CN1124255C - 抑制基质金属蛋白酶的苯烷基化合物及其用途 - Google Patents
抑制基质金属蛋白酶的苯烷基化合物及其用途 Download PDFInfo
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- CN1124255C CN1124255C CN97196457A CN97196457A CN1124255C CN 1124255 C CN1124255 C CN 1124255C CN 97196457 A CN97196457 A CN 97196457A CN 97196457 A CN97196457 A CN 97196457A CN 1124255 C CN1124255 C CN 1124255C
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Abstract
提供了基质金属蛋白酶抑制化合物,其药物组合物,和应用这类化合物治疗疾病的方法。本发明的化合物具有通式(I),其中T是取代基,M是CO2H或其酰胺或酯,而R24是取代的酰胺部分。这些化合物可用于抑制基质金属蛋白酶,因此,抗由MMP引起的疾病如骨关节炎,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,颞下颌骨关节疾病,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。本发明也提供治疗这类病症的药物组合物和方法。
Description
发明背景
发明领域
本发明涉及酶抑制剂,更具体地,涉及用于抑制基质金属蛋白酶的新的取代的苯乙基化合物。
相关技术
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.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)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.Arthritis Rheum.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,Peridontal Res.22,81-8(1987)),f)角膜溃疡(Burns,F.R.等,Invest.Ophthalmol.Vis.Sci.30,1569-75(1989)),g)蛋白尿(Baricos,W.H.等,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,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1)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),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 695,177,1983;Ray,J.M.等,Eur.Respir.J.7,2062,1994;Birkedal-Hansen,H等,Crit.Rev.Oral.Biol.Med.4,197,1993。
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.732,222,1994。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,等,癌症研究,54,4726,1994)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,53,2087,1993)。这些和相关化合物的应用已经在WO-A-9321942A2(931111)中描述。
有几份专利和专利申请要求保护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(例如Levy,et al.,WO-A-9519965A1;Beckett,et al.,WO-A-9519956A1;Beckett,et al.,WO-A-9519957A1;Beckett,et al.,WO-A-9519961A1;Brown,et al.,WO-A-9321942A2;Crimmin,et al.,WO-A-9421625A1;Dickens,et al.,USP-4599361;Hughs,et al.,USP-5190937;Broadhurst,et al.,EP-0574758A1;Broadhurst,et al.,EP-026436;和Myers et al.,EP-0520573A1)。这些专利的优选的化合物具有肽骨架,在一端带有锌配位基(异羟肟酸,硫醇,羧酸或次膦酸),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Brown,et al.,WO-A-9321942A2中描述的化合物,只能腹膜内给药。
某些3-联苯酰基丙酸和4-联芳基酰基丁酸在文献中被描述为消炎,抗血小板凝聚,抗炎,抗增生,低脂血,抗风湿,止痛,和血胆固醇过少的药剂。这些例子没有一个是如要求的治疗效果的机理那样产生MMP抑制的。某些相关化合物也在制备液晶时用作中间体。
具体地,Tomcufcik,et al.,美国专利3784701要求了某些取代的苯甲酰基丙酸治疗炎症和疼痛。这些化合物包括如下所示的3-联苯酰基丙酸(即联苯丁酮酸(fenbufen))。
联苯丁酮酸
Child,et al.,J.Pharm.Sci.,66,466,1977描述了几种联苯丁酮酸类似物的构效关系。这些包括几种这样的化合物,其中联苯环体系被取代,或丙酸部分被苯基,卤素,羟基或甲基取代,或羧酸或羰基官能团被转化为各种衍生物。没有描述含有4’-取代的联苯基和取代的丙酸部分结合在一个分子中的化合物。如下所示的苯基(化合物XLIX和LXXVII)和甲基(化合物XLVII)取代的化合物被描述为非活性的。
Kameo,et al.,Chem.Pharm.Bull.,36,2050,1988和Tomizawa,et al.,JP-62132825A2描述了某些取代的3-联苯酰基丙酸衍生物和其包括如下的类似物。描述了各种在丙酸部分带有其他取代基的化合物,但它们不含有联苯基残基。
其中X=H,4’-Br,4’-Cl,4’-CH3,或2’-Br。
Cousse,et al.,Eur.J.Med.Chem.,22,45,1987描述了如下甲基和亚甲基取代的3-联苯酰基-丙酸和-丙烯酸。也描述了其中羰基被CH2OH或CH2代替的相应化合物。
其中X=H,Cl,Br,CH3O,F,或NH2。
Nichl,et al.,德国专利1957750也描述了某些上述亚甲基取代的联苯甲酰基丙酸。
其中R1是1-10个碳原子的烷基。
Sammour,et al.,Egypt J.Chem.15,311,1972和Couquelet,et al.,Bull.Soc.Chim.Fr.9,3196,1971描述了某些包括如下的二烷基氨基取代的联苯酰基丙酸。在所有的情况下,联苯基都没有被取代。
