CN1139570C - 通过含乙炔基的化合物抑制基质金属蛋白酶 - Google Patents
通过含乙炔基的化合物抑制基质金属蛋白酶 Download PDFInfo
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Abstract
提供了基质金属蛋白酶抑制化合物,其药用组合物以及用此化合物治疗疾病的方法。本发明的化合物具有通式(I),其中R15选自:HOCH2,MeOCH2,(n-Pr)2NCH2,CH3CO2CH2,EtOCO2CH2,HO(CH2)2,CH3CO2(CH2)2,HO2C(CH2)2,OHC(CH2)3,HO(CH2)4,Ph,3-HO-Ph,和PhCH2OCH2;而R16是(a)或(b)。这些化合物用于抑制基质金属蛋白酶并因此消除MMP′s导致的疾病,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;肿瘤转移或创伤型关节损伤引起的变性的软骨损失;由动脉粥样硬化斑破裂引起的冠状动脉血栓形成。本发明也提供了治疗这些疾病的药用组合物和方法。
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含二芳基乙炔基的化合物或其衍生物。
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用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已经暗示作为其它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.;Chidwich,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.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)负膜溃疡(Burns,E.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),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的正常关节功能的进行性损失。没有市面上的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。MMP抑制剂被预期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MNP-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抑制剂(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,以及在天然氨基酸发现的和更新的官能团。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)。
药物
联苯丁酮酸(Fenbufen)
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。
Kitamura,et al.,JP-60209539描述了某些包括如下用于生产液晶的中间体。在这些中间体中,联苯基不被取代。其中R1是1-10个碳原子的烷基。
Sammour,et al.,Egypt J.Chem.151,311,1972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,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,它们抑制神经的内肽酶(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,et al.,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的N-羧基烷基衍生物是溶基质素-1(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 a1.,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,et al.,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,et al.,J.Med.Chem.37,206,1994;Grobelny,et al.,Biochemistry 24,6145,1985;Mookhtiar,etal.,Biochemistry27,4299,1988)。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哺乳动物的方法,包括对哺乳动物给予基质金属蛋白酶抑制量的本发明的化合物,其足以:(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,颞下颌骨关节疾病,或神经系统的脱髓鞘疾病;
(b)创伤型关节损伤引起的肿瘤转移的阻滞或变性的软骨损失;
(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)用于生育控制。
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表示取代的炔属部分。
在通式(L)中,B表示芳香6-员环或含有1-2个选自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,E代表带有取代基R6的n个碳原子的链,其中的R6基是独立的取代基,或构成螺旋或非螺旋环。环可以两种方式形成:a)两个R6基相连,联同这两个R6基附着的链原子,以及任何中间链原子,构成3-7员环,或b)一个R6基联结其R6停留的链,联同该R6基附着的链原子,以及任何中间链原子,构成3-7员环。碳原子n的数目是2或3,而R6取代基m的数目是1-3的整数。所有R6基的碳数目至少为2。
各个R6是烷基,链烯基,炔基,杂芳基,非芳香环,及其组合,其任选地用一个或多个下文详述的杂原子取代。在通式(L)中,E是取代的单一或二环部分,其任选用一个或多个杂原子取代。
在通式(L)中,G代表-PO3H2,-M,or
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一侧链。
