CN101421277A - 咪唑并化合物 - Google Patents
咪唑并化合物 Download PDFInfo
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- CN101421277A CN101421277A CNA2007800129595A CN200780012959A CN101421277A CN 101421277 A CN101421277 A CN 101421277A CN A2007800129595 A CNA2007800129595 A CN A2007800129595A CN 200780012959 A CN200780012959 A CN 200780012959A CN 101421277 A CN101421277 A CN 101421277A
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- Prior art keywords
- alkyl
- compound
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- formula
- acid
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 15
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Abstract
本申请涉及通式(I)的新颖杂环化合物及其盐、较好其医药上可接受盐,其中R、R1、R2、Q、m和n有本说明书中详细解释的含义,且*表示不对称碳原子,其制备方法,和这些化合物作为医药剂、尤其作为芳香酶抑制剂的用途。
Description
发明领域
本发明涉及新颖杂环化合物、涉及该化合物的制备方法、涉及含有该化合物的医药产品、和涉及其作为医药有效成分尤其作为芳香酶抑制剂的用途。
发明详细描述
本发明首先涉及通式(I)化合物
式中
R是氘、卤素或氢;
R1是芳基C0-C4烷基或杂环基C0-C4烷基,这些基团可以有1~4个以下基团取代:C1-C8烷氧基、C1-C8烷氧羰基、C1-C8烷基、C0-C8烷羰基、C1-C8烷磺酰基、任选地有取代芳基、芳基C0-C4烷氧羰基、氰基、卤素、任选地有取代杂环基、羟基、硝基、氧化物、氧代基、三C1-C4烷基甲硅烷基、三氟甲氧基或三氟甲基;
R2是a)氘、卤素、羟基、氰基或氢;或
b)C2-C8烯基、C2-C8炔基、C1-C8烷氧基、C1-C4烷氧羰基C1-C4烷基、C1-C8烷基、C0-C4烷羰基、芳基C0-C4烷基、羧C1-C4烷基、C3-C8环烷基、或杂环基C0-C4烷基,这些基团可以有1~4个下列基团取代:C1-C8烷氧基、C1-C8烷氧羰基、C1-C8烷基、C0-C8烷羰基、C1-C8烷磺酰基、任选地有取代芳基、芳基C0-C4烷氧羰基、氰基、卤素、任选地有取代杂环基、羟基、硝基、氧化物、氧代基、三C1-C4烷基甲硅烷基、三氟甲氧基或三氟甲基;
Q是氧或硫;
m是数字0、1或2;
n是数字0、1或2;且
*表示不对称碳原子;且
其中
m和n不同时为0;
及其盐、较好其医药上可接受盐。
