CN102361640A - 将取代的异噁唑吡啶酮用作离解的糖皮质激素的方法 - Google Patents
将取代的异噁唑吡啶酮用作离解的糖皮质激素的方法 Download PDFInfo
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- CN102361640A CN102361640A CN2010800045479A CN201080004547A CN102361640A CN 102361640 A CN102361640 A CN 102361640A CN 2010800045479 A CN2010800045479 A CN 2010800045479A CN 201080004547 A CN201080004547 A CN 201080004547A CN 102361640 A CN102361640 A CN 102361640A
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Abstract
一种用取代的异噁唑吡啶酮治疗有炎症或者自身免疫疾病的实验对象的方法。以及,一种向细胞给予取代的异噁唑吡啶酮以维持或者提高糖皮质激素受体反式阻抑活性同时仅有最小的糖皮质激素受体反式激活活性的方法。
Description
关于联邦赞助的研究或开发的声明
本发明一部分是在美国政府支持下进行的并由以下机构授权:国立卫生研究院(National Institutes of Health)NIH许可号DK 071662。美国对本发明拥有一定的权利。
发明背景
糖皮质激素受体(GR)为一种类固醇激素受体,其属于核受体超家族(核受体亚族3,属C,成员1)。GR通过染色体5(5q31)上的NR3C1基因编码。GR在许多生理过程中起重要作用,例如调节葡萄糖和脂类代谢、骨发育,以及保持身体盐分平衡。
GR通过与它的配体(例如肾上腺皮质激素)结合发挥其生理作用。GR的激活型具有两个主要的作用机理:靶基因表达的反式激活(transactivation)和反式阻抑(transrepression)。“反式激活”为直接的作用机理,包括GR的同源二聚体化,通过主动转运至核的易位,以及结合至特定DNA效应元件,由此活化基因转录。在反式阻抑中,GR没有直接结合靶DNA,作为代替地,GR通过蛋白质-蛋白质相互作用与其它转录因子例如NF-kB或AP-1连接,由此阻抑所连接转录因子的转录活性,例如,IL-6、IFN-b、ICAM1等基因上的NF-kB转录活性。
GR为治疗抗炎和自身免疫疾病的靶点,例如风湿性关节炎、哮喘、同种异体移植排斥和过敏性皮肤疾病。治疗是基于主要促炎细胞因子上GR的反式阻抑性质,例如TNF-α、IL-8、IL-6和IL-1β。GR也对NF-kB具有反式阻抑性质。NF-kB不是促炎细胞因子,但是是促炎细胞因子的主要调节物,即,它可以诱导许多促炎细胞因子,例如IL-1b、IL-6、IL-8、IFN-b。通常NF-kB的活化在炎症开始时发生。
GR也是治疗白血病尤其是儿童急性淋巴母细胞白血病(ALL)的重要靶点。该治疗基于在白血病细胞中用肾上腺皮质激素样GR激动剂例如地塞米松(DEX)诱导细胞凋亡。
不幸的是,由于GR的不期望的反式激活活性,肾上腺皮质激素样药物可以导致副作用。像这样,肾上腺皮质激素样药物的长期使用可以导致糖尿病、骨质疏松症、皮肤萎缩和生长迟缓。因此,肾上腺皮质激素样抗炎药物研发的一项重要工作是鉴别可以保持或者增加GR反式阻抑活性而仅有最小GR反式激活活性保留的GR配体。这样的GR配体被称作“离解的GR配体”。然而,所有已知鉴别离解的GR配体的尝试已经导致GR配体要么(a)仅保留它非常小部分的反式阻抑活性,要么(b)具有显著的反式激活活性,例如,不希望的副作用。如此这样,所有这些已知的化合物迄今为止没有被用于临床。
发明简述
本发明包括在有益的温血哺乳动物中治疗疾病的一种方法,所述疾病选自关节炎、哮喘、狼疮、同种异体移植排斥、过敏性皮肤疾病、白血病、多发性硬化、炎性肝病、自身免疫性肝炎、炎性肠病、代谢性疾病、动脉粥样硬化、脑水肿、休克、血癌、和肾上腺皮质缺乏,其包括给予治疗有效量的式(I)异唑[4,5-c]吡啶
其中:
X1为-N=和-CR1=;
R1为-H,
C1-C3烷基,
-(CH2)x-N(R1-1)(R1-2)其中x为0、1或2以及其中R1-1和R1-2为相同或不同并且为-H和C1-C3烷基,条件是当R1-1和R1-2都为C2烷基时,该烷基基团可以被环化以形成选自吡咯烷基、哌啶基、哌嗪基(piperizinyl)和N-甲基哌嗪基的杂环;
-O-R1-3,其中R1-3为-H、C1-C3烷基和苯基;
-(CH)yO-(CH2)y-O-R1-4,其中y为相同或不同并且是1或者2和其中R1-4是-H、C1-C3烷基、-CO-R1-5,其中R1-5为C1-C4和苯基;
R2为-H、C1-C3烷基和C3环烷基;
