CN1225621A - 通过2-取代的-4-(4-取代的苯基)-4-氧代丁酸抑制基质金属蛋白酶 - Google Patents
通过2-取代的-4-(4-取代的苯基)-4-氧代丁酸抑制基质金属蛋白酶 Download PDFInfo
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- CN1225621A CN1225621A CN97196454A CN97196454A CN1225621A CN 1225621 A CN1225621 A CN 1225621A CN 97196454 A CN97196454 A CN 97196454A CN 97196454 A CN97196454 A CN 97196454A CN 1225621 A CN1225621 A CN 1225621A
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Classifications
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C59/76—Unsaturated compounds containing keto groups
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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r是0—2,T选自(a)和(b),而R40是单或双杂环结构。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联芳基氧代丁酸化合物或其衍生物。
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)类风湿性关节炎(Mullins,D.E.;Rohrlich,S.T.Biochim.biophys.Acta695,117-214(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,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,Steroids54,491-9(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.Acta695,177,1983;,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,etal.,USP-4599361;Hughs,et al.,USP-5190937;Broadhurst,et al.,EP-0574758A1;Broadhurst,et al.,EP-026436;和Myers et al.,EP-0520573Al)。这些专利的优选的化合物具有肽骨架,其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。
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 a1.,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 a1.,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,etal.,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)。
相对于现有技术的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,et al.,J.Med.Chem.37,206,1994;Grobelny,et al.,Biochemistry24,6145,1985;Mookhtiar,etal.,Biochemistry 27,4299,1988)。然而,这些抑制剂一般都含有肽骨架,并因此通常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,本发明也提供治疗这些病症的药物组合物和方法。
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)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。
(d)临时降低繁殖能力(即作为有效的生育控制剂)。
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作用机理的科研工具。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1-2N,O,或S的原子的杂芳香5-6员环。T表示一个或多个取代基,下标x表示这的数目
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个独立地选自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表示带有m个取代基R6的n个碳原子链,其中R6基团是独立的取代基,或构成螺旋或非螺旋环。环可以由两种方式形成:a)两个基团R6结合,并与它们所连接的链原子和任何介入的链原子一起,构成3-7员环,或b)一个基团R6与其所属的链结合,并与R6基团所连接的链原子,和任何介入的链原子一起,构成3-7员环。在链中,碳原子的数量n是2或3,R6取代基的数量m是整数1-3。在R6基团中碳原子总数至少是2。
各个基团R6是烷基,烯基,炔基,杂芳基,非芳香环,它们非强制性地被一个或多个在下面更充分描述的杂原子取代。
在通式(L)中,E表示被单-或双-杂环结构取代的直链或环状烷基部分。
其中M表示-CO2H,-CON(R11)2,或-CO2R12,而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的失活。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该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,被考虑为实际药物的替代物。
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
更具体地,本发明的化合物是具有基质金属蛋白酶抑制活性和如下通式的物质:
(T)xA-B-D-E-G(L)
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。
其中R1表示H或1-3碳烷基。
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。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这样的基团,其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,否则将是有害的。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:
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。
