CN100543024C - 用于治疗阻塞性气道疾病的乙内酰脲衍生物 - Google Patents
用于治疗阻塞性气道疾病的乙内酰脲衍生物 Download PDFInfo
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- CN100543024C CN100543024C CNB2005800228017A CN200580022801A CN100543024C CN 100543024 C CN100543024 C CN 100543024C CN B2005800228017 A CNB2005800228017 A CN B2005800228017A CN 200580022801 A CN200580022801 A CN 200580022801A CN 100543024 C CN100543024 C CN 100543024C
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Abstract
本发明提供式(I)的化合物,其中R1和R2如说明书所定义;及其制备方法;含有它们的药物组合物;制备该药物组合物的方法以及它们在治疗中的用途。
Description
本发明涉及新乙内酰脲衍生物,它们的制备方法,含有它们的药物组合物以及它们在治疗中的用途。
金属蛋白酶是蛋白酶类(酶)的超家族,近年来,其数量显著地增加。基于结构和功能性的考虑,这些酶已经被分类到家族和亚家族中,如N.M.Hooper(1994)FEBS Letters354:1-6中所述。金属蛋白酶的例子包括基质金属蛋白酶(MMPs)例如胶原酶(MMP1,MMP8,MMP13),明胶酶(MMP2,MMP9),溶基质蛋白酶(stromelysins)(MMP3,MMP10,MMP11),基质溶解因子(matrilysin)(MMP7),金属弹性蛋白酶(MMP12),成釉溶素(enamelysin)(MMP19),MT-MMPs(MMP14,MMP15,MMP16,MMP17);reprolysin或釉质溶素(adamalysin)或MDC家族,其包括分泌酶和sheddases例如TNF转化酶(ADAM 10和TACE);龙虾肽酶家族(astacin family),包括酶例如溶胶原加工蛋白酶(PCP);及其它金属蛋白酶例如可聚蛋白聚糖(aggrecanase),内皮素转化酶家族和血管紧张肽转化酶家族。
人们认为金属蛋白酶在涉及组织再造(例如胚胎发育、骨形成和月经期间的子宫再造)的生理病过程的多血症中是重要的。这基于金属蛋白酶断裂大量基质底物例如胶原、蛋白多糖和纤连蛋白的能力。也认为金属蛋白酶在生物学重要细胞介质(例如肿瘤坏死因子(TNF))的加工或分泌、和生物学重要膜蛋白质(例如低亲合性IgE受体CD23)的后翻译蛋白酶解加工或脱落中是重要的(对于更全面的列举,见N.M.Hooper等人,(1997)Biochem J.321:265-279)。
金属蛋白酶与许多疾病或病症有关。抑制一或多种金属蛋白酶的活性可以在下列这些疾病或病症中是非常有益的,例如:各种炎症性和变态反应性疾病例如,关节炎(特别是类风湿性关节炎,骨关节炎和痛风),胃肠道炎症(特别是炎症性肠病,溃疡性结肠炎和胃炎),皮肤炎症(特别是牛皮癣,湿疹,皮炎);肿瘤转移或侵入;与细胞外基质的非受控降解有关的疾病,例如骨关节炎;骨再吸收性疾病(例如骨质疏松症和变形性骨炎);与异常血管生成有关的疾病;与糖尿病、牙周病(例如龈炎)、角膜溃疡形成、皮肤溃疡、手术后病症(例如结肠联结现象)和皮肤创伤愈合有关的胶原再造增加;中枢和外周神经系统的脱髓鞘疾病(例如多发性硬化);阿尔茨海默氏病;在心血管疾病例如再狭窄和动脉粥样硬化中观察到的细胞外基质再造;哮喘;鼻炎;和慢性阻塞性肺病(COPD)。
MMP12,又称为巨噬细胞弹性蛋白酶或金属弹性酶,最初由Shapiro等人在小鼠中克隆出[1992,Journal of Biological Chemistry 267:4664],并且在1995年由同一小组在人类中克隆出。MMP12优先在活化巨噬细胞中表达,并且已经证明,可以从吸烟者的肺泡巨噬细胞中分泌[Shapiro等人,1993,Journal of Biological Chemistry,268:23824],以及从动脉粥样硬化病变的泡沫细胞中分泌[Matsumoto等人,1998,Am J Pathol 153:109]。COPD的小鼠模型基于用香烟挑战小鼠,小鼠吸烟六个月,一天两只香烟,一周六天。这种处理之后,野生型小鼠出现肺气肿。当在该模型中对MMP12基因敲除小鼠进行测试时,它们没有出现显著的肺气肿,这强烈表明MMP12是COPD发病机理的关键酶。MMPs例如MMP12在COPD(肺气肿和支气管炎)中的作用已经,在Anderson和Shinagawa,1999,Current Opinion inAnti-inflammatory and Immunomodulatory Investigational Drugs1(1):29-38中进行了讨论。最近发现,吸烟增加了在人类的颈动脉斑点中的巨噬细胞渗透和巨噬细胞衍生的MMP-12的表达,Kangavari[Matetzky S,Fishbein MC等人,Circulation 102:(18),36-39 Suppl.S,Oct 31,2000]。
MMP9(明胶酶B;92kDaTypeIV胶原酶;92kDa明胶酶)是一种分泌的蛋白质,其在1989年首先被纯化、然后克隆和排序[S.M.Wilhelm等人(1989)J.Biol Chem.264(29):17213-17221;published erratum in J.Biol Chem.(1990)265(36):22570]。MMP9的最近综述对于这种蛋白酶的详细信息和参考文献提供了出色来源:T.H.Vu & Z.Werb(1998)(In:MatrixMetalloproteinases.1998.Edited by W.C.Parks & R.P.Mecham.pp 115-148.Academic Press.ISBN 0-12-545090-7)。下列要点来自T.H.Vu & Z.Werb(1998)的综述。
MMP9的表达通常被限制在几种细胞类型中,包括滋养母细胞、破骨细胞、嗜中性白细胞和巨噬细胞。然而,它的表达能在这些相同细胞和在其它细胞类型中由一些介质引起,包括细胞与生长因子或细胞因子的接触。这些是常常在初始炎症性反应中牵涉的相同介质。如同其它分泌的MMPs一样,MMP9被释放为非活性的酶原,随后酶原断裂,形成酶促的活性酶。这种体内活化所需的蛋白酶不是已知的。活性MMP9相对于非活性酶的平衡通过与一种天然存在的蛋白TIMP-1(金属蛋白酶-1的组织抑制剂)相互作用在体内进一步得到调节。TIMP-1与MMP9的C-末端区域结合,导致MMP9的催化区域的抑制作用。ProMMP9的诱发表达的平衡、前MMP9至活性MMP9的裂解和TIMP-1的存在结合在一起,以测定存在于局部位点的催化活性MMP9的量。蛋白水解活性MMP9攻击包括明胶、弹性蛋白和天然IV型和V型胶原的底物;它对天然I型胶原、粘蛋白或层粘连蛋白没有活性。
存在大量的数据,这些数据牵涉MMP9在各种生理学和病理过程中的作用。生理学作用包括:在胚胎移植的最初阶段胚胎滋养母细胞经过子宫上皮侵入;在骨生长发育中的一些作用;和炎性细胞从血管系统递送到组织。