其中R15是选自:HOCH2,MeOCH2,(n-Pr)2NCH2,CH3CO2CH2,EtOCO2CH2,HO(CH2)2,CH3CO2(CH2)2,HO2C(CH2)2,OHC(CH2)3,HO(CH2)4Ph,3-HO-Ph,和PhCH2OCH2;以及R16是或
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,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
更具体地,本发明的化合物具有基质金属蛋白酶抑制活性和如下通式:
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。T是取代的炔属部分,x是1。
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,若是那样将是有害的。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。
在通式(L)中,E代表带有m个取代基R6的n个碳原子的链,其中的R6是独立的取代基,或构成螺旋或非螺旋的环。环可以两种方式形成:a)两个R6结合,并连同该两个R6基所附着的链原子,以及任何中间链原子构成3-7员环,或b)一个R6基结合到其停留的链上,并连同该R6基附着的链原子,以及任何中间链原子构成3-7员环。链中的碳原子数n是2或3,而R6取代基的数目m是1-3的整数。在全部R6基中的碳原子数为至少2。
各个R6独立地选自下列1)-14)款中所列的取代基:
1)1-10碳烷基;条件是,若A单元是苯基,B单元是亚苯基,m是1,n是2,而烷基位于相对于D单元的α碳上,则x是1或2;
2)6-10碳芳基;条件是,若A单元是苯基,B单元是亚苯基,芳基是苯基,n是2,而m是1或2,则x是1或2;
3)含4-9碳并至少有一个N,O或S杂原子的杂芳基;
4)芳烷基,其中芳基部分含6-10碳而烷基部分含1-8碳;
5)杂芳基-烷基,其中的杂芳基含4-9个碳和至少一个N,O,或S杂原子,而烷基部分含1-8个碳;
6)2-10个碳的链烯基;
7)芳基-链烯基,其中的芳基部分含6-10个碳,而链烯基部分含2-5个碳;
8)杂芳基-链烯基,其中的杂芳基部分含4-9个碳以及至少一个N,O,或S杂原子,而该链烯部分含2-5个碳;
9)2-10个碳的炔基;
10)芳基-炔基,其中的芳基部分含6-10个碳,而炔基部分含2-5个碳;
11)杂芳基-炔基,其中杂芳基部分含4-9个碳和至少一个N,O,或S杂原子,而炔基部分含2-5个碳;
12)-(CH2)tR7,其中的t是0或1-5的整数,而R7选自
以及相应的杂芳基部分,其中的含芳基的R7的芳基部分含4-9个碳和至少一个N,O,或S杂原子。在该R7基中,Y代表O或S,R1如上定义,而μ=0,1或2,条件是当R7是或
A单元是苯基时,B单元是亚苯基,m是1,n是2,而t是0,x是1或2。
13)-(CH2)vZR8,其中v是1-4的整数,Z代表-S-,-S(O)-,-SO2-,或-O-,而R8选自1-12个碳的烷基;6-10个碳的芳基;含4-9个碳和至少一个N,O或S杂原子的杂芳基;其中的芳基部分含6-12个碳而烷基部分含1-4个碳的芳烷基;其中的芳基部分含6-12个碳和至少一个N,O或S杂原子且烷基部分含1-4个碳的杂芳基烷基;-C(O)R9,其中R9代表2-6个碳的烷基,6-10个碳的芳基,含4-9个碳和至少一个N,O或S杂原子的杂芳基;以及其中的芳基部分含6-10个碳或是含4-9个碳和至少一个N,O或S杂原子,而烷基部分含1-4个碳的芳烷基,条件是,当R8是-C(O)R9,Z是-S-或-O-;当Z是-O-,R8也是-(CqH2qO)rR5,其中的q、r或R5如上定义;且当A单元是苯基,该B单元是亚苯基,m是1,n是2,且v是0,则x是1或2。
14)-(CH2)wSiR10 3,其中W是1-3的整数,而R10代表1-2个碳的烷基。
此外,任何T或R6基的芳基或杂芳基部分可任选带有多达二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,-OC(R11)2O-,其中的两个氧原子均联结到芳环,-(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代表H或1-4个碳的烷基;而R12代表1-4个碳的烷基。
在通式(L)中,G表示-PO3H2,-M,或
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。
这些化合物的药用盐也在本发明的范围内。
G单元最优选地结合到E单元上的对D单元为β的碳上,并优选地是羧酸基。
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C6H13。
在这些方案之一中,本发明涉及其中至少一个单元A,B,和R6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。
在另一个实施方案中,本发明涉及通式(L)的化合物,在E单元中,n是2而m是1。这些化合物因此在D单元和G单元之间有两个碳原子,并在此二碳链上带有一个取代基。
在其另一个实施方案中,本发明涉及通式(L)的化合物,其中的A环是取代的或非取代的苯基,而B环是对-亚苯基,而任何含芳基的R6部分的芳基部分的环中仅含有碳。这些化合物因而不含芳香环。
在其另一个实施方案中,本发明涉及通式(L)的化合物,其中的m是1而R6是独立的取代基。这些化合物是这样的物质,即在其E单元上仅含单一的取代基R6,而此取代基并不包含在环中。此亚组中优选的化合物具有式:其中x是1而取代基T位于A环上相对于A和B环结合点的第4位。此亚组的对位取代基T更优选地是含乙炔基的部分,选自:MeOCH2C≡C-,(n-Pr)2NCH2C≡C-,CH3CO2CH2C≡C-,EtOCO2CH2C≡C-,HOCH2C≡C-,HO(CH2)2C≡C-,CH3CO2(CH2)2C≡C-,HO2C(CH2)2C≡C-,OHC(CH2)3C≡C-,HO(CH2)4C≡C-,PhC≡C-,3-HO-PhC≡Cand PhCH2OCH2C≡C-,
其中的R6是-(CH2)tR7的通式(L)的其它的化合物中的t为1-5的整数。其中R6是-(CH2)vZR8的优选的通式(L)化合物的v是1-4的整数且Z为-S-或-O-。其它的R6为烷基的通式(L)的化合物其烷基含有4个或更多个碳,而那些其中的R6是芳烷基的在所说的芳烷基的烷基部分含2-3个碳。