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连接的或是Q部分的部分中不饱和部位与任何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(n-Pr)2-,CH3CO2-,CH3CH2OCO2-,HO2C-,OHC-,Ph-,3-OH-Ph-,和PhCH2O-,条件是当R30是Ph或-OH-Ph-时,n=0。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的联合具有如下结构的化合物:
其中Z可以是(CH2)e-C6H4-(CH2)f或(CH2)g,e=0-8,f=0-5和g=0-14,r是0-6。R15可以是具有6-12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。
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个碳原子的直链,支链或环状烷基,优选1-3个碳原子和直键,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。
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-,而该基团优选是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。
当r是1或2时,分别形成环丁基或环戊基烷基。单或双杂环结构的各个环包含被1-3个独立地选自N,S和O的杂原子取代的5-7员环;环的一或二个碳原子非强制性地是羰基碳;环的任何硫非强制性地是-S(O)-或-S(O)2-;一个或多个环成员非强制性地被一个或两个甲基取代;而杂环结构连接在如下基团上
而A单元是苯基,B单元是亚苯基,m是1,n是2,t是0,则x是1或2。
13)-(CH2)vZR8其中v是整数1-4,Z表示-S-,-S(O)-,-SO2-,或-O-,而R8选自如下基团:1至12碳烷基,6至10碳芳基,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至12碳,而烷基部分含有1至4碳的芳烷基;其中芳基部分含有6至12碳和至少一个N,O或S杂原子,而烷基部分含有1至4碳的杂芳基烷基;-C(O)R9其中R9表示2至6碳的烷基,6至10碳的芳基,包含4至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至10碳或者是包含4至9碳和至少一个N,O或S杂原子的杂芳基,而烷基部分含有1至4碳的芳烷基,条件是当R8是-C(O)R9时,Z是-S-或-O-;当Z是-O-时,R8也可以是-(CqH2qO)rR5其中q,r,和R5如上定义;而当A单元是苯基,B单元是亚苯基,m是1,n是2,和v是0时,则x是1或2;和
14)-(CH2)wSiR10 3其中w是整数1至3,R10表示1至2碳烷基。
另外,任何T或R6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-,
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。
或PhCH2OCH2OCH2-,本文中的Ph是苯基。
G单元最优选地是羧酸基团,并且在2位与E单元连接,即,E单元的碳原子与D单元为β位。
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。
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,否则其为有害基团。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,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。
某些方案包括具有基质金属蛋白酶抑制活性和如下通式的化合物:
其中Z是(CH2)e-C6H4-(CH2)f或(CH2)g,e=0-8,f=0-5和g=0-14,r是0-6,其中y是0,2,或3。
本发明也涉及某些可用于合成一些要求保护的抑制剂的中间体。这些中间体是具有如下通式的化合物:
其中Bn是苄基,TMSE是三甲基甲硅烷基乙基,R40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:
Ⅰ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[(4-氧代-1,2,3-苯并三嗪-3(4H)-基)甲基]环戊烷羧酸,
Ⅱ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[苯氧基甲氧基甲基]环戊烷羧酸,
Ⅲ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[[(1-吡咯烷基硫甲基)硫基]甲基]环戊烷羧酸,
Ⅳ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[(1,1-二氧代-3-氧代-1,2-苯并异噻唑-2(3H)-基)甲基]环戊烷羧酸,
Ⅴ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[(1-氧代-2(1H)-2,3-二氮杂萘基)甲基]环戊烷羧酸,
Ⅵ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[(2-氧代-3(2H)-苯并噁唑基)甲基]环戊烷羧酸,
Ⅶ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[5,5-二甲基-2,4-二氧代-3-噁唑烷基)甲基]环戊烷羧酸,
Ⅷ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[2,4-二氧代-3-噻唑烷基)甲基]环戊烷羧酸,
Ⅸ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[2,4,5-三氧代-1-咪唑烷基)甲基]环戊烷羧酸,
Ⅹ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[3,6-二氢-2,6-二氧代-1(2H)-嘧啶基)甲基]环戊烷羧酸,
Ⅺ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[3,4-二氢-2,4-二氧代-1(2H)-嘧啶基)甲基]环戊烷羧酸,
Ⅻ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[1,4-二氢-2,4-二氧代-3(2H)-喹唑啉基)甲基]环戊烷羧酸,
ⅩⅢ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[3,4-二氢-1,3-二氧代-2(1H)-异喹啉基)甲基]环戊烷羧酸,
ⅩⅣ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[1,4-二氢-4-氧代-3(2H)-喹唑啉基)甲基]环戊烷羧酸,