与源于其它人群的液体和AM上清液相比较,在源于未经治疗的哮喘患者的液体和AM上清液中MMP9的释放显著地增加,MMP9的释放是使用酶免疫分析法测定的[Am.J.Resp.Cell & Mol.Biol.,Nov1997,17(5):583-591]。在某些其它病理学病症中也已经观察到MMP9表达增加,由此在例如COPD、关节炎、肿瘤转移病变、阿尔茨海默疾病、多发性硬化、和导致急性冠状动脉病症(例如心肌梗塞)的动脉粥样硬化的斑点破裂等疾病过程中牵涉MMP9。
许多金属蛋白酶抑制剂是已知的(例如,参见下列针对MMP抑制剂的综述:Beckett R.P.and Whittaker M.,1998,Exp.Opin.Ther.Patents,8(3):259-282,和Whittaker M.等人,1999,Chemical Reviews99(9):2735-2776)。
WO 02/074767公开了下式的乙内酰脲衍生物
其可以作为MMP抑制剂,特别是作为有效的MMP12抑制剂。WO02/074767具体公开了以下的三种化合物
现在,我们发现了一类化合物,它们是金属蛋白酶的抑制剂,并在抑制MMPs,例如MMP12和MMP9中特别具有特别的益处。本发明的化合物具有有益的功效、选择性和/或药物动力学性质。本发明的某些化合物包含在WO 02/074767的通式范围中,但是为其中没有具体示例的一类化合物。
因此,根据本发明,提供了式(I)的化合物或其药学可接受的盐:
其中
R1表示C1-2烷基、环丙基、OCH3、SCH3或OCF3;所述烷基或环丙基任选地进一步被一个或多个氟原子取代;和
R2表示C1-3烷基。
式(I)的化合物可以以对映体形式存在。应当理解,所有的对映体、非对映体、外消旋体和其混合物包括在本发明范围内。
式(I)的化合物也可以以各种互变异构形式存在。所有可能的互变异构形式和其混合物包括在本发明的范围内。
在一个实施方式中,R1表示C1-2烷基或环丙基;所述烷基或环丙基任选地进一步被一个或多个氟原子取代。
在另一实施方式中,R1表示C1-2烷基,其任选地进一步被一个或多个氟原子取代。
在一个实施方式中,R1表示环丙基,其任选地进一步被一个或多个氟原子取代。
在一个实施方式中,R1表示环丙基。
在一个实施方式中,R1表示三氟甲基.
在一个实施方式中,R1表示OCH3或SCH3。
在一个实施方式中,R2表示甲基或乙基。在一个实施方式中,R2表示甲基。
在一个实施方式中,R1表示C1-2烷基或环丙基;所述烷基或环丙基任选地进一步被一个或多个氟原子取代以及R2表示甲基或乙基。
在一个实施方式中,R1表示C1-2烷基或环丙基;所述烷基或环丙基任选地进一步被一个或多个氟原子取代以及R2表示甲基。
在一个实施方式中,R1表示任选地进一步被一个或多个氟原子取代的C1-2烷基以及R2表示甲基或乙基。
在一个实施方式中,R1表示CF3和R2表示甲基或乙基。
在一个实施方式中,R1表示环丙基和R2表示甲基或乙基。
除非另有说明,术语“C1-3烷基”在本文中表示具有1至3个碳原子的直链或支链烷基。这种基团的例子包括甲基,乙基,正丙基和异-丙基。术语“C1-2烷基”表示甲基或乙基。
任选地进一步被一个或多个氟原子取代的C1-2烷基的实例包括CF3、CH2F、CH2CF3、CF2CH3和CF2CF3。
任选地进一步被一个或多个氟原子取代的环丙基环的实例包括1-氟-1-环丙基、2,2-二氟-1-环丙基和2,3-二氟-1-环丙基:
本发明化合物的实例包括:
(5S)-5-({[4-[(2-环丙基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-基]磺酰基}甲基)-5-甲基咪唑烷-2,4-二酮;
(5S)-5-甲基-5-({[4-{[2-(甲硫基)嘧啶-5-基]乙炔基}-3,6-二氢吡啶-1(2H)-基]磺酰基}甲基)咪唑烷-2,4-二酮;
(5S)-5-甲基-5-({[4-{[2-(三氟甲基)嘧啶-5-基]乙炔基}-3,6-二氢吡啶-1(2H)-基]磺酰基}甲基)咪唑烷-2,4-二酮;
(5S)-5-甲基-5-({[4-[(2-甲基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-基]磺酰基}甲基)咪唑烷-2,4-二酮;
(5S)-5-({[4-[(2-乙基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-基]磺酰基}甲基)-5-甲基咪唑烷-2,4-二酮;
(5S)-5-({[4-[(2-甲氧基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-基]磺酰基}甲基)-5-甲基咪唑烷-2,4-二酮;
及其药学可接受的盐。
各示例的化合物代表了本发明的具体而又独立的方面。
式(I)的化合物可以以对映体形式存在。因此,所有的对映体、非对映体、外消旋体和其混合物,包括在本发明范围内。各种旋光异构体可以使用传统方法例如分步结晶或HPLC通过分离化合物的外消旋混合物而进行分离。可替换地,旋光异构体可以通过不对称合成或通过由光学活性起始原料合成而获得。
如果本发明的化合物中存在旋光异构体,作为本发明的独立具体实施方案,我们公开所有的独立光学活性形式和这些的组合,以及它们相应的外消旋体。
优选式(I)的化合物具有如下所示的(5S)-立体化学结构:
如果本发明的化合物中存在互变异构体,作为本发明的独立具体实施方案,我们公开所有的独立互变异构形式和这些的组合。
本发明包括盐形式的式(I)化合物。合适的盐包括那些与有机或无机酸或有机或无机碱形成的盐。尽管非药学可接受的盐在具体化合物的制备和纯化中具有应用性,但这种盐通常是药学可接受的盐。这种盐包括酸加成盐例如盐酸盐,氢溴酸盐,柠檬酸盐,甲苯磺酸盐和马来酸盐,和与磷酸或硫酸形成的盐。在另一个方面,合适的盐是碱盐(base salt),例如碱金属盐,例如钠或钾盐,碱土金属盐,例如钙或镁盐,或有机胺盐,例如三乙胺盐。
式(I)化合物的盐可以通过游离碱或其另一种盐与一个或多个当量的合适酸或碱反应来形成。
式(I)的化合物是有用的,因为它们在动物中具有药理学活性,并由此作为药物是潜在可用的。尤其是,本发明的化合物是金属蛋白酶抑制剂,并由此可以用于治疗由MMP12和/或MMP9介导的疾病或病症,例如哮喘,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),动脉粥样硬化和再狭窄,癌症,侵入和转移病变,涉及组织损坏的疾病,髋关节移位的松驰,牙周病,纤维化疾病,梗塞和心脏病,肝脏和肾纤维化,子宫内膜异位,与细胞外基质弱化有关的疾病,心力衰竭,主动脉瘤,CNS涉及的疾病例如阿尔茨海默氏病和多发性硬化(MS),和血液学病症。
通常,本发明的化合物是MMP9和MMP12的有效抑制剂。本发明的化合物对较少抑制各种其它MMPs(例如MMP8、MMP14和MMP19)还显示出良好的选择性。此外,本发明的化合物通常还具有改善的log D值,特别是具有0.5<log D<2.0范围内的log D值。Log D是反映化合物在生理pH下的亲油性的参数。由于这些有利的log D值,本发明的化合物具有改善的溶度特征(solubility characteristics)以及降低的血浆蛋白结合,从而导致改善的药物动力学和药效性质。