式(I)化合物要理解为一种在标记“*”的指定不对称碳原子周围有特定构型的化合物。如果使用了导致外消旋化合物的合成方法,则外消旋物拆析是按照惯常方法例如手性HPLC柱进行的。本发明中所述的式(I)化合物显示出显著的芳香酶(aromatase)抑制活性。以上提到的活性可以容易地和像以下所述那样使用一种商品Cyp 19酶抑制试剂盒、较好如以下所述的Cyp 19/甲氧基-4-三氟甲基香豆素(MFC)高产率抑制试剂盒(Becton Dickinson Biosciences公司,美国加利福尼亚州圣何塞)确定。在以上提到的抑制试剂盒中,式(I)化合物显示出比在标“*”的不对称碳原子周围有相反构型的式(I)物质高至少10倍、但较好高20倍、或更好高40倍的抑制活性。更高的抑制活性对应于更低的IC50值。
芳基这一术语代表一种符合休克尔规则、一般包含6~14、较好6~10个碳原子的单环、双环或三环芳香族烃,而且是诸如苯基、萘基,例如1-或2-萘基或蒽基。有6~10个碳原子的芳基、尤其苯基或者1-或2-萘基是较好的。所述基团可以是无取代的或有一次或多次例如一次或两次取代的,在这种情况下,该取代基可以在任何位置,例如在苯基的邻、间或对位或者在1-或2-萘基的3或4位,而且也可以有多个相同或不同的取代基存在。芳基或者较好的苯基或萘基上的取代基的实例是:C1-C8烷氧基、C1-C8烷氧羰基、C1-C8烷基、C0-C8烷羰基、C1-C8烷磺酰基、任选地有取代的芳基、芳基C0-C4烷氧羰基、氰基、卤素、任选地有取代的杂环基、羟基、硝基、三C1-C4烷基甲硅烷基、三氟甲氧基或三氟甲基。
芳基C0-C4烷基是诸如苯基、萘基或苄基。
杂环基这一术语代表一种饱和的、部分饱和的或不饱和的、4~8员特别好5员的单环型环系,代表一种饱和的、部分饱和的或不饱和的、7~12员特别好9~10员的双环型环系,也代表一种部分饱和的或不饱和的、9~12员的三环型、并在至少一个环中包含N、O或S原子的环系,在一个环中存在另外的N、O或S原子也是可能的。所述基团可以是无取代的或者有一次或多次例如一次或2次取代,而且也可以有多个相同或不同取代基存在。杂环基上取代基的实例是:C1-C8烷氧基、C1-C8烷氧羰基、C1-C8烷基、C0-C8烷羰基、C1-C8烷磺酰基、任选地有取代的芳基、芳基C0-C4烷氧羰基、氰基、卤素、任选地有取代的杂环基、羟基、硝基、氧化物、氧代基、三C1-C4烷基甲硅烷基、三氟甲氧基或三氟甲基。
饱和杂环基C0-C4烷基是,例如,氮杂环庚基、氮杂环丁基、氮丙啶基、3,4-二羟基吡咯烷基、2,6-二甲基吗啉基、3,5-二甲基吗啉基、二噁烷基、[1,4]二氧杂环庚基、二氧戊环基、4,4-二氧代噻吗啉基、二噻烷基、二硫戊环基、2-羟甲基吡咯烷基、3-羟基吡咯烷基、4-甲基哌嗪基、1-甲基哌啶基、1-甲基吡咯烷基、吗啉基、氧硫杂环己基、氧杂环庚基、2-氧代氮杂环庚基、2-氧代咪唑烷基、2-氧代噁唑烷基、2-氧代哌啶基、4-氧代哌啶基、2-氧代吡咯烷基、2-氧代四氢嘧啶基、4-氧代噻吗啉基、哌嗪基、哌啶基、吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢噻喃基、thiepanyl或噻吗啉基。
部分饱和的双环型杂环基C0-C4烷基是,例如,3,4-二氢-2H-苯并[1,4]噁嗪基、4,5,6,7-四氢苯并呋喃基或4,5,6,7-四氢苯并噻唑基。
不饱和双环型杂环基C0-C4烷基是,例如,苯并呋喃基、苯并咪唑基、苯并[d]异噻唑基、苯并[d]异噁唑基、苯并[b]噻吩基、喹啉基、咪唑并[1,5-a]吡啶基、吲唑基、吲哚基、或异喹啉基。