R3为-H、C1-C3烷基、-F、-Cl、-Br和-I;
R4为-H和-O-R4-1,条件是当R4为-O-R4-1时,X1为-R1=并且R1和R4共同形成亚甲二氧代基团;
R5为-H和-O-R5-1,其中R5-1为-H、C1-C3烷基和苯基,条件是R5-1和R1-3不能都是苯基;它们的对映体、非对映体、互变异构体、药学可接受的盐和水合物。
治疗疾病的本方法:被治疗的疾病可以是关节炎、哮喘、狼疮、同种异体移植排斥、过敏性皮肤病和白血病;有益的温血哺乳动物可以是人;有效量可以是从约1到约100mg/kg/天或者从约5到约50mg/kg/天;R2可以是C1烷基;或者R3可以是-H或者-F。
此外,用于治疗疾病本方法的异唑并[4,5-c]吡啶(I)可以是:6-(4-((二甲氨基)甲基)苯基)-5-甲基-3苯基异唑并[4,5-c]吡啶-4(5H)-酮;6-(4-((二甲氨基)甲基)苯基)-3-(4-氟苯基)-5甲基异唑并[4,5-c]吡啶-4(5H)-酮;6-(4-二乙氨基-苯基)-5-甲基-3-苯基-5H-异唑并[4,5c]吡啶-4-酮;6-(4-甲氧基苯基)-5-甲基-3-苯基异唑并[4,5-c]吡啶-4(5H)-酮;6-(2,4-二甲氧基苯基)-5-甲基-3-苯基异唑并[4,5-c]吡啶-4(5H)-酮;6-(苯并[d][1,3]间二氧杂环戊烯-5-基(dioxol-5-yl))-5-甲基-3-苯基异唑并[4,5c]吡啶-4(5H)-酮;6-(4-((2-羟乙氧基)甲基)苯基)-5-甲基-3苯基异唑并[4,5-c]吡啶-4(5H)-酮;6-(4-((2-甲氧乙氧基)甲基)苯基)-5-甲基-3苯基异唑并[4,5-c]吡啶-4(5H)-酮;6-(4-((2-异丙氧乙氧基)甲基)苯基)-5-甲基-3苯基异唑并[4,5-c]吡啶-4(5H)-酮;5-甲基-6-(4-苯氧苯基)-3-苯基-异唑并[4,5-c]吡啶-4(5H)-酮;5-甲基-6-(4-((4-甲基哌嗪-1-基)甲基)苯基)-3苯基异唑并[4,5-c]吡啶-4(5H)-酮;5-甲基-3-苯基-6-(吡啶-4-基)异唑并[4,5-c]吡啶-4(5H)-酮;或者5-甲基-3-苯基-6-对甲苯基异唑并[4,5-c]吡啶-4(5H)-酮。在一个实施方案中,所述异唑并[4,5-c]吡啶(I)可以是6-(4-((二甲氨基)甲基)苯基)-5-甲基-3苯基异唑并[4,5-c]吡啶4(5H)-酮。
本发明也包括在细胞中维持或者提高糖皮质激素受体反式阻抑活性同时仅有最小的糖皮质激素受体反式激活活性的方法,包括向需要修饰的细胞给予有用量的如本文所描述的式(I)的异唑并[4,5-c]吡啶;它们的对映体、非对映体、互变异构体、药学可接受的盐和水合物。
此外,在用于在细胞中维持或者提高糖皮质激素受体反式阻抑活性同时仅有最小的糖皮质激素受体反式激活活性的本方法中,所述异唑并[4,5-c]吡啶(I)可以是:6-(4-((二甲氨基)甲基)苯基)-5-甲基-3苯基异唑并[4,5-c]吡啶-4(5H)-酮;6-(4-((二甲氨基)甲基)苯基)-3-(4-氟苯基)-5甲基异唑并[4,5-c]吡啶-4(5H)-酮;6-(4-二乙氨基-苯基)-5-甲基-3-苯基-5H-异唑并[4,5c]吡啶-4-酮;6-(4-甲氧基苯基)-5-甲基3-苯基异唑并[4,5-c]吡啶-4(5H)-酮;6-(2,4-二甲氧基苯基)-5-甲基-3-苯基异唑并[4,5-c]吡啶-4(5H)-酮;6-(苯并[d][1,3]二氧杂环戊烯基-5-基)-5-甲基-3-苯基异唑并[4,5c]吡啶-4(5H)-酮;6-(4-((2-羟乙氧基)甲基)苯基)-5-甲基-苯基异唑并[4,5-c]吡啶-4(5H)-酮;6-(4-((2-甲氧乙氧基)甲基)苯基)-5-甲基3苯基异唑并[4,5-c]吡啶-4(5H)-酮;6-(4-((2-异丙氧乙氧基)甲基)苯基)-5-甲基-3苯基异唑并[4,5-c]吡啶-4(5H)-酮;5-甲基-6-(4-苯氧苯基)-3-苯基-异唑并[4,5-c]吡啶-4(5H)-酮;5-甲基-6-(4-((4-甲基哌嗪-1-基)甲基)苯基)-3苯基异唑并[4,5-c]吡啶-4(5H)-酮;5-甲基-3-苯基-6-(吡啶-4-基)异唑并[4,5-c]吡啶-4(5H)-酮;或者5-甲基-3-苯基-6-对甲苯基异唑并[4,5-c]吡啶-4(5H)-酮。在一个实施方案中,所述异唑并[4,5-c]吡啶(I)可以是6-(4-((二甲氨基)甲基)苯基)-5-甲基-3苯基异唑并[4,5-c]吡啶-4(5H)-酮。在另一个实施方案中,R2可以是C1烷基或者R3可以是-H或者-F。
附图简述
在前的简述,以及下列发明详述,当与附图结合起来读时将被更好的理解。为了解释该发明,在附图中表示有目前优选的特定实施方案(一个或多个)。然而可以理解的是,本发明不限于所示的精确的排列和手段。
图1表示结合在GRLBD中的DAC晶体结构(3BQD.pdb)。
图2表示DAC的2-维化学结构。