ⅩⅤ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[1,3-二氢-3-氧代-2H-吲唑-2-基)甲基]环戊烷羧酸,
ⅩⅥ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[2,3-二氢-1H-苯并咪唑-1-基)甲基]环戊烷羧酸,
ⅩⅦ)2-[(4’-氯[1,1’-联苯基]-4-基)羰基]-5-[(3,4-二氢-1,4-二氧代-2(1H)-2,3-二氮杂萘基)甲基]环戊烷羧酸,
ⅩⅧ)R/Sα-[2-[4’-氯[1,1’-联苯基]-4-基)-2-氧代乙基]-1-氧代-2(1H)-2,3-二氮杂萘丁酸,
ⅩⅨ)R-α-[2-[4’-氯[1,1’-联苯基]-4-基)-2-氧代乙基]-1-氧代-2(1H)-2,3-二氮杂萘丁酸,
ⅩⅩ)S-α-[2-[4’-氯[1,1’-联苯基]-4-基)-2-氧代乙基]-1-氧代-2(1H)-2,3-二氮杂萘丁酸,
ⅩⅪ)α-[2-[4’-氯[1,1’-联苯基]-4-基)-2-氧代乙基]-4-氧代-1,2,3-苯并三嗪-3(4H)丁酸,
ⅩⅩⅫ)α-[2-[4’-氯[1,1’-联苯基]-4-基)-2-氧代乙基]-2,3-二氢-5-甲基-2-氧代-1H-1,4-苯并二氮杂丫庚因-1-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,任何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 et al.,美国专利4771038中叙述过。
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。
或者,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)。
或者,含有R12=烯丙基的二酯中间体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,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。
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 a1.,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WO90/05719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,可以通过层析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。
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(Chapter1),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MⅩⅩⅢ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
MⅩⅫMⅩⅩⅢPd(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,如代替苯基的含有噻吩,呋喃,吡啶,吡咯,噁唑,噻唑,嘧啶或吡嗪环等化合物特别有用。
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,然后给出环状化合物MⅠ-F-I或MⅠ-F-2。
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Tetrahedron37,Suppl.,411(1981)所述的原始记录制备。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CLⅡ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Wittig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MⅪ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
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通过普通中和技术,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的少受影响。
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SciosNova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
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套管转移,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,只有二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 PaulAvenue,Milwaukee,WI53233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60A F-254250μm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,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-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将外-氧代双环[2.2.1]庚烷-7-羧酸[用Author.Tetrehedron,37,suppl.,411,1981所述的原始记录制备](3.04g,19.7mmol)的二氯甲烷(45ml)溶液冷却至0℃,并用2-(三甲基甲硅烷基)乙醇(2.7ml,18.6mmol),EDC(3.94g,20.55mmol)和DMAP(0.11g,0.9mmol)处理。温热至室温后,搅拌2小时,反应混合物用水淬灭,用二氯甲烷稀释。分层后,有机相用饱和氯化钠水溶液洗涤,硫酸镁干燥并浓缩。通过MPLC(0-25%乙酸乙酯-己烷)纯化,给出目标化合物(3.9g,78%)无色油状物。
步骤2将步骤1的酮(3.18g,12.50mmol)和2-[N,N-二(三氟甲磺酰基)氨基]-5-氯吡啶(6.6g,16.30mmol)的THF溶液冷却至-78℃,并小心地用0.5M KHMDS的甲苯(24ml,12mmol)溶液处理。加完后,将溶液甲苯2小时,将反应混合物用水(30ml)淬灭,温热至室温并用乙酸乙酯稀释。分开两相。有机层用饱和氯化钠水溶液洗涤,硫酸镁干燥并浓缩。通过MPLC(0-15%乙酸乙酯-己烷)纯化,给出目标化合物(4.2g,91%)无色油状物。
1H NMR(CDCl3)δ5.75(d,J=4.8Hz,1H),4.13(t,J=9.0Hz,2H),3.18(m.2H),2.62(m,1H),2.62(m,2H),1.41(t,J=9.3Hz,1H),1.23(t,J=9.1Hz,1H),0.96(t,J=8.4Hz,2H),0.04(s,9H).