在其另一个实施方案中,本发明涉及通式(L)的化合物,其中在E单元上的取代基m的数目是2或3;而当m是2时,两个R6是独立的取代基,或共同构成一种螺旋环,或者一个R6基是独立的取代基而另一个构成螺旋环;而当m是3时,两个R6基是独立的取代基而一个R6基构成环,或者两个R6基构成环而一个R6基是独立的取代基,或三个R6是基是独立的取代基。因此,此子结构包括这样的化合物,即其中的E单元是二或三取代的,而在二取代的情况下,任何由一个或两个R6基形成的环是螺旋环,而在三取代的情况下,该R6基可形成螺旋或非螺旋环。
在其另一个实施方案中,本发明涉及通式(L)的化合物,其中在E单元上取代基m的数目是1或2;而当m是1时,R6基构成非螺旋环;而当m是2时,两个R6共同构成非螺旋环或一个R6是独立的取代基而另一个构成非螺旋环。因而,此子结构包括这样的化合物,即其中的E单元带有一个或两个R6取代基,且至少一个取代基包括在非螺旋环中。
其中a是0,1,或2;b是0或1;c是0或1;d是0或1;c+d是0或1;e是1-5;f是1-4;g是3-5;h是2-4;i是0-4;j是0-3;k是0-2;R6的总数是0,1,或2;U代表O,S或NR1;而z是1或2;任一R14是独立的选自:1-9个碳的烷基;其中烷基部分含1-7个碳而芳基部分含6-10个碳的芳烷基;2-9个碳的链烯基;其中链烯基部分含2-4个碳而芳基部分含6-10个碳的芳基取代的链烯基;2-9个碳的炔基;其中炔基含2-4个碳而芳基部分含6-10个碳的芳基取代的炔基;6-10个碳的芳基;-COR2;-CO2R3;-CON(R2)2;-(CH2)tR7,其中t是0或1-4的整数;和-(CH2)vZR8,其中v是0或1-3的整数,Z代表-S-或-O-。R1,R7和R8如上定义。
取代基T优选地为含乙炔基的部分,具有通式:
R30(CH2)nC≡C-其中n′是1-4,而R30选自:HO,MeO-,(n-Pr)2N-,CH3CO2-,CH3CH2OCO2-,HO2C-,OHC-,Ph-,3-HO-Ph-和PhCH2O-,条件是,当R30是Ph或3-HO-Ph时,n′=0。
最优选地,T是:MeOCH2C≡C-,(n-Pr)2NCH2C≡C-,CH3CO2CH2C≡C-,EtOCO2CH2C≡C-,HOCH2C≡C-,HO(CH2)2C≡C-,CH3CO2(CH2)2C≡C-,HO2C(CH2)2C≡C-,OHC(CH2)3C≡C-,HO(CH2)4C≡C-,PhC≡C-,3-HO-PhC≡C-和PhCH2OCH2C≡C-,
定义T取代基数目的下标x优选地是1或2,最优选地是1,并且当x是1时,T优选地位于A环上的4位。
A环优选地是苯基或噻吩环,最优选地是苯基。
B环优选地是1,4-亚苯基或2,5-噻吩环,最优选是1,4-亚苯基。
D单元最优选地是羰基。
E基中,R6优选地是:
1)芳烷基,其中的芳基部分含6-10个碳而烷基部分含1-8个碳;
2)-(CH2)tR7,其中的t是0或1-5的整数,而R7是含芳香残基的亚氨基;或
3)-(CH2)vZR8,其中的v是0或1-4的整数,Z是S或O,而R8是6-10个碳的芳基或其中的芳基部分含6-12个碳而烷基部分含1-4个碳的芳烷基。
R6基最优选地如下,其中的任何芳香部分优选地是取代的:
1)其中的芳基部分是苯基而烷基部分含1-4个碳的芳烷基;
2)-(CH2)tR7,其中的t是1-3的整数,而R7是N-(1,2-萘-二羧基亚氨基),N-(2,3-萘-二羧基亚氨基),或N-(1,8-萘-二羧基亚氨基);或N-邻苯二(甲)酰亚氨基,
3)-(CH2)vZR8,其中的v是1-3的整数,Z是S,而R8是苯基。
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)R/S 4′-(3-羟基-1-丙炔)-γ-氧代-α-(3-苯基丙基)-[1,1′-二苯基]-4-丁酸,
II)S-4′-(3-羟基-1-丙炔)-γ-氧代-α-(3-苯基丙基)-[1,1′-二苯基]-4-丁酸,
III)R-4′-(3-羟基-1-丙炔)-γ-氧代-α-(3-苯基丙基)-[1,1′-二苯基]-4-丁酸,
IV)4′-(3-甲氧基-1-丙炔)-γ-氧代-α-(3-苯基丙基)-[1,1′-二苯基]-4-丁酸,
V)γ-氧代-α-(3-苯基丙基)-4′-(3-丙基-1-己炔基)-[1,1′-二苯基]-4-丁酸,
VI)4′-[3-(乙酰氧)-1-丙炔基]-γ-氧代-α-(3-苯基丙基)-[1,1′-二苯基]-4-丁酸,
VII)4′-[3-(乙氧羰基)氧]-1-丙炔基]-γ-氧代-α-(3-苯基丙基)-[1,1′-二苯基]-4-丁酸,
VIII)4′-(4-羟基-1-丁炔基)-γ-氧代-α-(3-苯基丙基)-[1,1′-二苯基]-4-丁酸,
IX)4′-[3-(乙酰氧)-1-丙炔]-γ-氧代-α-(3-苯基丙基)-[1,1′-二苯基]-4-丁酸,
X)4′-(4-羰基-1-丁炔基)-γ-氧代-α-(3-苯基丙基)-[1,1′-二苯基]-4-丁酸,
XI)γ-氧代-4′-(5-氧代-1-戊炔基)-α-(β-苯基丙基)-[1,1′-二苯基]-4-丁酸,
XII)4′-(6-羟基-1-己炔基)-γ-氧代-α-(3-苯基丙基)-[1,1′-二苯基]-4-丁酸,
XIII)γ-氧代-4′-(苯基乙炔基)-α-(3-苯基丙基)-[1,1′-二苯基]-4-丁酸,和
XIV)4′-[3-羟基苯基]-乙炔基]-γ-氧代-α-(3-苯基丙基)-[1,1′-二苯基]-4丁酸,
XV)1,3-二氢-1,3-二氧代-α-[2-氧代-α-[2-氧代-2-[4′-[3(苯基甲氧基)-1-丙炔基][1,1′-二苯基]-4-基]乙基]-2H-异吲哚-2-丁酸,和
XVI)1,3-二氢-α-[2-[4′-(羟基乙炔基)[1,1′-二苯基]-4-基]-2-氧代乙基]-1,3-二氧代-2H-异吲哚-2-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。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-其中环A和B分别是取代的苯基和亚苯基的本发明化合物通过用取代的联苯MII与含酰基的活化中间体如丁二酸酐或戊二酸酐衍生物MIII或酰氯MIV,在Lewis酸催化剂如氯化铝存在下,在非质子溶剂如1,1,2,2-四氯乙烷中的Friedel-Crafts反应方便地制备。公知的Friedel-Crafts反应可以用Berliner,Org.React.,5,229(1949)和H.Heaney,Comp.Org.Synth.,2,733,1991中所述的许多其他溶剂和酸催化剂完成。