不饱和单环型杂环基C0-C4烷基是,例如,咪唑基、噁唑基、吡啶基、吡咯基、四唑基、噻唑基、或噻吩基。
C2-C8烯基是,例如,乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、仲丁烯基、叔丁烯基、或戊烯基、己烯基或庚烯基。
C2-C8炔基是,例如,乙炔基、丙炔基、丁炔基、或戊炔基、己炔基或庚炔基。
C1-C8烷氧基是,例如,C1-C5烷氧基如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基或戊氧基,但也可以是已氧基或庚氧基。
C1-C8烷氧羰基较好是C1-C4烷氧羰基,例如甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基、异丁氧羰基、仲丁氧羰基或叔丁氧羰基。
C1-C4烷氧羰基C1-C4烷基是,例如,甲氧羰基甲基或乙氧羰基甲基、2-甲氧羰基乙基或2-乙氧羰基乙基、3-甲氧羰基丙基或3-乙氧羰基丙基或4-乙氧羰基丁基。
C1-C8烷基可以是直链或支化的和/或桥联的,且是例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或戊基、己基或庚基。
C0-C8烷羰基是,例如,甲酰基、乙酰基、丙酰基、丙羰基、异丙羰基、丁羰基、异丁羰基、仲丁羰基或叔丁羰基。
羧C1-C4烷基是,例如,羧甲基、2-羧基乙基、2-或3-羧基丙基、2-羧基-2-甲基丙基、2-羧基-2-乙基丁基、或4-羧基丁基、尤其羧甲基。
C3-C8环烷基较好是3员、5员或6员环烷基,例如环丙基、环戊基、环己基。
卤素是,例如,氟、氯、溴或碘。
以下提到的化合物基团不要视为关闭的;相反,这些化合物基团的一部分可以由另一种基团或由以上给出的定义以一种有意义的方式置换或省略,例如一般由更具体的定义置换。所提到的定义在一般化学原理范围内应用,例如在通常原子价范围内应用。
R较好是氘或氢。
R1较好是芳基、特别好地是有一取代、二取代或三取代的苯基,或杂环基、特别好地是任选地有一取代、二取代或三取代的苯并呋喃基、苯并[b]噻吩基、苯并咪唑基、苯并[d]异噻唑基、苯并[d]异噁唑基、苯并[b]噻吩基、咪唑基、吲唑基、吲哚基、噁唑基、吡啶基、吡咯基、噻唑基或噻吩基。
R2较好是C1-C8烷氧基、羟基、C1-C8烷基、芳基C0-C4烷基、氘、卤素、氰基或氢。
Q较好是氧。
n较好是数字0或1。n特别好地是数字1。
m特别好地是数字1。
芳基或杂芳基的较好取代基是C1-C8烷氧基、C1-C8烷基、C1-C8烷羰基、C1-C8烷磺酰基、任选地有取代的芳基、氰基、卤素、任选地有取代的杂环基、硝基、氧化物、三氟甲基、三氟甲氧基可三甲基甲硅烷基。芳基或杂芳基的非常特别好的取代基是乙酰基、溴、氯、氰基、氟、甲磺酰基、甲氧基、硝基、噁唑基、氧化物、任选地有取代的苯基、任选地有取代的四唑基、任选地有取代的噻唑基、或任选地有取代的噻吩基。
R1同样较好的是一种有一取代、二取代或三取代的不饱和杂环基取代基,其中该取代基较好选自下列组成的一组:C1-C8烷基、C1-C8烷氧基、C1-C8烷氧羰基、C0-C8烷羰基、C1-C8烷磺酰基、任选地有取代的芳基、芳基C0-C4烷氧羰基、氰基、卤素、任选地有取代的杂环基、羟基、硝基、氧化物、氧代基、三C1-C4烷基甲硅烷基、三氟甲氧基和三氟甲基。