因此,本发明提供了如上文所限定的用于治疗的式(I)化合物、或其药学可接受的盐。
另一方面,本发明提供了如上文所限定的式(I)化合物、或其药学可接受的盐在制备用于治疗的药物中的用途。
另一方面,本发明提供了如上文所限定的式(I)化合物、或其药学可接受的盐在制备用于治疗其中抑制MMP 12和/或MMP9是有益的疾病或病症的药物中的用途。
另一方面,本发明提供了如上文所限定的式(I)化合物、或其药学可接受的盐在制备用于治疗炎性疾病的药物中的用途。
另一方面,本发明提供了如上文所限定的式(I)化合物、或其药学可接受的盐在制备用于治疗阻塞性气道疾病例如哮喘或COPD的药物中的用途。
在本说明书的上下文中,除非有与此相反的具体说明,术语“治疗”也包括“预防”。应该相应地解释术语“治疗学的”和“治疗地”。
预防被认为与患有所述疾病或病症的先前发作的人员的治疗特别有关,或被认为与处于所述疾病或病症的增加危险之中的人员的治疗特别有关。处于形成具体疾病或病症的危险之中的人员,通常包括具有该疾病或病症的家族史的那些人员,或已经通过遗传学试验或筛选确定为对形成该疾病或病症特别敏感的那些人员。
本发明进一步提供了治疗其中抑制MMP12和/或MMP9是有益的疾病或病症的方法,该方法包括对患者给药治疗有效量的上文中定义的式(I)化合物或其药学可接受的盐。
本发明也提供了治疗阻塞性气道疾病(例如哮喘或COPD)的方法,该方法包括对患者给药治疗有效量的上文中定义的式(I)化合物或其药学可接受的盐。
当然,对于上述治疗用途,给药剂量随所采用的化合物、给药方式、所需要的治疗和所治疗的病症而变化。式(I)化合物/盐(活性组分)的每日剂量可以在0.001mg/kg至75mg/kg的范围,尤其是从0.5mg/kg至30mg/kg。这种日剂量可以根据需要以分开剂量的形式给予。典型地,单位剂型含有约1mg至500mg的本发明的化合物。
可以单独使用式(I)的化合物和其药学可接受的盐,但通常以药物组合物的形式给药,在药物组合物中,式(I)化合物/盐(活性组分)与药学可接受的助剂、稀释剂或载体结合。根据给药方式,药物组合物优选包含0.05至99% w(重量百分比)、更优选0.10至70% w的活性组分,和1至99.95% w、更优选30至99.90% w的药学可接受的助剂、稀释剂或载体,所有的重量百分数基于全部组合物。例如,选择和制备合适药物制剂的常规方法描述在下面中:“Pharmaceuticals-The Science of Dosage Form Designs”,M.E.Aulton,Churchill Livingstone,1988。
由此,本发明也提供了一种药物组合物,其包括如上文所限定的式(I)化合物或其药学可接受的盐,以及结合有药学可接受的助剂、稀释剂或载体。
本发明进一步提供了制备本发明药物组合物的方法,其包括将上文中定义的式(I)化合物或其药学可接受的盐与药学可接受的助剂、稀释剂或载体混合。
对所希望治疗的疾病或病症,可以以标准方式给药本发明的药物组合物,例如通过口服、局部、肠胃外、口腔、经鼻、阴道或直肠给药或通过吸入给药。为了达到上述目的,可以将本发明化合物通过本领域已知的方法配制成下列形式:例如片剂,胶囊,水溶液或油性溶液,悬浊液,乳状液,乳膏剂,油膏,凝胶剂,鼻腔喷雾剂(nasal spray),栓剂,用于吸入的微细粉末或气雾剂,和用于肠胃外使用(包括静脉内,肌肉内或输液)的无菌水溶液或油性溶液或悬浊液或无菌乳状液。
除了本发明的化合物之外,本发明的药物组合物也可以含有对于治疗一或多种上文所指疾病或病症中有价值的药理学试剂例如“Symbicort”(商标)产品,或与其共同给药(同时或顺序)。
本发明进一步提供了制备如以上所定义的式(I)化合物或其药学可接受的盐的方法,其包括:
a)使式(II)的化合物和式(III)化合物(或其盐)反应
其中R2如式(I)所定义和L1表示离去基团
其中R1如式(I)中所定义;或
b)使式(X)的化合物与式(IX)的炔属化合物反应,
其中R2如式(I)中所定义,R3为H或合适的保护基团和X为离去基团,例如卤素或三氟甲磺酸酯基(triflate);
其中R1如式(I)中所定义;或
c)使式(XI)的化合物与式(VI)的芳基卤或芳基三氟甲磺酸酯反应。
其中R表示H或三甲基甲硅烷基,R2如式(I)中所定义和R3表示H或合适的保护基团;
其中R1如式(I)中所定义和X表示卤素或三氟甲磺酸酯基;和
其后任选形成药学可接受的盐。
在上述方法(a)中,合适的离去基团L1包括卤素,特别是氯。反应优选在合适的溶剂中、任选在加入碱的情况下、在环境至回流温度下进行合适的时间,典型地是0.5至24小时。通常,使用溶剂例如吡啶,二甲基甲酰胺,四氢呋喃,乙腈或二氯甲烷。当使用时,加入的碱可以是有机碱例如三乙胺,二异丙基乙基胺,N-甲基吗啉或吡啶,或无机碱例如碱金属碳酸盐。反应典型地在室温进行0.5至16小时,或直至已经达到反应结束,通过色谱或光谱方法测定。磺酰基卤化物与各种伯胺和仲胺的反应是文献中已知的,并且反应条件的改变对本领域的技术人员是显然的。
式(II)的磺酰氯(其中L1表示氯)使用本领域技术人员明显的方法,通过氧化氯化式(IV)化合物而便利地制备(Mosher,J.,J.Org.Chem.1958.23,1257;Griffith,O.,J.Biol.Chem.1983.258,(3),1591;WO 02/074767)
可以通过文献中所述的各种方法以及其变化形式制备式(III)化合物,正如有机合成化学领域技术人员将认识到的。合适的方法包括但不限于下述方案1所显示的方法。
方案1
在方案1中,PG表示合适的保护基团,例如t-Boc(叔丁氧基羰基);X表示离去基团例如卤素或三氟甲磺酸酯基;R表示氢或三甲基甲硅烷基;tms表示三甲基甲硅烷基;Ar表示在2位被R1取代的5-嘧啶基环;和R1如式(I)中所定义。
芳基-或乙烯基衍生物[(V)或(VI)]和炔[(VII),(VIII)或(IX)]之间的反应可以任选地在有机溶剂存在下,使用催化剂,例如合适的钯盐,如PdCl2(PPh3)2,添加/或不添加铜盐以及胺碱,例如哌啶、三乙胺、二异丙胺或二异丙乙基胺下进行反应。当使用溶剂时,添加的溶剂可以为例如四氢呋喃、乙腈或N,N-二甲基甲酰胺。在环境温度至回流温度下反应20分钟至几小时,直至色谱法或分光法显示反应完全。涉及炔属化合物的钯催化反应在文献中是已知的,条件的改变对于本领域技术人员是明显的。这类型的通常方法描述于例如Brandsma,L.,Synthesis of Acetylenes,Allenes和Cumulenes:Methods和Techniques,2004,Elsiever Academic Press,.Chapter 16,pages293-317;Transition Metals-Catalysed Couplings of Acetylenes withsp2-halides,Sonogashira,K.J.Organomet.Chem.,2002,653,46-49;Tykwinski,R.R.,Angew.Chem.Int.Ed.,2003,42,1566-1568。
可根据文献(Wustrow,D.J.,Synthesis,1991,993-995)所述制备乙烯基三氟甲磺酸酯(V)(其中X为O-三氟甲磺酸酯基和PG为t-Boc)。