其中R1,R2=烷基,苄基,H,或与氮原子一起是吗啉基。
其他已经公开了一系列的含联苯基的羧酸,其例子示于如下,它们抑制天然的内切肽酶(NEP24.11),一种膜结合的锌金属蛋白酶(Stanton,et al.,Bioor.Med.Chem.Lett.4,539,1994;Lombaert,et al.,Bioor:Med.Chem.Lett.4,2715,1994;Lombaert,et al.,Bioor.Med.Chem.Lett.5,145,1995;Lombaert,etal.,Bioor.Med.Chem.Lett.5,151,1995)。
已经报道,由如下所示的化合物举例说明的含有联苯基乙基甘氨酸是溶基质素(MMP-3),72kDa明胶酶(MMP-2)和胶原蛋白酶(Durette,et al.,WO-9529689)。
相对于现有技术以肽为基础的化合物具有改进的生物利用率和生物学稳定性,并可以最佳地用于抗特定的靶MMP的有效的MMP抑制剂将是需要的。这类化合物是本申请的主题。
有效的MMP抑制剂的开发将提供对于由于MMP活性存在,或过量的MMP活性介导的疾病,包括骨关节炎,类风湿性关节炎,脓毒性关节炎,肿瘤转移,牙周疾病,角膜溃疡,蛋白尿的治疗方法。几种MMP抑制剂已经在文献中描述,包括硫醇(beszant,et al.,J.Med.Chem.36,4030,1993),异羟肟酸(Wahl,et al.,Bioor.Med.Chem.Lett.5,349,1995;Conway,et al.,J.Exp.Med.182,449,1995;Porter,et al.,Bioor.Med.Chem.Lett.4,2741,1994;Tomczuk,et al.,Bioor.Med Chem.Lett.5,343,1995;Castelhano,et al.,Bioor.Med.Chem.Lett.5,1415,1995),含磷酸(Bird,et al.,J.Med.Chem.37,158,1994;Morphy,et al.,Bioor.Med Chem.Lett.4,2747,1994;Kortylewicz,et al.,J.Med.Chem.33,263,1990)和羧酸(Chapman,et al.,J.Med.Chem.36,4293;Brown,etal.,J.Med.Chem.37,674,1994;Morphy,et al.,Bioor.Med.Chem.Lett.4,2747,1994;Stack,et al.,Arch.Biochem.Biophys.287,240,1991;Ye,etal.,J.Med.Chem.37,206,1994;Grobelny,et al.,Biochemistry 24,6145,1985;Mookhtiar,etal.,Biochemistry 27,4299,1988)。然而,这些抑制剂一般都含有肽骨架,由于其低吸收而显示低的口服生物活性,和由于快速蛋白水解显示短半衰期。因此,需要改进的MMP抑制剂。
发明提要
本发明提供具有基质金属蛋白酶抑制活性的化合物。这些化合物可用于抑制基质金属蛋白酶,因此,抗由MMP引起的疾病。所以,本发明也提供药物组合物和治疗这些病症的方法。所述化合物涉及治疗人以实现一种效果的方法,其中效果有: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,颞下颌骨关节疾病,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。本发明化合物也用于生育控制。根据本发明的方法包括施用一定量的上述本发明化合物或组合物,在下面详述中更详细地说明,该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。本发明化合物也用作在体外和体内体系中研究基质金属蛋白酶功能和机理的科研工具。由于其MMP-抑制活性,本发明化合物科研用于调节MMP作用,从而使研究者能够观察研究中实验生物体系内降低的MMP活性的作用。
本发明涉及具有基质金属蛋白酶抑制活性和如下通式的化合物:
(T)xA-B-D-E-G(L)
在上述通式(L)中,(T)xA表示取代或未取代的芳香6-员环或含有1-2个N,O,或S原子的杂芳香5-6员环。T表示一个或多个取代基,下标x表示这类取代基的数量,A表示芳香或杂芳香环,指定为A环或A单元。当N被用于与A环中的S或O结合时,这些杂原子被至少一个碳原子分开。
取代基T独立地选自卤素;烷基;卤代烷基;烯基;炔基,苄氧基,烷氧基;-(CH2)pQ其中p是0或1-4的整数;和-烯基-Q其中烯基部分包含2-4个碳原子。在后两个基团中Q选自芳基,杂芳基,-CN,-CHO,-NO2,-CO2R2,-OCOR2,-SOR3,-SO2R3,-CON(R2)2,-SO2N(R2)2,-COR2,-N(R2)2,-N(R2)COR2,N(R2)CO2R3,-N(R2)CON(R2)2,-CHN4,-OR4,和-SR4组成的基团。在这些式中,R2表示H,烷基,芳基,杂芳基,芳烷基,或杂芳基-烷基;R3表示烷基,芳基,杂芳基,芳烷基,或杂芳基-烷基;而R4表示H,烷基,芳基,芳烷基,杂芳基-烷基,烯基,炔基,卤代烷基,酰基,或亚烷氧基或由H,烷基,或苯基封端的聚亚烷氧基。在与Q连接的部分中或是Q部分的不饱和部位与任何Q的N,O,或S被至少一个碳原子分开。A环可以是未取代的,或带有至多2个取代基T。而且,下标x是0,1,或2。
在通式(L)中,B表示芳香6-员环或含有1-2个N,O,或S原子的杂芳香5-6员环。称为B环或B单元。当N用于在B环中与S或O联合时,这些杂原子被至少一个碳原子分开。
在通式(L)中,D表示
其中r是0-2,z是1-4,Y1是H或CH3,Y2是3-6个碳原子的烷基,3-6个碳原子的伯或仲氨基烷基,2-5个碳原子的羧酸,其中烷基有0-5个碳原子的(1-吗啉基)烷基,3-5个碳原子的酯,3-5个碳原子的酮,或其中烷基有3-5个碳原子的芳烷基;或Y1和Y2与它们所连接的氮原子一起形成1-哌啶基或1-吗啉基环。用于上述结构中的D和G表示通式(L)中的D和G单元,而不是E单元的部分;它们只是指明D,E和G基团是如何连接的。当r=0时,上述结构采取如下形式:当r=2时,烷基部分包括环丁基环,当r=3时,烷基部分包括环戊基环。在通式(L)中,G表示-PO3H2,-M,
其中M表示-CO2H,-CON(R11)2,或-CO2R12,R12表示1-4碳的烷基,R13表示19种非环状天然氨基酸的任何一种侧链。
这些化合物的药用盐也在本发明的范围内。
在现有技术的最相关的参照化合物中,分子的联苯基部分是未取代的,而丙酸或丁酸部分要么是未取代的,要么具有一个甲基或苯基。已经报道,较大苯基的存在引起现有技术化合物作为消炎止痛药失活。参见,例如,Child,et al.,Pharm.Sci.66,466,1977。相反,现已发现,显示很强的MMP抑制活性的化合物在分子的丙酸或丁酸部分含有可观大小的取代基。最好的MMP抑制剂的联苯基部分也优选地在4’-位含有取代基,尽管当丙酸或丁酸部分被最理想地取代时,本发明未取代的联苯基化合物具有足够的活性,被考虑为实用药物的替代物。