图3表示结合在GR LBD中的通过分子对接程序GOLD所预测的化合物#53的结构。
图4表示化合物#53的2-维化学结构。
图5为表示化合物#53在AD293细胞中对MMTV的反式激活活性的条形图。
图6为表示化合物#53在AD293细胞中对AP1的GR反式阻抑活性的条形图。
图7为表示化合物#53在AD293细胞中对AP1的GR反式阻抑活性的条形图。
图8为表示化合物#53在AD293细胞中对NF-kB的GR反式阻抑活性的条形图。
图9为表示化合物#53对在AD293细胞中AP1的GR反式阻抑剂量响应的条形图。
图10为表示化合物#53对在AD293细胞中NF-kB的GR反式阻抑剂量响应的条形图。
优选实施方案的详述
在进一步地描述主题发明之前,应该理解本发明不限于以下描述发明的特定实施方案,因为可以变化特定实施方案并且其仍然落入所附权利要求的范围之内。还应理解所使用的术语是为了描述特定实施方案的目的,并不是为了进行限制。相反,本发明范围将由所附权利要求所确定。
当某范围的值被提供时,应该理解在该范围的上限值和下限值之间,每个插入值都(达到下限值单位的十分之一除非上下文另有清楚描述,以及在说明的范围中任意其它说明或者插入值)被包括入本发明中。这些更小范围的上限值和下限值可以被独立地包括在更小的范围内,并且也被包括入发明中,接受在所说明的范围任意特定排除的限值。在所说明的范围包括一个或者两个限值的情况下,排除了一个或者两个这些包括的限值也被包括在发明中。
在本申请中提及的所有参考、专利、专利公开、文章、和数据库在此处以它们全部通过引用并入,如同它们各自在此特定地和独立地通过引用并入。这样的专利、专利公开、文章、和数据库被并入是为了描述和公开在那些专利、专利公开、文章和数据库中所描述的本发明的内容组成部分,其组成部分可以被用于同目前所描述的发明相联系。下面提供的信息不被承认为是本发明的现有技术,而是单独提供以帮助阅读者理解。
本发明一个或者更多实施方案的详细内容在附图和以下描述中说明。本发明的其他特征、实施方案和优点从说明书和附图中以及从权利要求中可以显而易见地得到。可以通过参考以下详细描述的特定实施方案和后面所包括的实施例更容易地理解本发明优选的实施方案。
为了清楚公开,并不是为了进行限制,发明的详述内容被分为以下一些小节。
除非另有定义,所有本文描述的技术和科学术语具有本发明所属领域技术人员通常理解的含义。一般而言,本文使用的命名法和以下描述的在细胞培养、分子遗传学、有机化学和核酸化学中的实验室操作是本领域的公知常识并被普遍应用。虽然与本文描述的那些方法、装置和材料类似或者等同的任意方法、装置和材料可以在发明的实践或实验中被使用,但现在对优选的方法、装置和材料进行描述。
在该说明书和所附权利要求中,单数形式″a,″″an″和″the″包括复数参考除非上下文另有清楚说明。
当术语″Cx-Cy烷基″被使用时,它意指由Cx开始包括并穿过Cy的烷基基团,并在所述存在中包括其同分异构体但不包括环形式。因此,″C1-C3烷基″包括甲基、乙基、正丙基和异丙基。
一个或者更多申请人最近已经测定GR结合至deacyclortivazol(DAC)(一种有效糖皮质激素)的晶体结构。Suino-Powell,K.,等,Molecular and CellularBiology,第28卷,No.6,1915-1923(2008年3月)。GR-DAC结构显示出扩大的GR DAC-结合口袋,其两倍于GRDEX-结合口袋的大小(图1)。图2表示DAC的2-维化学结构。
通过筛选将适合扩大的结合口袋的分子的公共化学数据库,并通过分子对接研究,发明人鉴定出一类与GR的结合能力同DAC与GR的结合能力类似的化合物。这一类别化合物包括式(I)的异唑并[4,5-c]吡啶
其中:
X1为-N=和-CR1=;
R1为-H,
C1-C3烷基,
-(CH2)x-N(R1-1)(R1-2),其中x为0、1或2以及其中R1-1和R1-2为相同或不同并且为-H和C1-C3烷基,条件是当R1-1和R1-2都为C2烷基时,该烷基基团可以被环化以形成选自吡咯烷基、哌啶基、哌嗪基和N-甲基哌嗪基的杂环;
-O-R1-3,其中R1-3为-H、C1-C3烷基和苯基;
-(CH)y-O-(CH2)y-O-R1-4,其中y为相同或不同并且是1或者2和其中R1-4是-H、C1-C3烷基、-CO-R1-5,其中R1-5为C1-C4和苯基;
R2为-H、C1-C3烷基和C3环烷基;
R3为-H、C1-C3烷基、-F、-Cl、-Br和-I;
R4为-H和-O-R4-1,条件是当R4为-O-R4-1时,X1为-R1=并且R1和R4共同形成亚甲二氧代基团;
R5为-H和-O-R5-1,其中R5-1为-H、C1-C3烷基和苯基,条件是R5-1和R1-3不能都是苯基;它们的对映体、非对映体、互变异构体、药学可接受的盐和水合物。
