CN1509273A - 金属蛋白酶抑制剂 - Google Patents
金属蛋白酶抑制剂 Download PDFInfo
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- CN1509273A CN1509273A CNA028097890A CN02809789A CN1509273A CN 1509273 A CN1509273 A CN 1509273A CN A028097890 A CNA028097890 A CN A028097890A CN 02809789 A CN02809789 A CN 02809789A CN 1509273 A CN1509273 A CN 1509273A
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- Prior art keywords
- alkyl
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- compound
- phenyl
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Abstract
式(I)化合物可用作金属蛋白酶抑制剂,尤其是MMP-12的抑制剂,其中R5是单环基团。
Description
本发明涉及可用于抑制金属蛋白酶的化合物,特别是包含它们的药物组合物,以及它们的用途。
本发明的化合物是一种或多种金属蛋白酶的抑制剂。金属蛋白酶是一超家族的蛋白酶(酶),它的数量在最近几年剧增。基于结构和功能上的考虑,这些酶已被分为若干家族和亚家族,如N.M.Hooper(1994)FEBS Letters 354:1-6所述。金属蛋白酶的实例包括基质金属蛋白酶(MMP),例如胶原酶(MMP-1,MMP-8,MMP-13)、明胶酶(MMP-2,MMP-9)、溶基质素(stromelysins)(MMP-3,MMP-10,MMP-11)、基质溶素(MMP-7)、金属弹性蛋白酶(MMP-12)、釉质溶素(enamelysin)(MMP-19)、MT-MMP(MMP-14,MMP-15,MMP-16,MMP-17);reprolysin或蛇毒蛋白酶(adamalysin)或MDC家族,包括分泌酶(secretases)和脱落酶(sheddases),例如TNF转化酶(ADAM10和TACE);虾红素家族,包括诸如前胶原加工蛋白酶(PCP)等酶;和其他金属蛋白酶,例如聚集蛋白聚糖酶、内皮素转化酶家族和血管紧张素转化酶家族。
金属蛋白酶据信在大量涉及组织构型重建(remodeling)的生理疾病过程中都是重要的,例如胚胎发育、骨生成和月经期间的子宫构型重建。这是基于金属蛋白酶裂解多种基质底物,例如胶原、蛋白聚糖和纤连蛋白的能力。金属蛋白酶据信在下列过程中也是重要的:生物学重要的细胞介质的加工或分泌,例如肿瘤坏死因子(TNF);生物学重要的膜蛋白的翻译后蛋白水解加工或脱落,例如低亲合性IgE受体CD23(关于更完整的列表,参见N.M.Hooper等,(1997)Biochem J.
321:265-279)。
金属蛋白酶与很多疾病或病症有关。抑制一种或多种金属蛋白酶的活性可以在这些疾病或病症中产生有益效果,例如:各种炎性与变应性疾病,例如关节的炎症(尤其是类风湿性关节炎、骨关节炎和痛风)、胃肠道的炎症(尤其是炎性肠疾病、溃疡性结肠炎和胃炎)、皮肤的炎症(尤其是牛皮癣、湿疹、皮炎);肿瘤转移或侵入;与细胞外基质降解失控有关的疾病,例如骨关节炎;骨吸收疾病(例如骨质疏松和佩吉特氏病);与异常血管生成有关的疾病;与糖尿病有关的胶原构型重建增强、牙周疾病(例如齿龈炎)、角膜溃疡、皮肤的溃疡、术后病症(例如结肠吻合术)和皮肤伤口愈合;中枢与外周神经系统的脱髓鞘性疾病(例如多发性硬化);阿尔茨海默氏病;在心血管疾病中所观察到的细胞外基质构型重建,例如再狭窄和动脉粥样硬化;哮喘;鼻炎;和慢性阻塞性肺疾病(COPD)。
MMP-12已知也称巨噬细胞弹性酶或金属弹性蛋白酶,最初由Shapiro等克隆到小鼠中(1992,Journal of Biological Chemistry 267:4664),并于1995年再由他们克隆到人中。MMP-12优先在活化的巨噬细胞内被表达,已经显示是从吸烟者的肺泡巨噬细胞中(Shapiro等,1993,Journal of Biological Chemistry,268:23824)以及动脉粥样硬化损伤的泡沫细胞中分泌的(Matsumoto等,1998,Am J Pathol 153:109)。COPD的小鼠模型是基于用烟草攻击小鼠六个月,每天两支,每周六天。野生型小鼠在这种处理后发展为肺气肿。当在这种模型中试验剔除了MMP-12的小鼠时,它们没有发展为显著的气肿,显然表明MMP-12是COPD发病机理中关键的酶。MMP,例如MMP-12在COPD(气肿和支气管炎)中的作用讨论见Anderson和Shinagawa,1999,Current Opinion inAnti-inflammatory and Immunomodulatory Investigational Drugs
1(1):29-38。最近发现,吸烟增加人颈动脉斑Kangavari中的巨噬细胞浸润和源于巨噬细胞的MMP-12表达(Matetzky S,Fishbein MC等,Circulation102:(18),36-39 Suppl.S,Oct 31,2000)。
MMP-13或胶原酶3最初是从源于乳腺肿瘤的cDNA文库中克隆的(J.M.P.Freije等(1994)Journal of Biological Chemistry
269(24):16766-16773)。来自广泛组织的RNA的PCR-RNA分析表明,MMP-13的表达仅限于乳腺癌症,因为它没有见于乳腺纤维腺瘤、正常或休眠(resting)的乳腺、胎盘、肝脏、卵巢、子宫、前列腺或腮腺或者乳腺癌细胞系(T47-D,MCF-7和ZR75-1)。这种观察结果之后,在下列场合中检测到MMP-13:转化的表皮角质细胞(N.Johansson等,(1997)Cell GrowthDiffer.
8(2):243-250)、鳞状细胞癌症(N.Johansson等,(1997)Am.J.Pathol.
151(2):499-508)和表皮肿瘤(K.Airola等,(1997)J.Invest.Dermatol.
109(2):225-231)。这些结果提示,MMP-13是由被转化的上皮细胞分泌的,可以参与与转移有关的细胞外基质降解和细胞-基质相互作用,尤其见于侵入性乳腺癌损害和皮肤癌发生中的恶性上皮生长。
最近公布的数据暗示:MMP-13在其他结缔组织的更新中起作用。例如,与MMP-13的底物特异性和降解II型胶原的优先性(P.G.Mitchell等,(1996)J.Clin.Invest.
97(3):761-768;V.Knauper等,(1996)TheBiochemical Journal
271:1544-1550)一致的是,假设MMP-13在下述中起作用:初期成骨和骨骼构型重建期间(M.Stahle-Backdahl等,(1997)Lab.Invest.
76(5):717-728;N.Johansson等,(1997)Dev.Dyn.
208(3):387-397);破坏性关节疾病,例如类风湿性与骨关节炎(D.Wernicke等,(1996)J.Rheumatol.23:590-595;P.G.Mitchell等,(1996)J.Clin.Invest.97(3):761-768;O.Lindy等,(1997)Arthritis Rheum
40(8):1391-1399);和髋部复位的无菌性松弛期间(S.Imai等,(1998)J.Bone Joint Surg.Br.80(4):701-710)。MMP-13还与慢性成人牙周炎相关,因为它固定于人齿龈组织慢性发炎的粘膜的上皮(V.J.Uitto等,(1998)Am.J.Pathol
152 (6):1489-1499),和慢性伤口的胶原性基质构型重建(M.Vaalamo等,(1997)J.Invest.Dermatol.
109(1):96-101)。
MMP-9(明胶酶B;92kDa IV型胶原酶;92kDa明胶酶)是一种被分泌的蛋白质,在1989年先被纯化,再被克隆和测序(S.M.Wilhelm等(1989)J.Biol Chem.