步骤3将4-氯联苯(3.0g,15.9mmol)的乙酸(50ml)溶液小心地用溴(1.1ml,20.7mmol)在室温下处理。反应混合物被加热回流4小时,冷却至室温,并用过量的丙烯处理,直至混合物变清。将溶液浓缩至稠浆状物,用二氯甲烷(50ml)稀释,依次用水和2N氢氧化钠洗涤。有机萃取液用硫酸镁干燥,过滤并浓缩。从乙酸乙酯重结晶纯化,给出芳基溴化物(3.57g,84%)白色晶状固体。
1H NMR(CDCl3)δ7.57(m,2H),7.48(m,2H),7.41(m,4H)
步骤4将4-溴-4’-氯联苯(8.0g,30.0mmol)的THF(120ml)溶液冷却至-78℃,并小心地用正丁基锂(19.7ml,1.6M己烷溶液,31.5mmol)处理。搅拌1小时后,将混合物用氯三甲基锡(33ml,1.0M溶液,33.0mmol)处理。再过30分钟后,将溶液温热至室温并浓缩。将米色固体用二氯甲烷(300ml)稀释,并依次用水和饱和氯化钠水溶液洗涤。有机层用硫酸镁干燥,过滤并浓缩。通过MPLC(己烷)纯化,给出所需的芳基锡化合物(9.38g,89%)白色晶状固体。
步骤5将步骤2的三氟甲磺酸酯(4.2g,10.89mmol),CuI(0.215g,1.1mmol),AsPh3(0.339g,1.1mmol),Cl2Pd(MeCN)2(0.215g,0.56mmol)和少量BHT晶体的1-甲基-2-吡咯烷酮(11.5ml)溶液放在预热至85℃的油浴上。搅拌4分钟后,一次加入步骤4的联苯基锡衍生物(7.3g,20.7mmol)。将混合物搅拌30分钟,冷却至室温,并用乙酸乙酯稀释。分开两相后,水相用乙酸乙酯反萃取,合并的有机层用硫酸镁干燥并浓缩。产生的残余物吸附在硅胶上,并通过MPLC(0-15%乙酸乙酯-己烷)纯化,给出偶合的产物(4.0g,86%)白色晶状固体。
1H NMR(CDCl3)δ7.52(m,6H),7.42(m,2H),6.40(d,J=3.3Hz,1H),4.19(t,J=10.2Hz,2H),3.58(m,1H),3.23(m,1H),2.60(m,1H),1.95(m,2H),1.20(m.2H),1.02(d.J=7.5Hz,2H),0.08(s,9H)
步骤6将步骤5的烯烃(3.60g,8.47mmol)在10%甲醇-二氯甲烷(200mL)中的溶液冷却至-78℃,并用臭氧处理,其作为气体直接加入反应混合物中(10min.1L/min.)。TLC指示原料不存在后,将溶液用氩气(15分钟)清洗,用二甲硫(13ml)处理,并温热至室温。搅拌过夜后,将溶液浓缩为残余物,通过MPLC(0-15%乙酸乙酯-己烷)纯化,给出所需的醛和相应的二甲基缩醛的混合物。将产物混合物溶于丙酮(45ml),并用CSA(0.192g,0.83mmol)和水(0.13ml,16.5mmol)处理。搅拌过夜后,将溶液浓缩,并通过MPLC(0-15%乙酸乙酯-己烷)纯化给出所需的醛(3.45g,89%)无色油状物。
NMR(CDCl3)δ9.78(d.J=9.0Hz,1H),8.05(d,J=6.6Hz,2H),7.65(d,J=6.6Hz,2H),7.55(d,J=9.0Hz,2H),7.44(d,J=9.0Hz,2H),4.15(m,3H),3.87(t,J=7.2Hz,1H).3.15(m,1H),2.20(m,1H),2.03(m,1H),1.86(m,1H),1.58(s,1H),1.25(t,J=6.9Hz,1H),0.93(m,2H),0.00(s,9H)
步骤7.将氢化铝锂(1.9ml,1.0M THF)的THF溶液用3-乙基-3-戊醇(0.83g,5.77mmol)处理,并加热至轻微回流1小时。混合物然后冷却至室温。
将步骤6的醛中间体(0.85g,1.86mmol)的THF(15ml)溶液冷却至-78℃,并用预制的LTEPA的THF溶液以导管滴加的方式处理。加完后,将溶液在-78℃搅拌4小时,并随后用2N盐酸(4.6ml)淬灭。反应混合物用乙酸乙酯稀释,水洗。有机层用硫酸镁干燥,过滤并浓缩。通过MPLC(5-40%乙酸乙酯-己烷)纯化,给出所需的醛(0.640g,75%)白色晶状固体。
1H NMR(CDCl3)δ8.05(d,J=8.7Hz,2H),7.65(d,J=8.5Hz,2H),7.55(d,=8.4Hz,2H),7.44(d,J=8.4Hz,2H),4.15(m,2H),3.76(t,J=6.3Hz,2H),3.28(t,J=6.3Hz,2H),2.48(m,1H),2.35(t,J=6.0Hz,1H),2.18(m,1H),1.91(m,2H),1.57(s,1H),1.35(t,J=6.9Hz,1H),0.91(m,2H),-0.01(s,9H).