有第二个不对称碳原子的化合物可以以光学纯非对映异构体、非对映异构体混合物、非对映异构体外消旋物、非对映异构体外消旋物混合物、或内消旋化合物的形式存在。本发明涵盖所有这些形式。
非对映异构体、非对映异构体外消旋物、或非对映异构体外消旋物混合物的混合物可以用惯常方法例如外消旋物拆析法、柱色谱法、薄层色谱法、HPLC等分级。
“医药上可接受盐”这一表达涵盖与有机酸或无机酸例如盐酸、氢溴酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等的盐。含成盐基团的化合物的盐具体地是酸加成盐、与碱的盐、要不然当适当时若有2个或更多个成盐基团存在则是混合盐或内盐。
式(I)化合物可以以一种类似于本身在文献上公开的制备方法的方式制备:(1H-咪唑-4-基)甲醇转化成(1H-咪唑-4-基甲氧基)乙酸甲酯,随后格利雅加成、随后还原(或反之亦然)和闭环、随后分离成关于标“*”碳原子的对映体。(流程I)。
流程I:
替而代之,式(I)化合物可以以一种类似于本身在文献上公开的制备方法得到,即从羟基苯乙酸衍生物出发,与(1H-咪唑-4-基)甲醇反应,随后还原和随后闭环,随后分离成关于标“*”碳原子的对映体。(流程II)。
流程II
具体制备变种的细节可参阅实施例。
对映体的分离可以用本身已知的方法进行,要么较好在合成的初期阶段通过与一种光学活性酸例如(+)-或(-)-扁桃酸生成盐并以分步结晶法分离非对映体盐,要么较好在相当晚期阶段通过与一种手性辅助成分例如(+)-或(-)-莰基氯衍生化并以色谱法和/或结晶法分离非对映体产物且随后使该键断裂成手性辅助成分。该纯粹的非对映体盐和衍生物可以使用惯常分光镜法以代表一种特别适当方法的单晶X射线分光镜法分析,以确定所存在化合物的绝对构型。
盐主要是式(I)化合物的医药上可接受盐或无毒盐。这样的盐是诸如由含有酸性基团例如羧基或磺基的式(I)化合物生成的,而且是例如其与适当碱的盐,例如从《化学元素周期表》Ia族、Ib族、IIa族和IIb族的金属衍生的无毒金属盐,例如碱金属盐尤其锂盐、钠盐或钾盐,碱土金属盐如镁盐或钙盐,以及锌盐或铵盐,还有与下列有机胺例如无取代或有羟基取代的一烷基胺、二烷基胺或三烷基胺、尤其一低级烷基胺、二低级烷基胺或三低级烷基胺、或与季铵碱生成的盐:例如甲胺、乙胺、二乙胺或三乙胺,一、二或三(2-羟基低级烷基)胺例如乙醇胺、二乙醇胺或三乙醇胺、三(羟甲基)甲胺或2-羟基叔丁胺、N,N-二低级烷基-N-(羟基低级烷基)胺如N,N-二甲基-N-(2-羟基乙基)胺、或N-甲基-D-葡糖胺,或氢氧化季铵如氢氧化四丁铵。含有碱性基团例如氨基的式(I)化合物可以与下列酸生成酸加成盐:适用无机酸,例如氢卤酸如盐酸、氢溴酸、或置换了一个或2个质子的硫酸、置换了一个或多个质子的磷酸、置换了一个或多个质子的正磷酸或偏磷酸或焦磷酸;或有机羧酸、磺酸或膦酸或有N-取代的氨磺酸,例如乙酸、丙酸、羟基乙酸、琥珀酸、马来酸、羟基马来酸、甲基马来酸、富马酸、苹果酸、酒石酸、葡糖酸、葡糖二酸、葡糖醛酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、水杨酸、4-氨基水杨酸、2-苯氧基苯甲酸、2-乙氧基苯甲酸、embonic酸、烟酸、异烟酸,以及氨基酸,例如以上规定的α-氨基酸,还有甲磺酸、乙磺酸、2-羟基乙磺酸、乙-1,2-二磺酸、苯磺酸、4-甲苯磺酸、萘-2-磺酸、2-或3-磷酸甘油酸、葡萄糖-6-磷酸、N-环己基氨磺酸(生成环己烷氨磺酸盐),或其它酸性有机化合物,例如抗坏血酸。含有酸性基团和碱性基团的式(I)化合物也可以生成内盐。