合适取代的式(VI)的嘧啶卤化物或三氟甲磺酸酯可由文献中描述的各种方法来制备,例如Budesinsky,Z.et al.,Coll.Czech.Chem.Commun.,1949,14,223-235;Takahashi et al.,Chem.Pharm.Bull.,1958,6,334-337;US4,558,039。
可以从三氟甲磺酸酯(V),通过与三甲基甲硅烷基乙炔的钯催化偶合反应,然后如果需要使用例如氟化钾,在合适的溶剂中使三甲基甲硅烷基去保护,从而制备炔属化合物(VIII)。可替换地,可以通过式(VII)化合物的脱水,例如通过甲磺酰化,接着用合适的碱(例如二异丙乙基胺)处理而制备其中R为H和PG为t-Boc的化合物(VIII)。
式(IX)的炔属杂芳基化合物可以通过文献中所述的各种方法制备。
在方法(b)中,使用与上述制备式(VIII)化合物的方法类似的方法进行反应。如果需要,在钯催化反应进行前,可以使用SEMCl(R3=SEM)保护式(X)化合物的乙内酰脲环中的一个氮。可以通过式(V)(PG=t-Boc)化合物的酸催化去保护,接着与式(II)化合物反应,以上述制备式(I)化合物相似的方式制备式(X)化合物。
在方法(c)中,以上述制备式(VIII)化合物相似的方式进行反应。如果需要,在钯催化反应进行前,可以使用SEMCl(R3=SEM)保护式(XI)化合物的乙内酰脲环中的一个氮。从其中R为三甲基甲硅烷基和PG为t-Boc的化合物(VIII)通过酸催化除去t-Boc基团(例如,使用乙酰氯的甲醇溶液),接着与式(II)化合物反应,如上述式(II)和(III)化合物之间的反应,便利地制备化合物(XI)。
本领域技术人员可以理解,在本发明的方法中,起始试剂或中间体化合物中的某些潜在地反应性官能团例如羟基或氨基,可以需要通过合适的保护基进行保护。由此,在各步骤中,本发明化合物制备可以包括一或多种保护基的添加和除去。
合适的保护基和添加与除去这种基团的详细方法描述在‘ProtectiveGroups in Organic Chemistry’,edited by J.W.F.McOmie,Plenum Press(1973)and′Protective Groups in Organic Synthesis′,3rd Edition,T.W.Greene and P.G.M.Wuts,Wiley-Interscience(1999)中。
本发明的化合物和其中间体可以从它们的反应混合物中分离,并且如果需要的话,可以使用标准技术进一步纯化。
现在将参考下列说明性的实施例进一步解释本发明。
一般方法
在Varian Inova 400MHz或Varian Mercury-VX 300MHz仪器上记录1HNMR和13C NMR谱图。氯仿-d(δH 7.27ppm)、二甲基亚砜-d6(δH2.50ppm)、乙腈-d3(δH1.95ppm)或甲醇-d4(δH3.31ppm)的中心峰用作内标。使用硅胶(0.040-0.063mm,Merck)进行柱色谱分析。使用Kromasil KR-100-5-C18柱(250×20mm,Akzo Nobel)和乙腈/水的混合物以及0.1%TFA,10mL/min的流量用于制备型HPLC。除非另外说明,原料是市售的。所有的溶剂和商用试剂是实验室级的,并且原样使用。
下面的方法用于LC/MS分析:
仪器Agilent 1100;Column Waters Symmetry 2.1×30mm;质量APCI;流量0.7mL/min;波长254或220nm;溶剂A:水+0.1% TFA;溶剂B:乙腈+0.1% TFA;梯度15-95%/B 2.7分钟,95%B 0.3分钟。
下面的方法用于LC分析:
方法A.仪器Agilent 1100;柱:Kromasil C18 100×3mm,5μ粒度,溶剂A:0.1%TFA/水,溶剂B:0.08%TFA/乙腈;流量1mL/min,
梯度10-100%/B 20分钟,100%B 1分钟。在220、254和280nm处测量吸收。
方法B.仪器Agilent 1100;柱:XTerra C 8,100×3mm,5μ粒度,溶剂A:15mM NH3/水,溶剂B:乙腈;流量1mL/min;梯度10-100%/B 20分钟,100%B 1分钟。在220、254和280nm处测量吸收。
缩写:
Ac 乙酰基
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
eq. 当量
Et 乙基
LDA 二异丙基氨基锂(lithium diisopropyl amide)
Me 甲基
MS 质谱
tert 叔
THF 四氢呋喃
TFA 三氟乙酸
实施例1
(5S)-5-({[4-[(2-环丙基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-基]磺酰基}
甲基)-5-甲基咪唑烷-2,4-二酮
按照Yamanaka等人,Synth.Commun.,1983,312-314的一般方法制备标题化合物。35℃下,向5-溴-2-环丙基嘧啶(110mg,0.55mmol)和(5S)-5-{[(4-乙炔基-3,6-二氢吡啶-1(2H)-基)磺酰基]甲基}-5-甲基咪唑烷-2,4-二酮(180mg,0.61mmol)的THF(3mL)溶液中加入Et3N(1mL)和DMF(1mL)。在形成溶液后,加入CuI(4mol%)和PdCl2(PPh3)2(2mol%),在72℃加热混合物6小时。在EtOAc(15mL)和水(10mL)之间分配混合物,用EtOAc洗涤水层3次。干燥并浓缩合并的有机层,得到粗产物,其为黄色油状物。使用制备型HPLC纯化,获得标题化合物(65mg)。
1H-NMR(DMSO-d6):δ 10.75(1H,s);8.72(2H,s);8.03(1H,s);6.28(1H,m);3.84(2H,m);3.47(2H,q);3.30(2H,m);2.37(2H,m);2.21(1H,m);1.33(3H,s);1.10(2H,m);1.02(2H,m).
APCI-MS m/z:416[MH+].
a)5-溴-2-环丙基嘧啶
根据Budesinsky,Z.,Coll.Czech.Chem.Commun.,1949,14,223-235的方法制备5-溴-2-环丙基嘧啶。将环丙烷甲脒盐酸盐(Cyclopropanecarboximidamide hydrochloride)(2.5g,20.7mmol)溶于EtOH(4mL),然后加入新制备的4.1M NaOEt的EtOH(4.8mL)溶液,接着加入粘溴酸(mucobromicacid)(2.7g,10.3mmol)。将混合物加热到56℃,保持30分钟,加入更多的NaOEt的EtOH(4.1M,3.2mL)溶液,在56℃将混合物再搅拌15分钟,然后在室温搅拌过夜。蒸去溶剂,加入HCl水溶液(2M,10mL),滤出棕色固体。用二氯甲烷洗涤水层三次。将合并的有机层干燥并浓缩,得到棕色油状物,其和固体一起得到粗中间体5-溴-2-环丙基嘧啶-4-羧酸(1.6g)。在140℃将中间体加热8分钟,得到棕色粘稠油状物,将其部分溶解在二氯甲烷中。从混合物中滗析出该溶液,浓缩得到标题化合物,其为油状物(673mg)。
1H-NMR(CDCl3):δ 8.61(2H,s);2.25(1H,m);1.13(4H,m).