前面仅仅概述了本发明的某些方面,而不在任何意义上限制本发明。在本说明书中引用的所有专利和其他公开物都全文引作本文参考。
优选方案的说明
本发明提供具有基质金属蛋白酶抑制活性的化合物。这些化合物可用于抑制基质金属蛋白酶,因此,抗由MMP引起的疾病。所以,本发明也提供药物组合物和治疗这些病症的方法。所述化合物涉及治疗人以实现一种效果的方法,其中效果有: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,颞下颌骨关节疾病,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。本发明化合物也用于生育控制。根据本发明的方法包括施用一定量的上述本发明化合物或组合物,在下面详述中更详细地说明,该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。本发明化合物也用作在体外和体内体系中研究基质金属蛋白酶功能和机理的科研工具。由于其MMP-抑制活性,本发明化合物可以用于调节MMP作用,从而使研究者能够观察研究中实验生物体系内降低的MMP活性的作用。
更具体地,本发明涉及具有基质金属蛋白酶抑制活性和如下通式的化合物:
(T)xA-B-D-E-G(L)
其中(T)xA表示选自如下的取代或未取代的芳香或杂芳香部分:
其中R1表示H或1-3碳烷基。
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。
在这些结构中,芳香环称为A环或A单元,各个T表示取代基,称为T基团或T单元。取代基T独立地选自卤素-F,-Cl,-Br,和-I;1-10碳的烷基;1-10碳的卤代烷基;2-10碳的烯基;2-10碳的炔基;苄氧基,1-5碳的烷氧基;-(CH2)pQ其中p是0或1-4的整数;和-烯基-Q其中烯基部分包含2-4个碳原子。在后两个基团中Q选自6-10碳的芳基,包含4-9碳和至少一个N,O,或S杂原子的杂芳基,-CN,-CHO,-NO2,-CO2R2,-OCOR2,-SOR3,-SO2R3,-CON(R2)2,-SO2N(R2)2,-C(O)R2,-N(R2)2,-N(R2)COR2,N(R2)CO2R3,-N(R2)CON(R2)2,-CHN4,-OR4,和-SR4组成的基团。基团R2,R3,和R4如下定义。
R2表示H,1-6碳烷基;6-10碳的芳基,包含4-9碳和至少一个N,O,或S杂原子的杂芳基,其中芳基部分含有6-10个碳,而烷基部分含有1-4碳的芳烷基;或其中杂芳基部分包含4-9碳和至少一个N,O,或S杂原子,而烷基部分含有1-4碳的杂芳基-烷基。
R3表示1-4碳烷基;6-10碳芳基;其中芳基部分含有6-10个碳,而烷基部分含有1-4碳的芳烷基;或其中杂芳基部分包含4-9碳和至少一个N,O,或S杂原子,而烷基部分含有1-4碳的杂芳基-烷基。
R4表示H;1-12碳烷基;6-10碳的芳基;包含4-9碳和至少一个N,O,或S杂原子的杂芳基;其中芳基部分含有6-10个碳,而烷基部分含有1-4碳的芳烷基;或其中杂芳基部分包含4-9碳和至少一个N,O,或S杂原子,而烷基部分含有1-4碳的杂芳基-烷基;2-12碳烯基;2-12碳炔基;-(CqH2qO)rR5其中q是1-3,r是1-3,R5是H,条件是q大于1,或R5是1-4碳烷基,或苯基;其中s是2-3,X是卤素的-(CH2)sX;或-C(O)R2。
在与Q连接的部分中或是作为Q的部分的任何不饱和部位与任何Q的N,O,或S被至少一个碳原子分开,取代基的数量,标为x,是0,1,或2。
取代基T也可以含有如下通式部分的乙炔:
R30(CH2)nC≡C-
其中n是1-4,R30选自:HO-,MeO-,(n-Pr)2N-,CH3CO2-,CH3CO2OCO2-,HO2C-,HOC-,Ph-,3-OH-Ph-,和PhCH2O-,条件是当R30是Ph或-OH-Ph-时,n=0。
通式(L)的B环是取代或未取代的芳香或杂芳香环,其中任何取代基都是不使分子与靶酶的活性位点不配,或破坏A和B环相对构型的有害基团。这类基团可以是诸如低级烷基,低级烷氧基,CN,NO2,卤素,等等的部分,但不限于这类基团。在通式(L)中,B表示选自如下的芳香或杂芳香环:
其中R1如上定义。这些环被称为B环或B单元。
通式(L)的化合物包括其中(T)x-A-B的联合不采取上述形式之一,而具有如下结构的化合物:
R15-Z-CH2-
其中Z可以是(CH2)e-C6H4-(CH2)f或(CH2)g,e=0-8,f=0-5和g=0-10。R156-12个碳原子,优选7-11个碳原子的直链,或环状烷基,并非强制性地可以带有一个或多个在下面更详细讨论的药学上可接受的取代基。任何支化或取代都在R15基团与苯环的连接点相隔至少3个链原子的地方.。
R15也可以是式R32O(C2H4O)h的聚醚,其中下标“h”是1或2,而基团R32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。R32非强制性地可以带有一个或多个在下面更详细讨论的药学上可接受的取代基。任何支化或取代都在R15基团与苯环的连接点相隔至少3个链原子的地方。
R15也可以是下式取代的炔基:
R33(CH2)b-C≡C-
其中下标“b”是1-10,而基团R33是H-,HO-或R34O-,优选HO-基团。R34可以是1-3个碳原子的烷基,或苯基或苄基。R33非强制性地可以带有一个或多个在下面更详细讨论的药学上可接受的取代基。
R15也可以是-H,-Cl,-OMe或
其中n是0-4,而R17是C2H5,烯丙基或苄基。
在通式(L)中,D表示如下部分:
其中r是0-2,z是1-4,Y1是H或CH3,Y2是3-6个碳原子的烷基,3-6个碳原子的伯或仲氨基烷基,2-5个碳原子的羧酸,其中烷基有0-5个碳原子的(1-吗啉基)烷基,3-5个碳原子的酯,3-5个碳原子的酮,或其中烷基有3-5个碳原子的芳烷基;或Y1和Y2与它们所连接的氮原子一起形成1-哌啶基或1-吗啉基环。用于上述结构中的D和G表示通式(L)中的D和G单元,而不是E单元的部分;它们只是指明D,E和G基团是如何连接的。当r=0时,上述结构采取如下形式:
当r=2时,烷基部分包括环丁基环,当r=3时,烷基部分包括环戊基环。
另外,任何T基团的芳基或杂芳基部分可以非强制性地带有至多两个选自如下的取代基:-(CH2)yC(R11)(R12)OH,-(CH2)yOR11,-(CH2)ySR11,-(CH2)yS(O)R11,-(CH2)yS(O)2R11,-(CH2)ySO2N(R11)2,-(CH2)yN(R11)2,-(CH2)yN(R11)COR12其中两个氧原子都连接在芳环上的-OC(R11)2O-,-(CH2)yCOR11,-(CH2)yCON(R11)2,-(CH2)yCO2R11,-(CH2)yOCOR11,卤素,-CHO,-CF3,-NO2,-CN,和-R12,其中y是0-4;R11表示H或1-4碳烷基;R12表示1-4碳烷基。