通过GR反式阻抑和GR反式激活研究,发明人发现这一类式I化合物具有离解的GR配体性质。因此,本发明包括在细胞中维持或者提高糖皮质激素受体反式阻抑活性同时仅有最小的糖皮质激素受体反式激活活性的方法,其包括向需要修饰的细胞给予有用量的式I化合物,
其中:
X1为-N=和-CR1=;
R1为-H,
C1-C3烷基,
-(CH2)x-N(R1-1)(R1-2),其中x为0、1或2以及其中R1-1和R1-2为相同或不同并且为-H和C1-C3烷基,条件是当R1-1和R1-2都为C2烷基时,所述烷基基团可以被环化以形成选自吡咯烷基、哌啶基、哌嗪基和N-甲基哌嗪基的杂环;
-O-R1-3,其中R1-3为-H、C1-C3烷基和苯基;
-(CH)y-O-(CH2)y-O-R1-4,其中y为相同或不同并且是1或者2和其中R1-4是-H、C1-C3烷基、-CO-R1-5,其中R1-5为C1-C4和苯基;
R2为-H、C1-C3烷基和C3环烷基;
R3为-H、C1-C3烷基、-F、-Cl、-Br和-I;
R4为-H和-O-R4-1,条件是当R4为-O-R4-1时,X1为-R1=并且R1和R4共同形成亚甲二氧代基团;
R5为-H和-O-R5-1,其中R5-1为-H、C1-C3烷基和苯基,条件是R5-1和R1-3不能都是苯基;其对映体、非对映体、互变异构体、药学可接受的盐和水合物。在一个实施方案中,所给予的化合物为6-(4-((二甲氨基)甲基)苯基)-5-甲基-3-苯基异唑并[4,5-c]吡啶-4(5H)-酮[该化合物被称为″化合物#53]。式(I)的异唑并吡啶酮对本领域技术人员是已知的或者可以通过已知方式由本领域技术人员从本领技术人员已知化合物中轻易制备得到。实施例5-17的异唑并吡啶酮(I)对本领域技术人员来说是已知的。
对于″有用量″本文意指式(I)的异唑并[4,5-c]吡啶给予至细胞产生效果的量。例如,有用量的式(I)的异唑并[4,5-c]吡啶为式(I)的异唑并[4,5-c]吡啶在细胞中维持或提高糖皮质激素受体反式阻抑活性同时仅有最小糖皮质激素受体反式激活活性的量。以在细胞中维持或者提高糖皮质激素受体反式阻活性同时仅有最小糖皮质激素受体反式激活活性的量给予所选式I化合物,其中用量是从约1μM到约50μM,或者从约5μM到约10μM。
如本文所使用的,术语″维持(retaining)或提高(increasing)糖皮质激素受体反式阻抑活性″或者″维持(retains)或提高(increases)糖皮质激素受体反式阻抑活性″意指与通过标准GR配体例如地塞米松的给药引起的细胞中糖皮质激素受体反式阻抑活性相比在细胞中糖皮质激素受体反式阻抑活性相同或者增加。
如本文所使用的,术语″最小糖皮质激素受体反式激活活性″意指糖皮质激素受体反式激活活性,其小于或等于向细胞给予地塞米松引起的糖皮质激素受体反式激活活性的15%。最小糖皮质激素受体反式激活活性也可以是糖皮质激素受体反式激活活性,其为向细胞给予地塞米松引起的糖皮质激素受体反式激活活性的20%、30%、40%、50%、60、70%、80%、或者90%。
图3显示了通过分子对接程序GOLD所预测的结合在GR配体结合区域(LBD)中的化合物#53的结构。图4显示了化合物#53的2维化学结构(实施例5也显示了化合物#53的化学结构)。发明人的研究表明化合物#53为显著的离解GR配体,与目前使用的GR配体相比有最小GR反式激活活性(图5)和更强GR反式阻抑活性(图6-8)。此外,化合物#53对AP1和NF-kB作用的剂量响应抑制实验表明通过提高化合物#53浓度,加倍抑制(fold repression)增加。这些研究表明化合物#53阻断AP-1和NF-kB对AD293细胞中报道基因的活性至几乎为零。例如,在50μM下,对AP1的加倍抑制(fold repression)约为2000和NF-kB的加倍抑制(fold repression)约为1000(分别图9和10)。也就是说,化合物#53具有显著的GR反式阻抑性质。
其它式I化合物也预期具有出色的离解GR配体性质。这些其它化合物的化学结构显示在实施例6-17中。预期具有出色的离解GR配体性质的另外的其它化合物被描述在表1、Hintermann,S.等,Bioorganic & Medicinal ChemistryLetters,17(2007)193-196;和美国专利号:4,086,421;4,049,813;和7,087,756中;它们所有的化合物通过参考被引入到本申请中。
本发明也包括一种用于治疗对象的关节炎、哮喘、狼疮、同种异体移植排斥、过敏性皮肤疾病、白血病、多发性硬化、炎性肝病、自身免疫性肝炎、炎性肠病、代谢性疾病、动脉粥样硬化、脑水肿、休克、血癌、或者肾上腺皮质缺乏的方法,其通过给予具有关节炎、哮喘、狼疮、同种异体移植排斥、过敏性皮肤疾病、白血病、多发性硬化、炎性肝病、自身免疫性肝炎、炎性肠病、代谢性疾病、动脉粥样硬化、脑水肿、休克、血癌、或者肾上腺皮质缺乏的对象治疗有效量的式I化合物,
其中:
X1为-N=和-CR1=;
R1为-H,
C1-C3烷基,