APCI-MS m/z:199/2011:1[MH+].
b)(5S)-5-{[(4-乙炔基-3,6-二氢吡啶-1(2H)-基)磺酰基]甲基}-5-甲基咪唑
烷-2,4-二酮
(5S)-5-甲基-5-({[4-[(三甲基甲硅烷基)乙炔基]-3,6-二氢吡啶-1(2H)-基]磺酰基}甲基)咪唑烷-2,4-二酮(2.27g,6.0mmol)和氟化钾(1.07g,18.4mmol)在室温在甲醇(50mL)中搅拌过夜。蒸去溶剂,将残余物溶解在EtOAc中,用水洗涤接着用盐水洗涤,干燥(硫酸钠)和蒸发。通过柱色谱,使用异己烷/EtOAc 1:1纯化残余物,得到固体产物(1.81g)。
1H NMR(CDCl3)δ 1.66(3H,s),2.37(2H,dt),2.95(1H,s),3.24-3.50(4H,m),3.89(2H,t),6.11(1H,s),6.68(1H,s),8.75(1H,s).
APCI-MS m/z:298[MH+].
c)(5S)-5-甲基-5-({[4-[(三甲基甲硅烷基)乙炔基]-3,6-二氢吡啶-1(2H)-基]
磺酰基}甲基)咪唑烷-2,4-二酮
4-[(三甲基甲硅烷基)乙炔基]-1,2,3,6-四氢吡啶盐酸盐(3.43g,15.9mmol)在THF(100mL)溶液和[(4S)-4-甲基-2,5-二氧代咪唑烷-4-基]甲磺酰氯(3.39g,15mmol)一起搅拌,并在冰盐浴(温度为约-10℃)中冷却。N-乙基二异丙基胺(5.13mL,30mmol)的THF(100mL)溶液在2小时内滴加,将混合物再搅拌2小时。用水洗涤反应混合物,水层萃取到EtOAc(×2)中,合并有机层,用2M HCl(×2)、饱和碳酸氢盐溶液(×2),接着用盐水洗涤,干燥(硫酸钠)和蒸发得到粗产物(5.06g)。将其直接使用而没有进一步纯化。
1H NMR(DMSO-d6)δ 10.74(1H,s),8.01(1H,s),6.13(1H,五重峰),3.75(2H,d),3.44(2H,dd),3.23(2H,t),2.18-2.28(2H,m),1.32(3H,s),1.32(9H,s).
APCI-MS m/z:370[MH+].
d)4-[(三甲基甲硅烷基)乙炔基]-1,2,3,6-四氢吡啶盐酸盐
4-[(三甲基甲硅烷基)乙炔基]-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(2.75g,9.8mmol)在甲醇(10mL)中搅拌,滴加乙酰氯(2.1mL,29.2mmol)。滴加过程中温度从18℃升到30℃,将混合物保持在40℃,直到tlc不再发现原料。将混合物冷却到室温,加入EtOAc(15mL),滤出固体得到灰白色固体(1.6g)。
1H NMR(DMSO-d6)δ 9.46(2H,s),6.09(1H,五重峰),3.60(2H,dd),3.13(2H,t),2.35(2H,td),0.17(8H,s).
APCI-MS m/z:180[MH+].
e)4-[(三甲基甲硅烷基)乙炔基]-3,6-二氢吡啶-1(2H)-羧酸叔丁酯
按照WO 96/05200,从N-Boc-哌啶-4-酮制得。
1H NMR(CDCl3)δ 6.05(1H,s),3.94(2H,dd),3.47(2H,t),2.23(2H,dq),1.45(10H,s),0.15(8H,s).
GCMS-MS m/z:223[M-55].
f)[(4S)-4-甲基-2,5-二氧代咪唑烷-4-基]甲磺酰氯
按照下述文献的方法,制备标题化合物:Mosher,J.,J.Org.Chem.1958.23,1257;Griffith,O.,J.Biol.Chem.1983.258,(3),1591;和WO 02/074767。
实施例2
(5S)-5-甲基-5-({[4-{[2-(甲硫基)嘧啶-5-基]乙炔基}-3,6-二氢吡啶-1(2H)-
基]磺酰基}甲基)咪唑烷-2,4-二酮
通过Nishihara等人.,J.Org.Chem.,2000,65,1780-1787描述的一般方法制备标题化合物。向2-(甲硫基)-5-[(三甲基甲硅烷基)乙炔基]嘧啶(0.55g,2.47mmol)和1-{[(4-甲基-2,5-二氧代咪唑烷-4-基)甲基]磺酰基}-1,2,3,6-四氢吡啶-4-基三氟甲磺酸酯(0.94g,2.22mmol)的DMF(5mL)溶液中加入CuI(10mol%)和PdCl2(PPh3)2(5mol%)和将混合物在85℃加热6小时。
将混合物在EtOAc(20mL)和水(10mL)之间分配,用EtOAc萃取水层三次。用盐水、水洗涤合并的有机层,浓缩得到棕色油状物(1.6g)。在通过制备型HPLC(使用Xterra-Prep-MS-C18(50×19)柱,12分钟梯度:5-35%的乙腈水溶液和0.06% NH3)纯化后获得标题化合物,其为固体(10mg)。
1H-NMR(DMSO-d6):δ 10.75(1H,s);8.73(2H,s);8.02(1H,s);6.29(1H,m);3.84(2H,m);3.48(2H,q);3.30(2H,m);2.53(3H,s);2.38(2H,m);1.33(3H,s).
APCI-MS m/z:422[MH+].
a)5-溴-2-(甲硫基)嘧啶
按照Takahashi等人.,Chem.Pharm.Bull.,1958,6,334-337所述的方法获得小标题化合物。在室温下,向5-溴-2-氯嘧啶(1.0g,5.2mmol)的EtOH溶液中加入甲硫醇钠(0.36g,5.2mmol),将反应混合物搅拌过夜。将混合物在EtOAc(15mL)和水(10mL)之间分配。用EtOAc洗涤水层两次,用盐水洗涤。干燥合并的有机层,浓缩得到小标题化合物,其为白色固体(1.1g)。
1H-NMR(CD3OD):δ 8.66(2H,s);2.54(3H,s).
APCI-MS m/z:204/2061:1[MH+].
b)2-(甲硫基)-5-[(三甲基甲硅烷基)乙炔基]嘧啶
按照Yamanaka等人,Synth.Commun.,1983,312-314的方法制备小标题化合物。向5-溴-2-(甲硫基)嘧啶(0.60g,2.9mmol)的Et3N(3mL)溶液中加入DMF(0.5mL)、CuI(5mol%)和PdCl2(PPh3)2(3mol%)。在密封管中将混合物在95℃加热12小时,然后在Et2O(30mL)和水(10mL)之间分配。用Et2O萃取水层两次,用水洗涤合并的有机层,干燥并浓缩得到粗产物,其为棕色油状物。通过快速色谱,使用10至60% EtOAc/庚烷梯度进行洗脱,纯化化合物,得到小标题化合物,其为无色油状物(0.55g)。
1H-NMR(CDCl3):δ 8.56(2H,s);2.58(3H,s);0.27(9H,s).
