验中合成的大部分化合物通过质谱分析,并且在各种情况下,光谱与假设的结构一致。
一般解释:
对于多步工艺,相继的步骤用数字标明。步骤内的变化用字母标明。在表格数据中的划线指连接点。
实验过程
将2-L三颈圆底烧瓶装上搅拌棒,等压滴液漏斗,氩气导管和温度计。将烧瓶内装上氢化钠(8.4g 95%的NaH;~0.33mol)的干燥THF(700mL)悬浮液,并用冰水浴冷却。在25分钟内从滴液漏斗滴加丙二酸二乙基酯(48.54g,0.30mol)。继续搅拌1.5小时,然后在10分钟内通过滴液漏斗加入1-溴-3-苯基丙烷(47mL,~61g,~0.30mol)。滴液漏斗的清洗液(THF,2×10mL)被加入反应混合物中并继续搅拌30分钟。滴液漏斗和温度计用回流冷凝管和塞子代替,反应加热回流19小时。将混合物冷却至室温,然后用冰水浴冷却。在搅拌下慢慢加入蒸馏水(400mL)。分层,水相用氯仿(100mL)萃取。合并的有机层用10%盐酸(250mL)洗涤,分出的水相用氯仿(100mL)反萃取。合并的有机层用保护碳酸氢钠(250mL)洗涤,分出的水相用氯仿(100mL)反萃取。有机相被干燥(硫酸钠)并浓缩,产生黄色油状物,在减压下(0.4torr)用Vigreux柱蒸馏纯化。在124-138℃沸腾的馏分是纯的所需的化合物(57.21g,0.206mol;68%的产率)。TLC(己烷-二氯甲烷,1∶1):Rf=0.32。
步骤2:制备2-(3-苯基丙基)-2-(2-氧代-(4-溴苯基)乙基)丙二酸二乙基酯
往配有橡胶隔膜和氩气针导管的一颈1000mL圆底烧瓶中装入THF(300mL)和(3-苯基丙基)丙二酸二乙基酯(75.0g,270mmol)。在0℃往溶液中慢慢地分批加入氢化钠(6.48g,270mmol)。产生的混合物在0℃搅拌30分钟,并在室温下搅拌1小时。然后将反应混合物冷却至0℃,并加入2,4’-二溴苯乙酮(90.3g,325mmol)。产生的混合物在室温下搅拌30小时。将反应混合物用食盐水(300mL)稀释,并用乙酸乙酯(200ml,150ml×3)萃取。合并的有机相用硫酸镁干燥,过滤,并浓缩产生褐色油状物,在步骤3中直接使用。TLC(5%乙酸乙酯-己烷)Rf=0.24。
往配有氩气导管接管的一颈1000mL圆底烧瓶中装入乙醇(150mL),THF(150mL),步骤2的产物,和2N氢氧化钠水溶液(300mL)。产生的混合物在室温下搅拌48小时,之后,TLC分析表明反应未完成。再加入氢氧化钠(166g 50%水溶液),反应混合物在室温下搅拌24小时。反应混合物然后用50%盐酸水溶液酸化至pH 1,用乙酸乙酯(200mL和150ml×3)萃取。合并的有机相用硫酸镁干燥,过滤,并浓缩产生150g黄色固体,直接在步骤4中使用。
步骤4:
将上述步骤3的产物溶于200ml二烷,并在85-90℃搅拌12小时,然后回流24小时。然后将反应混合物真空浓缩,产生的残余物用乙酸乙酯/己烷重结晶给出53g(43%)4-(4-溴苯基)-4-氧代-2-(3-苯基丙基)丁酸(化合物A)黄色固体。MP147℃。
步骤1:制备丙二酸二烯丙基酯
将丙二酸(100g,0.96mol)的烯丙基醇(250mL)溶液用硫酸(0.25mL)处理并加热至70℃12小时。冷却至室温后,将溶液浓缩至原体积的1/3,并用己烷(500mL)稀释。混合物依次用饱和碳酸钠和氯化钠水溶液洗涤。有机层用硫酸钠干燥,过滤并减压浓缩。通过蒸馏(85℃@0.01mmHg)纯化,产生丙二酸二烯丙基酯(156g,88%)无色油状物。
1H NMR(300MHz,CDCl3)d 5.85(m,2H),5.30(m,2H),5.20(m,2H),4.60(m,4H),3.40(s,2H).
将氢化钠(4.35g,0.18mol)在新鲜蒸馏的THF(100mL)中的溶液冷却至0℃,并在40分钟内通过滴液漏斗用丙二酸二烯丙基酯(35g,0.19mol)处理。室温搅拌30分钟后,往溶液中一次加入N-(2-溴乙基)苯二甲酰亚胺(43.9g,0.17mol),混合物被加热回流。48小时后,溶液被冷却至0℃,用2N盐酸淬灭,并浓缩至原体积的约20%。浓缩物用乙酸乙酯(300mL)稀释,并依次用碳酸钠和氯化钠水溶液洗涤。有机层用硫酸镁干燥,过滤并减压浓缩。通过快速层析纯化(5-25%乙酸乙酯∶己烷)产生(2-苯二甲酰亚氨基乙基)丙二酸二烯丙基酯(41.2g,67%)无色油状物。1H NMR(300 MHz,CDCl3)d 7.82(m,2H),7.72(m,2H),5.85(m,2H),5.30(m,2H),5.22(m,2H),4.60(m,4H),3.80(t,J=6.6Hz,2H),3.46(t,J=7.2Hz,1H),2.30(dd,J=13.8,6.9Hz,2H).