如果酸酐MIII是通过进攻两个羰基的任何一个的酸酐而以不对称方式单取代或多取代,则粗产物MI-A经常以异构体混合物的形式存在。产生的异构体可以通过用本专业已知的标准方法结晶或层析而分离为纯的形式。
当不能购买到时,丁二酸酐MIII可以通过丁二酸二烷基酯与醛或酮的Stobbe缩合(导致侧链R6),接着催化氢化,将半酯中间体水解为二酸,然后通过与乙酰氯或乙酸酐反应转化为酸酐MIII。另外,半酯中间体通过用亚硫酰氯或草酰氯处理,转化为酰氯MIV。Stobbe缩合的综述,包括列出的酰氯或草酰氯处理,转化为酰氯MIV。Stobbe缩合的综述,包括列出的合适的溶剂和碱,参见Johnson和Daub,Org.React.,6,1,1951。
此方法,用于制备MIII(R6=H,异丁基和H,正戊基),已经在Wolanin等人,美国专利4771038中叙述过。方法A
方法A对于制备环状化合物如MI-A-3,其中两个R6基团结合亚甲基链形成3-7员环特别有用。小环(3-5员)酐容易只以产生顺式本发明化合物MI-A-3的顺式异构体的形式获得。然后,通过用诸如DBU的碱在THF中处理MI-A-3而制备反式化合物MI-A-4。取代的四员环原料酐如MIII-A-1以如下所示的光化学2+2反应形成。此法对于制备其中R14是乙酰氧基或乙酰氧基亚甲基的化合物特别有用。Friedel-Crafts反应之后,乙酸酯可以通过碱性水解除去,而羧基通过转化为2-(三甲基甲硅烷基)乙基酯而保护。产生的R14=CH2OH的中间体可以通过用在一般方法G中所述的工艺转化为其他R14的本发明化合物。
当双键在丁二酰基链的C-2和C-3之间(例如,马来酸酐或1-环戊烯-1,2-二羧酸酐),或双键在侧链上时,Friedel-Crafts法也是有用的,如用于衣康酸酐作原料,产生其中R6基团在一个链碳上一起形成外-亚甲基(=CH2)的产物。这些化合物的后续应用在方法D中叙述。
一般方法B-另外,化合物MI可以通过这样的反应程序制备:丙二酸二烷基酯MVI用烷基卤化物一烷基化形成中间体MVII,接着用卤代甲基联苯酮MVIII烷基化,产生中间体MIX。结构MIX的化合物然后用碱水溶液水解并加热,使丙二酸中间体脱羧基,产生MI-B-2(方法B-1)。通过用一当量的碱水溶液,R12作为烷基的酯MI-B-2被得到,用多于2当量的碱水溶液,得到酸化合物(R12=H)。非强制性地,不加热,得到二酸或酸-酯MI-B-1。
另外,二酯中间体MIX可以与强酸如浓盐酸在乙酸中,在封管内,约110℃加热约24小时产生MI-B-1(R12=H)。另外,MVI与MVIII的反应在与烷基卤化物反应之前进行,产生同样的MIX(方法B-2)。
另外,含有R12=烷基的二酯中间体MXIX可以在吡咯烷存在下与Pd催化剂接触,产生MI-B-2(R12=H)(Dezeil,Tetrahedron Lett.28,4371,1990)。
从联苯MII,在与卤代乙酰卤如溴代乙酰溴或氯代乙酰氯的Friedel-Crafts反应,形成中间体MVII。另外,联苯可以与乙酰氯或乙酸酐反应,产生的产物用,例如,用溴卤化,产生中间体MVIII(X=Br)。
当方法A产生混合物时,方法B具有产生单个区域异构体的优点。当侧链R6含有芳香或杂芳香环,如果使用方法A,它们将参与分子内酰化反应,给出副产物,此时方法B特别有用。当与最终化合物的羧基相邻的R6基团含有杂原子如氧,硫,或氮,或更复杂的官能团如亚酰胺环时,此法也特别有用。方法B
当R6含有选择的官能团Z时,丙二酸酯MVII可以通过用异戊二烯基或烯丙基卤化物使购买的未取代丙二酸酯烷基化而制备,使此产物臭氧解,还原性处理,所需的Z基团可以通过Mitsunobu反应(Mitsunobu,Synthesis1,1981)偶合。另外,中间体醇可以在烷基化条件下提供含有所需的Z基团的丙二酸酯MVII。
一般方法C-特别有用的是用手性HPLC分离外消旋混合物的对映体(参见,例如,Arit,et al.,Chem.Int.Ed.Engl.12,30(1991))。本发明化合物可以通过用手性辅助途径以纯对映体的形式制备。参见,例如,Evans,Aldrichimica Acta,15(2),23,1982和其他本专业已知的相似参考文献。
一般方法D-其中R6是烷基-或芳基-或杂芳基-或酰基-或杂芳基羰基-硫代亚甲基的化合物通过类似于专利WO 90/05719所述的方法制备。因此,取代的衣康酸酐MXVI(n=1)在Friedel-Crafts条件下反应,产生酸MI-D-1,可以通过色谱或结晶与少量的异构体MI-D-5分离。另外,MI-D-5通过本发明化合物MI-D-4(由方法A至C的任何一种获得)与甲醛在碱存在下反应而得到。
化合物MI-D-1或MI-D-5然后与巯基衍生物MXVII或MXVIII在催化剂如碳酸钾,乙基二异丁基胺,氟化四丁基铵或游离基引发剂如偶氮二异丁腈(AIBN)存在下,在溶剂如二乙基甲酰胺或四氢呋喃中反应,产生本发明化合物MI-D-2,MI-D-3,MI-D-6或MI-D-7。方法D
一般方法E-如本申请的联芳基化合物也可以通过其中金属是锌,锡,镁,锂,硼,硅,铜,镉等等的芳基或杂芳基金属化合物与芳基或杂芳基卤化物或三氟甲磺酸酯等等的Suzuki或Stille交叉-偶合反应制备。在下面的方程中,Met或X之一是金属,另一个是卤素或三氟甲磺酸基(OTf)。Pd(com)是钯的可溶性配合物如四(三苯膦)-钯(O)或二(三苯膦)钯(III)氯化物。这些方法在本专业是已知的。参见,例如,Suzuki,Pure Appl.Chem.63,213(1994);Suzuki,Pure Appl.Chem.63,419(1991);和farina和Roth.“Metal-Organic Chemistry”Vol.5(Chapterl),1994。
原料MXXIII(B=1,4-亚苯基)用类似于方法A,B,C或D的方法,但用卤代苯而不用联苯作原料而容易地形成。需要时,其中X是卤素的原料可以通过本专业已知的反应转化为其中X是金属的化合物,如用六甲基二锡和四(三苯膦)钯在甲苯中回流处理溴代中间体,产生三甲基锡中间体。原料MXXIII(B=杂芳基)最容易通过方法C,但用容易获得的杂芳基而不是联苯原料制备。中间体MXXII既可以购买,也可以通过本专业已知的方法,从购买的原料容易地制备。方法E