-(CH2)x-N(R1-1)(R1-2),其中x为0、1或2以及其中R1-1和R1-2为相同或不同并且为-H和C1-C3烷基,条件是当R1-1和R1-2都为C2烷基时,该烷基基团可以被环化以形成选自吡咯烷基、哌啶基、哌嗪基和N-甲基哌嗪基的杂环;
-O-R1-3,其中R1-3为-H、C1-C3烷基和苯基;
-(CH)y-O-(CH2)y-O-R1-4,其中y为相同或不同并且是1或者2和其中R1-4是-H、C1-C3烷基、-CO-R1-5,其中R1-5为C1-C4和苯基;
R2为-H、C1-C3烷基和C3环烷基;
R3为-H、C1-C3烷基、-F、-Cl、-Br和-I;
R4为-H和-O-R4-1,条件是当R4为-O-R4-1时,X1为-R1=并且R1和R4共同形成亚甲二氧代基团;
R5为-H和-O-R5-1,其中R5-1为-H、C1-C3烷基和苯基,条件是R5-1和R1-3不能都是苯基;其对映体、非对映体、互变异构体、药学可接受的盐和水合物。在一个实施方案中,所给予的化合物为化合物#53。
如本文所使用的术语″治疗″意指对对象给予药物或者执行医学操作以减轻或者减少疾病/病情的临床症状或者医学上测量得到的参数到某种程度。但它可能并不是要求必须治愈疾病或者病情。例如,如果个体具有高血压,治疗包括降低血压但并不要求降低至正常值。
对于本文的″治疗有效量″意指式(I)的异唑并[4,5-c]吡啶对其给药的对象产生效果的量。准确剂量将取决于治疗的目的,并且本领域技术人员使用已知技术可确定(例如,参见Lieberman,Pharmaceutical Dosage Forms(卷1-3,1992);Lloyd,The Art,Science and Technology of PharmaceuticalCompounding(1999);和Pickar,Dosage Calculations(1999))。例如,治疗有效量可以意指足以预防或者减少至少约25%,至少约50%,或者至少约90%的病理特征的临床上显著变化的量,例如为,提高的血压、发热、或者白细胞计数,其可以通过注意它的存在和活性观察得到。同本发明相关的,该术语也可以意指足以预防、改善或者逆转一种或者多种同炎症或者自身免疫疾病相关症状的量。
本发明的治疗方法是肠胃外、经口、局部(经皮)或者直肠给药。肠胃外给药包括静脉内(IV)、肌内、真皮内、腹膜内(IP)或者皮下(SQ)。肠胃外给药需要缓冲至对所选式I化合物合适的pH值的无菌等渗水溶液或者用于持续释放给药的混悬液或者乳状液。
式I化合物可以通过例如片剂、胶囊、可分散颗粒或者锭剂的固体剂型和通过例如溶液、糖浆、混悬液和乳状液的液体剂型口服给药。这些剂型将包括用于速释的药物剂型以及12或者24小时给药的缓释药物剂型。
式I化合物可以通过透皮贴剂的方式给药,其特别适于那些不能吞咽且不希望肠胃外给药的化合物。此外,式I化合物可以被配制入栓剂用于直肠给药,其特别适于那些不能吞咽且不希望肠胃外给药的化合物。本领域技术人员已知如何制备式I化合物的用于肠胃外给药的无菌肠胃外制剂、用于口服给药的固体和液体剂型、透皮贴剂和栓剂。式I化合物也可以以适于局部给药的剂型给药,其包括但不限于,乳膏剂、软膏剂、洗剂、溶液剂、混悬液、乳状液和浸渍有所选式I化合物的绷带。本领域技术人员公知如何制备局部药物剂型以给予式I化合物。
所选式I化合物以治疗有效量肠胃外或者口服给药以治疗对象的关节炎、哮喘、狼疮、同种异体移植排斥、过敏性皮肤疾病、白血病、多发性硬化、炎性肝病、自身免疫性肝炎、炎性肠病、代谢性疾病、动脉粥样硬化、脑水肿、休克、血癌、或者肾上腺皮质缺乏,其用量是从约5到约100mg/kg/天。以每日一次到四次注射Ⅳ的方式持续肠胃外给予式I化合物。当使用输注Ⅳ时,其应当根据将要给予混合物的浓度以约60至120ml/hr给药。服用量可以以每天一次或者分为一日两次或者四次剂量口服给药。局部给药地,局部制剂应当具有有效量的从约0.05%至5%的所选式I化合物。
给药的确切剂量和频率取决于所使用的特定式I化合物、将要治疗的特定病情、将要治疗病情的严重程度、特定对象的年龄、体重、一般身体健康状况、对象所使用的其它药物,和/或对象对将要治疗的特定病情的响应,这对本领域技术人员来说是已知的。此外,医师可以通过监测血液标记物以及式I化合物的血液水平来监测治疗的进程,这对本领域技术人员来说是已知的。
将被治疗的对象为温血哺乳动物,包括,人类、耕作动物例如马、羊、牛、美洲驼(lamas)、猪等等,以及宠物例如猫和狗。在一个实施方案中,温血哺乳动物为人类。
现已对本发明进行普遍描述,通过参考以下实施例将更容易理解本发明,所述实施例以具体说明的方式提供,并不打算成为本发明的限制,除非指明。
实施例
实施例1:在用0.5ng GR转染的AD293细胞中对MMTV的GR反式激活。AD293细胞被0.5ng GR、100ng pHHLuc报道基因和5ng Renilla对照质粒转染,随后被EtOH(赋形剂对照)、地塞米松(10nM)、化合物#53(5μM)、AL438(1μM)和DMSO(赋形剂对照)所诱导。通过Promega标准手册测量双荧光素酶值。在AD293细胞中的化合物#53对MMTV的反式激活活性被表示在图5中。