步骤3:制备2-(2-苯二甲酰亚氨基乙基)-2-(2-氧代-2-(4-溴苯基)乙基)丙二酸二烯丙基酯用于制备化合物A的步骤2的一般操作被用于制备上述取代的丙二酸二烯丙基酯中间体,用(2-苯二甲酰亚氨基乙基)丙二酸二烯丙基酯代替(3-苯基丙基)丙二酸二乙基酯,而叔丁醇钠代替氢化钠。
往配有氩气入口接管的一颈100mL圆底烧瓶中装入二烷(50mL),步骤3的粗产物(26mmol,对于步骤3产率100%),和吡咯烷(4.8mL,57mmol,2.2eq.)。混合物通过轻微的真空脱气,并用氩气冲洗。然后加入反式-二氯二(三苯膦)钯(325mg,0.26mmol)。产生的混合物在室温下搅拌5天并浓缩。残余物直接在步骤5中使用。
步骤5:
用于制备化合物A的一般方法被用于从上述步骤4的产物制备4-(4-溴苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸(化合物B)。MP185℃(分解)。
化合物C:制备4-苯基-4-氧代-2-(3-苯基丙基)丁酸往配有橡胶隔膜,搅拌棒和回流冷凝管的一颈,25mL圆底烧瓶内装入化合物A(0.750g,2.0mmol)和三苄基胺(1.334g,4.8mmol)。将系统真空干燥并用氩气冲洗。加入四(三苯膦)钯(0)(0.124g,0.10mmol),将系统真空干燥并再次用氩气冲洗。加入乙腈(5mL)和DMSO(5mL),混合物在室温下搅拌15分钟。往产生的清亮黄色油状物中加入聚(甲基氢硅氧烷)(0.8mL),混合物在105℃搅拌16小时。然后将反应混合物冷却至室温,用乙酸乙酯(200mL)稀释,并用1N盐酸(50mL×3)洗涤。分出有机层,用硫酸镁干燥并浓缩给出1.5g粗产物,在50g硅胶上用柱层析纯化(15%,30%和45%乙酸乙酯含有0.5%乙酸的己烷溶液,各500mL),随后用二氯甲烷/己烷重结晶给出0.181g(31%)化合物C。MP84-85℃;MS HRMS 297.14907(M+H)+,计算值296.1407。
用于制备化合物C的一般操作被用于从化合物B制备化合物D。MP165-166℃;MS HRMS 352.11850(M+H)+,计算值351.1102。
实施例1:制备4-(4-(3-羟基丙-1-炔基)苯基)-4-氧代-2-(3-苯基丙基)丁酸
结构示于表1中
往配有氩气入口接管的一颈,25mL圆底烧瓶内装入化合物A(750mg,2mmol),CuI(19mg,0.10mmol)和反式-二氯二(三苯膦)钯(70mg,0.056mmol)。将产生的混合物真空干燥并用氩气冲洗。加入DMF(5mL),三乙胺(5mL)和炔丙基醇(3mL),产生的混合物在95℃搅拌3天。然后将反应混合物用乙酸乙酯(100mL)稀释,滤过硅藻土并真空浓缩。残余物用硅胶纯化两次(用第一柱用5%异丙醇的二氯甲烷溶液,第二柱用含有0.5%乙酸的25%乙酸乙酯的己烷溶液)给出108mg所需的产物油状物。MS(FAB-LSIMS)352[M+1]+。
实施例2和3:制备4-(4-(己-1-炔基)苯基)-4-氧代-2-(3-苯基丙基)丁酸和4-(4-(6-羟基己-12-炔基)苯基)-4-氧代-2-(3-苯基丙基)丁酸
结构示于表1中
实施例1的一般操作被用于制备所需的化合物,从合适的取代的乙炔代替炔丙基醇。
化合物E和实施例4:制备4-(6-(叔丁基二甲基甲硅烷氧基)己-1-炔基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸和4-(己-1-炔基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
结构示于表2中
实施例1的一般操作被用于制备化合物E和实施例4的化合物,用合适的乙炔类代替炔丙基醇,化合物B代替化合物A。
实施例5:制备4-(4-(6-羟基己-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
结构示于表2中
往配有氩气入口接管的一颈,25mL圆底烧瓶内装入化合物E(150mg,0.27mmol)的二氯甲烷(4mL)溶液。加入氟化氢-吡啶试剂(2mL,Fluka),产生的混合物在0℃搅拌10分钟,然后在室温下搅拌25分钟。然后将反应混合物倒入碳酸氢钠水溶液(150mL)中,并用二氯甲烷(100mL)萃取。有机层用1N盐酸洗涤两次,硫酸镁干燥并浓缩给出160mg粗产物,色谱纯化给出100mg所需的产物。
实施例6:制备4-(4-(3-羟基丙-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
结构示于表2中
用于制备化合物E和实施例5的化合物的一般操作被用于程序中,从3-(叔丁基二甲基甲硅烷氧基)丙炔开始,而不是6-(叔丁基二甲基甲硅烷氧基)己炔,制备所需的产物。MS HRMS 406.12906(M+H),计算值405.1207。
实施例7:制备4-(4-己基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
结构示于表2中
往配有橡胶隔膜和通过针状导管连接的氢气球的一颈,10mL圆底烧瓶内装入2mL二烷,实施例4的化合物(0.200g,0.46mmol)和5%Pd/C(0.005g)。产生的混合物在室温下搅拌24小时并滤过硅藻土。真空除去溶剂后,残余物用乙酸乙酯/己烷重结晶给出所需的产物(130mg,65%)。