(T)xA-Met+X-B-E-G → (T)xA-B-D-E-G
MXXII MXXIII Pd(com) MI-E
T,x,A,B,E和G如结构(L)中
Met=金属,X=卤素或三氟甲磺酸基
或
Met=卤素或三氟甲磺酸基,X=金属
这些一般方法对于制备由各种联芳基酰化方案的Friedel-Crafts反应,如方法A,B,C或D,将产生混合物的化合物是有用的。方法E对于制备其中芳基,A或B含有一个或多个杂原子(杂芳基)的产物,如含有噻吩,呋喃,吡啶,吡咯,噁唑,噻唑,嘧啶或吡嗪环等代替苯基的化合物特别有用。
一般方法F-当方法F的R6基团如下面中间体MXXV中一起形成4-7员碳环时,双键可以通过用2当量强碱如二异丙基氨化锂或六甲基甲硅烷基氨化锂等等处理,接着用酸淬灭,除去与酮的共轭,产生结构MXXVI的化合物。MXXVI与巯基衍生物用类似于一般方法D的方法反应,然后方法F
一般方法G-其中两个R6基团联合形成取代的5-员环的本发明化合物最方便地通过方法G制备。在此方法中,酸CLII(R=H)用Tetrahedron 37,Suppl.,411(1981)所述的方案制备。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公知的方法,将酸保护为酯[例如R=苄基(Bn)或2-(三甲基甲硅烷基)乙基(TMSE)]。取代的溴代联苯CIII通过用镁处理转化为其Grignard试剂,并与CI反应产生醇CVI。醇CVI通过用本专业公知的条件,碱处理其甲磺酸酯而消除,产生烯烃CVII。另外,通过先在低温(-78℃)用正丁基锂将溴化物金属化,接着用氯三甲基锡处理,将CIII转化为三甲基锡中间体,通过在强非质子碱存在下与2-[N,N-二(三氟甲磺酰基)氨基]-5-氯吡啶反应,将CI转化为烯醇三氟甲磺酸酯(CII)。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CVII。CVII臭氧解(用二甲硫处理)产生醛CVIII。另外,用OsO4处理,接着用HIO4处理,将CVII转化为CVIII。方法G
关键的中间体CVIII向靶专利化合物的转化以几种方式完成,取决于侧链官能团Z的性质。CVIII与Witting试剂反应,接着氢化,产生其中Z是烷基或芳烷基的产物。将醛CVIII用还原剂如三[(3-乙基-3-戊基)氧基]氢化铝锂(LTEPA)选择性还原,产生醇CIX。该醇转化为苯基醚或多种杂原子取代的衍生物,该衍生物经用本专业公知的条件(参见Mitsunobu,Synthesis,1(1981))的Mitsunobu反应用于产生侧链Z。另外,CIX的醇通过本专业公知的条件转化为离去基,如甲苯磺酸酯(CX)或溴化物,然后离去基由合适的亲核试剂置换。这类反应的几个例子可以在Norman et al.,J.Med.Chem.37,2552(1994)中发现。醇CIX直接酰化产生其中Z=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。在各种情况下,最后一步都是用取决于R和Z的稳定性,但在各种情况下都是本专业技术人员公知的条件,脱除酸封闭基团R,如通过碱水解脱除苄基,或用氟化四丁基铵处理,脱除2-(三甲基甲硅烷基)乙基,产生酸(R=H)。
一般方法H-本发明化合物酸的酰胺可以从酸通过在合适的溶剂如二氯甲烷或二甲基甲酰胺中,用伯或仲胺和偶合剂如二环己基碳二亚胺处理而制备。这些反应是本专业公知的。胺成分可以是简单烷基或芳烷基取代的,或可以是其中羧基被封闭而氨基是游离的氨基酸衍生物。
一般方法I-其中(T)x是炔基或取代的炔基的本发明化合物根据一般方法I(Austin,J.Org.Chem.46,2280(1981))制备。中间体MX根据方法A,B,C,D或G,从购买的MIII(R1=Br)开始制备。MX与取代的乙炔MIX在Cu(I)/钯试剂存在下反应,给出本发明化合物MI-I-1。在某些情况下,R3可以是用三烷基甲硅烷基封闭的醇。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。方法I
双三苯基膦钯
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,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。
治疗基质金属蛋白酶-介导的病症的方法可以在患有这类病症的哺乳动物,包括人体内实施。
本发明的抑制剂被期望用于兽医和人。因此,它们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,取决于给药方式和期望的剂量形式。
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。
实验
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60AF-254 250μm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%浓硫酸的四氧基苯甲醛的3%乙醇溶液,然后加热,和e)将板浸入含有5%碳酸钠的5%高锰酸钾水溶液中,接着加热。
柱层析用230-400目EM Science硅胶进行。
分析性高效液相色谱(HPLC)在1mL min-1在4.6×250mm Microsorb柱上进行,在288nm监测,而半制备性HPLC在24mLmin-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-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 Concept 1-H光谱仪上,用液体-铯二代离子(LCIMS),一个最新快速原子轰击(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。