APCI-MS m/z:223[MH+].
c)1-({[(4S)-4-甲基-2,5-二氧代咪唑烷-4-基]甲基}磺酰基)-1,2,3,6-四氢吡
啶-4-基三氟甲磺酸酯
4-{[(三氟甲基)磺酰基]氧}-1,2,3,6-四氢吡啶氯化物与[(4S)-4-甲基-2,5-二氧代咪唑烷-4-基]甲磺酰氯(实施例1f)以实施例1c的方式进行反应。
1H NMR(DMSO-d6)δ 10.77(1H,s),8.04(1H,d),6.10(1H,t),3.88(2H,q),3.36-3.58(4H,m),2.50-2.56(2H,m),1.32(3H,s).
APCI-MS m/z:422[MH+].
d)4-{[(三氟甲基)磺酰基]氧}-1,2,3,6-四氢吡啶氯化物
4-{[(三氟甲基)磺酰基]氧}-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(3.77g,11.4mmol)与THF(15mL)和浓盐酸(15mL)混合。1小时后,蒸发混合物并通过与甲苯和甲醇共沸蒸发进行干燥,得到米色固体(88%),其可以使用而无需进一步纯化。
1H NMR(CDCl3)δ 9.72(2H,s),6.22(1H,s),3.75(2H,q),3.30(2H,t),2.65(2H,td).
APCI-MS m/z:232[MH+].
e)4-{[(三氟甲基)磺酰基]氧}-3,6-二氢吡啶-1(2H)-羧酸叔丁酯
将N-boc-哌啶-4-酮(10.14g,50mmol)的THF(80mL)溶液加入到2MLDA的THF(30mL,60mmol,1.2eq.)和THF(80mL)的冷溶液(-78℃)中,历时大约30分钟。再搅拌10分钟后,加入1,1,1-三氟-N-苯基-N-[(三氟甲基)磺酰基]甲磺酰胺(20g,56mmol,1.1eq.)的THF(80mL)溶液,使混合物温热到室温。用水洗涤溶液,用EtOAc(×2)洗涤水层,合并有机相并用饱和氯化铵溶液、盐水洗涤,干燥(硫酸钠)和蒸发。残余物过滤通过中性氧化铝(200g),使用正庚烷接着是正庚烷/EtOAc 9:1洗脱。蒸发后,1H-NMR显示三氟甲酸化试剂仍然存在,但是直接使用粗产物而没有进一步纯化。产率(13.17g,79.5%)。(Wustrow,D.J.,Synthesis,1991,993-995).
1H NMR(CDCl3)δ 5.77(1H,s),4.05(2H,q),3.64(2H,t),2.45(2H,五重峰),1.48(9H,s).
GCMS-MS m/z:274[M-57].
实施例3
(5S)-5-甲基-5-({[4-{[2-(三氟甲基)嘧啶-5-基]乙炔基}-3,6-二氢吡啶
-1(2H)-基]磺酰基}甲基)咪唑烷-2,4-二酮
按照实施例2的相同方法,从2-(三氟甲基)-5-[(三甲基甲硅烷基)乙炔基]嘧啶以48%的产率制备标题化合物。从95%EtOH中获得白色固体,分解点240-245℃。
1H NMR(DMSO-d6)δ 10.8(1H,br s),9.16(2H,s),8.05(1H,s),6.42(1H,m),3.88(2H,m),3.56(1H,d),3.42(1H,d),3.32(2H,m),2.41(2H,m)和1.33(3H,s).
APCI-MS m/z:444[MH+].
a)2-(三氟甲基)-5-[(三甲基甲硅烷基)乙炔基]嘧啶
2-(三氟甲基)嘧啶-5-基三氟甲磺酸酯(0.45g,1.5mmol)和无水三乙胺(1.0mL)在带螺帽的瓶中混合。用干燥氩气吹扫溶液10分钟。加入三甲基甲硅烷基乙炔(0.43mL,3.0mmol)、细磨的CuI(0.010g,0.05mmol)和PdCl2(PPh3)2(0.020g,0.030mmol)。将试瓶密封,并在铝块中在80℃加热。搅拌5小时后,在室温下蒸去挥发物(产物在35-40℃/10毫巴下升华)。将黑色残余物吸收在EtOAc(20mL)中,用氧化硅浓缩(约5至10g)至干燥。在氧化硅上进行快速色谱,使用EtOAc/庚烷(1:30),得到2-(三氟甲基)-5-[(三甲基甲硅烷基)乙炔基]嘧啶,其为白色固体(0.35g,95%),熔点75.5-76.0℃。
1H NMR(CDCl3)δ 8.90(2H,s)和0.30(9H,s).
APCI-MS m/z:245[MH+].
b)2-(三氟甲基)嘧啶-5-基三氟甲磺酸酯
在冰浴温度下,将三氟甲酸酐(1.01mL,6.0mmol)滴加到2-(三氟甲基)嘧啶-5-醇(根据美国专利US Patent 4,558,039制备)(0.82g,5.0mmol)、甲苯(10mL)和含水磷酸三钾(30%重量,10mL)混合物中(Frantz等人.,OrganicLetters,2002,4(26),4717-4718)。滴加完成后,移去冰浴,在环境温度下搅拌溶液30分钟。分离澄清相,用水然后用盐水洗涤有机相。在无水硫酸钠上干燥有机相,过滤并通过旋转蒸发器在室温下浓缩得到2-(三氟甲基)-嘧啶-5-基三氟甲磺酸酯,其为无色油状物(1.38g,93%).沸点77℃(10毫巴)。
1H NMR(CDCl3)δ 8.90(2H,s).
实施例4
(5S)-5-甲基-5-({[4-[(2-甲基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-基]
磺酰基}甲基)咪唑烷-2,4-二酮
4-[(2-甲基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-羧酸叔丁酯用TFA的EtOH溶液处理,反应完成后蒸去溶剂,降混合物冷冻干燥。将残余物吸收在DMF(1.5mL)中,将混合物冷却到4℃。加入N-乙基二异丙基胺(2.2eq.),将混合物搅拌20分钟,然后加入[(4S)-4-甲基-2,5-二氧代咪唑烷-4-基]甲磺酰氯(实施例1f)(1.1eq.)的DMF(1mL)溶液。在4℃下将混合物搅拌10分钟,然后在室温搅拌2h,接着蒸去溶剂。通过制备型HPLC纯化溶剂,得到标题化合物(0.022g,30%)。
1H NMR(DMSO-d6);10.75(1H,s);8.80(2H,s);8.02(1H,s);7.80(1H,m);7.32(1H,d,J=8.1Hz);6.24(1H,s);3.81(2H,d,J=3.2Hz);3.34-3.21(2H,m);3.30(3H,s);2.75(2H,q,J=20.8Hz);2.34(2H,m);1.29(3H,s);1.19(3H,t,J=7.6Hz).