264(29):17213-17221;J.Biol Chem.(1990)
265(36):22570中的勘误表)。最近对MMP-9的综述提供了优异的关于这种蛋白酶的详细信息和参考文献来源:T.H.Vu & Z.Werb(1998)(In:MatrixMetalloproteinases.1998.由W.C.Parks & R.P.Mecham编辑,pp115-148.Academic Press.ISBN 0-12-545090-7)。下列观点来自T.H.Vu & Z.Werb(1998)的综述。
MMP-9的表达在正常情况下仅限于几种细胞类型,包括滋养层、破骨细胞、嗜中性白细胞和巨噬细胞。不过,它的表达可以在这些相同细胞和其他细胞类型中被若干介质所诱导,包括所述细胞与生长因子或细胞因子的接触。这些介质经常引发炎性反应。关于其他所分泌的MMP,MMP9是作为无活性酶原而被释放的,它随后裂解生成具有酶活性的酶。这种体内活化作用所需的蛋白酶是未知的。活性MMP-9与无活性酶之间的平衡进一步受与TIMP-1(金属蛋白酶-1组织抑制剂,一种天然存在的蛋白质)相互作用的体内调节。TIMP-1与MMP9的C-末端区结合,引起MMP-9催化结构域的抑制。所诱导的前MMP-9表达的平衡、前MMP-9向活性MMP-9的裂解和TIMP-1的存在联合决定了位于局部位点的催化活性MMP-9数量。蛋白水解活性MMP-9攻击的底物包括明胶、弹性蛋白和天然IV型与V型胶原;它对天然I型胶原、蛋白聚糖或昆布氨酸没有活性。
越来越多的数据暗示了MMP-9在各种生理学与病理学过程中的作用。生理学作用包括胚胎滋养层在胚胎植入早期阶段通过子宫上皮的侵入;在骨生长和发育中的一些作用;和炎性细胞从脉管组织移行进入组织。
利用酶免疫测定法测量的MMP-9的释放,与其他群体相比,在未治疗的哮喘患者体液和AM上清液中显著增强了(Am.J.Resp.Cell &Mol.Biol.,Nov 1997,
17(5):583-591)。而且,在某些其他病理学病症中也观察到MMP-9表达增加,由此暗示了MMP-9与疾病过程的关系,例如COPD、关节炎、肿瘤转移、阿尔茨海默氏病、多发性硬化、和动脉粥样硬化中的斑块破裂,其引起急性冠状病症,例如心肌梗塞。
MMP-8(胶原酶-2,嗜中性白细胞胶原酶)是基质金属蛋白酶家族的53kD酶,它优先在嗜中性白细胞内被表达。以后的研究表明,MMP-8也在其他细胞内被表达,例如骨关节炎的软骨细胞(Shlopov等,1997,Arthritis Rheum,40:2065)。由嗜中性白细胞产生的MMP能够导致组织构型重建,因此,阻滞MMP-8应当在例如肺的纤维变性(fibrotic)疾病中具有积极效果,在降解性疾病中也是如此,象肺气肿。还发现MMP-8在骨关节炎中被上调,表明阻滞MMP-8还可能在这种疾病中是有益的。
MMP-3(溶基质素-1)是基质金属蛋白酶家族的53kD酶。MMP-3活性已经在从发炎的齿龈分离的成纤维细胞中得到证实(Uitto V.J.等,1981,J.Periodontal Res.,
16:417-424),酶水平已经与牙床疾病(gumdisease)的严重性有相互关系(Overall C.M.等,1987,J.Periodontal Res.,22:81-88)。在各种慢性溃疡中,MMP-3还是由基底角质细胞产生的(Saarialho-Kere U.K.等,1994,J.Clin.Invest.,
94:79-88)。在与伤口边缘相邻而远侧的基底角质细胞中检测到MMP-3 mRNA和蛋白质,这些细胞很可能代表了增生表皮的位置。MMP-3因而可以防止表皮愈合。若干研究人员已经证明,与对照相比,类风湿性与骨关节炎患者滑液中的MMP-3持续升高(Walakovits L.A.等,1992,Arthritis Rheum.,
35:35-42;Zafarullah M.等,1993,J.Rheumatol.,
20:693-697)。这些研究为这样一种信念提供了基础,MMP-3的抑制剂将治疗涉及细胞外基质破坏的疾病,由于淋巴细胞浸润导致炎症,或者导致器官功能所必需的结构完整性的丧失。
大量金属蛋白酶抑制剂是已知的(例如参见Beckett R.P.和WhittakerM.,1998,Exp.Opin.Ther.Patents,8(3):259-282的MMP抑制剂综述)。不同种类的化合物可以具有不同程度的抑制各种金属蛋白酶的效力(potency)和选择性。
Whittaker M.等(1999,Chemical Reviews
99(9):2735-2776)综述了多种已知的MMP抑制剂化合物。他们认为,有效的MMP抑制剂需要一个锌结合基团或ZBG(能够螯合活性位点锌(II)离子的官能团)、至少一个提供与酶骨架发生氢键相互作用的官能团和一条或多条与酶亚位点进行有效的范德华相互作用的侧链。已知的MMP抑制剂中的锌结合基团包括羧酸基团、异羟肟酸基团、硫氢基(sulfhydryl)或巯基(mercapto)等。例如,Whittaker M.等讨论了下列MMP抑制剂:
上述化合物已进入临床开发阶段。它在P1位具有巯基酰基锌结合基团和三甲基乙内酰脲基乙基基团,及亮氨酰-叔丁基甘氨酰骨架。
上述化合物在P1位具有巯基酰基锌结合基团和亚酰胺基团。
上述化合物被开发用于关节炎的治疗。它在P1位具有非肽类琥珀酰异羟肟酸锌结合基团和三甲基乙内酰脲基乙基。
上述化合物是一种抑制胶原酶的邻苯二酰亚氨基衍生物。它在P1位具有非肽类琥珀酰异羟肟酸锌结合基团和环状亚酰胺基团。WhittakerM.等还讨论了其他MMP抑制剂,它们具有P1环状亚酰氨基和各种锌结合基团(琥珀酰异羟肟酸、羧酸、硫醇基团、磷类基团)。
上述化合物似乎是良好的MMP-8与MMP-9抑制剂(PCT专利申请WO 98/58925,WO 98/58915)。它们具有嘧啶-2,3,4-三酮锌结合基团。
下列化合物不是已知的MMP抑制剂:
日本专利5097814(1993)描述了制备化合物的方法,这些化合物可用作抗生素生产的中间体,包括下式化合物:
Morton等(1993,J Agric Food Chem 41:148-152)描述了具有杀真菌活性的化合物的制备,包括下式化合物:
Dalgatov,D等(1967,Khim.Geterotsikl.Soedin.5:908-909)描述了下列化合物的合成,没有提示该化合物的用途:
Crooks,P等(1989,J.Heterocyclic Chem.26:1113-17)描述了下列化合物的合成,并试验了它们抗小鼠惊厥的活性:
Gramain,J.C.等((1990)Recl.Trav.Chim.Pays-Bas
109:325-331)描述了下列化合物的合成:
日本专利63079879(1988)描述了重要氨基酸中间体的合成方法。下列化合物被用作原料:
Wolfe,J等(1971,Synthesis
6:310-311)描述了下列化合物的合成,没有提示该化合物的用途:
Moharram等(1983,Egypt J.Chem.