步骤8.将步骤7的醇(0.050g,0.109mmol),三苯膦(0.057g,0.217mmol)和苯并-1,2,3-三嗪-4(3H)-酮(0.034g,0.231mmol)的THF(2.5ml)溶液用偶氮二羧酸二乙酯(0.035ml,0.222mmol)处理。混合物在室温下搅拌16小时,减压浓缩,并通过MPLC(0-20%乙酸乙酯-己烷)纯化,给出目标化合物(0.034g,53%)。TLC:Rf0.16(硅胶,20%乙酸乙酯-己烷)。
步骤9.将步骤8的酯(0.031g,0.052mmol)的二氯甲烷(2ml)溶液冷却至0℃,并用TFA(0.25ml)处理。搅拌5小时后,将溶液减压浓缩,并用快速柱层析(0-5%甲醇-二氯甲烷)纯化,给出所需的酸(0.023g,90%)白色晶状固体。MP198-199℃。
步骤2.将步骤1的中间体(0.02g,0.045mmol)和二异丙基乙基胺(0.025ml,0.144mmol)的二氯甲烷(1.5ml)溶液用苄基氯甲基醚(0.016ml,0.099mmol)处理,并在室温下搅拌6小时。浓缩的反应混合物通过快速柱层析(5-20%乙酸乙酯-己烷)纯化,给出所需的醚(0.022g,86%)。TLC:Rf0.25(硅胶,20%乙酸乙酯-己烷)。
步骤3.将步骤2的中间体苄基酯(0.020g,0.035mmol)的THF(0.4mmol)和乙醇(0.4mmol)溶液用氢氧化钠溶液(0.14ml,0.5g/10ml水)处理。在室温下搅拌45分钟后,将混合物用乙酸乙酯稀释,并用2N盐酸(0.2ml)淬灭。有机层用饱和氯化钠水溶液洗涤,硫酸镁干燥,并浓缩,给出所需的酸(0.012g,72%)。MP112-113℃。
步骤1.将实施例2,步骤1的醇(0.100g,0.223mmol)和二异丙基乙基胺(0.05ml,0.287mmol)的二氯甲烷(3.0ml)溶液用对甲苯磺酰氯(0.048g,0.249mmol)和DMAP晶体处理。混合物在室温下搅拌16小时,减压浓缩,并用MPLC(0-20%乙酸乙酯-己烷)纯化,给出所需的甲磺酸酯(0.118g,88%)。TLC:Rf0.23(硅胶,0-20%乙酸乙酯-己烷)。
步骤2.将步骤1的甲苯磺酸酯(0.039g,0.066mmol)和18-冠-6(0.044g,0.166mmol)的DMF(0.7ml)溶液用吡咯烷二硫代氨基甲酸钠(0.035g,0.165mmol)处理,并在室温下搅拌16小时。将反应混合物用乙酸乙酯和水稀释。分开两相后,有机层用饱和氯化钠水溶液洗涤,硫酸镁干燥,过滤并浓缩。通过MPLC(3-15%乙酸乙酯-己烷)纯化,给出所需的产物(0.038g,99%)。TLC:Rf0.34(硅胶,0-20%乙酸乙酯-己烷)。
步骤3.步骤2的苄基酯中间体的脱保护用与实施例2步骤3所述相同的方法完成。MP177-178℃。
上述实施例1-3的制备方法被,或可被用于制备下表中的一系列含有联苯的产物。
步骤1.将2,3-二氮杂萘酮(1.00g,6.84mmol),三苯膦(1.79g,6.84mmol)的THF(25ml)溶液冷却至0℃,并用2-溴乙醇(0.480ml,6.84mmol)和偶氮二羧酸二乙酯(1.07ml,6.84mmol)处理。在0℃搅拌1小时后,将溶液温热至室温,并再搅拌12小时。将产生的混合物浓缩并通过快速柱层析(35%乙酸乙酯-己烷)纯化,给出1.40g(81%)溴代乙基-2,3-二氮杂萘白色固体。TLC:Rf:0.65(40%乙酸乙酯-己烷)。