也可以使用医药上不适用的盐进行分离和精制。
式(I)化合物也包括那些有一个或多个原子由其稳定的非放射性同位素置换、例如氢原子由氘原子置换的化合物。
现在所述化合物的药物前体衍生物是其当用于活体内时由于化学过程或生理过程的结果而能释放出原来化合物的衍生物。药物前体诸如当达到某一生理pH时或作为酶促转化的结果可以转化成原来化合物。可能药物前体衍生物的实例包括可供自由利用的羧酸的酯,硫醇类、醇类或苯酚类的S-或O-酰基衍生物,该酰基同以上定义。给予优先的是能在生理介质中转化成原来羧酸的医药上有用酯衍生物,例如低级烷酯、环烷酯、低级烯酯、苄酯、有一取代或二取代低级烷酯如低级ω-(氨基、一烷或二烷胺基、羧基、低级烷羰基)烷酯或如低级α-(烷酰氧基、烷氧羰基、或二烷胺基羰基)烷酯;新戊酰氧甲酯和类似酯惯常用来作为这一类的酯衍生物。
由于游离化合物、药物前体衍生物和盐化合物之间的密切关系,本发明中定义的化合物也包括其药物前体衍生物和盐形式,只要这是可能的和适当的。
天然存在的雌激素17β-雌二醇(E2)、雌酮(E1)和雌三醇(E3)是从胆甾醇衍生的C18类固醇。在与脂蛋白受体结合之后,胆固醇被类固醇原细胞吸收、贮存并移动到类固醇合成部位。类固醇脚手架中A环的芳香化是雌激素生成的最后步骤。这个反应是由P450芳香酶加单氧酶酶复合物(Cyp 19)催化的,该酶复合物存在于平滑内质网中并作为脱甲基酶发挥作用。在三个相继羟基化反应中,雌酮和雌二醇是分别从其专性前体雄烯二酮和睾酮生成的。
女人中雌二醇的主要来源是卵巢的膜细胞和颗粒状细胞和这些细胞的黄体素化衍生物。按照雌激素合成的“双细胞”理论,膜细胞分泌雄激素,后者扩散到要芳香化成雌激素的颗粒状细胞。然而,有证据表明,这两种细胞类型都能生成雄激素和雌激素两者。雌酮和雌三醇主要是在肝中从雌二醇生成的。芳香酶活性也已经在肌肉、脂肪、神经组织和睾丸的间质细胞中检出。性腺外组织中雌激素合成的水平随年龄和体重增长而提高。
在血清中,雌二醇可逆地结合到性激素结合性球蛋白—一种β-球蛋白—上且对清蛋白的亲合性较低;约2~3%是未结合的。雌激素是通过硫酸化作用或葡糖苷酸化作用代谢的,并将共轭物分泌到胆汁或尿中。肠内微生物区系对这些共轭物的水解和随后该雌激素的再吸收导致肠肝循环。
雌激素刺激生长、血液流动、和性器官中的水分保持,而且参与引起乳腺癌和子宫内膜肿瘤。在肝中,雌激素增加脂蛋白受体的表达,从而导致降低低密度脂蛋白胆固醇的血清浓度。雌激素也通过刺激肝中凝血因子的产生而提高凝血潜力。在骨中,破骨细胞和成骨细胞都是雌激素的直接靶子,但总体上将雌激素分类为抗吸收剂。
在乳腺组织中,雌激素刺激小管上皮的生长和分化,诱导小管圆柱状细胞的有丝分裂活性,并刺激结缔组织生长。雌激素刺激乳腺癌细胞生长。在有乳腺癌的绝经后女人中,肿瘤中雌二醇浓度高,是由原位芳香化引起的,尽管有低血清雌二醇浓度存在。
本发明中所述的化合物由于它们能选择性地抑制哺乳动物包括人类中的芳香酶(Cyp 19)这种酶而具有有用的药理学性能。作为结果,雄激素向雌激素的代谢转化受到抑制。因此,该化合物适用于诸如治疗雌激素依赖型疾病,包括尤其绝经后妇女的雌激素依赖型乳腺癌。它们也可用于诸如治疗男子女性型乳房,就是说男子乳腺的发育,因为类固醇的芳香化会受到所述化合物抑制。