APCI-MS m/z:390[MH+].
a)2-甲基-5-[(三甲基甲硅烷基)乙炔基]嘧啶
5-溴-2-甲基-嘧啶(根据UK专利申请GB 2 157 288制备)(0.2g,1.16mmol)、(三甲基甲硅烷基)乙炔(164μL,1.3mmol)、CuI(0.022g,0.116mmol)和PdCl2(PPh3)2(0.082g,0.116mmol)的Et3N(2mL)和THF(2mL)溶液在80℃搅拌4h。冷却后,真空除去溶剂,将残余物进行色谱分离得到小标题化合物(0.16g,50%)。
APCI-MS m/z:191[MH+].
b)4-[(2-甲基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-羧酸叔丁酯
在室温下,向CuCl(1mg,0.01mmol)和PdCl2(PPh3)2(0.003g,0.004mmol)的DMF(2mL)溶液加入2-甲基-5-[(三甲基甲硅烷基)乙炔基]嘧啶(0.088g,0.462mmol)和4-{[(三氟甲基)磺酰基]氧}-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(实施例2e)(0.183g,0.555mmol)。将反应混合物在80℃搅拌8小时。冷却后,用1N HCl骤冷混合物,用乙醚(3×)萃取。用饱和NaHCO3水溶液、盐水洗涤有机层,干燥。过滤并蒸发得到棕色油状物,在HPLC上将其纯化得到小标题化合物(0.062g,45%)。
APCI-MS m/z:300[MH+].
实施例5
(5S)-5-({[4-[(2-乙基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-基]磺酰基}
甲基)-5-甲基咪唑烷-2,4-二酮三氟乙酸盐
按照实施例4相同的方式制备标题化合物。使用GB 2 157 288的方法,制备原料5-溴-2-乙基-嘧啶。
1H NMR(DMSO-d6);10.75(1H,s);8.82(2H,s);8.05(1H,s);6.24(1H,s);3.81(2H,d,J=3.2Hz);3.34-3.21(2H,m);3.30(3H,s);2.92(2H,q,J=17.8Hz);2.75(2H,q,J=20.8Hz);2.34(2H,m);1.26(3H,t,J=12.8Hz);1.19(1H,s).
APCI-MS m/z:404[MH+].
实施例6
(5S)-5-({[4-[(2-甲氧基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-基]磺酰基}
甲基)-5-甲基咪唑烷-2,4-二酮
以实施例1描述的相同方式,从5-溴-2-甲氧基嘧啶和(5S)-5-{[(4-乙炔基-3,6-二氢吡啶-1(2H)-基)磺酰基]甲基}-5-甲基咪唑烷-2,4-二酮制备标题化合物。
1HNMR(DMSO-d6):δ 10.75(1H,s);8.73(2H,s);8.04(1H,s);6.26(1H,s);3.95(3H,s);3.81(2H,d,J=3.2Hz);3.34-3.21(2H,m);3.30(3H,s);2.75(2H,q,J=20.8Hz);2.34(2H,m);1.19(3H,t,J=7.6Hz).
APCI-MS m/z:406[MH+].
药理学实施例
分离的酶测定
MMP12
重组人类MMP12催化区域可以按照Parkar A.A.等人(2000),ProteinExpression and Purification,20:152的描述来表达和纯化。纯化的酶能够用于监测抑制剂的活性,如下所述:在存在抑制剂(10倍浓度)或不存在抑制剂的条件下,在室温下,将MMP12(50ng/ml最终浓度)在测定缓冲液(0.1M“Tris-HCl”(商标)缓冲液,pH值7.3,含有0.1M NaCl、20mM CaCl2、0.020mMZnCl和0.05%(w/v)“Brij 35”(商标)清净剂)中用合成底物Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2(10μM)培养60分钟。通过在λex320nm和λem405nm处测定荧光来测定活性。百分数抑制计算如下:
%抑制等于[荧光加抑制剂-荧光背景]/[荧光无抑制剂-荧光背景]。
MMP8
纯化的前MMP8购自Calbiochem。通过1mM的对氨基-苯基-乙酸汞(APMA)在35℃将酶(10μg/ml)活化2.5h。活化的酶能够用于如下监测抑制剂的活性:在35℃(80% H2O),在存在抑制剂(10倍浓度)或不存在抑制剂的条件下,将MMP8(200ng/ml的最终浓度)在测定缓冲液(0.1M“Tris-HCl”(商标)缓冲液,pH 7.5,含0.1M NaCl、30mM CaCl2、0.040mM ZnCl和0.05%(w/v)、“Brij 35”(商标)清净剂)中,用合成底物Mca-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2(12.5μM)培养90分钟。通过在λex320nm和λem405nm处测定荧光来测定活性。百分数抑制计算如下:
%抑制等于[荧光加抑制剂-荧光背景]/[荧光无抑制剂-荧光背景]。
MMP9
表达重组人类MMP9催化区域,然后通过螯合Zn柱色谱并接着通过氧肟酸酯亲合柱色谱来纯化。该酶能够用于如下监测抑制剂的活性:在室温,在存在抑制剂(10倍浓度)或不存在抑制剂的条件下,将MMP9(5ng/ml的最终浓度)在测定缓冲液(0.1M“Tris-HCl”(商标)缓冲液,pH 7.3,含0.1M NaCl、20mM CaCl2、0.020mM ZnCl和0.05%(w/v)、“Brij 35”(商标)清净剂)中,用合成底物Mca-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2(5μM)培养30分钟。通过在λex 320nm和λem405nm处测定荧光来测定活性。百分数抑制计算如下:
%抑制等于[荧光加抑制剂-荧光背景]/[荧光无抑制剂-荧光背景]。
MMP14
重组人类MMP14催化区域可以按照Parkar A.A.等人(2000),ProteinExpression and Purification,20,152来表达和纯化。纯化的酶能够用于监测抑制剂的活性,如下所述:在存在抑制剂(5倍浓度)或不存在抑制剂的条件下,在室温下,将MMP14(10ng/ml最终浓度)在测定缓冲液(0.1M“Tris-HCl”(商标)缓冲液,pH值7.5,含有0.1M NaCl、20mM CaCl2、0.020mM ZnCl和0.05%(w/v)“Brij 35”(商标)清净剂)中用合成底物Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2(10μM)培养60分钟。通过在λex320nm和λem405nm处测定荧光来测定活性。百分数抑制计算如下:
%抑制等于[荧光加抑制剂-荧光背景]/[荧光无抑制剂-荧光背景]。
使用表达和纯化的前MMP来试验其它基质金属蛋白酶(包括MMP9)的方案,描述在例如C.Graham Knight等人(1992)FEBS Lett.296(3):263-266中。
MMP19
重组人类MMP19催化区域可以按照Parkar A.A.等人(2000),ProteinExpression and Purification,20,152来表达和纯化。纯化的酶能够用于监测抑制剂的活性,如下所述:在存在抑制剂(5倍浓度)或不存在抑制剂的条件下,在35℃下,将MMP19(40ng/ml最终浓度)在测定缓冲液(0.1M“Tris-HCl”(商标)缓冲液,pH值7.3,含有0.1M NaCl、20mM CaCl2、0.020mM ZnCl和0.05%(w/v)“Brij 35”(商标)清净剂)中用合成底物Mca-Pro-Leu-Ala-Nva-Dpa-Ala-Arg-NH2(5μM)培养120分钟。通过在λex320nm和λem 405nm处测定荧光来测定活性。百分数抑制计算如下:
%抑制等于[荧光加抑制剂-荧光背景]/[荧光无抑制剂-荧光背景]。
蛋白质结合