步骤2.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。温热至室温并搅拌20分钟后,一次加入步骤1的溴代乙基-2,3-二氮杂萘(0.325g,1.28mmol),混合物被加热回流18小时。将反应混合物用饱和氯化铵水溶液(20ml)和乙酸乙酯(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.将一2L三颈圆底烧瓶配上机械搅拌器,温度计和氩气导管。往烧瓶中装入4-氯联苯(48.30g,0.256mmol)的二氯甲烷(500ml)溶液。经注射器加入溴代乙酰溴(23ml,0.26mol),将溶液用冰浴冷却至内温3℃。暂时除去温度计,在5分钟内分批加入氯化铝。将内温升至10℃,从暗橄榄绿色的反应混合物中逸出白色气体。24小时后,反应通过小心地倒入冷10%盐酸(1L)而淬灭。有机层变为浑浊的黄绿色。加入氯仿帮助溶解固体,但有机层不再变为透明。有机层在旋转蒸发器中浓缩,再真空干燥。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)。将母液浓缩,接着加入己烷,得到第二批晶体(11.06g),其NMR谱与第一批的相同。产物的总产率是87%。TLC:Rf0.30(硅胶,70%己烷-二氯甲烷)。
步骤4.将氢化钠(0.020g,0.775mmol)的THF(2.0ml)溶液冷却至0℃,并小心地用步骤2的二酯处理。将冰浴移走,并将产生的混合物搅拌20分钟。将反应混合物再冷却至0℃,并一次用1-(2-溴代乙酮)-4-(4-氯苯基)苯(0.200g,0.646mmol)处理。将混合物在30分钟内温热至室温,随后加热回流12小时。将反应混合物加入饱和的氯化铵水溶液(10ml)中,并用乙酸乙酯(10ml)稀释。产生的有机相用水(10ml)洗涤,硫酸镁干燥,过滤并浓缩,给出0.327g(78%)黄色油状物。TLC:Rf0.40(硅胶,40%乙酸乙酯-己烷)。
步骤5.将步骤4的二酯产物(0.327g,0.558mmol)的1,4-二噁烷(5ml)溶液用四(三苯膦)钯(0.006g,0.005mmol)一次处理,并在15分钟内滴加吡咯烷酮(0.102ml,1.22mmol)。在室温搅拌30分钟后,反应混合物用1N盐酸(20ml)和乙酸乙酯(20ml)稀释。产生的有机相用饱和氯化钠水溶液洗涤,硫酸镁干燥,过滤,并浓缩,产生二酸褐色粗油状物,将其立即进行步骤6。TLC:Rf0.29(硅胶,5%甲醇二氯甲烷)。
步骤6.将步骤5的二酸产物的1,4-二噁烷(25ml)溶液加热回流24小时。冷却至室温后,将产生的混合物浓缩为灰色固体。用乙酸乙酯重结晶给出0.044g(18%,两步)化合物ⅩⅧ白色固体。MP232℃。TLC:Rf0.5(硅胶,10%甲醇-二氯甲烷)。实施例19-制备化合物ⅩⅨ
步骤1-将氢化钠(0.040g,1.54mmol)的THF(100ml)溶液冷却至0℃,并在20分钟内经滴液漏斗滴加丙二酸二叔丁基酯(20.73ml,92.47mmol)处理。室温搅拌30分钟后,加入3,3-二甲基烯丙基溴(9.7ml,83.22mmol)。再搅拌19小时后,将反应混合物用10%盐酸溶液(100ml)和乙酸乙酯(100ml)稀释。产生的有机相用饱和氯化钠水溶液洗涤,硫酸镁干燥,过滤,并浓缩,给出25.74g(94%)粗黄色油状物。TLC:Rf0.60(硅胶,10%乙酸乙酯-己烷)。
步骤2.将步骤1的粗烯烃(25.74g,90.50mmol)的二氯甲烷(350ml)和甲醇(90ml)溶液冷却至-78℃,用氧气清洗20分钟,鼓入臭氧,直至保持蓝色(2小时)。将溶液用氧气清洗,直至溶液变为无色。温热至0℃后,一次加入硼氢化钠(3.42g,90.50mmol)。几分钟后,除去冰浴,将混合物搅拌过夜。将混合物浓缩,在二氯甲烷中再稀释,用水(100ml),10%盐酸(100ml),食盐水(50ml)洗涤,硫酸镁干燥,过滤并浓缩为无色油状物。通过快速层析(30%乙酸乙酯-己烷)将15.0g粗物纯化,给出6.86g(50%)无色油状物。TLC:Rf0.30(硅胶,35%乙酸乙酯-己烷)。
步骤3.以类似于实施例18,步骤1的制备中所述的方式制备丙二酸中间体。对于此实施例,苯并-1,2,3-三嗪-4(3H)-酮被用于代替2,3-二氮杂萘酮,步骤2的醇形式用于代替2-溴乙醇。TLC:Rf0.40(硅胶,40%乙酸乙酯-己烷)。