26:301-11)描述了下列化合物:
匈牙利专利26403(1983)描述了下列化合物的合成和作为食品添加剂的用途:
我们现已发现一类新的化合物,它们是金属蛋白酶的抑制剂,具体而言抑制MMP,例如MMP-12。这些化合物是这样的金属蛋白酶抑制剂,它们具有在已知金属蛋白酶抑制剂中没有被发现的金属结合基团。具体地,我们已经发现这样的化合物,它们是有效的MMP-12抑制剂,具有所需的活性。本发明的化合物具有有益的效力、选择性和/或药物动力学性质。
本发明的金属蛋白酶抑制剂化合物包含金属结合基团和一个或多个其他官能团或侧链,其特征在于该金属结合基团具有式(k)
其中X选自NR1、O、S;
Y1和Y2独立地选自O、S;
R1选自H、烷基、卤代烷基;
上述任何烷基基团都可以是直链或支链的;上述任何烷基基团优选地是(C1-7)烷基,最优选是(C1-6)烷基。
金属蛋白酶抑制剂化合物是抑制金属蛋白酶(例如MMP)的活性的化合物。借助非限制性实例,抑制剂化合物可以显示的体外IC50为0.1-10000纳摩尔,优选为0.1-1000纳摩尔。
金属结合基团是能够在酶的活性位点内结合金属离子的官能团。例如,该金属结合基团在MMP抑制剂中将是锌结合基团,结合活性位点锌(II)离子。式(k)的金属结合基团基于五元环结构,优选地是乙内酰脲基团,最优选地是5-取代的1-H,3-H-咪唑烷-2,4-二酮。
在本发明的第一方面,我们提供式I化合物
其中
X选自NR1、O、S;
Y1和Y2独立地选自O、S;
Z选自NR2、O、S;
m是0或1;
A选自直接的键、(C1-6)烷基、(C1-6)链烯基、(C1-6)卤代烷基、或(C1-6)杂烷基,它含有一个选自N、O、S、SO、SO2的杂基团,或者含有两个选自N、O、S、SO、SO2的杂基团且被至少两个碳原子分开;
R1选自H、烷基、卤代烷基;
R2选自H、烷基、卤代烷基;
R3和R6独立地选自H、卤素(优选F)、烷基、卤代烷基、烷氧基烷基、杂烷基、环烷基、芳基、烷基芳基、杂烷基-芳基、杂芳基、烷基杂芳基、杂烷基-杂芳基、芳基烷基、芳基-杂烷基、杂芳基-烷基、杂芳基-杂烷基、双芳基、芳基-杂芳基、杂芳基-芳基、双杂芳基、环烷基或杂环烷基,其包含3至7个环原子,其中烷基、杂烷基、芳基、杂芳基、环烷基或杂环烷基基团可以被一个或多个基团任选取代,该取代基独立地选自羟基、烷基、杂烷基、环烷基、芳基、杂芳基、卤代、卤代烷基、羟基烷基、烷氧基、烷氧基烷基、卤代烷氧基、卤代烷氧基烷基、羧基、羧基烷基、烷基羧基、氨基、N-烷基氨基、N,N-二烷基氨基、烷基氨基、烷基(N-烷基)氨基、烷基(N,N-二烷基)氨基、酰氨基、N-烷基酰氨基、N,N-二烷基酰氨基、烷基酰氨基、烷基(N-烷基)酰氨基、烷基(N,N-二烷基)酰氨基、巯基(thiol)、砜、磺酰氨基(sulfonamino)、烷基磺酰氨基、芳基磺酰氨基、亚磺酰氨基(sulfonamido)、卤代烷基砜、烷硫基、芳硫基、烷基砜、芳基砜、氨基砜、N-烷基氨基砜、N,N-二烷基氨基砜、烷基氨基砜、芳基氨基砜、氰基、烷基氰基、胍基、N-氰基-胍基、硫代胍基、脒基、N-氨基磺酰-脒基、硝基、烷基硝基、2-硝基-亚乙基-1,1-二胺;
R4选自H、烷基、羟基烷基、卤代烷基、烷氧基烷基、卤代烷氧基、氨基烷基、酰氨基烷基、硫代烷基;
R5是包含3至7个环原子的单环基团,独立地选自环烷基、芳基、杂环烷基或杂芳基,其被一个或多个取代基任选取代,所述取代基独立地选自卤素、羟基、卤代烷氧基、氨基、N-烷基氨基、N,N-二烷基氨基、氰基、硝基、烷基、烷氧基、烷基砜、卤代烷基砜、羰基、羧基,其中任何取代基内的任何烷基基团本身被一个或多个基团任选取代,该取代基选自卤素、羟基、氨基、N-烷基氨基、N,N-二烷基氨基、烷基磺酰氨基、烷基羧基氨基、氰基、硝基、巯基、烷硫基(alkylthiol)、烷基sulfono、烷基氨基sulfono、烷基羧酸酯基、酰氨基、N-烷基酰氨基、N,N-二烷基酰氨基、烷氧基、卤代烷氧基、羰基、羧基;
上述任何杂烷基基团是杂原子取代的烷基,含有一个或多个独立地选自N、O、S、SO、SO2(杂基团是杂原子或原子团)的杂基团;
上述任何杂环烷基或杂芳基基团含有一个或多个独立地选自N、O、S、SO、SO2的杂基团;
上述任何烷基、链烯基或炔基可以是直链或支链的;除非另有规定,上述任何烷基优选地是(C1-7)烷基,最优选地是(C1-6)烷基;
其条件是:
若X是NR1,R1是H,Y1是O,Y2是O,Z是O,m是0,A是直接的键,R3是H,R4是H,R6是H,则R5不是苯基、硝基苯基、羟基苯基、烷氧基苯基或吡啶;
若X是NR1,R1是H或甲基,Y1是O,Y2是O,Z是O,m是0,A是直接的键,R3是H,R4是H,R6是苯基,则R5不是苯基;
若X是NR1,R1是H,Y1是O,Y2是O,Z是O,m是0,A是直接的键,R3是苯基,R4是H,R6是H,则R5不是苯基;
若X是S,Y1和Y2至少有一个是O,m是0,A是直接的键,R3是H或甲基,R6是H或甲基,则R5不是苯基、吡啶、吡咯、噻吩或呋喃;
若X是O,Y1是O,Y2是O,Z是O,m是0,A是直接的键,R3是甲基氯,R4是H,R6是H,则R5不是苯基。
优选的式I化合物是这样的,其中适用任何一种或多种下列情形:
X是NR1;
Y1和Y2中至少有一个是O;尤其是Y1和Y2都是O;
Z是O;
m是0;
A是直接的键;
R1是H、(C1-3)烷基或(C1-3)卤代烷基;尤其R1是H或(C1-3)烷基;最尤其地R1是H;
R3是H、烷基或卤代烷基;尤其R3是H、(C1-6)烷基或(C1-6)卤代烷基;最尤其地R3是H;
R4是H、烷基或卤代烷基;尤其R4是H、(C1-6)烷基或(C1-6)卤代烷基;最尤其地R4是H;
R5是任选被取代的5或6元环,独立地选自环烷基、芳基、杂环烷基或杂芳基;尤其R5是5或6元芳基或杂芳基;
R6是H、烷基、羟基烷基、氨基烷基、环烷基-烷基、烷基-环烷基、芳基烷基、烷基芳基、杂烷基、杂环烷基-烷基、烷基-杂环烷基、杂芳基-烷基或杂烷基-芳基;尤其R6是烷基、氨基烷基或杂芳基-烷基。
本发明的具体化合物包括式II化合物:
式II
其中
Ar是5或6元芳基或杂芳基基团,被一个或两个取代基任选取代,所述取代基选自卤素、氨基、硝基、(C1-6)烷基、(C1-6)烷氧基或(C1-6)卤代烷氧基;
R6选自H、芳基或(C1-6)烷基,R6被选自羟基、硫代烷基、苯基、卤代苯基、吡啶基或氨基甲酸酯的基团任选取代。
优选的式II化合物是这样的,其中适用任何一种或多种下列情形:
Ar是苯基或取代的苯基,尤其是被一个或两个卤素取代的苯基;或者Ar是5元杂芳基环,包含两个独立选自O和N的杂原子;
R6是苯基、被卤素取代的苯基、亚甲基吡啶、或(C1-3)烷基,被羟基、硫代甲基任选取代或苄基氨基甲酸酯。
式I化合物中适合的R5或式II化合物中适合的Ar包括:
R=H,(C1-6)烷基,OH,CH3O,CF3,CF3O,F,Cl,Br,I
X=O,S或N
式I或式II化合物中适合的R6包括如下:
将被理解的是,选择式I或式II化合物中特定的取代基和取代基的数量,以避免空间上不可取的组合。
每种所例证的化合物代表了本发明特定的和独立的方面。
若在式I或式II化合物中存在旋光中心,我们公开了全部个别的旋光体和它们的组合作为本发明的个别具体实施方式,以及它们对应的外消旋物。外消旋物可以被分离为个别的旋光形式,利用已知工艺(参见:Advanced Organic Chemistry:3rd Edition:author J March,p104-107),例如包括生成具有适宜旋光辅助成分(species)的非对映异构衍生物,然后分离,再裂解辅助成分。
将被理解的是,根据本发明的化合物可以含有一个或多个不对称取代的碳原子。一个或多个这些不对称中心(手性中心)在式I或式II化合物中的存在能够产生立体异构体,在每种情况下本发明被理解为延及到全部这类立体异构体,包括对映异构体和非对映异构体,和包括其外消旋混合物的混合物。
若在式I或式II化合物中存在互变异构体,我们公开了全部个别的互变异构形式和它们的组合作为本发明的个别具体实施方式。
如前面所述,本发明的化合物是金属蛋白酶抑制剂,具体地它们是MMP-12的抑制剂。关于式I或式II化合物的每种上述适应症代表了本发明独立的和特定的实施方式。
本发明的某些化合物特别可用作MMP-13和/或MMP-9和/或MMP-8和/或MMP-3的抑制剂。本发明的某些化合物特别可用作聚集蛋白聚糖酶抑制剂,也就是聚集蛋白聚糖降解的抑制剂。
本发明的化合物显示可取的选择性。尽管我们不希望局限于理论上的考虑,不过据信本发明的化合物对任何一种上述适应症显示出相对于任何MMP1抑制活性的选择性抑制作用,借助非限制性实施例,它们可以显示100-1000倍于任何MMP1抑制活性的选择性。
本发明的化合物可以以可药用的盐的形式提供。它们包括酸加成盐,例如盐酸盐、氢溴酸盐、柠檬酸盐和马来酸盐,和与磷酸和硫酸所生成的盐。另一方面,适合的盐是碱盐,例如碱金属盐,例如钠或钾盐,碱土金属盐,例如钙或镁盐,或者有机胺盐,例如三乙胺盐。
它们还可以以体内可水解的酯的形式提供。它们是药学上可接受的酯,它在人体内水解产生母体化合物。这类酯可以通过给药来鉴别,例如向供试动物静脉内给药供试化合物,随后检查供试动物的体液。适合的体内可水解的酯对于羧基包括甲氧基甲基,对于羟基包括甲酰基和乙酰基,尤其是乙酰基。
为了使用本发明的金属蛋白酶抑制剂化合物(式I或式II的化合物)或其可药用的盐或体内可水解的酯用于哺乳动物、包括人的治疗性处理(包括预防性处理),通常按照标准药学实践配制成药物组合物。
因此,本发明在另一方面提供药物组合物,它包含本发明的化合物(式I或II化合物)或其可药用的盐或体内可水解的酯和药学上可接受的载体。
本发明的药物组合物可以按用于需要治疗的疾病或病症的标准方式给药,例如口服、局部、肠胃外、颊、鼻、阴道或直肠给药或者通过吸入。为此,本发明的化合物可以借助本领域已知的手段配制成例如片剂、胶囊剂、水或油性溶液、悬液、乳剂、霜剂、软膏剂、凝胶剂、鼻喷雾剂、栓剂、微细粉碎的粉剂或吸入气雾剂,和肠胃外使用(包括静脉内、肌内或输注(infusion))的无菌水或油溶液或悬液或者无菌乳剂。
除了本发明的化合物以外,本发明的药物组合物还可以含有一种或多种可用于治疗一种或多种上文提到的疾病或病症的药理学成分,或者与之共同给药(同时或先后)。
本发明的药物组合物通常将对人给药,从而接受的每日剂量例如为0.5至75mg/kg体重(优选0.5至30mg/kg体重)。该每日剂量可以根据需要分剂给予,根据本领域已知的原理,所接受的化合物的精确量和给药途径取决于所治疗的患者的体重、年龄与性别和所治疗的特定疾病或病症。
通常,单剂型将含有1mg至500mg的本发明化合物。
因此在进一步的方面,我们提供式I或式II化合物或其可药用的盐或体内可水解的酯,用在人或动物体的治疗性处理方法中或者用作治疗剂。我们公开了在治疗由一种或多种金属蛋白酶介导的疾病或病症中的用途。具体而言,我们公开了在治疗由MMP-12和/或MMP-13和/或MMP-9和/或MMP-8和/或MMP-3和/或聚集蛋白聚糖酶介导的疾病或病症中的用途;尤其是在治疗由MMP-12或MMP-9介导的疾病或病症中的用途;更尤其是在治疗由MMP-12介导的疾病或病症中的用途。
在更进一步的方面,我们提供治疗金属蛋白酶介导疾病或病症的方法,它包含向温血(warm-blooded)动物给药治疗有效量的式I或式II化合物或其可药用的盐或体内可水解的酯。我们还公开式I或式II化合物或其可药用的盐或体内可水解的母体在制备药物中的用途,该药物用于治疗由一种或多种金属蛋白酶介导的疾病或病症。
金属蛋白酶介导的疾病或病症包括哮喘、鼻炎、慢性阻塞性肺疾病(COPD)、关节炎(例如类风湿性关节炎和骨关节炎)、动脉粥样硬化与再狭窄、癌症、侵入与转移、涉及组织破坏的疾病、髋关节复位的松弛、牙周疾病、纤维变性疾病、梗塞与心脏病、肝与肾纤维变性、子宫内膜异位、涉及细胞外基质弱化的疾病、心力衰竭、主动脉瘤、CNS相关性疾病(例如阿尔茨海默氏病和多发性硬化(MS))、血液学紊乱。
本发明化合物的制备
本发明在另一方面提供了制备式I的化合物或其可药用的盐或体内可水解的酯的方法,如下(a)至(g)所述(X、Y1、Y2、Z、m、A和R1-R6是如上式I化合物所定义的)。
(a)通过已知方法,式I化合物可以转化为盐,尤其是可药用的盐,反之亦然;通过已知方法,式I化合物的盐、尤其是可药用的盐可以转化为另一种不同的盐,尤其是可药用的盐。
(b)其中Z=O、R4=H的式I化合物可以这样制备,使式IIa化合物与式IIIa化合物或式IIIa化合物适当被保护的形式反应(如流程1所示),然后任选生成其可药用的盐或体内可水解的酯:
流程1
将式IIa的醛或酮和式IIIa的化合物在适合的溶剂中用碱处理,优选地在环境温度至回流的温度范围内。优选的碱-溶剂组合包括脂族胺例如三甲胺、吡咯烷或哌啶,在溶剂例如甲醇、乙醇、四氢呋喃、乙腈或二甲基甲酰胺中,在必要时加入水以溶解试剂(Phillips,AP and Murphy,JG,1951,J.Org.Chem.