实施例8和9:制备4-(4-十二碳-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸和4-(4-(3-苯氧基丙-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
结构示于表2中
用于制备实施例1化合物的一般操作被用于制备实施例8和9的化合物,分别用1-十二炔或苯基炔丙基醚代替炔丙基醇,化合物B代替化合物A。表2实施例 R 异构体 MP.(℃)/ 其它特征对比例 t-BuMe2SiO(CH2)4C≡C R,S 151-1524 CH3(CH2)3C≡C R,S 1365 HO(CH2)4C≡C R,S 131-1326 HOCH2C≡C R,S NA7 n-C6H13 R,S 1098 CH3(CH2)9C≡C R,S9 C6H5OCH2C≡C R,S
实施例10:制备4-(4-庚氧基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
结构示于表3中
将含有4’-羟基苯乙酮(Aldrich,1.00g,7.35mmol)和干燥的碳酸钾(1.02g,7.35mmol)的25mL圆底烧瓶用氩气冲洗,并装入无水DMF(Aldrich,7.5mL),接着装入1-碘代庚烷(Aldrich,1.20mL,7.35mmol)。混合物在室温下搅拌47小时,然后用水稀释,并用乙酸乙酯(2×)萃取。将有机相合并,依次用饱和碳酸氢钠和食盐水洗涤,硫酸镁干燥,过滤并浓缩给出1.7626g米色油状物。粗产物开始色谱(40mL,硅胶,20%乙酸乙酯-己烷),给出1.5346g(6.5487mmol,89%)纯的4’-庚氧基苯乙酮无色油状物。Rf0.48(25%乙酸乙酯-己烷)。
往配有搅拌棒,滴液漏斗,隔膜,和氩气导管的25mL三颈圆底烧瓶用氩气冲洗,然后用加热枪干燥。往烧瓶中装入无水THF(Aldrich,5.58mL),冷却至约-70℃,然后加入二(三甲基甲硅烷基)氨化锂(Aldrich,1.0M,3.36mL,3.36mmol)和氯代三甲基甲硅烷(Aldrich,0.43mL,3.36mmol)。在氩气中,20分钟内,滴加4’-庚氧基苯乙酮(第一步的)无水THF(3.72mL)溶液,保持内部温度约-70℃,将溶液在-78℃再搅拌38分钟。一次加入净N-溴代丁二酰亚胺(Aldrich,658mg,3.70mmol),然后在-78℃再搅拌40分钟,将溶液分配在水和己烷之间。分出有机层,用食盐水洗涤两次,硫酸镁干燥,过滤,浓缩给出1.0740g(1.447mmol,43%)所需产物白色固体。Rf0.52(25%乙酸乙酯-己烷)。
将叔丁醇钠(Aldrich,150mg,1.56mmol)的THF(Aldrich,1.0mL)溶液在冰浴中冷却。往此溶液中加入(2-苯二甲酰亚氨基乙基)丙二酸二烯丙基酯(507mg,1.42mmol)的干燥THF(0.9mL)溶液。约20分钟后,通过注射器加入2-溴-4’-庚氧基苯乙酮(步骤2的,444mg,1.42mmol)的干燥THF(1.4mL)溶液,并在室温下搅拌1.5小时,然后加入碘化钠(净,2.1mg,0.01mmol)。混合物被搅拌89小时,然后用10%盐酸(8mL)淬灭,用水稀释,乙酸乙酯萃取。有机层用水和食盐水(2×)洗涤,硫酸镁干燥,过滤,浓缩给出721.3mg黄色油状物。硅胶柱层析(10%乙酸乙酯-己烷)给出415.4mg(0.704mmol,50%)所需产物的无色油状物。Rf0.22(25%乙酸乙酯-己烷)。
步骤4:
将含有步骤3产物的25mL圆底烧瓶(415.4mg,0.7044mmol)在氩气中装入二烷(14.6mL)并脱气。往此溶液中加入四(三苯膦)钯(Alfa,11mg,10μmol),接着加入吡咯烷(Aldrich,129μL,1.55mmol),混合物在室温下搅拌24小时,乳白色混合物被加热回流2小时。产生的米色溶液被冷却至室温并浓缩给出375.6mg米色油状物。快速色谱(硅胶,1%甲醇-二氯甲烷)给出35.9mg(0.077mmol,11%)标题化合物无色油状物,最清的部分放置固化。MP121-122℃;TLC(10%甲醇-二氯甲烷)Rf0.56。
实施例11:制备4-(4-己氧基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
结构示于表3中
将碘代己烷(1.56mL,10.6mmol)和苯酚(1.0g,10.6mmol)的无水THF(25mL)溶液与碳酸钾(1.46g)在氩气中,在圆底烧瓶内回流过夜。产生的反应混合物用乙酸乙酯稀释,并依次用饱和碳酸钠,10%盐酸,和食盐水洗涤。萃取液用硫酸镁干燥并真空蒸发,产生1.35g所需的产物,不经进一步纯化直接用于下步。
将步骤1的产物(250mg,1.40mmol)的二氯甲烷(5mL)溶液在氩气中搅拌,然后依次加入三氯化铝(205.5mg,1.5mmol)和溴代乙酰基溴(0.03mL,1.5mmol)。反应混合物在室温下搅拌过夜,然后倒入冰/浓盐酸中,用二氯甲烷萃取。将萃取液真空干燥。反应用500mg步骤1的产物和按比例的其它试剂重复,唯一的改变是最后在0℃加入氯化铝,然后在0℃搅拌2小时,最后在室温搅拌过夜,然后如在第一种操作中分离产物。两种操作中的粗产物被合并,并在硅胶上用己烷和乙酸乙酯混合物层析给出233mg纯化的所需产物。