实施例2:在用10ng GR转染的AD293细胞中AP1的GR反式阻抑。AD293细胞被10ng GR、100ng AP1-Luc报道基因和5ng Renilla对照质粒转染,随后被EtOH(赋形剂对照)、地塞米松(10nM)、化合物#53(5μM)、AL438(1μM)所诱导。通过Promega标准手册测量双荧光素酶值。在AD293细胞中的化合物#53的对AP1的GR反式阻抑活性被表示在图6中。
实施例3:在用50ng GR转染的AD293细胞中AP1的GR反式阻抑。AD293细胞被50ng GR、100ng AP1-Luc报道基因和5ng Renilla对照质粒转染,随后被PMA+EtOH(赋形剂对照)、PMA+地塞米松(10nM)、PMA+化合物#53(5μM)所诱导。通过Promega标准手册测量双荧光素酶值。在AD293细胞中的化合物#53的对AP1的GR反式阻抑活性被表示在图7中。
实施例4:在用100ng GR转染的AD293细胞中NF-kB的GR反式阻抑。AD293细胞被100ng GR、100ng pNF-kB-Luc报道基因和5ng Renilla对照质粒转染,随后被TNFa+EtOH(赋形剂对照)、TNFa+地塞米松(1μM)、TNFa+化合物#53(5μM)、TNFa+DMSO所诱导。通过Promega标准手册测量双荧光素酶值。在AD293细胞中的化合物#53的对NF-kB的GR反式阻抑活性被表示在图8中。
实施例6:6-(4-((二甲氨基)甲基)苯基)-3-(4-氟苯基)-5-甲基异唑并[4,5-c]吡啶-4(5H)-酮(I)
实施例15:5-甲基-6-(4-((4-甲基哌嗪基-1-基)甲基)苯基)-3-苯基异唑并[4,5-c]吡啶-4(5H)-酮[CAS号:500164-70-5](I)
尽管上述说明书已经就某些优选的实施方案进行描述,并且为了解释说明的目的许多详细内容已经被公开,但对本领域技术人员来说显而易见的是本发明可以接受各种修饰和另外的实施方案,并且本文所描述的特定详细内容可以进行大的变化而不脱离本发明的精神和范围。这样的修饰、等量变化和另外的实施方案也预期落入所附权利要求的范围之内。
Claims (12)
其中:
X1为-N=和-CR1=;
R1为-H,
C1-C3烷基,
-(CH2)x-N(R1-1)(R1-2),其中x为0、1或2以及其中R1-1和R1-2为相同或不同并且为-H和C1-C3烷基,条件是当R1-1和R1-2都为C2烷基时,该烷基基团能够被环化以形成选自吡咯烷基、哌啶基、哌嗪基和N-甲基哌嗪基的杂环;
-O-R1-3,其中R1-3为-H、C1-C3烷基和苯基;
-(CH)y-O-(CH2)y-O-R1-4,其中y为相同或不同并且是1或者2和其中R1-4是-H、C1-C3烷基、-CO-R1-5,其中R1-5为C1-C4和苯基;
R2为-H、C1-C3烷基和C3环烷基;
R3为-H、C1-C3烷基、-F、-Cl、-Br和-I;
R4为-H和-O-R4-1,条件是当R4为-O-R4-1时,X1为-R1=并且R1和R4共同形成亚甲二氧代基团;
R5为-H和-O-R5-1,其中R5-1为-H、C1-C3烷基和苯基,条件是R5-1和R1-3不能都是苯基;其用于制备用于缓解或者减轻有益的温血哺乳动物中关节炎、哮喘、狼疮、同种异体移植排斥、过敏性皮肤疾病、白血病、多发性硬化、炎性肝病、自身免疫性肝炎、炎性肠病、代谢性疾病、动脉粥样硬化、脑水肿、休克、血癌、和肾上腺皮质缺乏的症状的药物。
2.根据权利要求1的方法,其中关节炎、哮喘、狼疮、同种异体移植排斥、过敏性皮肤疾病或者白血病的症状被缓解或者减轻。
3.根据权利要求1的方法,其中所述有用的温血哺乳动物为人。
4.根据权利要求1的方法,其中R2为C1烷基。
5.根据权利要求1的方法,其中R3为-H或者-F。
6-(4-甲氧基苯基)-5-甲基-3-苯基异唑并[4,5-c]吡啶-4(5H)-酮,
5-甲基3-苯基-6-对甲苯基异唑并[4,5-c]吡啶-4(5H)-酮。
8.在细胞中维持或者提高糖皮质激素受体反式阻抑活性同时仅有最小糖皮质激素受体反式激活活性的方法,包括给予需要修饰的细胞有用量的式(I)的异唑并[4,5-c]吡啶,其对映体、非对映体、互变异构体、药学可接受的盐和水合物
其中:
X1为-N=和-CR1=;
R1为-H,
C1-C3烷基,
-(CH2)x-N(R1-1)(R1-2),其中x为0、1或2以及其中R1-1和R1-2为相同或不同并且为-H和C1-C3烷基,条件是当R1-1和R1-2都为C2烷基时,该烷基基团可以被环化以形成选自吡咯烷基、哌啶基、哌嗪基和N-甲基哌嗪基的杂环;
-O-R1-3,其中R1-3为-H、C1-C3烷基和苯基;