16);或者六甲基二硅氮烷基锂在四氢呋喃中(Mio,S等,1991,Tetrahedron
47:2121-2132);或者氢氧化钡八水合物在异丙醇/水中(Ajinomoto KK,1993,日本专利号05097814)。
优选地,在通过这种方法制备式I化合物时,R3、R5或R6将不含有另外的官能团,例如醛、酮、卤代基团或本领域技术人员熟知的任何其他基团,它们具有干扰、竞争或抑制键生成反应的潜力。
将被理解的是,很多有关的原料是市场上可买到的或以其它方式得到的,或者可以通过已知方法合成,或者可以见于科技文献中。
为了制备通式IIIa化合物(如上所述的R6),可以通过本领域技术人员熟知的方法,使其中R6是H的式IIIa的化合物与适当的醛或酮反应,然后脱水,随后还原所得双键。
(c)其中Z=O、R4=H、X=N或NR1的式I化合物、尤其是其特定的立体异构体也可以如下流程2和3中四种可能的立体异构体中的两种所述加以制备。
流程2
从式IV的丙烯酸酯衍生物开始,经由二醇VIa或VIb,通过不对称环氧化,随后用水进行区域选择性打开,或者通过不对称二羟基化。根据环氧化或二羟基化中的手性助剂,可以得到式VIa或VIb二醇的所示立体异构体或它们的对映异构体(例如Ogino,Y.等,1991,TetrahedronLett.
32(41):5761-5764;Jacobsen,E.N.等,1994,Tetrahedron,
50(15):4323-4334;Song,C.E.等,1997,Tetrahedron Asymmetry,
8(6):841-844)。用有机碱和亚硫酰氯处理,随后进行四氧化钌催化的氧化,得到环状硫酸酯VIIa和VIIb。
式VIIa和VIIb环状硫酸酯是这样转化为式VIIIa和VIIIb羟基叠氮化物的(流程3),在二甲基甲酰胺中用叠氮化钠处理,然后小心地水解半硫酸酯中间体,再进行含水处理(Gao,Sharpless,1988,J.Am.Chem.Soc.,
110:7538;Kim,Sharpless,1989,Tetrahedron Lett.,
30:655)。式VIIIa和VIIIb的羟基叠氮化物被水解和还原为β-羟基-α-氨基酸(流程3中没有显示),优选地在THF中用LiOH水解,然后通过Staudinger法用硫化氢、镁的甲醇溶液或有机膦还原。在含水介质中用氰酸盐和酸处理,B-羟基-α-氨基酸继而得到式Ia化合物。
(d)其中Z=O、R4不是H的式I化合物、尤其是其特定的立体异构体也可以如流程2和3中四种可能的立体异构体中的两种所述加以制备。化合物可以这样制备,使流程2中的式V环氧化物与式R4-OH的醇反应,得到醇VIa。随后用phosphoazidate转化为叠氮化物(Thompson,A.s.等,1993,J.Org.Chem.
58.(22):5886-5888),得到流程3中VIII叠氮基酯的醚类似物,可以如方法(c)所述进行得到最终产物。醇R4-OH中的基团R4和基团R3、R5和R6可以被适当地保护。在转化为式I的乙内酰脲之后,作为最后一步可以除去保护基团。
(e)其中z是S或NR2、Y1和/或Y2是O的式I化合物、尤其是其特定的立体异构体也可以如流程2和3中四种可能的立体异构体中的两种所述加以制备。化合物可以这样合成,用硫醇R4-SH或胺R4-NH2打开式V的环氧化物(流程2),然后对其进行类似于对流程3中醇VIIIa和VIIIb所述的转化。当使用R4-NH2胺时,可能有必要N-保护中间体氨基醇,尤其是当基团R4是正-烷基基团时。
(f)其中x是S、Y1和/或Y2是O的式I化合物、尤其是其立体异构体也可以如流程2和3中四种可能的立体异构体中的两种所述加以制备。化合物可以这样制备,使式VIIa或VIIb的环状硫酸酯或式VIa的α-羟基酯经由它们的磺酸酯与硫脲和酸反应(1997,日本专利号09025273)。
式Iv的丙烯酸酯衍生物是可以普遍得到的,例如从醛和乙酸的鏻或膦酸酯衍生物经由Wittig或Horner Emmons反应(例如van Heerden,P.S.等,1997,J.Chem.Soc,Perkin Trans.
1(8):141-1146)。
(g)其中x=NRl、R1=H的式I化合物可以这样制备,在50-100℃下,在密封的容器内,使式IId的适当取代的醛或酮与碳酸铵和氰化钾在含水醇中反应4-24小时。
本发明的化合物例如可以在下列测定法中加以评价:
分离酶测定法
基质金属蛋白酶家族,例如包括MMP-12、MMP-13
重组人MMP-12催化结构域可以如Parkar A.A.等,(2000),ProteinExpression and Purification,20:152所述被表达和纯化。纯化酶可以用于监测抑制剂的活性如下:在有或没有抑制剂的存在下,使用合成的底物Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2,在测定缓冲液(0.1M Tris-HCl,pH7.3,含有0.1M NaCl,20mM CaCl2,0.040mM ZnCl2和0.05%(w/v)Brij35)中将MMP-12(最终浓度为50ng/ml)在RT下培育30分钟。通过在λex328nm和λem 393nm下测量荧光,确定活性。抑制百分率是如下计算的:抑制%等于[荧光加抑制剂-荧光背景]除以[荧光减抑制剂-荧光背景]。
重组人MMP-13原可以如Knauper等[V.Knauper等,(1996)TheBiochemical Journal
271:1544-1550(1996)]所述被表达和纯化。纯化酶可以用于监测抑制剂的活性如下:将MMP-13原用1mM氨基苯基汞酸(APMA)在21℃下活20小时;在有或没有抑制剂的存在下,使用合成的底物7-甲氧基香豆素-4-基乙酰.Pro.Leu.Gly.Leu.N-3-(2,4-二硝基苯基)-L-2,3-二氨基丙酰.Ala.Arg.NH2,在测定缓冲液(0.1M Tris-HCl,pH7.5,含有0.1M NaCl,20mM CaCl2,0.02mM ZnCl2和0.05%(w/v)Brij 35)中将活化的MMP-13(11.25ng每项测定)在35℃下培育45小时。通过在λex 328nm和λem 393nm下测量荧光,确定活性。抑制百分率是如下计算的:抑制%等于[荧光加抑制剂-荧光背景]除以[荧光减抑制剂-荧光背景]。
相似的方案可被用于其他被表达和纯化的MMP原,采用对特定MMP最理想的底物和缓冲液条件,例如C.Graham Knight等,(1992)FEBS Lett.296(3):263-266所述。
蛇毒蛋白酶家族,例如包括TNF转化酶
化合物抑制TNFα转化酶原(proTNFα convertase enzyme)的能力可以利用部分纯化的、分离的酶测定法加以评估,酶是从THP-1的膜得到的,如K.M.Mohler等,(1994)Nature
370:218-220所述。纯化酶活性和其抑制作用是这样测定的,在供试化合物的存在或不存在下,使用底物4',5'-二甲氧基-荧光素基Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys(4-(3-琥珀酰亚胺-1-基)-荧光素)-NH2,在测定缓冲液(50mM Tris-HCl,pH7.4,含有0.1%(w/v)Triton X-100和2mM CaCl2)中将部分纯化的酶在26℃培育18小时。除了使用λex 490nm和λem 530nm以外,如MMP-13所述测定抑制量。底物是如下合成的。通过标准方法,使用Fmoc-氨基酸和O-苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(HBTU)作为偶联剂,Fmoc-氨基酸和HBTU是至少4或5倍过量的,手工或者利用自动肽合成仪在Fmoc-NH-Rink-MBHA-聚苯乙烯树脂上装配底物的肽部分。Ser1和Pro2被双重偶联。采用下列侧链保护策略:Ser1(But),Gln5(三苯甲基(trityl)),Arg8,12(Pmc或Pbf),Ser9,10,11(三苯甲基),Cys13(三苯甲基)。装配后,将Fmoc-肽基-树脂用DMF处理,除去N-末端的Fmoc-保护基团。通过用1.5-2当量4',5'-二甲氧基-荧光素-4(5)-羧酸[Khanna & Ullman,(1980)Anal Biochem.