步骤4.以类似于实施例18,步骤2的制备中所述的方式制备二烷基化的丙二酸中间体。在此实施例中,步骤3的一烷基化的丙二酸酯用1-(2-溴代乙酮)-4-(4-氯苯基)苯烷基化。TLC:Rf0.50(硅胶,40%乙酸乙酯-己烷)。
步骤5.将步骤4的二酯产物(4.61g,0.746mmol)的1,4-二噁烷(10ml)溶液用4N盐酸处理,并加热回流10小时。浓缩为油状物后,残余物通过快速层析(0-10%甲醇-二氯甲烷)纯化,给出黄色固体。MP195℃。
实施例20和实施例21-制备化合物ⅩⅩ和ⅩⅪ
实施例19的产物通过在手性HPLC柱上层析(二氯甲烷乙酸乙酯-己烷)分开。实施例20首先从柱上得到。实施例21第二洗脱。
实施例20.MS(FAB-LSMIS)462[M+H]+
实施例21.C25H20ClN3O4的分析计算值:C,65.01;H,4.36;N,9.10;实测:C,64.70;H,4.06;N,8.72。
实施例22-制备化合物ⅩⅫ
步骤1.将(2-羟基乙基)丙二酸二叔丁基酯(0.500g,1.92mmol),PPh3(0.555g,2.12mmol)和CBr4(0.704g,2.12mmol)的二氯甲烷(4.0ml)溶液在0℃搅拌5分钟,然后温热至室温。再搅拌16小时后,将反应混合物真空浓缩,并经柱层析(5-10%乙酸乙酯-己烷)纯化,给出0.615g(99%)所需的产物。TLC:Rf0.7(硅胶,10%乙酸乙酯-己烷)。
步骤2.将含有1,3-二氢-5-甲基-2H-1,4-苯并二氮杂卓-2-酮(0.324g,1.03mmol)和Cs2CO3(0.900g,2.76mmol)的烧瓶真空干燥,用氩气清洗,在0℃装入(2-溴乙基)丙二酸二叔丁基酯(0.300g,0.929mmol)的DMF(3.0ml)溶液。将混合物在0℃搅拌15分钟,室温搅拌15分钟,120℃搅拌21小时。反应混合物用乙酸乙酯(250ml)稀释,并用水(2×50ml)洗涤。分出有机层,硫酸镁干燥并浓缩。通过柱层析(50-100%乙酸乙酯-己烷)纯化,给出0.017g所需的产物。TLC:Rf0.5(硅胶,100%乙酸乙酯)。
步骤3.将含有步骤2的一烷基化的丙二酸酯(0.37g)和叔丁醇钠(0.009g,0.089mmol)的烧瓶真空干燥,用氩气清洗,在0℃THF(1.0)稀释。在0℃搅拌30分钟后,往反应混合物中装入4-溴乙酰基-4’-氯联苯(0.027g,0.089mmol),随后在室温下再搅拌5小时。将反应混合物用二氯甲烷(75ml)稀释,并用水(25ml)洗涤。分出有机层,硫酸镁干燥并浓缩。通过柱层析(50-100%乙酸乙酯-己烷),给出所需的产物(0.100g,0.154mmol),直接用于步骤4。
步骤4.将步骤3的丙二酸酯(0.100g,0.154mmol)的甲酸(1.0ml)溶液在室温下搅拌6小时。将产生的溶液真空浓缩并直接用于步骤5。
步骤5.将步骤4产物的1,4-二噁烷(2.0ml)溶液加热至100℃16小时。冷却至室温,真空除去溶剂。柱层析(乙酸乙酯-己烷-乙酸,60∶40∶1)纯化,给出0.020g含有所需的产物的混合物。将混合物在C18柱上HPLC(乙腈-水)纯化,给出2mg目标化合物。HRMS489.15720(m+1),(计算488.15029)。
实施例23
本发明化合物的生物试验
MMP抑制的P218熄灭荧光试验
P218熄灭荧光试验(P218 quenched fluore scence 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(MW1332.2)
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):
重组人Pro-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-明胶酶A(Pro-MMP-2)。