实施例1-制备化合物I步骤1将2升的干燥,三颈,圆底烧瓶装上搅拌棒,等压加入漏斗,氩气入口和温度计。在该烧瓶中装入NaH(8.4克95%NaH;~0.33mol)的干燥THF(700ml)悬浮液并用冰水浴冷却。用加液漏斗在25分钟内滴加丙二酸二乙酯(48.54g,0.30mol)。持续搅拌1.5小时,接着通过加液漏斗在十分钟内加入1-溴-3-苯基丙烷(47)ml,~61g,~0.30mol)。加液漏斗的漂洗液(THF,2×10ml)加入该反应混合物并连续搅拌30分钟。用回流冷凝器和塞子代替该加液漏斗和温度计,并回流加热该反应液19小时。冷却该混合物至室温,然后用冰水浴。边搅拌边缓慢加入蒸馏水(400ml)。分层,而水相用氯仿(100ml)萃取。用10%HCl(250ml)洗涤合并的有机相,而分离的水相用氯仿(100ml)反萃取。用饱和的NaHCO3(250ml)洗涤该合并的有机相,用氯仿(100mL)反萃取该分离的水相。干燥有机相(Na2SO4)并浓缩得到黄色油,其通过Vigreux柱减压(0.4托)蒸馏纯化。124-138℃沸腾的级分是纯净的所需产物(57.21g,0.206mol;68%收率)。TLC(50%己烷-二氯甲烷):Rf=0.32。步骤2将1升,一颈圆底烧瓶配以橡胶隔膜和氩气入口。在该烧瓶中装入市售的4-溴代二苯基(50.00g,0.215mol)的二氯甲烷(100ml)溶液。用注射器加入溴乙酰溴(21.0ml,48.7g,0.230mol)并用冰水浴冷却该溶液至0℃,并分批加入AlCl3(34.3g,0.258mol)。从不透明的橄榄绿色反应混合物中析出气体。室温下24小时后,将反应混和物小心地注入冷的饱和的NaHCO3水溶液中。用每份200ml的乙酸乙酯萃取所得的混合液三次,并将合并的有机层用Na2SO4干燥,浓缩得到定量产率的黄色固体的所需产物。TLC(30%二氯乙烷-己烷),Rf=0.30步骤3将干燥的2升,三颈,圆底烧瓶装以磁搅拌棒,氩气入口,和等压加液漏斗。在此瓶中充入步骤1的产物(63.0g,0.227mol)的THF(500ml)溶液。用冰水浴冷却反应容器,同时缓慢分批加入NaH(5.40g,95%NaH,0.214mmol)。0℃下搅拌该反应混合物1小时,并通过加液漏斗在大约20分钟的时间内加入步骤2的产物(80.0g,0.215mol)的无水THF(300ml)溶液。在室温下于氩气的氛围中搅拌该深橙色的反应混合物3小时。在冰水浴中冷却该反应容器,并同时小心加入蒸馏水(150ml)。用每次300ml的乙酸乙酯萃取该水相三次,用MgSO4干燥该合并的有机相,并浓缩得到124g深橙色油。此物质无需纯化而用于下步操作。
将橙色油溶解于400ml 1∶1的THF∶甲醇中,并加入NaOH水溶液(4N,500ml,2.00mol)中。将该反应混合物在室温下搅拌24小时,50℃下48小时,以及室温下24小时。真空除去大部分MeOH并用200ml份的1∶1乙酸乙酯∶己烷和200ml份的己烷萃取该残留物。用HCl酸化该水相,用2×200ml份,和3×100ml份的乙酸乙酯萃取。MgSO4干燥该合并的有机相并浓缩得到定量产率的二酸。TLC(10%甲醇-氯仿,含1%乙酸):Rf=0.45步骤4将步骤3的未纯化的二酸溶于1,4-二噁烷(500ml)并加热至回流24小时。真空除去溶剂,将10g份残留物在硅胶(含1%乙酸的10-50%乙酸乙酯-己烷梯度洗脱)上色谱得到0.840g(10%)所需的黄色固体产物。MP174℃。步骤5将一颈,15ml,圆底烧瓶装以橡胶隔膜和氩气入口,并充以2.6ml二乙胺,步骤4的产物(0.300g,0.667mmol),炔丙醇(1.0ml,0.96g,17mmol),碘化酮(7)(0.0220g,0.115mmol),和反式-二氯双(三苯基膦)钯(0.110g,0.157mmol)。在室温下搅拌所得的混合物4天。浓缩反应混合物(290mg残留物)并在50g硅胶(20%乙酸乙酯-己烷,含0.5%乙酸)上柱色谱纯化部分残留物(90mg)得到偶联产物白色固体(0.035g,40%)。MP 130℃。实施例2和实施例3-化合物II和III的制备
在Chiralcel AD②柱(2cm×25cm)上用5%EtOH,4.75%H2O和0.095%HOAc的CH3CN溶液,流速20ml/分钟通过手性分离实施例1的产物来制备实施例2和3。实施例2首先从Chiralcel AD②柱上洗脱的:
1H NMR(300MHz,CDCl3)δ8.02(d,J=8.4Hz2H),7.67(d,J=8.7Hz,2H),7.58(d,J=8.7Hz,2H),7.53(d,J=8.4Hz,2H),7.17-7.33(m,5H),4.54(s,2H),3.46(dd,J=8.1,16.8Hz,1H),3.14-3.02(m,2H),2.65(t,J=7.2Hz,2H),1.64-1.84(m,4H)。实施例3接着从Chiralcel AD②柱上洗脱的:
1H NMR(300MHz,CDCl3)δ8.02(d,J=8.4Hz2H),7.67(d,J=8.7Hz,2H),7.58(d,J=8.7Hz,2H),7.53(d,J=8.4Hz,2H),7.17-7.33(m,5H),4.54(s,2H),3.46(dd,J=8.1,16.8Hz,1H),3.14-3.02(m,2H),2.65(t,J=7.2Hz,2H),1.64-1.84(m,4H)。
实施例6-制备化合物VI
将配有橡胶隔膜和氩气针入口的一颈,10ml,圆底烧瓶充入0.5ml吡啶,实施例1产物(0.0070g,0.014mmol),和乙酸酐(0.020ml,22mg,0.21mmol)。室温下搅拌该反应混合物2小时,并加入到30ml 1NHCl。用3×30ml乙酸乙酯萃取所得到的混合物,MgSO4干燥合并的有机相并浓缩。通过HPLC(2.5%乙酸乙酯-二氯甲烷,含0.1%三氟乙酸)纯化得到3mg(38%)实施例6的化合物。MP137℃。实施例7-制备化合物VII
将配有橡胶隔膜和氩气针入口的一颈,15ml,圆底烧瓶充入2ml三乙胺,2ml THF,化合物I(0.0570g,0.134mmol),和氯甲酸乙酯(0.032ml,36mg,0.34mmol)。室温下搅拌该反应混合物16小时并加到50ml 1NHCl中。用3×50ml的乙酸乙酯萃取所得的混合物,将合并的有机相用MgSO4干燥并浓缩。在10g硅胶(40%乙酸乙酯-己烷,含0.5%HOAc)上柱色谱,随后通过HPLC(1.5%乙酸乙酯-二氯甲烷,含0.01%三氟乙酸)纯化得到1mg(1.5%)实施例7化合物。MS(FAB-LSIMS)499[M+H]+。实施例11-制备化合物XI
将配有橡胶隔膜和氩气针入口的一颈,25ml,圆底烧瓶充入1mlCH2Cl2,实施例12化合物(0.012g,0.026mmol),和按Dess等,有机化学杂志,
48,4156,1983制备的Dess-Martin试剂(16mg,0.038mmol)。在0℃下搅拌该所得的混合物30分钟,用30ml乙酸乙酯稀释,并用2×20ml 1NHCl洗涤。将有机层用MgSO4干燥,并浓缩。通过HPLC纯化(1.5%乙酸乙酯-二氯甲烷,含0.01%三氟乙酸)得到1mg(9%)实施例11化合物。