步骤3和4:
实施例10的步骤3和4的一般操作,但用上述步骤2的产物代替4’-庚氧基-2-溴代苯乙酮,用于制备实施例11的化合物。
实施例12:制备4-(4-癸氧基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
结构示于表3中
所需的癸基化合物以类似于实施例10的方式制备,但用碘代癸烷代替碘代庚烷。
实施例13:制备4-(4-(2-苄氧基乙氧基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
结构示于表3中
步骤1:制备4’-((2-苄氧基乙氧基)苯基)苯乙酮往三苯膦(Aldrich,11.56g,44.07mmol)在50ml乙醚和50mL THF中的溶液中加入二乙基偶氮二羧酸(Aldrich,6.94mL,44.07mmol)。将溶液在室温下搅拌5分钟,然后加入4’-羟基苯乙酮(Aldrich,5.00g,36.72mmol),搅拌约10分钟后,加入2-苄氧基乙醇(Aldrich,5.22mL,36.72mmol)。搅拌4.75小时后,将溶液浓缩,用乙醚稀释,用水(3×)和食盐水洗涤,硫酸镁干燥,过滤,并浓缩给出27.96g褐色油状物。将此物溶于乙醚,过滤沉淀,将滤液浓缩给出25.71g米色油状物。柱层析(硅胶,2%甲醇-二氯甲烷)给出1.6767g(6.20mmol,17%)所需化合物的米色油状物。TLC(25%乙酸乙酯-己烷)Rf0.24。
步骤2-4:
所需的物质用实施例10步骤2至4的一般方法生产,只是用上述步骤1的产物代替4’-庚氧基苯乙酮。
化合物F:制备4-(4-十四烷氧基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
结构示于表3中
用实施例10步骤3和4的一般方法制备所需的化合物,只是用购买的中间体2-溴-4’-十四烷氧基苯乙酮(Salor)代替2-溴-4’-庚氧基苯乙酮。
化合物G:制备4-(4-甲氧基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸
结构示于表3中
用实施例10,步骤3的一般方法制备所需的化合物,只是用购买的中间体2-溴-4’-甲氧基苯乙酮(Aldrich)代替2-溴-4’-庚氧基苯乙酮,双-二甲基酯代替双-二烯丙基酯。
步骤2:
将步骤1的双-二甲基酯(94.4mg)放入一个2mL的小瓶内,溶于20%盐酸-乙酸中,将小瓶密封并加热至约105℃。15小时后,将溶液冷却至室温,用水稀释,分配于乙酸乙酯中。有机层用水洗涤5次,合并的水层用乙酸乙酯反萃取,将有机层合并,硫酸镁干燥,过滤,浓缩给出73.3mg黑色半固体。用乙酸乙酯-己烷结晶给出28.1mg褐色固体。该物然后用乙酸乙酯洗涤几次,保留的固体作为所需的产物分离(10.8mg米色固体,28.3μmol,14%)。MP 191-192℃。
表3实施例 R 异构体 m.p.(℃)/其它特征10 n-C7H15O R,S 121-12211 n-C6H13O R,S12 n-C10H21O R,S 119-12013
R,S 161-162对比. F n-C14H29O R,S 125-126对比. G CH3O R,S 191-192
将2,3-二氮杂萘酮(1.00g,6.84mmol)和三苯膦(1.79g,6.84mmol)的THF(25mL)溶液冷却至0℃,并用溴代乙醇(0.480mL,6.84mmol)和二乙基偶氮二羧酸酯(1.07mL,6.84mmol)处理。在0℃搅拌1小时后,将溶液温热至室温,再搅拌12小时。将产生的混合物浓缩,通过柱层析纯化(35%乙酸乙酯-己烷)给出1.40g(81%)所需的化合物白色固体。TLC:Rf0.65(40%乙酸乙酯-己烷)。
将氢化钠(0.040g,1.54mmol)的THF(5mL)溶液冷却至0℃,并小心地用丙二酸二烯丙基酯(0.260g,1.41mmol)处理。温热至室温后,搅拌20分钟,一次加入步骤1的溴代乙基2,3-二氮杂萘(0.325g,1.28mmol),混合物加热回流18小时。反应混合物用饱和NH4Cl(20ml)和EtOAc(20ml)稀释。产生的有机相用水洗涤,硫酸镁干燥,过滤并浓缩给出0.240g(52%)黄色油状物。TLC:Rf0.60(40%乙酸乙酯-己烷)。
步骤3:制备2-溴-4’-十二烷硫基苯乙酮
实施例11步骤1和2的一般方法可以通过用碘代十二烷代替碘代己烷,硫代苯酚代替苯酚而用于制备所需的化合物。
步骤4和5:
实施例10步骤3和4的一般方法,但用上述步骤3的产物代替4’-庚氧基-2-溴代苯乙酮,上述步骤2的产物代替(2-苯二甲酰亚氨基乙基)丙二酸二烯丙基酯,可以被用于制备实施例14的化合物。
实施例15:制备4-(4-戊氧基苯基)-4-氧代-2-(2-((3H)-苯并-1,2,3-三嗪-4-酮-3-基)乙基)丁酸
结构示于表4中
步骤1和2:制备2-(2-((3H)-苯并-1,2,3-三嗪-4-酮-3-基)乙基)丙二酸二烯丙基酯