Pro-MMP-2的活化:252mg/mL的Pro-MMP-2在由pH7.5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):
重组人Pro-MMp-9:用杆状病毒蛋白质表达体系将如Wilhelm等,生物化学杂志,264,17213(1989)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pH7.4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除去AMPA。
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 CytofluorⅡ:温育之后,将板在CytofluorⅡ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CytofluorⅡ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。
表1
实施例 | MMP-3荧光团IC50 | MMP-9荧光团IC50 | MMP-2荧光团IC50 |
1 | 1.7 | 0.34 | 0.39 |
2 | 17 | 24 | 9.5 |
3 | 31 | 67 | 21 |
4 | 9.2 | 2.1 | 4.2 |
5 | 4.2 | 2.3 | 1.4 |
6 | 4.1 | 4.3 | 0.5 |
7 | 14 | 110 | 10 |
8 | 2.0 | 6.2 | 1.0 |
18 | 59 | 32 | 13 |
19 | 47 | 4.7 | 2.4 |
20 | 320 | 84 | 57 |
21 | 6.5 | 2.1 | 1.5 |
22 | 140 | 120 | 24 |
考虑本文公开的本发明说明书或实施,本发明的其它方案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 (7)
2.具有基质金属蛋白酶抑制活性的组合物,包含权利要求1的化合物和药物可接受的载体。
3.抑制哺乳动物基质金属蛋白酶的方法,包括对所说的哺乳动物施用有效量的权利要求1的基质金属蛋白酶抑制化合物。
4.权利要求3的方法,其中所说的哺乳动物是人。
5.治疗哺乳动物的方法,包括对哺乳动物施用足以产生如下效果的基质金属蛋白酶抑制量的权利要求1的化合物:
(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)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。
6.权利要求5的方法,其中的效果是减轻骨关节炎。
7.权利要求5的方法,其中的效果是阻滞肿瘤转移。
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CN113979992A (zh) * | 2021-11-19 | 2022-01-28 | 西安欧得光电材料有限公司 | 一种3-取代二苯并噻吩及其合成方法 |
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US9643922B2 (en) | 2008-08-18 | 2017-05-09 | Yale University | MIF modulators |
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CN113979992A (zh) * | 2021-11-19 | 2022-01-28 | 西安欧得光电材料有限公司 | 一种3-取代二苯并噻吩及其合成方法 |
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