其中M表示-CO2H,-CON(R11)2,或-CO2R12,R13表示19种非环状天然氨基酸的任何一种侧链。通式(L)范围内的化合物的药用盐也在本发明的范围内。
在本发明的化合物中,下列是优选的。
定义T取代基数量的下标x优选地是1或2,最优选地是1,该取代基在A环的4-位。
A环优选地是苯基或噻吩环,最优选苯基。
B环优选地是1,4-亚苯基或2,5-噻吩环,最优选地是1,4-亚苯基。
D单元最优选地是羰基。
G单元最优选地是羧酸基团。
应该理解,本文所用的术语“烷基”指直链,支链,环状,和多环物。术语“卤代烷基”指部分或全卤代的烷基,例如-(CH2)2Cl,-CF3和-C6F13。
在这些方案之一中,本发明涉及其中至少一个单元A,B,T,和E包含杂芳香环的通式(L)化合物。优选的含杂芳香环的化合物是其中杂芳基是4-9碳,包括含有O,S,或NR1(当环是5-员时),和N(当所说的环是6-员时)的5-6员杂芳香环。特别优选的含杂芳香环的化合物是A和B单元之一包含噻吩环的化合物。当A单元是噻吩时,它优选地在位置2与B单元连接,并在位置5带有一个取代基T。当B单元是噻吩时,它优选地分别通过位置2和5与D和A单元连接。
在通式(L)中,A和B环优选地分别是苯基和亚苯基,A环优选地带有至少一个取代基T,优选地位于与A环和B环相连的位置最远处,D单元优选地是羰基,而G单元优选地是羧基。
其中x是1或2,取代基T之一位于A环的4-位(相对于A和B环之间的连接点),n=1-5,R24在(CH2)n的邻,间或对位,并选自下列之一:
本发明也涉及某些可用于一些要求保护的抑制剂合成的中间体。这些中间体是具有如下通式的化合物
其中n=1-5,R21是卤素,R22是H或烷基(优选乙基)或烯丙基烷基(其中烷基优选地是甲基)。
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:
I)4’-氯-γ-氧代-α-[2-[2-[[(2-苯基乙基)氨基]羰基]苯基]乙基]-[1,1’-联苯基]-4-丁酸,
II)4’-氯-α-[2-[2-[[(4-吗啉基羰基)苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
III)4’-氯-γ-氧代-α-[2-[2-[[(苯基甲基)氨基]羰基]苯基]乙基]-[1,1’-联苯基]-4-丁酸,
IV)4’-氯-γ-氧代-α-[2-[2-[[(3-苯基丙基)氨基]羰基]苯基]乙基]-[1,1’-联苯基]-4-丁酸,
V)4’-氯-γ-氧代-α-[2-[2-(1-哌啶基羰基)苯基]乙基]-[1,1’-联苯基]-4-丁酸,
VI)4’-氯-α-[2-[2-[[(3-甲基丁基)氨基]羰基]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
VII)4’-氯-α-[2-[2-[[(3-乙氧基丁基)氨基]羰基]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
VIII)4’-氯-α-[2-[2-[[(2-乙氧基乙基)氨基]羰基]苯基]乙基-γ-氧代-[1,1’-联苯基]-4-丁酸,
IX)4’-氯-α-[2-[2-[[(2-乙氧基-2-氧代乙基)甲基氨基]羰基]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
X)4’-氯-α-[2-[3-(4-吗啉基羰基)苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
XI)4’-氯-γ-氧代-α-[2-[3-(1-哌啶基羰基)苯基]乙基]-[1,1’-联苯基]-4-丁酸,
XII)4’-氯-γ-氧代-α-[2-[3-[[(2-苯基乙基)氨基]羰基]苯基]乙基]-[1,1’-联苯基]-4-丁酸,
XIII)4’-氯-γ-氧代-α-[2-[3-[[(3-苯基丙基)氨基]羰基]苯基]乙基]-[1,1’-联苯基]-4-丁酸,
XIV)4’-氯-α-[2-[3-[[(3-甲基丁基)氨基]羰基]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
XV)4’-氯-γ-氧代-α-[2-[3-[[(苯基甲基)氨基]羰基]苯基]乙基]-[1,1’-联苯基]-4-丁酸,
XVI)4’-氯-α-[2-[3-[[(2-乙氧基-2-氧代乙基)甲基氨基]羰基]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
XVII)4’-氯-α-[2-[4-(4-吗啉基羰基)]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
XVIII)4’-氯-α-[2-[4-[[(3-甲基丁基)氨基]羰基]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
XIX)4’-氯-α-[2-[4-[[(2-乙氧基-2-氧代乙基)氨基]羰基]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
XX)4’-氯-γ-氧代-α-[2-[4-[[(2-苯基乙基)氨基]羰基]苯基]乙基]-[1,1’-联苯基]-4-丁酸,
XXI)4’-氯-γ-氧代-α-[2-[4-(1-哌啶基羰基)苯基]乙基]-[1,1’-联苯基]-4-丁酸,
XXII)4’-氯-γ-氧代-α-[2-[2-[[(2-苯基乙基)氨基]羰基]苯基]乙基]-[1,1’-联苯基]-4-丁酸,
XXIII)α-[2-[4-[[(2-羧基乙基)氨基]羰基]苯基]乙基]-4’-氯-γ-氧代-[1,1’-联苯基]-4-丁酸,
XXIV)α-[2-[4-[[(羧基甲基)氨基]羰基]苯基]乙基]-4’-氯-γ-氧代-[1,1’-联苯基]-4-丁酸,
XXV)4’-氯-α-[2-[2-[[[2-(4-吗啉基)乙基]氨基]羰基]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
XXVI)α-[2-[3-[[(2-羧基乙基)氨基]羰基]苯基]乙基]-4’-氯-γ-氧代-[1,1’-联苯基]-4-丁酸,
XXVII)4’-氯-α-[2-[3-[[[2-(吗啉基)乙基]氨基]羰基]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
XXVIII)4’-氯-α-[2-[4-[[[2-(4-吗啉基)乙基]氨基]羰基]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
XXIX)4’-氯-α-[2-[3-[[[2-(二甲基氨基)-2-氧代乙基]甲基氨基]羰基]苯基]乙基]-γ-氧代-[1,1’-联苯基]-4-丁酸,
XXX)-γ-氧代-4’-(苯基甲氧基)-α-[2-[3-(1-哌啶基羰基)苯基]乙基]-[1,1’-联苯基]-4-丁酸,