这些效果可在使用无细胞系统和有细胞系统的离体试验测试中证实。本发明化合物的芳香酶活性离体抑制可以通过使用一种商品Cyp 19酶抑制试剂盒来证实。Cyp 19/甲氧基-4-三氟甲基香豆素(MFC)高通过量抑制试剂盒(Becton Dickinson Biosciences公司,美国加利福尼亚州圣何塞)是为了以96孔格式进行Cyp 19催化活性的潜在抑制剂筛选设计的。该试剂盒包括呈超粒体形式的重组体人Cyp 19酶、荧光P450基质、NADPH再生系统、反应缓冲剂和终止试剂。MFC这种荧光团基质被Cyp 19超粒体迅速转化成高荧光产物7-羟基-4-三氟甲基香豆素(7-HFC)。按照制造商的说明,该试验在0.2nM~20mM范围内的各种浓度的抑制剂化合物的存在下进行。
抑制曲线是通过使用最小二乘法使一种4参数逻辑函数拟合各样品的原始数据产生的。该函数描述如下:
Y=(d-a)/((1+(x/c)-b)+a)
式中
a=最小数据值
b=斜率
c=IC50
d=最大数据值
x=抑制剂浓度
本发明中所述化合物显示在10-3~10-10mol/L之间的最小浓度时的Cyp 19抑制性能。
CYP 19抑制的实例:
实施例号 | IC50值[nM] |
1 | 4.8 |
1的对映体 | 8346.3 |
本发明中所述化合物的Cyp 19抑制性能也可以用细胞试验证实。NCI-H295R人肾上腺皮质癌细胞系在文献上已有详细表征,而且已被显示能表达类固醇发生所需的大多数关键酶。这些包括Cyp 11A(胆固醇侧链裂解)、Cyp 11B1(类固醇11β-羟基酶)、Cyp 11B2(醛固酮合成醛)、Cyp 17(类固醇17α-羟基酶和/或17,20裂合酶)、Cyp 19(芳香酶)、Cyp 21B2(类固醇21-羟基酶)和3β-HSD(羟基类固醇脱氢酶)。细胞有区域上未分化人胎儿肾上腺细胞的生理学特征,能产生在成人肾上腺皮质中发现的三个表型各异的区域中每一个的类固醇激素。
NCI-H295R细胞(美洲型培养物收集(ATCC),美国马里兰州洛克维尔)是用Dulbecco氏改进Eagle’Ham F-12培养基(DME/F12)培养的,该培养基补充了Ultroser SF血清(Soprachem,Cergy-Saint-Christophe,法国)以及胰岛素、转铁蛋白、亚硒酸盐(I-T-S,Becton Dickinson Biosciences公司,美国新泽西州弗兰克林湖)和抗生素,在75cm2细胞培养烧瓶中在37℃和95%空气/5%CO2加湿气氛下进行。该细胞随后转移到24孔平皿上并在DME/F12培养基的存在下接种,该培养基补充了0.1%牛血清清蛋白代替Ultroser SF血清。实验是通过让该细胞在补充了0.1%牛血清清蛋白和试验化合物的DME/F12培养基中细胞刺激剂的存在或不存在下培养72小时启动的。试验化合物是以0.2nM~20mM的浓度范围添加的。作为细胞刺激剂,使用的是血管紧张素-II(以10或100nM浓度)、钾离子(以16mM浓度)、forskolin(以10μM浓度)或2种剂的组合。细胞中雌酮、雌二醇、二氢表雄烯二酮、醛固酮、皮质酮和/或皮质醇向细胞培养基的分泌可以用市售免疫试验和专用单克隆抗体按照制造商的说明定量评价。一种选择性类固醇的分泌程度用来作为分别在试验化合物的存在或不存在下的酶抑制作用中酶活性的一种量度。化合物的剂量依赖型酶抑制活性反映在以IC50值表征的抑制曲线上。