108:156-161,它已在DMF中被二异丙基碳二亚胺和1-羟基苯并三唑预活化]在70℃下处理.5-2小时,使所得氨基-肽-树脂被酰化。然后通过用含有水和三乙基硅烷各5%的三氟乙酸处理,使二甲氧基荧光素基-肽同时去保护和从树脂上裂解。通过蒸发、用二乙醚研制和过滤,分离二甲氧基荧光素基-肽。使所分离的肽与4-(N-马来酰亚氨基)-荧光素在含有二异丙基乙胺的DMF中反应,产物经过RP-HPLC纯化,最后从含水乙酸中通过冷冻干燥加以分离。对产物进行MALDI-TOF MS和氨基酸分析来表征。
天然底物
本发明化合物作为聚集蛋白聚糖降解抑制剂的活性可以利用这样的方法测定,例如基于E.C.Arner等,(1998)Osteoarthritis and Cartilage6:214-228;(1999)Journal of Biological Chemistry,
274(10),6594-6601的公开内容,和其中所述的抗体。化合物充当胶原酶抑制剂的效力可以如T.Cawston and A.Barrett(1979)Anal.Biochem.99:340-345所述加以测定。
对细胞/组织类活动中的金属蛋白酶活性的抑制作用
试剂抑制膜脱落酶(sheddases)、例如TNF转化酶的试验
本发明化合物抑制TNFα产生的细胞加工的能力可以在THP-1细胞中加以评估,利用ELISA检测所释放的TNF,基本上如K.M.Mohler等,(1994)Nature
370:218-220所述。按照相似的方式,其他膜分子的加工或脱落,例如N.M.Hooper等,(1997)Biochem.J.
321:265-279所述的那些,可以使用适当的细胞系和适合的抗体加以试验,以检测脱落蛋白。
试剂抑制细胞类侵入的试验
本发明化合物抑制细胞在侵入测定法中的移动的能力可以如A.Albini等,(1987)Cancer Research 47:3239-3245所述加以测定。
试剂抑制全血TNF脱落酶活性的试验
本发明化合物抑制TNFα产生的能力是在人全血测定法中评估的,其中LPS用于刺激TNFα的释放。将从志愿者得到的肝素化(10单位/ml)人血用培养基(RPMI1640+碳酸氢盐,青霉素,链霉素和谷氨酰胺)稀释1∶5,在潮湿的(5%CO2/95%空气)恒温箱内,在DMSO或适当的介质中,每160μl与20μl供试化合物(一式三份)在37℃下培30分钟,然后加入20μl LPS(大肠杆菌0111:B4;最终浓度10μg/ml)。每项测定包括单独用培养基(6孔/板)培育的稀释血液对照或作为标物的已知的TNFα抑制剂。然后将平板在37℃下培育6小(潮湿的恒温箱),离心(2000rpm,10min,4℃),收获血浆50-100μl),贮存在-70℃ 96孔平板内,后用ELISA分析TNFα浓度。
试剂抑制体外软骨降解的试验
本发明化合物抑制软骨聚集蛋白聚糖或胶原组分降解的能力可以基本上如K.M.Bottomley等,(1997)Biochem J.
323:483-488所述加以评估。
药效试验
为了评价本发明化合物的清除性质和生物利用度,采用间接体内药效试验,它利用上述合成底物测定法或者可供选择的HPLC或质谱分析。这是一类能够用于估计化合物在数个物种的清除率的试验。向动物(例如大鼠、绒猴)静脉内(i.V.)或经口(p.o.)给以化合物的可溶性制剂(例如20%w/v DMSO,60%w/v PEG400),在随后的时间点(例如5,15,30,60,120,240,480,720,1220分钟)用适当的容器采集血样加入到10U肝素中。离心后得到血浆部分,将血浆蛋白用乙腈(最终浓度80%w/v)沉淀出来。在-20℃下30分钟后,通过离心使血浆蛋白沉降,将上清液部分用Savantspeed vac蒸发至干。使沉降物在测定缓冲液中重构,随后利用合成底物测定法分析化合物含量。简而言之,构建所评价的化合物的化合物的浓度-响应曲线。评估重构的血浆提取物的系列稀释液的活性,利用浓度-响应曲线并考虑总血浆稀释系数,计算原始血浆样本中存在的化合物量。
体内评估
作为抗TNF剂的试验
本发明化合物作为间接体内TNFα抑制剂的能力是在大鼠中评估的。简而言之,用适当的给药途径例如经口(p.o.)、腹膜内(i.p.)、皮下(s.c.)向雄性Wistar Alderley Park(AP)大鼠(180-210g)组给以化合物(6只大鼠)或药物媒介物(10只大鼠)。90分钟后,用提高浓度的CO2来处死大鼠,经由后腔静脉放血到5单位肝素钠/ml血液中。将血样立即置于冰上,在4℃、2000rpm下离心10分钟,收获血浆,冷冻在-20℃下,随后测定它们对LPS-刺激人血产生TNFα的影响。将大鼠血浆样本融化,向96U孔平板按固定格式加入175μl每份样本。然后向每孔加入50μl肝素化人血,混合,将平板在37℃下培育30分钟(潮湿的恒温箱)。向小孔加入LPS(25μl,最终浓度10μg/ml),继续培育另外5.5小时。对照小孔是用25μl培养基单独培育的。然后将平板在2000rpm下离心10分钟,将200μl上清液转移至96孔平板内,冷冻在-20℃下,随后用ELISA分析TNF浓度。
用专用软件进行数据分析,计算每种化合物/剂量:
作为抗关节炎剂的试验
化合物作为抗关节炎剂的活性是在由D.E.Trentham等,(1977)J.Exp.Med.
146:857所定义的胶原诱发的关节炎(CIA)中试验的。在这种
模型中,当在弗氏不完全佐剂中给药时,酸溶性天然II型胶原导致大鼠多关节炎。相似的条件可以用于诱发小鼠和灵长类的关节炎。
作为抗癌剂的试验
化合物作为抗癌剂的活性可以基本上如I.J.Fidler(1978)Methodsin Cancer Research
15:399-439所述加以评估,例如使用B16细胞系(B.Hibner等,Abstract 283 p75 10th NCI-EORTC Symposium,AmsterdamJune 16-19 1998)。
作为抗肺气肿剂的试验
化合物作为抗肺气肿剂的活性可以基本上如Hautamaki等(1997)Science,
277:2002所述加以评估。
下列实施例将阐述而非限制本发明:
原料的制备
按照下列流程4,乙内酰脲5是在两个步骤中、从通用的氨基酸3,并分离中间体4制备的。
流程4
表1列举了一些所合成的原料5。通用的制备方法如下。将氨基酸3(25mmol)与氰酸钾(5.1g,63mmol)在水(75ml)中的浆液在0℃下加热大约1小时。将澄清的溶液冷却至0℃,用浓盐酸(aq)酸化至大约pH1。将所得白色沉淀4在回流下加热0.5-1小时,然后在冰上冷却。在有些情形中,加热1小时后没有达到完全的转化。在这些情况下,在相同条件下再次处理粗原料。过滤白色固体,用水洗涤,干燥,用HNMR和LC-MS分析。
表1:原料
流程4中的化合物5 | 收率(%) | APCI-MS m/z:[MH+] |
5-(4-氯-苄基)-咪唑烷-2,4-二酮 | 87 | 224.9 |
[3-(2,5-二氧代-咪唑啉-4-基)-丙基]-氨甲酸苄基酯 | 50 | 292.0 |
5-异丁基-咪唑烷-2,4-二酮 | 85 | 157.0 |
5-甲硫基甲基-咪唑烷-2,4-二酮 | 45 | 161.0 |