XXXI)γ-氧代-4’-(戊氧基)-α-[2-[3-(1-哌啶基羰基)苯基]乙基]-[1,1’-联苯基]-4-丁酸,
XXXII)γ-氧代-α-[2-[2-[(2-氧代-1-哌啶基)甲基)苯基]乙基]-4’-(苯基甲氧基)-[1,1’-联苯基]-4-丁酸,
一般制备方法:
本发明的化合物可以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。
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。
这些和其它不需要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,并较小程度地抑制MMP-1,因此可以用于治疗或预防在背景部分列出的病症。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。改变分子中联芳基部分上的取代基,以及所要求的化合物的丙酸或丁酸链的取代基,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。
治疗基质金属蛋白酶-介导的病症的方法可以在显示这类病症的哺乳动物,包括人身上实施。
本发明的抑制剂被期望用于兽医和人。因此,它们将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。合适的肠胃外给药的例子包括静脉内,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。改进的半衰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。对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。
与在本申请背景部分列出的各种肽化合物相反,本发明化合物的突出贡献是本发明化合物所表现的口服活性。某些化合物已经在各种动物模型中显示出高达90-98%的生物利用率。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 DrugDelivery 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。
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。
实施例
下列实施例仅用于举例说明,而不在任何意义上限制本发明。
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EM Science得到。
色谱:
分析薄层色谱(TLC)在Whatman预涂的玻璃支载的硅胶GHLF 250mm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。
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-OMEGA300(300MHz)光谱仪测量,碳13(13C)NMR谱用General Electric GN-OMEGA300(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 Conceptl-H光谱仪上,用液体-铯二代离子(LCIMS),一个快速原子轰击(FAB)的最新版本,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。
步骤1将o-碘代苯基乙酸(19.87g,75.83mmol)在无水的四氢呋喃(110mL)中的溶液在41分钟内滴加到硼烷的四氢呋喃(151mL 1M溶液,约151.0mmol)溶液中,用冰水浴冷却。在0至10℃将反应搅拌2小时15分钟。将反应混合物冷却至0℃后,通过在20分钟内小心地加入(起泡)10(体积)%乙酸的甲醇溶液。继续搅拌25分钟,然后用旋转蒸发器浓缩反应。将残余物溶于乙酸乙酯,并用饱和氯化铵洗涤,接着用饱和碳酸氢钠洗涤。将有机层干燥(硫酸钠)并浓缩为黄色油状物(18.07g),不经纯化用于下步。将纯净的2-(2-碘代苯基)乙醇(17.75g,71.55mmol)通过在6分钟内滴加三溴化磷(3.5mL,36.85mmol)处理,反应容器放在水浴中以调节放热反应。在室温下搅拌15分钟,然后在油浴中于100℃将混合物加热搅拌2小时。将反应冷却至室温,用乙醚稀释,小心地用水(起泡/放热)淬灭。分层,有机层用饱和碳酸氢钠洗涤并干燥(硫酸钠)。浓缩给出油状物,通过Kugelrohr蒸馏(140℃/700毫托)给出无色油状物(19.50g,62.71mmol;上两步83%的产率)。MS(EI)310,312[M]+。
步骤2将干燥的250mL圆底烧瓶配上搅拌棒和氩气导管。往烧瓶中装入氢化钠(1.65g 95%NaH;~65.1mmol)在干燥THF(25mL)中的悬浮液。通过注射器在25分钟内滴加丙二酸二乙基酯。用新鲜THF(10mL)洗涤注射器,进入反应瓶内。继续搅拌10分钟,然后迅速加入步骤1的溴化物(19.36g,62.26mmol)的THF(20mL)溶液。加液注射器被洗涤(10mL THF)到反应中。该浅黄色溶液在氩气中回流搅拌过夜。将白色悬浮液分配在10%盐酸和乙醚之间。乙醚层用碳酸氢钠洗涤两次,干燥(硫酸钠)并浓缩为油状物,通过球-至-球蒸馏纯化:前馏分(在145℃,700-900毫托收集)被丢弃,主要部分在220℃(500-600毫托)蒸馏。主馏分通过在150℃(300-500毫托)蒸出低沸点物进一步纯化,在锅内留下清亮的所需产物(15.28g,39.16mmol;63%产率)。TLC(在己烷-乙酸乙酯20∶1中展开两次):Rf=0.33。
步骤3将2-L三颈圆底烧瓶装上机械搅拌器,温度计和氩气导管。将烧瓶内装上4-氯联苯(48.30g,0.256mol)的二氯甲烷(500mL,新开瓶的)溶液。通过注射器加入溴代乙酰溴(23mL,~53.3g,~0.26mol),将溶液用冰水浴冷却至内温3℃。暂时取出温度计,在5分钟内分批加入氯化铝。内温升至10℃,从暗橄榄绿的反应混合物中逸出白色气体。搅拌24小时后,通过小心地倒入冷的10%盐酸(1L)淬灭反应。有机层变成浑黄绿色。加入帮助溶解固体,但有机层不再变为透明的。在旋转蒸发器上浓缩有机物,并在高真空下干燥。粗产物是浅绿色固体(~82g),用热乙酸乙酯重结晶给出1-(2-溴代乙酮)-4-(4-氯苯基)苯褐色针状物(58.16g)。浓缩母液,接着加入己烷,给出第二批晶体(11.06g),与第一批的NMR谱相同。标题产物的总产率为87%。TLC(己烷-二氯甲烷,2∶1):Rf=0.30。
步骤4将干燥的250mL三颈圆底烧瓶装上搅拌棒和氩气导管。将烧瓶内装上氢化钠(1.07g 95%NaH;~42.4mmol)在干燥THF(100mL)中的悬浮液,用冰水浴冷却。在30分钟内滴加步骤2的丙二酸酯(15.25g,39.08mmol)的THF(30mL)溶液。通过注射器往反应瓶内加入新鲜的THF(10mL),移去冷浴。搅拌10分钟后,一次加入步骤3的溴代甲基酮。将橙色混合物在氩气中搅拌过夜,同时缓慢温热至室温。往反应混合物中小心地加入10%盐酸。分层,水层用乙酸乙酯萃取。合并的有机层依次用10%盐酸和饱和碳酸氢钠洗涤。将合并的有机层干燥(硫酸钠)并浓缩给出橙色油状物(24.41g)。此粗物不经纯化直接用于下步。