该抑制曲线是通过使用最小二乘法使一种4参数逻辑函数拟合各样品的原始数据产生的。该函数描述如下:
Y=(d-a)/((1+(x/c)-b)+a)
式中
a=最小数据值
b=斜率
c=IC50
d=最大数据值
x=抑制剂浓度
本发明中所述的化合物显示在10-3~10-10mol/L之间的最低浓度时的Cyp 19抑制性能。
所述化合物的芳香酶抑制效果也可以在有利地使用豚鼠、小鼠、大鼠、猫、狗、或猴等哺乳动物模型的活体试验中得到证实。
芳香酶活性的化合物介入活体抑制可以通过像以下实验方案中所述那样监测血浆类固醇水平变化来测试:对交变负荷的雌性大鼠隔日以0.1mL无菌食盐水中100 IU妊娠母马血清促性腺激素(PMSG,Sigma公司)经皮下注射5次。最后一次注射后24小时,该动物以0.01~10mg/kg范围内的剂量用试验化合物口服治疗。治疗后24小时,对该动物进行末端放血。肝素化的血浆在-20℃贮存直至分析。类固醇(17β-雌二醇、雌酮、雌三醇、黄体酮、睾酮、醛固酮和皮质固酮)的血浆水平是用市售放射性免疫试验试剂盒按照制造商说明测定的。需要一个精制和浓缩步骤才能测定雌性大鼠中的血浆睾酮:将4体积二乙醚添加到各样品中,用轻轻来回颠倒法混合15min,然后以2000rpm离心分离5min。水相用干冰冷冻,将有机相回收、在氮气流下蒸发至干。干燥的萃取物再溶解于试验缓冲剂中。
芳香酶活性的化合物介入活性抑制可以通过监测卵巢雌激素含量而测试如下:对21天大的雌性大鼠经皮下注射10IU妊娠母马血清促性腺激素(PMSG,Sigma公司)。2天后,对相同大鼠经皮下注射30IU人绒膜促性腺激素(hCG,Sigma公司)。hCG治疗后一天,对该大鼠经皮下注射要么丙二醇(0.2mL)要么各种剂量的试验化合物。1小时后,所有大鼠都经皮下注射2.25mg4-雄烯-3,17-二酮/0.1mL油进行治疗。雄烯二酮注射后4小时,将该大鼠宰杀、取出其卵巢、剥离粘附组织、成对贮存于-50℃。为了测定这些卵巢的总雌激素含量,向这些组织中添加1.5mL 0.05M磷酸钾水溶液缓冲剂(pH 7.4)和0.2mL 0.1N NaOH水溶液,然后均化。该均化物用15mL二乙醚萃取—5mL等分样品用对雌酮、雌二醇和雌三醇有100%交叉反应性的抗血清进行放射性免疫试验。结果表达为ng雌激素/对卵巢。
抗肿瘤活性,尤其在雌激素依赖型肿瘤中的抗肿瘤活性,可以用在雌性Sprague-Dawley大鼠中二甲基苯并蒽(DMBA)诱发哺乳动物肿瘤等的活体试验来证实(见Proc.Soc.Exp.Biol.Med.160,296-301,1979)。本发明化合物当日剂量为约1~约20mg/kg(口服)或更低时引起现存肿瘤退缩和抑制新肿瘤出现。
为了在要治疗的患者中达到所希望的效果,本发明的化合物可以经口地或非经肠地例如经静脉内地、经腹膜内地、经肌内地、经直肠地、经皮下地、要不然通过该活性物质局部地直接注射到组织中或肿瘤中给药。患者这一术语涵盖温血物种和哺乳动物,例如人类、灵长类动物、牛、狗、猫、马、绵羊、小鼠、大鼠和猪。该化合物可以作为医药产品给药,也可以掺入能确保该化合物缓释的给药器具中。要给药的物质数量可以在广阔范围内变化,而且代表每一个有效剂量。因要治疗的患者或要治疗的病情和给药方式而异,该有效物质每日的剂量可以在约0.005~50mg/kg体重之间,但较好在约0.05~5mg/kg体重/日之间。