5-仲丁基-咪唑烷-2,4-二酮 | 52 | 157.0 |
5-(2-羟基-乙基)-咪唑烷-2,4-二酮 | 36 |
实施例1
5-[羟基-(4-碘-苯基)-甲基]-5-甲基-咪唑烷-2,4-二酮
在氮气氛下,将4-碘苯甲醛(9.280g,40.0mmol)、5-甲基-乙内酰脲(4.564g,40.0mmol)和45%含水三甲胺(6.40ml,40.0mmol)在回流下、在乙醇(60ml)与水(40ml)中加热20小时。有白色沉淀生成。在室温下冷却大约15分钟后,过滤收集沉淀,随后用乙醇(50%,50ml)、水(50ml)和二乙醚(50ml)洗涤。通过空气抽吸干燥,得到标题化合物(7.968g,23.0mol),收率为57.5%,为白色固体,是纯非对映异构体的形式。
1H NMR(300MHz,DMSO-d6):δ10.19(1H,s);8.08(1H,s);7.64(2H,d,J=8.6Hz);7.07(2H,d,J=8.4Hz);5.98(1H,d,J=4.5Hz);4.57(1H,d,J=4.3Hz);1.40(3H,s)。
APCI-MS m/z:346.9[MH+]。
色谱拆分:
将0.158g非对映异构的纯5-(羟基-(4-碘苯基)-甲基)-5-甲基-咪唑烷-2,4-二酮溶于205ml绝对乙醇/异己烷(50∶50)中,通过0.45μm尼龙滤器过滤。将5.0ml体积反复(repeatedly)注射到手性柱上(Chiralpak AD-H(2cm ID×25cm L)),柱子与UV检测器(254nm)和馏分收集器连接。使用绝对乙醇/异己烷(50∶50)作为洗脱剂进行分离,流速为6.0ml/min,洗脱纯的对映异构体。合并含有相同对映异构体的部分,浓缩,通过手性色谱评估旋光纯度(见下文)。
对映异构体A(“较早”部分)
收率:0.068g,白色薄片
手性色谱(Chiralpak AD-H(0.45cm ID×25cm L):0.43ml/min
绝对乙醇/异己烷(50∶50)
保留时间:10.5分钟
旋光纯度:99.9%e.e.(不含对映异构体B)。
对映异构体B(“较晚”部分)
收率:0.071g,白色薄片
手性色谱(Chiralpak AD-H(0.45cm ID×25cm L):0.43ml/min
绝对乙醇/异己烷(50∶50)
保留时间:12.2分钟
旋光纯度:99.6%e.e.(含有0.24%对映异构体B)。
纯对映异构体的NMR光谱匹配纯非对映异构体。遵照实施例1的方法制备下列实施例。如果没有相反指示,最终的化合物代表四种立体异构体的混合物。利用柱色谱进行非对映异构体的最终纯化或分离。
实施例2
5-[(4-氯-苯基)-羟基-甲基]-咪唑烷-2,4-二酮
非对映异构体A
1H NMR(400MHz,DMSO-d6):10.32(1H,s);8.07(1H,s);7.37(2H,d,J=8.5Hz);7.30(2H,d,J=8.5Hz);5.94(1H,d,J=3.9Hz);4.92(1H,t,J=3.2Hz);4.35(1H,dd,J=3.1,1.0Hz)。
13C NMR(400MHz,DMSO-d6):173.00;157.36;138.41;131.98;128.86;127.52;71.65;63.88。
APCI-MS m/z:241[MH+]。
非对映异构体B
1H NMR(400MHz,DMSO-d6):10.53(1H,s);7.54(1H,s);7.42-7.37(4H,m);5.83(1H,d,J=5.6Hz);4.91(1H,dd,J=5.6,2.6Hz);4.23(1H,dd,J=2.6,1.5Hz)。
13C NMR(400MHz,DMSO-d6):173.97;158.04;140.62;131.67;128.15;127.89;70.08;63.93。
APCI-MS m/z:241[MH+]。
实施例3
5-[(4-氯-苯基)-羟基-甲基]-5-苯基-咪唑烷-2,4-二酮
APCI-MS m/z:317.1[MH+]。
实施例4
5-[(4-氰基-苯基)-羟基-甲基]-5-异丁基-咪唑烷-2,4-二酮
APCI-MS m/z:288.1[MH+]。
实施例5
5-[(4-三氟甲基-苯基)-羟基-甲基]-咪唑烷-2,4-二酮
APCI-MS m/z:275.1[MH+]。
实施例6
5-[(3-三氟甲基-苯基)-羟基-甲基]-咪唑烷-2,4-二酮
APCI-MS m/z:275.2[MH+]。
实施例7
5-[(2-三氟甲基-苯基)-羟基-甲基]-咪唑烷-2,4-二酮
APCI-MS m/z:275.1[MH+]。
实施例8
5-[(4-三氟甲氧基-苯基)-羟基-甲基]-咪唑烷-2,4-二酮
APCI-MS m/z:291.3[MH+]。
实施例9
5-[(3-氯-苯基)-羟基-甲基]-咪唑烷-2,4-二酮
APCI-MS m/z:241.0[MH+]。
实施例10
5-[(2-氯-苯基)-羟基-甲基]-咪唑烷-2,4-二酮
APCI-MS m/z:241.0[MH+]。
实施例11
5-[(4-氯-3-氟-苯基)-羟基-甲基]-咪唑烷-2,4-二酮
APCI-MS m/z:259.0[MH+]。
实施例12
5-[(4-氯-3-氟-苯基)-羟基-甲基]-5-甲基-咪唑烷-2,4-二酮
APCI-MS m/z:272.9[MH+]。
实施例13
5-[(4-氯-3-氟-苯基)-羟基-甲基]-5-异丁基-咪唑烷-2,4-二酮
APCI-MS m/z:315.9[MH+]。
实施例14
5-(1-羟基-3-苯基-烯丙基)-5-甲基-咪唑烷-2,4-二酮
1H NMR(400MHz,DMSO-d6):δ10.45(1H,s);7.88(1H,s);7.38-7.22(5H,m);6.54(1H,d,J=16.1Hz);6.22(1H,dd,J=7.3,7.6Hz);5.56(1H,d,J=4.5Hz);4.09(1H,d,J=3.6,4.5Hz);1.27(3H,s)。
APCI-MS m/z:247.1[MH+]。
实施例15
5-[羟基-(4-碘-苯基)-甲基]-咪唑烷-2,4-二酮
1H NMR(300MHz,DMSO-d6):δ10.32(1H,s);8.06(1H,s);7.66(2H,d,J=8.1Hz);7.10(2H,d,J=8.3Hz);5.91(1H,d,J=3.9Hz);4.87(1H,t,J=2.7Hz);4.34(1H,d,J=2.5Hz)。
APCI-MS m/z:333.1[MH+]。
实施例16
(3-{4-[羟基-(4-碘-苯基)-甲基]-2,5-二氧代-咪唑啉-4-基}-丙基)-氨甲酸苄基酯
APCI-MS m/z:524.1[MH+]。
实施例17
5-[(4-溴-苯基)-羟基-甲基]-5-甲基-咪唑烷-2,4-二酮
通过4-溴-苯甲醛与5-甲基-咪唑烷-2,4-二酮的羟醛缩合制备。
1H NMR(400MHz,DMSO-d6):δ10.18(1H,s);8.08(1H,s);7.46(2H,d,J=8.4Hz);7.20(2H,d,J=8.4Hz);5.99(1H,d,J=4.4Hz);4.59(1H,d,3.81Hz);1.39(3H,s)。
APCI-MS m/z:298.9[MH+]。
实施例18