-(CH)y-O-(CH2)y-O-R1-4,其中y为相同或不同并且是1或者2和其中R1-4是-H、C1-C3烷基、-CO-R1-5,其中R1-5为C1-C4和苯基;
R2为-H、C1-C3烷基和C3环烷基;
R3为-H、C1-C3烷基、-F、-Cl、-Br和-I;
R4为-H和-O-R4-1,条件是当R4为-O-R4-1时,X1为-R1=并且R1和R4共同形成亚甲二氧代基团;
R5为-H和-O-R5-1,其中R5-1为-H、C1-C3烷基和苯基,条件是R5-1和R1-3不能都是苯基。
6-(2,4-二甲氧基苯基)-5-甲基-3-苯基异唑并[4,5-c]吡啶-4(5H)-酮,
6-(4-((2-异丙氧乙氧基)甲基)苯基)-5-甲基-3苯基异唑并[4,5-c]吡啶-4(5H)-酮,
5-甲基-6-(4-((4-甲基哌嗪-1-基)甲基)苯基)-3苯基异唑并[4,5-c]吡啶-4(5H)-酮,
11.根据权利要求8的方法,其中R2为C1烷基。
12.根据权利要求8的方法,其中R3为-H或者-F。
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Families Citing this family (24)
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KR101897881B1 (ko) | 2008-01-04 | 2018-09-12 | 인텔리카인, 엘엘씨 | 특정 화학 물질, 조성물 및 방법 |
US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
US8703778B2 (en) | 2008-09-26 | 2014-04-22 | Intellikine Llc | Heterocyclic kinase inhibitors |
JP5789252B2 (ja) | 2009-05-07 | 2015-10-07 | インテリカイン, エルエルシー | 複素環式化合物およびその使用 |
EP2571357B1 (en) | 2010-05-21 | 2016-07-06 | Infinity Pharmaceuticals, Inc. | Chemical compounds, compositions and methods for kinase modulation |
WO2012064973A2 (en) | 2010-11-10 | 2012-05-18 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US8809349B2 (en) | 2011-01-10 | 2014-08-19 | Infinity Pharmaceuticals, Inc. | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
JP6027611B2 (ja) | 2011-07-19 | 2016-11-16 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | 複素環式化合物及びその使用 |
CN103930422A (zh) | 2011-07-19 | 2014-07-16 | 无限药品股份有限公司 | 杂环化合物及其用途 |
AU2012302197B2 (en) | 2011-08-29 | 2016-01-07 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
US9481667B2 (en) | 2013-03-15 | 2016-11-01 | Infinity Pharmaceuticals, Inc. | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
AU2014324961A1 (en) * | 2013-09-25 | 2016-04-14 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Highly potent glucocorticoids |
US9751888B2 (en) | 2013-10-04 | 2017-09-05 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
JP6466924B2 (ja) | 2013-10-04 | 2019-02-06 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | 複素環式化合物及びその使用 |