通过在自动化96孔格式实验(format assay)中进行超滤,确定血浆蛋白结合。对于每一次实验,平行监测参比化合物(budesonide)的血浆蛋白结合。将测试化合物(10mM,溶于DMSO)加入到血浆中,得到10μM的最终浓度,并在室温下平衡10分钟。将350μL血浆转移到Microcon-96超滤板(10kDa cutoff,)。在室温下将超滤板以3000G离心70分钟。离心后,通过LC-MS/MS,使用三点校正曲线并与原始增敏血浆(spiked plasma)浓度相比较,确定在所获血浆水(未结合部分)中的化合物的浓度。
使用梯度色谱系统,使用乙酸/乙腈作为流动相,进行分析。使用来自Applied Biosystems具有电喷雾界面的三重四倍质谱仪(triple quadropolemass spectrometer),API3000或API4000进行测量。
溶度测量方案
如下所述测量测试化合物在0.1M磷酸盐缓冲溶液,pH 7.4中的溶度:
将测试化合物(1mg)称量到2mL具有螺帽的玻璃瓶中,并加入0.1M磷酸盐缓冲液pH7.4.(1.00mL)。然后将样品瓶超声处理约10分钟,之后在20℃下在振动板上过夜。然后通过Millipore Millex-LH0.45μm过滤器,将样品瓶中的内含物过滤到新的2mL玻璃瓶中,得到澄清溶液。将该澄清溶液(40μL)转移到新的2mL玻璃瓶中,用0.1M磷酸盐缓冲液pH 7.4(960μL)稀释。
对于每个特定的测试化合物,使用已知浓度的溶液建立标准校正曲线。通常选择这些已知浓度的溶液,以具有~10μg/mL和~50μg/mL的浓度。通过将已知重量的化合物溶解在99.5%乙醇(500μL)中,然后根据需要超声处理1分钟,从而制备这些溶液。如果化合物仍然没有完全溶解,加入DMSO(500μL),再超声处理混合物1分钟。然后将所得溶液用乙腈/100mM乙酸铵pH 5.520-50/80-50稀释到适当体积。如果需要,通过稀释制备更稀的标准溶液。
然后通过具有UV检测功能的HPLC,使用下列参数分析测试化合物溶液和标准溶液,由此确定测试化合物在0.1M磷酸盐缓冲液中的溶度。
HPLC-设备 HP1100/HP1050
柱 HyPURITY Advanced,5μm,125 x 3mm
柱温度 RT
流量 1mL/min
流动相 A=乙腈
B=100mM乙酸铵pH 5.5
等度比例 A/B 20-50/80-50
UV检测器 254nm(220-280nm)
注射体积 20μL
色谱数据处理系统 ATLAS/Xchrome
确定Log D的方案
使用摇瓶法测量在pH 7.4的Log D值。在室温下,将适量的少量测试化合物置于2mL具有螺帽的玻璃瓶中,并加入600μL的1-辛醇(用10mM磷酸盐缓冲液pH 7.4饱和)。然后将瓶超声处理1分钟,以将化合物完全溶解。然后加入600μL的10mM磷酸盐缓冲液pH 7.4(用1-辛醇饱和),将瓶振动4分钟,混合两相。然后在室温下以1000g将样品离心10分钟,从而分离两相。最后,使用下面的条件,通过HPLC重复分析分离的水相和有机相:
注射器 Spark Holland,Endurance
泵 HP1050
检测器 Kratos,Spectroflow 783
柱 YMC Pro C18,5μm,50x4mm,Part no.AS12S050504QT
柱温度 室温
流量 1mL/min
流动相 A=乙腈
B=25mM甲酸
C=100mM乙酸铵,pH 5.5
D=0.05%乙酸铵
梯度 0.00分钟A/B或A/C或A/D 5/95
5.00分钟A/B或A/C或A/D 100/0
7.00分钟A/B或A/C或A/D 100/0
7.02分钟A/B或A/C或A/D 5/95
UV检测器 254nm
注射体积 50μL未稀释的水相和5μL 10倍稀释的(用甲醇)有机相
注射循环时间 11分钟
离心 Hettich,Universal 30RF
涡流 Scientific Industries,Vortex-2genie
色谱数据处理系统 ATLAS/Xchrome
通过Excel表格,在人工输入化合物峰面积响应后,自动计算log DpH7.4值(参见下式),所述响应得自ATLAS色谱数据处理系统。
通过下式计算log DpH 7.4:
其中
Analyte: 分析物
org: 有机相
aq: 水相
Area: 面积
Dilution factor:稀释因子
Vini: 注射体积
下表显示了本发明化合物代表性选择和选自WO 02/074767化合物的数据。
Claims (14)
2.权利要求1的化合物或其药学可接受的盐,其中R1表示C1-2烷基,其任选进一步被一个或多个氟原子取代。
3.权利要求2的化合物或其药学可接受的盐,其中R1表示CF3。
4.权利要求1的化合物或其药学可接受的盐,其中R1表示环丙基。
5.权利要求1-4任一项的化合物或其药学可接受的盐,其中R2表示甲基或乙基。
6.权利要求5的化合物或其药学可接受的盐,其中R2表示甲基。
7.权利要求1的化合物或其药学可接受的盐,所述化合物选自:
(5S)-5-甲基-5-({[4-{[2-(三氟甲基)嘧啶-5-基]乙炔基}-3,6-二氢吡啶-1(2H)-基]磺酰基}甲基)咪唑烷-2,4-二酮;
(5S)-5-甲基-5-({[4-[(2-甲基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-基]磺酰基}甲基)咪唑烷-2,4-二酮;和
(5S)-5-({[4-[(2-乙基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-基]磺酰基}甲基)-5-甲基咪唑烷-2,4-二酮。
8.权利要求1的化合物或其药学可接受的盐,所述化合物为(5S)-5-({[4-[(2-环丙基嘧啶-5-基)乙炔基]-3,6-二氢吡啶-1(2H)-基]磺酰基}甲基)-5-甲基咪唑烷-2,4-二酮。
10.一种药物组合物,包括如权利要求1-8中任一项定义的式(I)的化合物或其药学可接受的盐,以及结合有药学可接受的助剂、稀释剂或载体。
11.一种制备权利要求10所要求的药物组合物的方法,其包括将权利要求1-8中任一项的式(I)的化合物或其药学可接受的盐与药学可接受的助剂、稀释剂或载体混合。
12.权利要求1-8中任一项所要求的式(I)的化合物或其药学可接受的盐在制备用于治疗由MMP12和/或MMP9介导的疾病或病症的药物中的用途。
13.权利要求12的用途,其中所述疾病或病症为阻塞性气道疾病。
14.权利要求13的用途,其中阻塞性气道疾病是哮喘或慢性阻塞性肺病。
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SE0202539D0 (sv) | 2002-08-27 | 2002-08-27 | Astrazeneca Ab | Compounds |
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TWI220073B (en) | 2003-07-24 | 2004-08-01 | Au Optronics Corp | Method for manufacturing polysilicon film |
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SE0401762D0 (sv) | 2004-07-05 | 2004-07-05 | Astrazeneca Ab | Novel compounds |
SE0401763D0 (sv) | 2004-07-05 | 2004-07-05 | Astrazeneca Ab | Compounds |
SE0403086D0 (sv) | 2004-12-17 | 2004-12-17 | Astrazeneca Ab | Compounds |
SE0403085D0 (sv) | 2004-12-17 | 2004-12-17 | Astrazeneca Ab | Novel componds |
TW200740769A (en) | 2006-03-16 | 2007-11-01 | Astrazeneca Ab | Novel process |
TW200800954A (en) | 2006-03-16 | 2008-01-01 | Astrazeneca Ab | Novel crystal modifications |
TW200831488A (en) | 2006-11-29 | 2008-08-01 | Astrazeneca Ab | Novel compounds |
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