1H NMR(300MHz,CDCl3)δ9.70(t,J=1.3Hz,1H),8.05(d,J=8.4Hz,2H),7.70(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.44(d,J=8.4Hz,2H),7.15-7.35(m,5H),3.46(dd,J=8.1,16.8Hz,1H),3.14-3.02(m,2H),2.67(t,J=7.2Hz,2H),2.48(t,J=7.5Hz,2H),2.41(dt,J=1.3Hz and 6.3Hz,2H),1.96(m,2H),1.64-1.84(m,4H)。
上述制备实施例1,2,6,7和11的方法可用于制备下列含二苯基的产物。
表I对比 R 异构体 m.p.(℃)/其它特征I HOCH2C≡C R.S 130II HOCH2C≡C S 1H NMR(300MHz,CDCl3)δ8.02(d,J=
8.4Hz,2H),7.67(d,J=8.7Hz,2H),7.58
(d,J=8.7Hz,2H),7.53(d,J=8.4Hz,2H),
7.17-7.33(m,5H),4.54(s,2H),3.46(dd,J
=8.1,16.8Hz,1H,3.02-3.14(m,2H,2.65
(t,J=7.2Hz,2H),1.64-1.84(m,4H).III HOCH2C≡C R 1H NMR(300MHz,CDCl3)δ8.02(d,J=
8.4Hz,2H),7.67(d,J=8.7Hz,2H),7.58
(d,J=8.7Hz,2H),7.53(d,J=8.4Hz,2H),
7.17-7.33(m,5H),4.54(s,2H),3.46(dd,J
=8.1,16.8Hz,1H),3.02-3.14(m,2H),2.65
(t,J=7.2Hz,2H),1.64-1.84(m,4H).IV MeOCH2C≡C R.S 136V (n-Pr)2NCH2C≡C R.S MS(FAB-LSIMS)510[M+H]-VI CH3CO2CH2C=C R.S 137VII EtOCO2CH2C≡C R.S MS(FAB-LSIMS)499[M+H]-VIII HO(CH2)2C≡C R.S 124IX CH3CO2(CH2)2C≡C R.S MS(FAB-LSIMS)483[M+H]-X HO2C(CH2)2C≡C R.S 184XI OHC(CH2)3C≡C R.S 1H NMR(300MHz,CDCl3)δ9.70(t,J=
1.3Hz,1H),8.05(d,J=8.4Hz,2H,7.70
(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),
7.44(d,J=8.4Hz,2H),7.15-7.35(m,5H),
3.46(dd,J=8.1,16.8Hz,1H),3.14-3.02
(m,2H),2.67(t,J=7.2Hz,2H),2.48(t,J
=7.5Hz,2H),2.41(dt,J=1.3Hz and 6.3
Hz,2H),1.96(m,2H),1.64-1.84(m,4H).XII HO(CH2)4C≡C R.S 123XIII PhC≡C R.S 154XIV 3-HO-PhC≡C R.S 237
实施例15制备化合物XV
步骤1将NaH(4.35g,181mmol)的新鲜蒸馏的THF(100ml)溶液冷却至0℃并用通过滴液漏斗在40分钟内用市售的丙二酸二烯丙酯(35.0,190mmol)处理。室温下搅拌30分钟后,一次性加入N-(2-溴乙基)邻苯二酰亚胺(43.9g,247mmol)到该溶液中并加热该混合物至回流。48小时后,冷却该溶液至0℃,用2N HCl骤冷并浓缩到其原始体积的大约20%。用乙酸乙酯(300ml)稀释该提取物并用饱和的K2CO3和NaCl水溶液连续洗涤。将该有机层用MgSO4干燥,过滤并减压浓缩。用闪蒸塔色谱(用5-25%乙酸乙酯-己烷梯度洗脱)纯化得到2-邻苯二酰亚氨乙基丙二酸二烯丙酯(41.2g,64%),无色油状物。1H NMR(300MHz,CDCl3)δ7.82(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)。注:Allyl为烯丙基
步骤2步骤1产物(5.20g,14.6mmol)的新鲜蒸馏的THF(100ml)溶液冷却至0℃,同时缓慢加入NaH(385mg,16.1mmol)。40分钟后,将该反应混合物温至室温,分批加入实施例1步骤2(4.55g,14.6mmol)的产物,并搅拌该混合物24小时。将该反应混合物冷却至0℃,用2NHCl(300ml)缓慢骤冷,用1×100ml二氯甲烷和2×100ml的二氯甲烷萃取。用MgSO4干燥该合并的有机相,过滤并浓缩得到6.50g(71%)所需的产物,其无需纯化而用于步骤3。TLC(30%乙酸乙酯-己烷):Rf=0.4步骤3将步骤2的产物(6.50g,10.4mmol)的1,4-二噁烷(100ml)溶液冷却至0℃,同时相继加入四(三苯基膦)钯(0.180g,146mmol)和吡咯烷(2.40ml,29.2mmol)。在0℃下搅拌2小时后,并在室温下4小时,将该反应混合物注入2NHCl(100ml)。用4×100ml的二氯甲烷萃取所得的混合物,用MgSO4干燥该合并的有机相并浓缩得到黄色固体二酸(9.70g)。将3.8g的此物质样品溶解于1,4-二噁烷(150ml)并回流加热1小时。冷却至室温后,冷缩该溶液并在300g硅胶上色谱(5%-15%甲醇-二氯甲烷)该残留物得到所需的酸(0.300g),其通过重结晶纯化得到0.170g(自步骤2的总收率为59%)白色晶状固体的所需产物。MP290-210℃。步骤4 将配有橡胶隔膜和氩气针入口并含有2ml THF的一颈,100ml,圆底烧瓶充入NaH(435mg,17.2mmol)并冷却至0℃,同时通过注射器在大约5分钟中加入炔丙醇(1.0ml,0.963g,17.2mmol)。0℃下搅拌该所得混合物10分钟并在室温下30分钟,加入苄基溴(1.8ml,2.59g,15.1mmol),室温下搅拌该反应混合物36小时,注入戊烷(150ml),并用100ml份的盐水洗涤。蒸馏除去该溶剂并将该残留物(3.5g黄色油)直接用于步骤5。1H NMR(300MHz,CDCl3)δ7.36-7.31(m,5H),4.61(s,2H),4.17(d,J=2.4Hz,2H),2.47(t,J=2.4Hz,1H)。步骤5用实施例1,步骤5的方法,用步骤4和3的产物作为起始材料制备实施例15的化合物。MP151℃。