将粗油状物(24.19g~39.08mmol)溶于THF(150mL)和无水乙醇(100mL)。往此混合物中加入氢氧化钠溶液(10mL 50wt%氢氧化钠水溶液,~0.125mol),反应在氩气中,室温下搅拌过夜。通过加入10%盐酸使pH~1,浑浊的黄色溶液用乙酸乙酯萃取。合并的有机层用食盐水洗涤,干燥(硫酸钠)并浓缩为橙色泡沫体(22.06g)。此物不经纯化直接用于下步。TLC(氯仿-甲醇,20∶1带有痕量乙酸):Rf=0.12。
步骤5将步骤4的二酸产物(22.06g)溶于1,4-二恶烷(400mL),并在氩气中回流过夜。浓缩给出粗产物黄色固体(19.50g),用氯仿重结晶,在真空炉中于66℃干燥过夜后,给出两批实施例1的标题化合物松散的固体(11.55g,22.26mmol;57%总产率)。TLC(氯仿-甲醇,20∶1带有痕量乙酸):Rf=0.54。
化合物I
步骤6将一部分步骤5的酸(405.7mg,0.78mmol)溶于二甲亚砜(3.0mL)。加入三乙胺(0.34mL),接着加入醋酸钯(II)(20.3mg,0.09mmol),1,3-二(二苯基膦基)丙烷(35.2mg,0.085mmol)和苯乙胺(1.42g,11.7mmol)。在5分钟内鼓入一氧化碳。将溶液在一氧化碳气氛中放置,并在70-75℃的油浴中加热过夜。将混合物冷却至室温,用乙酸乙酯(50mL)稀释,并用10%盐酸洗涤,接着用水洗。水相用乙酸乙酯反萃取,合并的有机层被干燥(硫酸镁)并浓缩给出橙黄色固体。快速色谱纯化(氯仿-甲醇,95∶5)给出米色固体,将其用乙酸乙酯-己烷重结晶给出标题化合物(219.7mg,0.41mmol;53%产率)。分析(C33H30NO4Cl)C:计算,73.39;实测,73.11,H:计算,5.60;实测,5.40,N:计算,2.59;实测2.32。
表I中的例子通过实施例1的钯-介导的羰基化法,用合适的胺代替苯乙胺而制备。而且,所需的异构体碘化物前体通过实施例1的方法,用m-或p-碘代苯基乙酸作原料而制备。
实施例22-制备化合物XXII
化合物XXII
将实施例7的酸(200mg,0.37mmol)溶于乙醇(15mL),并用1N氢氧化钠(1.8mL,1.8mmol)处理。将混合物在室温下搅拌过周末。将反应浓缩至干,残余物分配在氯仿和10%盐酸之间。分层,水相再用氯仿萃取。将合并的有机层干燥(硫酸钠)并浓缩为米色固体。粗产物用乙醇-己烷重结晶给出产物米色晶体(65mg,0.128mmol;35%产率)。MP 189.5-190.5℃。
实施例23-制备化合物XXIII
化合物XXIII
将实施例8的酸(180mg,0.34mmol)根据实施例22的一般方法皂化给出二酸产物黄色固体(142mg,85%产率)。MP 71-75℃。
化合物XXIV
将实施例19的酸(104mg,0.199mmol)根据实施例22的一般方法皂化给出二酸产物无色晶体(79mg,80%产率)。MP 164.5-165.5℃。
实施例25-制备化合物XXV
步骤1将实施例1,步骤5的碘代酸样品(1.0g,1.93mmol)悬浮于无水二氯甲烷(20mL)中。往搅拌的悬浮液中加入苄基醇(0.44mL,4.05mmol),DCC(0.6g,2.89mmol)和DMAP(50mg,0.39mmol)。将黄色悬浮液在室温下搅拌过夜。混合物用己烷(60mL)和水(5mL)稀释。将混合物搅拌并过滤,滤饼用己烷洗涤。分出有机层,干燥(硫酸镁)并浓缩为油状物。快速色谱(梯度洗脱,己烷-乙酸乙酯,9∶1至1∶1)给出纯化的酯油状物(0.95g,1.56mmol;81%产率)。TLC(己烷-乙酸乙酯,1∶1):Rf=0.64。
步骤2将步骤1的碘代酯(0.910g,1.49mmol)进行实施例1方法的钯-介导的羰基化,用水代替苯乙胺,给出半酸酯产物(475mg,0.90mmo;61%产率)。MS(FAB-LSIMS)527[M+H]+
步骤3步骤2的半酸酯(0.46g,0.87mmol)溶于二氯甲烷(8mL)。往此溶液中加入4-(2-氨基乙基)吗啉(0.31g,0.96mmol)和1-羟基苯并三唑(0.12g,0.87mmol)。将烧瓶用二氯甲烷洗下,并在冰浴中冷却。加入4-甲基吗啉(97mg,0.96mmol),接着加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(0.18g,0.96mmol)。将黄色溶液温热至室温并搅拌过夜。混合物用二氯甲烷(40mL)稀释,水洗。水层用二氯甲烷反萃取。合并的有机层被干燥(硫酸钠)并浓缩。通过快速色谱(氯仿-甲醇,95∶5)纯化给出产物浅黄色油状物(0.438g,0.685mmol;78%产率)。TLC(氯仿-甲醇,9∶1):Rf=0.70。
化合物XXV
步骤4将步骤3的酸(0.15g,0.47mmol)根据实施例22的一般方法皂化,给出产物乳色泡沫体(65.2mg,52%)。MP127-129℃。
步骤1实施例1,步骤5的间位-碘代异构体(即,根据实施例1的工艺,从m-碘代苯基乙酸开始制备的;2.0g,3.86mmol)溶于1,2-二氯乙烷(8mL)。往溶液中加入乙醇(0.68mL,11.57mmol)和几滴浓硫酸。将溶液回流过夜。将混合物冷却,载于硅胶上并快速层析(己烷-乙酸乙酯,3∶1)给出产物黄色油状物(2.142g),通过质子NMR分析,表明残留溶剂。TLC(氯仿-甲醇,10∶1):Rf=0.91。
步骤2将步骤1的碘代酯(2.1g,3.84mmol)进行实施例1方法的钯-介导的羰基化,用水代替苯乙胺,给出半酸酯产物(1.1g,2.37mmo;62%产率)。TLC(1∶1己烷-乙酸乙酯,带有1%乙酸):Rf=0.70。
化合物XXVI
步骤3用b-丙氨酸乙酯,以实施例25的一般方法,将步骤2的半酸酯转化为实施例26的。MP261-261℃。
表II中的例子通过实施例25的一般多步法,用合适的碘代酸和胺前体制备。
实施例30-制备化合物XXX
步骤1往配有氩气导管入口的一颈1000mL圆底烧瓶中装入500mL二氯甲烷,4-苯基苯酚乙酸酯(50.0g,235mmol),溴代乙酰溴(73.2g,31.6mL,363mmol),冷却至0℃,同时以小批在约5分钟内加入氯化铝(94.2g,707mmol)。产生的混合物在0℃搅拌30分钟,在室温下搅拌12小时。将反应混合物加入冷的10%盐酸溶液(500mL)中,每次用200-mL乙酸乙酯萃取3次。有机相用硫酸镁干燥,过滤,浓缩给出黑色固体。用乙酸乙酯-己烷重结晶给出44.3g(56%)所需化合物褐色固体。TLC(己烷-乙酸乙酯,9∶1)Rf=0.14。