实施例14步骤1和2的一般方法可以用苯并-1,2,3-三嗪-4(3H)-酮代替2,3-二氮杂萘酮开始,用于制备上述苯并三嗪酮中间体。
实施例11步骤1和2的一般方法可以用碘代戊烷代替碘代己烷而用于制备2-溴-4’-戊氧基苯乙酮。
步骤4和5:
实施例10步骤3和4的一般方法,但用上述步骤3的产物代替4’-庚氧基-2-溴代苯乙酮,上述步骤2的产物代替(2-苯二甲酰亚氨基乙基)丙二酸二烯丙基酯,可以用于制备实施例15的化合物。
实施例16,17,18和19:制备4-(4-戊氧基苯基)-4-氧代-2-(2-(N-糖精基)乙基)丁酸;4-(4-戊氧基苯基)-4-氧代-2-(2-(苯并 唑啉-2-酮-3-基)乙基)丁酸;4-(4-戊氧基苯基)-4-氧代-2-(2-(5,5-二甲基唑烷-2,4-二酮-3-基)乙基)丁酸;和4-(4-戊氧基苯基)-4-氧代-2-(2-(噻唑烷-2,4-二酮-3-基)乙基)丁酸
结构示于表4中
与实施例15有关的一般方法通过分别用糖精,2-苯并唑啉酮,5,5-二甲基唑烷-2,4-二酮,或噻唑烷-2,4-二酮代替苯并-1,2,3-三嗪-4(3H)-酮,制备这些化合物。
生物学方法和体外试验数据
MMP抑制剂的P218熄灭荧光试验
P218熄灭荧光试验(P218 quenched fluorescence assay)(微荧光计剖面分析试验(profiling assay))是最初由C.G.Knight等,FEBS Letters,296,163-266(1992)所述的,在小杯中对于相关底物和许多基质金属蛋白酶(MMP)试验的修改。该试验用本发明的各个实施例化合物和三种MMP,MMP-3,MMP-9和MMP-2进行,适合于在96-孔微滴板和Hamilton AT工作站中如下平行地分析。
P218荧光团底物(Fluorogenic Substrates)
P218是在N-端位置含有4-乙酰基-7-甲氧基香豆素(MCA)基团,并在内部含有3-(2,4-二硝基苯基)-(L)-2,3-二氨基丙酰基(DPA)基团的合成底物。这是由Knight(1992)报道的,用作基质金属蛋白酶底物的肽的修饰物。一旦P218肽裂解(在Ala-Leu键上推定的剪断位点),MCA基团的荧光可以在荧光计上被检测,在328nm激发,在393nm发射。P218目前由BACHEMBioscience,Inc.为Bayer Corp独家生产。P218具有如下结构:
H-MCA-Pro-Lys-Pro-Leu-Ala-Leu-DPA-Ala-Arg-NH2(MW 1332.2)重组人CHO溶基质素(MMP-3):
重组人CHO Pro-MMP-3:人CHO Pro-溶基质素-257(pro-MMP-3)如T.J.Housley等,生物化学杂志,268,4481-4487(1993)所述的被表达和纯化。
Pro-MMP-3的活化:Pro-MMP-3以1.72μM(100μg/mL)在由pH 7.5的5mM Tris,5mM氯化钙,25mM氯化钠,和0.005%Brij-35组成的MMP-3活化缓冲液中用TPCK(N-甲磺酰基-(L)-苯丙氨酸氯甲基酮)胰蛋白酶(1∶100w/w对pro-MMP)在25℃温育30分钟而活化。反应通过加入大豆胰蛋白酶抑制剂(SBTI;5∶1w/w对胰蛋白酶浓度)而终止。此活化的方法导致45kDa活性MMP-3的形成,其还含有酶的C-端部分。
制备人重组Pro-明胶酶A(MMP-2):
根据R.Fridman等,生物化学杂志,267,15398-405,(1992)的方法,用痘苗表达系统制备人重组Pro-MMP-2:人pro-明胶酶A(Pro-MMP-2)。
Pro-MMP-2的活化:252mg/mL的Pro-MMP-2在由pH 7.5的25mMTris,5mM氯化钙,150mM氯化钠,和0.005%Brij-35组成的MMP-2活化缓冲液中稀释1∶5至最终浓度50mg/mL。对氨基苯基汞乙酸盐(APMA)以10mM(3.5mg/mL)在0.05N氢氧化钠中制备。以1/20反应体积加入APMA溶液,使最终APMA浓度为0.5mM,将酶在37℃温育30分钟。将活化的MMP-2(15mL)对2L MMP-2活化缓冲液(渗透膜用由MMP-2活化缓冲液中0.1%BSA组成的溶液预处理1分钟,接着彻底水洗)。将酶在Centricon浓缩器(浓缩器也用由MMP-2活化缓冲液中0.1%BSA组成的溶液预处理1分钟,接着水洗,然后用MMP-2活化缓冲液洗涤),再稀释,接着重复再浓缩两次。将酶用MMP-2活化缓冲液稀释至7.5mL(原始体积的0.5倍)。
制备人重组Pro-明胶酶B(MMP-9):
用杆状病毒蛋白质表达体系将如S.M.Wilhelm等,生物化学杂志,264,17213-17221(1989)所述的从U937 cDNA衍生的人重组Pro-MMP-9:人重组Pro-明胶酶B(PFo-MMP-9)表达为全-长形式。该前-酶用由M.S.Hibbs等,生物化学杂志,260,2493-500(1984)所述的方法纯化。
Pro-MMP-9的活化:在由pH 7.4的50mM Tris,150mM氯化钠,10mM氯化钙,和0.005%Brij-35组成的MMP-9活化缓冲液中的Pro-MMP-9(20μg/mL)通过在37℃,用0.5mM对氨基苯基汞乙酸盐(APMA)温育3.5小时而活化。该酶相对同样的缓冲液渗析而除去APMA。