DK3119397T3 (da) | 2014-03-19 | 2022-03-28 | Infinity Pharmaceuticals Inc | Heterocykliske forbindelser til anvendelse i behandling af PI3K-gamma-medierede lidelser |
WO2015160975A2 (en) | 2014-04-16 | 2015-10-22 | Infinity Pharmaceuticals, Inc. | Combination therapies |
WO2016054491A1 (en) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
KR20180058741A (ko) | 2015-09-14 | 2018-06-01 | 인피니티 파마슈티칼스, 인코포레이티드 | 이소퀴놀리논의 고체형, 그의 제조 방법, 이를 포함하는 조성물 및 이를 사용하는 방법 |
WO2017161116A1 (en) | 2016-03-17 | 2017-09-21 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors |
US10919914B2 (en) | 2016-06-08 | 2021-02-16 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
CA3028718A1 (en) | 2016-06-24 | 2017-12-28 | Infinity Pharmaceuticals, Inc. | Combination therapies |
CN110382033B (zh) | 2016-10-14 | 2022-04-15 | 范安德尔研究所 | 用于设计高效力糖皮质激素的结构与机制 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1408042A1 (en) * | 2001-06-14 | 2004-04-14 | Banyu Pharmaceutical Co., Ltd. | Novel isoxazolopyridone derivatives and use thereof |
Family Cites Families (2)
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US4049813A (en) * | 1976-07-15 | 1977-09-20 | Sandoz, Inc. | Substituted isoxazolo pyridinones |
GB0119911D0 (en) * | 2001-08-15 | 2001-10-10 | Novartis Ag | Organic Compounds |
-
2010
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- 2010-01-13 CA CA2749585A patent/CA2749585A1/en not_active Abandoned
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EP1408042A1 (en) * | 2001-06-14 | 2004-04-14 | Banyu Pharmaceutical Co., Ltd. | Novel isoxazolopyridone derivatives and use thereof |
Non-Patent Citations (1)
Title |
---|
HINTERMANN ET AL: "Identification of a series of highly potent activators of the Nurr1 signaling pathway", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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CA2749585A1 (en) | 2010-07-22 |
US20110251211A9 (en) | 2011-10-13 |
US20100179167A1 (en) | 2010-07-15 |
US8173670B2 (en) | 2012-05-08 |
EP2376079B1 (en) | 2016-08-10 |
CN102361640B (zh) | 2016-10-19 |
WO2010083218A1 (en) | 2010-07-22 |
EP2376079A1 (en) | 2011-10-19 |
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