步骤3将步骤2产物(18.4g)的四氢呋喃(400mL)和乙醇(50mL)溶液用碳酸钾处理,并在氩气中,于室温下搅拌过夜。由于保留了相对多的原料,因此将反应体积减至一半,再加入碳酸钾(12g)。3小时后反应完成。将反应物浓缩并用10%盐酸酸化。产物用乙酸乙酯萃取,干燥(硫酸钠)并浓缩为褐色油状残余物。快速层析纯化(己烷-乙酸乙酯,3∶1)给出产物黄色油状物(14.8g;86%)。TLC(己烷-乙酸乙酯,3∶1)Rf=0.20。
步骤4氢化钠(95%重量,143mg~5.95mmol)在无水DMF(10mL)中的悬浮液用冰水浴冷却,并用步骤3的苯酚(3.4g,5.66mmol)在无水DMF(20mL)中的溶液处理。将混合物温热至室温,一批加入溴化苄(3.4mL,~28.3mmol)。烧瓶在室温下搅拌过夜。混合物用10%盐酸稀释,并用乙酸乙酯萃取。有机层被干燥(硫酸镁)并浓缩为黄色油状物。快速层析(梯度洗脱,己烷-乙酸乙酯,9∶1至3∶2)给出中间体二酯(3.32g)。将此物溶于THF(25mL),乙醇(100mL)和1N氢氧化钠(22mL)的混合物中,并将溶液搅拌过夜。将反应混合物浓缩,残余物分配于10%盐酸和乙酸乙酯之间。将有机层干燥(硫酸钠)并浓缩为白色固体(2.51g)。将从二酸溶于1,4-二恶烷(250mL),将溶液回流过夜。将溶液冷却并浓缩为黄-白色固体(2.36g)。用乙酸乙酯重结晶给出浅黄色晶体(1.77g)。MP 173-174℃。TLC(己烷-乙酸乙酯,3∶1带有痕量乙酸)Rf=0.43。
化合物XXX
实施例31-制备化合物XXXI
实施例31通过实施例30的一般工艺,在烷基化步骤中用碘代戊烷,而在钯-介导的羰基化法中用哌啶作为亲核试剂而制备。MP 105.5-107.5℃。
化合物XXXII
实施例32-制备化合物XXXII
实施例32通过实施例30的一般工艺,用合适的异构的碘代前体制备。MP 168-169℃。
实施例33
本发明化合物的生物试验
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(Microfluorometric Profiling Assay))是最初由C.G.Knight等,FEBSLetters,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
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)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,267,15398,1992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pH7.5的25mM Tris,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):
重组人Pro-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,264,172131989所述的从U937 cDNA衍生的人重组Pro-明胶酶B(Pro-MMP-9)被表达为全-长形式。该酶原用由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,10mM氯化钙,150mM氯化钠,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,放大装置在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)中制造。
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和ki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元)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。
每一个测试酶的Ki’用下列等式自动计算:
Ki=((Km×IC50)/(Km+[S])
其中[S]=底物浓度=6μM。这是Williams等,酶学方法,63,437,1979中的方法。
表III
化合物 | MMP-3Ki(nM) | MMP-9Ki(nM) | MMP-2Ki(nM) |
I | 127 | 173 | 41.1 |
II | 122 | 323 | 12.1 |
III | 174 | 475 | 60.3 |
IV | 175 | 246 | 68.7 |
V | 54.7 | 146 | 13.8 |
VI | 214 | 431 | 58.1 |
VII | 131 | 478 | 27.1 |
VIII | 165 | 806 | 56.8 |
IX | 43.6 | 254 | 17.5 |
X | 73.8 | 251 | 26.1 |
XI | 34.4 | 58.1 | 10.3 |
XII | 450 | 2650 | 125 |
XIII | 236 | 552 | 157 |
XIV | 308 | 707 | 110 |
XV | 364 | 493 | 104 |
XVI | 24.8 | 137 | 9.86 |
XVII | 236 | 606 | 53.6 |
XVIII | 677 | 452 | 137 |
XIX | 376 | 423 | 823 |
XX | - | 2000 | 446 |
XXI | 242 | 806 | 84.1 |
XXII | 166 | 1130 | 63.5 |
XXIII | 259 | 1590 | 96.0 |
XXIV | 293 | 915 | 82.4 |
XV | 371 | 744 | 51.4 |
XVI | 178 | 706 | 76.6 |
XVII | 353 | 786 | 48.0 |
XVIII | 42.8 | 201 | 24.1 |
XXIX | 465 | 449 | 81.4 |
XXX | 12.5 | 102 | 4.44 |
XXXI | 35.8 | 373 | 17.0 |
XXXII | 14.8 | 167 | 13.0 |
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 (9)
2.权利要求1的化合物,其中n是1-4。
3.权利要求1的化合物,其中T是氯,X是1,n是2。
4.具有基质金属蛋白酶抑制活性的组合物,包含权利要求1的化合物和药作载体。
5.权利要求1的化合物在制备能抑制哺乳动物基质金属蛋白酶的药物中的用途。
6.权利要求5的用途,其中所说的哺乳动物是人。
7.权利要求1的化合物在制备具有如下治疗效果的药物中的用途:
(a)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;
(b)阻滞肿瘤转移或创伤型关节损伤引起的变性的软骨损失;
(c)降低由动脉粥样硬化斑破裂引起的冠状动脉血栓形成;或
(d)实施生育控制。
8.权利要求7的用途,其中的效果是减轻骨关节炎。
9.权利要求7的用途,其中的效果是阻滞肿瘤转移。