5-[(3,5-二甲基-异噁唑-4-基)-羟基-甲基]-5-甲基-咪唑烷-2,4-二酮
通过3,5-二甲基-异噁唑-4-醛与5-甲基-咪唑烷-2,4-二酮的羟醛缩合制备。
APCI-MS m/z:240[MH+]。
实施例19
5-[(4-溴-苯基)-羟基-甲基]-5-甲硫基甲基-咪唑烷-2,4-二酮
通过4-溴-苯甲醛与5-甲硫基甲基-咪唑烷-2,4-二酮的羟醛缩合制备。
APCI-MS m/z:347.1[MH+]。
实施例20
5-[(4-溴-苯基)-羟基-甲基]-5-(2-羟基-乙基)-咪唑烷-2,4-二酮
通过4-溴-苯甲醛与5-(2-羟基-乙基)-咪唑烷-2,4-二酮的羟醛缩合制备。
APCI-MS m/z:311.2[MH+-H2O]。
实施例21
5-[(4-溴-苯基)-羟基-甲基]-5-(4-氯-苄基)-咪唑烷-2,4-二酮
通过4-溴-苯甲醛与5-(4-氯-苄基)-咪唑烷-2,4-二酮的羟醛缩合制备。
APCI-MS m/z:411[MH+]。
实施例22
5-[(4-溴苯基)-羟基-甲基]-5-吡啶-2-基甲基-咪唑烷-2,4-二酮
通过4-溴-苯甲醛与5-吡啶-4-基甲基-咪唑烷-2,4-二酮的羟醛缩合制备。
APCI-MS m/z:378.1[MH+]。
Claims (12)
1.式I化合物或其可药用的盐或体内可水解的酯
其中
X选自NR1、O、S;
Y1和Y2独立地选自O、S;
Z选自NR2、O、S;
m是0或1;
A选自直接的键、(C1-6)烷基、(C1-6)链烯基、(C1-6)卤代烷基、或(C1-6)杂烷基,该(C1-6)杂烷基含有一个选自N、O、S、SO、SO2的杂基团,或者含有两个选自N、O、S、SO、SO2的杂基团且被至少两个碳原子分开;
R1选自H、烷基、卤代烷基;
R2选自H、烷基、卤代烷基;
R3和R6独立地选自H、卤素(优选F)、烷基、卤代烷基、烷氧基烷基、杂烷基、环烷基、芳基、烷基芳基、杂烷基-芳基、杂芳基、烷基杂芳基、杂烷基-杂芳基、芳基烷基、芳基-杂烷基、杂芳基-烷基、杂芳基-杂烷基、双芳基、芳基-杂芳基、杂芳基-芳基、双杂芳基、环烷基或杂环烷基,其包含3至7个环原子,其中烷基、杂烷基、芳基、杂芳基、环烷基或杂环烷基基团可以被一个或多个基团任选取代,该取代基独立地选自羟基、烷基、杂烷基、环烷基、芳基、杂芳基、卤代、卤代烷基、羟基烷基、烷氧基、烷氧基烷基、卤代烷氧基、卤代烷氧基烷基、羧基、羧基烷基、烷基羧基、氨基、N-烷基氨基、N,N-二烷基氨基、烷基氨基、烷基(N-烷基)氨基、烷基(N,N-二烷基)氨基、酰氨基、N-烷基酰氨基、N,N-二烷基酰氨基、烷基酰氨基、烷基(N-烷基)酰氨基、烷基(N,N-二烷基)酰氨基、巯基、砜、磺酰氨基、烷基磺酰氨基、芳基磺酰氨基、亚磺酰氨基、卤代烷基砜、烷硫基、芳硫基、烷基砜、芳基砜、氨基砜、N-烷基氨基砜、N,N-二烷基氨基砜、烷基氨基砜、芳基氨基砜、氰基、烷基氰基、胍基、N-氰基-胍基、硫代胍基、脒基、N-氨基磺酰-脒基、硝基、烷基硝基、2-硝基-亚乙基-1,1-二胺;
R4选自H、烷基、羟基烷基、卤代烷基、烷氧基烷基、卤代烷氧基、氨基烷基、酰氨基烷基、硫代烷基;
R5是包含3至7个环原子的单环基团,独立地选自环烷基、芳基、杂环烷基或杂芳基,被一个或多个取代基任选取代,所述取代基独立地选自卤素、羟基、卤代烷氧基、氨基、N-烷基氨基、N,N-二烷基氨基、氰基、硝基、烷基、烷氧基、烷基砜、卤代烷基砜、羰基、羧基,其中任何取代基内的任何烷基基团本身被一个或多个基团任选取代,该取代基选自卤素、羟基、氨基、N-烷基氨基、N,N-二烷基氨基、烷基磺酰氨基、烷基羧基氨基、氰基、硝基、巯基、烷硫基、烷基sulfono、烷基氨基sulfono、烷基羧酸酯基、酰氨基、N-烷基酰氨基、N,N-二烷基酰氨基、烷氧基、卤代烷氧基、羰基、羧基;
其条件是:
若X是NR1,R1是H,Y1是O,Y2是O,Z是O,m是0,A是直接的键,R3是H,R4是H,R6是H,则R5不是苯基、硝基苯基、羟基苯基、烷氧基苯基或吡啶;
若X是NR1,R1是H或甲基,Y1是O,Y2是O,Z是O,m是O,A是直接的键,R3是H,R4是H,R6是苯基,则R5不是苯基;
若X是NR1,R1是H,Y1是O,Y2是O,Z是O,m是0,A是直接的键,R3是苯基,R4是H,R6是H,则R5不是苯基;
若X是S,Y1和Y2中至少有一个是O,m是0,A是直接的键,R3是H或甲基,R6是H或甲基,则R5不是苯基、吡啶、吡咯、噻吩或呋喃;
若X是O,Y1是O,Y2是O,Z是O,m是0,A是直接的键,R3是甲基氯,R4是H,R6是H,则R5不是苯基。
2.如权利要求1所述的式I化合物或其可药用的盐或体内可水解的酯,其中X是NR1,R1是H或(C1-3)烷基,Y1和Y2至少有一个是O,Z是O,m是0,A是直接的键。
3.如权利要求1或权利要求2所述的式I化合物或其可药用的盐或体内可水解的酯,其中R3是H、烷基或卤代烷基,R4是H、烷基或卤代烷基。
4.如前述权利要求之一所述的式I化合物或其可药用的盐或体内可水解的酯,其中R5是任选被取代的5或6元环,独立地选自环烷基、芳基、杂环烷基或杂芳基。
5.如前述权利要求之一所述的式I化合物或其可药用的盐或体内可水解的酯,其中R6是H、烷基、羟基烷基、氨基烷基、环烷基-烷基、烷基-环烷基、芳基烷基、烷基芳基、杂烷基、杂环烷基-烷基、烷基-杂环烷基、杂芳基-烷基或杂烷基-芳基。
7.如权利要求6所述的式II化合物或其可药用的盐或体内可水解的酯,其中Ar是苯基或取代的苯基,或者Ar是包含两个独立选自O和N的杂原子的5元杂芳基环。
8.如权利要求6或7所述的式II化合物或其可药用的盐或体内可水解的酯,其中R6是苯基、被卤素取代的苯基、亚甲基吡啶、或(C1-3)烷基,被羟基、硫代甲基任选取代,或苄基氨基甲酸酯。
9.药物组合物,其包含如权利要求1所述的式I化合物或其可药用的盐或体内可水解的酯和药学上可接受的载体。
10.药物组合物,其包含如权利要求6所述的式II化合物或其可药用的盐或体内可水解的酯和药学上可接受的载体。
11.治疗金属蛋白酶介导的疾病或病症的方法,包含向温血动物给予治疗有效量的式I或II化合物或其可药用的盐或体内可水解的酯。
12.式I或II化合物或其可药用的盐或体内可水解的酯在制备用于治疗由一种或多种金属蛋白酶介导的疾病或病症的药物中的用途。
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SE0100903A SE0100903D0 (sv) | 2001-03-15 | 2001-03-15 | Compounds |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101014338B (zh) * | 2004-08-19 | 2010-06-16 | 奎斯特药物服务 | 作为巨噬细胞弹性蛋白酶抑制剂的5-[3-(4-苄氧基苯基硫代)-呋喃-2-基]-咪唑烷-2,4-二酮和类似物 |
CN101080403B (zh) * | 2004-12-17 | 2010-09-08 | 阿斯利康(瑞典)有限公司 | 作为金属蛋白酶抑制剂的新乙内酰脲衍生物 |
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