实施例16 制备化合物XVI步骤1将配有橡胶隔膜和氩气针入口的一颈,100ml,圆底烧瓶充入炔丙醇(1.0ml,0.963g,17.2mmol),醚(20ml),并冷却至0℃,同时缓慢加入NaH(435mg,17.2mmol)。室温下搅拌该所得的混合物一小时,并加入叔丁基二甲基甲硅烷基氯(2.60g,17.2mmol)。室温下搅拌该反应混合物6小时,注入己烷(150ml),并用1N HCl洗涤。将该有机相用MgSO4干燥并浓缩得到2.88g黄色油,其无需纯化而用于步骤2。2步骤2用实施例1,步骤2的方法,用市售的4-碘二苯基和乙酰氯制备所需的乙酰二苯基。TLC(10%乙酸乙酯-己烷):Rf=0.3步骤3用实施例1,步骤5的方法,利用步骤1和2的产物制备所需的二苯基乙炔。TLC(10%乙酸乙酯-己烷):Rf=0.4。步骤4将配有橡胶隔膜和氩气针入口的一颈,50ml,圆底烧瓶充入5mlTHF,步骤3的产物(1.06g,2.94mmol),并冷却至-78℃并通过注射器滴加六甲基乙硅烷叠氮钾(617mg,2.94mmol)。在-78℃下搅拌该反应混合物30分钟,通过注射器滴加三甲基硅烷氯(0.374ml,0.320g,2.94mmol),并在-78℃下搅拌该所得混合物3小时。将该反应混合物温至0℃,一小时,加入N-溴琥珀酰亚胺(0.540g,2.94mmol),并将该混合物温至室温并搅拌16小时。将该反应混合物注入100ml份的饱和的NH4Cl水溶液并用3×50ml的二氯甲烷萃取。该合并的有机相用MgSO4干燥并浓缩。在200g硅胶上柱色谱(用0-5%乙酸乙酯-己烷)梯度洗脱)得到0.264g(20%)溴甲基酮。TLC(10%乙酸乙酯-己烷):Rf=0.5。步骤5利用实施例15,步骤2-3的方法和步骤4的产物制备所需的二苯基邻苯二甲酰亚胺。TLC(50%乙酸乙酯-己烷,含1%乙酸):Rf=0.3步骤6:将配有橡胶隔膜和氩气针入口的单颈50ml的圆底烧瓶中充入10mlCH2Cl2,步骤5产物(0.040g,0.067mmol),和2ml HF-吡啶。在室温下搅拌该所得的混合物10分钟,用75ml份的水稀释,并用75ml份的CH2Cl2萃取。该有机相用MgSO4干燥并浓缩。在5g硅胶上柱色谱(25%乙酸乙酯-己烷,含1%HOAc)得到6mg(19%)实施例16的产物。MP145℃。
实施例17
本发明化合物的生物学检测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(proifilingassag))是最初由C.G.Knight等,FEBS Letters,297,163-266(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pH7.5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):
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(Pro-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pH7.4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 Cyofluor 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pH6.5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1mLMarsh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107μLP218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pH7.5的50mMTHs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。
表II
对比# | MMP-3荧光团IC-50 | MMP-9荧光团IC-50 | MMP-2荧光团IC-50 |
I | 21 | 106 | 4 |
II | 2184 | I=35% | 252 |
III | 5 | 37 | 1 |
IV | 38 | 704 | 21 |
V | 327 | 2630 | 235 |
VI | 36 | 834 | 14 |
VII | 67 | 2460 | 103 |
VIII | 32 | 122 | 6 |
IX | 57 | 542 | 37 |
X | 203 | I=27% | 108 |
XI | 1730 | I=24% | 596 |
XII | 56.6 | 614 | 36 |
XIII | 405 | 245 | |
XIV | 125 | I=46% | 85 |
XV | 11 | 40 | 5 |
XVI | 4 | 2 | 1 |
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。
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。
Claims (7)
2.具有基质金属蛋白酶抑制活性的组合物,包括权利要求1的化合物和药用载体。
3.权利要求1的基质金属蛋白酶抑制化合物在制备抑制哺乳动物体内基质金属蛋白酶活性的药物组合物中的用途。
4.权利要求3的用途,其中所说的哺乳动物是人。
5.权利要求1的基质金属蛋白酶抑制化合物在制备具有下述效果的药物组合物中的用途:
(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,由基质金属蛋白酶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;
(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)实现生育控制。
6.权利要求5的用途,其中所说的效果是减轻骨关节炎。
7.权利要求5的用途,其中所说的效果是阻滞肿瘤转移。
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