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US64502696A | 1996-05-15 | 1996-05-15 | |
US08/645,026 | 1996-05-15 |
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CN1124255C true CN1124255C (zh) | 2003-10-15 |
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JP (1) | JP3305328B2 (zh) |
CN (1) | CN1124255C (zh) |
AR (1) | AR007100A1 (zh) |
AT (1) | ATE229497T1 (zh) |
AU (1) | AU727899B2 (zh) |
BR (1) | BR9709084A (zh) |
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WO (1) | WO1997043247A1 (zh) |
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US6288063B1 (en) * | 1998-05-27 | 2001-09-11 | Bayer Corporation | Substituted 4-biarylbutyric and 5-biarylpentanoic acid derivatives as matrix metalloprotease inhibitors |
JP2002534404A (ja) | 1998-12-30 | 2002-10-15 | バイエル アクチェンゲゼルシャフト | 呼吸器疾患の治療のためのマトリックスメタロプロテアーゼ阻害剤としての置換4−ビアリール酪酸および5−ビアリールペンタン酸誘導体の使用 |
EP1031349A1 (en) * | 1999-02-25 | 2000-08-30 | Bayer Aktiengesellschaft | Use of substituted 4-biarylbutyric and 5-biarylpentanoic acid derivatives for the treatment of cerebral diseases |
US7141607B1 (en) | 2000-03-10 | 2006-11-28 | Insite Vision Incorporated | Methods and compositions for treating and inhibiting retinal neovascularization |
FR2901320B1 (fr) * | 2006-05-17 | 2008-07-04 | Univ Savoie Etablissement Publ | Dispositif miniaturise apte a fonctionner comme moteur ou refroidisseur selon un cycle thermodynamique de stirling |
US20170022171A1 (en) | 2014-04-03 | 2017-01-26 | Bayer Pharma Aktiengesellschaft | 2,5-disubstituted cyclopentanecarboxylic acids and their use |
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 |
US20170114049A1 (en) | 2014-04-03 | 2017-04-27 | Bayer Pharma Aktiengesellschaft | 2,5-disubstituted cyclopentane carboxylic acids for the treatment of respiratory tract diseases |
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DE2112716A1 (de) * | 1971-03-17 | 1972-10-05 | Thomae Gmbh Dr K | Neue 4-(4-Biphenylyl)-4-oxobuttersaeuren,ihre Salze und ihre Ester |
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PA8429801A1 (es) | 2000-05-24 |
PE66298A1 (es) | 1998-10-23 |
YU18497A (en) | 1999-11-22 |
JPH11510517A (ja) | 1999-09-14 |
JP3305328B2 (ja) | 2002-07-22 |
ATE229497T1 (de) | 2002-12-15 |
TW363056B (en) | 1999-07-01 |
DE69717811T2 (de) | 2003-05-28 |
CA2253870A1 (en) | 1997-11-20 |
WO1997043247A1 (en) | 1997-11-20 |
TNSN97082A1 (fr) | 2005-03-15 |
CN1225624A (zh) | 1999-08-11 |
HN1997000071A (es) | 1997-06-18 |
SV1997000037A (es) | 1999-01-14 |
CO5070565A1 (es) | 2001-08-28 |
ES2188943T3 (es) | 2003-07-01 |
CA2253870C (en) | 2004-01-06 |
EP0907632A1 (en) | 1999-04-14 |
HRP970243A2 (en) | 1998-04-30 |
EP0907632B1 (en) | 2002-12-11 |
ZA974029B (en) | 1998-02-19 |
BR9709084A (pt) | 1999-08-03 |
AR007100A1 (es) | 1999-10-13 |
ID17424A (id) | 1997-12-24 |
PT907632E (pt) | 2003-04-30 |
AU727899B2 (en) | 2001-01-04 |
DK0907632T3 (da) | 2003-04-07 |
DE69717811D1 (en) | 2003-01-23 |
AU2938597A (en) | 1997-12-05 |
HRP970243B1 (en) | 2002-06-30 |
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