仪器:
Hamilton Microlab AT Plus:MMP-剖面分析试验用Hamilton MicrolabAT Plus自动化进行。Hamilton被编程为:(1)用抑制剂在100%DMSO中的2.5mM贮存溶液自动连续稀释至11潜在抑制剂;(2)将底物分配在96-孔Cytofluor板中,接种分配抑制剂;和(3)往板中加入单个酶,混合以启动反应。各个附加酶的后续板通过在底物加入的时刻启动程序而自动制备,再与稀释的抑制剂混合,通过加入酶启动反应。以这种方式,所有的MMP试验都用相同的抑制剂稀释液进行。
Millipore Cytofluor II:温育之后,将板在Cytofluor II荧光读数计上读数,该读数计在340nm激发,在395nm发射,放大置于80。
缓冲液:
微荧光计反应缓冲液(MRB):用于微荧光计试验的试验化合物,酶和P218底物的稀释液在由pH 6.5的50mM 2-(N-吗啉代)乙磺酸(MES)与10mM氯化钙,150mM氯化钠,和0.005%Brij-35和1%DMSO组成的微荧光计反应缓冲液(MRB)中制备。
方法:
MMP微荧光计剖面分析试验。该试验用最终P218浓度6μM,大约0.5至0.8nM活化的MMP(每96-孔板1MMP),和可变的抑制剂浓度进行。Hamilton Microlab AT Plus被编程为在试验中,从2.5mM贮存(100%DMSO)连续稀释至11化合物,至最终化合物浓度的10-倍。开始,仪器将各种量的微荧光计反应缓冲液(MRB)输送到96-管架的1mL Marsh稀释管内。该仪器取20μL抑制剂(2.5mM),并将其与Marsh架中A排的缓冲液混合,产生50μM的抑制剂浓度。该抑制剂然后系列地稀释至10,5,1,0.2,0.05和0.01μM。在样品架的位置1上只含有用于试验中的“仅有酶”孔的DMSO,这导致在第1列,A排至H排中没有抑制剂。仪器然后分配107μL P218至单个96-孔Cytofluor微滴板中。将仪器再混合,并从Marsh架上的A排至G排装载14.5μL稀释的化合物到微滴板的相应的排中。(H排表示“背景”排。往其中加入39.5μL微荧光计反应缓冲液代替药物或酶)。通过从BSA-处理的试剂储罐中将25μL合适的酶(最终酶浓度的5.86倍)到各个孔中,排除H排,“背景”排。(酶储罐用在含有150mM氯化钠的pH 7.5的50mM Tris中的1%BSA在室温下预处理1小时,接着用水充分洗涤,并在室温下干燥)。
加入酶并混合后,将该板覆盖并在37℃温育25分钟。附加的酶以相同的方式通过启动Hamilton程序而试验,将P218底物分配在微滴板中,接着再混合,并从相同的Marsh架上将药物分配到微滴板上。然后将第二种(或第三种,等等)被试验的MMP从试剂架上分配到微滴板上,混合然后覆盖和温育。
在微荧光计试验中的IC50测定:在Cytofluor II上产生的数据被从输出的“CSV”文件复制到户主的Excel展开页上。从各种MMP(每个MMP一个96-孔板)得到的数据被同时计算。各个药物浓度的抑制百分数通过比较含有化合物的孔与在1列中“仅有酶”孔的水解量(水解25分钟时产生的荧光单位)而测定。减去背景,如下计算抑制百分数:
((对照值-处理值)/对照值)×100
对于抑制剂浓度5,1,0.5,0.1,0.02,0.005和0.001μM,测定抑制百分数。抑制百分数对抑制剂浓度的对数的线性回归分析被用于获得IC50值。
某些本发明化合物的剖面分析试验数据
表5
MMP-剖面分析数据。所用IC50值都被表达为nM。当显示“I=x%”时,x表示在5μM的%抑制。
实施例号或对照化合物 | MMP-3IC50 | MMP-9:IC50 | MMP-2IC50 |
B | I=46% | 1,450 | 2,400 |
C | I=20% | I=23% | I=36% |
D | 5,000 | 1,000 | 1,400 |
1 | 3,300 | 1,850 | 485 |
2 | 1,875 | 1,575 | 460 |
3 | I=43% | 4,350 | 640 |
E | 5,100 | 5,050 | 1,450 |
4 | 125 | 20 | 42 |
5 | 870 | 150 | 92 |
6 | 565 | 76 | 130 |
7 | 1,040 | 400 | 295 |
10 | 61 | 85 | 40 |
11 | 114 | 68 | 79 |
12 | 135 | 360 | 135 |
13 | 82 | 355 | 53 |
F | I=18% | I=6% | I=16% |
G | I=29% | I=46% | I=48% |
从上面表5的试验数据可以清楚地看出,最佳MMP抑制由约4-13个原子(排除H)的4-苯基环上的取代基的化合物实现。如果取代基的大小较小,如中间体B中的Br,或在对照D中的H,或在对照G中的CH3O,则活性较低。另一方面,如果取代基非常大,如在对照F中的C14H29O,活性也低。
也可以清楚地看出,在4-苯环上的取代基的具体结构影响MMP中的活性的选择性。因此,某些化合物如乙炔类(实施例4-6)对于明胶酶(MMP-2和MMP-9)比溶基质素(MMP-3)显示更高的效力,而醚类对于MMP-3和MMP-2比对MMP-9(实施例12和13)要么显示广泛的高活性(实施例10和11),要么高选择性。施用选择性MMP抑制剂的能力将导致药物对于其中明胶酶扮演重要角色,而溶基质素不是很重要的的疾病如癌症,或其中溶基质素被认为扮演最重要的角色,而明胶酶不那么重要的骨关节炎具有更小的副作用。
本发明的其它方案考虑本文公开的本发明说明书或实施,对于本专业技术人员将是显而易见的。说明书和实施例被认为只是举例性的,本发明真正的范围和精神在权利要求书中给出。
Claims (13)
1.具有基质金属蛋白酶抑制活性和如下通式的化合物:其中R1表示独立地选自如下组成的取代基C6-C12烷基;C5-C12烷氧基;C5-C12烷硫基;式R2O(C2H4O)a-的聚醚;其中a是1或2;和R2是C1-C5烷基,苯基,或苄基;和式R3(000CH2)b-C≡C-的取代的炔基;其中b是1-10;和R3是H-,HO-,或R4O-,其中R4是C1-C3烷基,苯基,或苄基;R1的烷基,苯基,和苄基可以带有至少一个药学上可接受的取代基;下标n是2-4;R5表示独立地选自如下组成的基团苯基;4-12个碳原子的亚氨基;(3H)-苯并-1,2,3-三嗪-4-酮-3-基N-糖精基;(2H)-2,3-二氮杂萘-1-酮-3-基;2-苯并噁唑啉-2-酮-3-基;
5,5-二甲基噁唑烷-2,4-二酮-3-基;和
噻唑烷-2,4-二酮-3-基;
R5的苯基和苯并部分可以带有至少一个药学上可接受的取代基;
和其药用盐。
2.权利要求1的化合物,其中R1表示烷基。
3.权利要求1的化合物,其中R1表示烷氧基或烷硫基。
4.权利要求1的化合物,其中R1表示聚醚基。
5.权利要求1的化合物,其中R1表示取代的炔基。
6.权利要求1的化合物,其中R5表示苯基。
7.权利要求1的化合物,其中R5表示亚氨基或(3H)苯并-1,2,3-三嗪-4-酮-3基。
8.权利要求1的化合物,其中R5选自N-糖精基,(2H)-2,3-二氮杂萘-1-酮-2-基,2-苯并噁唑啉-2-酮-3-基,5,5-二甲基噁唑烷-2,4-二酮-3-基,和噻唑烷-2,4-二酮-3-基。
9.权利要求1的化合物,选自:
4-(4-(3-羟基丙-1-炔基)苯基)-4-氧代-2-(3-苯基丙基)丁酸,
4-(4-(己-1-炔基)苯基)-4-氧代-2-(3-苯基丙基)丁酸,
4-(4-(6-羟基己-1-炔基)苯基)-4-氧代-2-(3-苯基丙基)丁酸,
4-(4-(己-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸,
4-(4-(6-羟基己-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸,
4-(4-(3-羟基丙-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸,
4-(4-己基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸,
4-(4-(癸-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸,
4-(4-(3-苯氧基丙-1-炔基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸,
4-(4-庚氧基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸,
4-(4-己氧基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸,
4-(4-癸氧基苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸,
4-(4-(2-苄氧基乙氧基)苯基)-4-氧代-2-(2-苯二甲酰亚氨基乙基)丁酸。
10.一种具有基质金属蛋白酶抑制活性的药物组合物,该组合物包含权利要求1的化合物和药用载体。
11.一种在哺乳动物体内治疗基质金属蛋白酶-介导的病症以达到效果的方法,包括对所说的哺乳动物施用能有效治疗所说的病症的量的权利要求1的化合物。
12.权利要求11的方法,其中所说的哺乳动物是人。
13.权利要求11的方法,其中所说的效果是:减轻骨关节炎,类风湿性关节炎,脓毒性关节炎,牙周疾病,角膜溃疡,蛋白尿,动脉瘤的主动脉疾病,营养不良表皮松解疱,导致炎症反应的病症,由MMP活性介导的骨质减少,颞下领骨关节疾病,或神经系统的脱髓鞘疾病;阻滞肿瘤转移或创伤型关节损伤引起的变性的软骨损失;降低由动脉粥样硬化斑破裂引起的冠状动脉血栓形成;或改进的生育控制;权利要求1的化合物的所述量是在所说的哺乳动物体内有效抑制至少一种基质金属蛋白酶活性,从而实现所说的效果的。
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FR2832925B1 (fr) * | 2001-12-03 | 2006-07-14 | Lipha | Utilisation de derives de l'acide 4-oxobutanoique dans le traitement de l'inflammation |
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US20170022171A1 (en) | 2014-04-03 | 2017-01-26 | Bayer Pharma Aktiengesellschaft | 2,5-disubstituted cyclopentanecarboxylic acids and their use |
WO2015150364A1 (de) * | 2014-04-03 | 2015-10-08 | Bayer Pharma Aktiengesellschaft | Substituierte benzotriazinonbutansäuren und ihre verwendung |
CN106458938A (zh) | 2014-04-03 | 2017-02-22 | 拜耳制药股份公司 | 手性2,5‑二取代的环戊烷甲酸衍生物及其用途 |
WO2015189117A1 (de) * | 2014-06-12 | 2015-12-17 | Bayer Pharma Aktiengesellschaft | Heterobicyclisch substituierte 4-oxobutansäure-derivate und ihre verwendung |
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BE650081A (zh) * | 1963-07-03 | |||
FR2378741A1 (fr) * | 1977-02-01 | 1978-08-25 | Fabre Sa Pierre | Acides garyl goxo isovaleriques doues de proprietes antiphlogistiques et antalgiques |
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- 1997-05-12 WO PCT/US1997/007951 patent/WO1997043237A1/en active IP Right Grant
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- 1997-05-12 AT AT97923625T patent/ATE205822T1/de not_active IP Right Cessation
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN106661008A (zh) * | 2014-04-03 | 2017-05-10 | 拜耳制药股份公司 | 用于治疗呼吸道疾病的2,5‑二取代的环戊烷甲酸 |
Also Published As
Publication number | Publication date |
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EP0923529B1 (en) | 2001-09-19 |
YU18897A (en) | 1999-11-22 |
DE69706874T2 (de) | 2002-03-28 |
WO1997043237A1 (en) | 1997-11-20 |
TNSN97086A1 (fr) | 2005-03-15 |
ES2160955T3 (es) | 2001-11-16 |
TW442468B (en) | 2001-06-23 |
DE69706874D1 (en) | 2001-10-25 |
JP3354941B2 (ja) | 2002-12-09 |
ID17326A (id) | 1997-12-18 |
CA2253795C (en) | 2002-10-15 |
CO5011113A1 (es) | 2001-02-28 |
ZA974033B (en) | 1998-02-19 |
SV1997000033A (es) | 1999-01-14 |
HRP970247A2 (en) | 1998-04-30 |
BR9709075A (pt) | 1999-08-03 |
AU2938997A (en) | 1997-12-05 |
CA2253795A1 (en) | 1997-11-20 |
ATE205822T1 (de) | 2001-10-15 |
JPH11510518A (ja) | 1999-09-14 |
EP0923529A1 (en) | 1999-06-23 |
AR007101A1 (es) | 1999-10-13 |
HRP970247B1 (en) | 2002-02-28 |
MY116903A (en) | 2004-04-30 |
AU727468B2 (en) | 2000-12-14 |
PA8429501A1 (es) | 2000-05-24 |
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