为了经口给药,该化合物可以配制成固体或液体医药剂型,例如胶囊剂、丸剂、片剂、包衣片剂、颗粒剂、散剂、溶液剂、悬浮液剂或乳状液剂。固体医药剂型的剂量可以是一种通常硬明胶胶囊,该胶囊可以填充有效成分和赋形剂例如润滑剂和填料例如乳糖、蔗糖及玉米淀粉。另一种给药形式可以由本发明活性物质压片表示。该压片可以用惯常压片赋形剂例如乳糖、蔗糖、玉米淀粉,并与选自阿拉伯胶、玉米淀粉或明胶的粘结剂,崩解剂例如马铃薯淀粉或交联的聚乙烯基吡咯烷酮(PVPP)和润滑剂例如硬脂酸或硬脂酸镁组合进行。
适用于软明胶胶囊剂的赋形剂的实例是植物油、蜡、脂肪、半固体和液体多醇等。
适用于生产溶液剂和糖浆剂的赋形剂的实例是水、多醇、蔗糖、转化糖、葡萄糖等。
为了经直肠给药,该化合物可以配制成固体或液体医药剂型例如栓剂。适用于栓剂的赋形剂的实例是天然的或硬化的油、蜡、脂肪、半液体或液体多醇等。
为了非经肠给药,该化合物可以配制成有效成分在液体或悬浮液中的注射剂。该制剂通常包含一种生理上可忍受的无菌溶剂,该溶剂可以包含一种有或无表面活剂的油包水型乳状液、及其它医药上可接受赋形剂。可以用于这样的制剂的油是石蜡以及植物源、动物源或合成源的三酸甘油酯,例如花生油、大豆油和矿物油。可注射溶液剂一般包含液体载剂,例如较好水、食盐水、葡萄糖或相关的糖溶液、乙醇和二醇例如丙二醇或聚乙二醇。
该物质可以作为经皮贴剂系统、作为沉积注射剂或植入物给药,只要该配方使有效成分的长期输送成为可能。该活性物质可以压缩成为颗粒或细圆柱体,而且可以作为沉积注射剂或植入物经皮下或经肌肉给药。
该医药产品还可以包含防腐剂、增溶剂、增粘物质、稳定剂、润湿剂、乳化剂、增甜剂、着色剂、芳香化剂、能改变渗透压的盐、缓冲剂、包衣剂、或抗氧化剂。它们也可以包含其它治疗上有价值的物质。
本发明进一步提供式(I)化合物及其医药上可接受盐用于治疗或预防对芳香酶抑制作出反应的疾病或病情的用途,尤其增生性疾病例如乳腺癌或类似软组织内分泌敏感性癌、最好雌激素依赖型病症如男子女性型乳房、乳房和子宫内膜肿瘤、子宫内膜异位和早产。该化合物也可用于治疗或预防激素受体阳性或未知的绝经后妇女中局部晚期或转移的乳腺癌。
式(I)化合物及其医药上可接受盐也可以与一种或多种有抗肿瘤作用的药剂组合给药,例如为诸如依西美坦、托瑞米芬、fulvestrant、他莫昔芬所述的有抗雌激素活性者;例如为诸如帕米膦酸盐、唑来膦酸所述的骨吸收抑制活性者;例如为白消安、替莫唑胺、美法仑、氯氨布西、盐酸氮芥(mechlorethalamine)所述的有烷基化活性者;例如为诸如亚得里亚霉素、柔红霉素、放线菌素D、多柔比星、表柔比星、伊达比星所述的有核苷酸碱基插层活性者;例如为诸如阿糖胞苷、氟达拉滨、克拉屈滨、巯嘌呤、巯鸟嘌呤、卡培他滨所述的有抗代谢活性者;例如为诸如abarelix、比卡鲁胺所述的抗雄激素活性者;例如为诸如尼鲁米特、甲基睾酮所述的有雄激素活性者;例如为诸如醋酸亮丙瑞林、曲普瑞林、戈舍瑞林所述的有促性腺激素释放激素活性者;例如为诸如甲氧基黄体酮所述的有孕激素活性者;例如为诸如吉西他滨所述的有核苷类似物活性者;例如为诸如托普替康、伊立替康所述的有拓扑异构酶I抑制活性者;例如为诸如伊马替尼所述的有激酶抑制活性者;例如为诸如gefitinib、司徒曼布所述的有生长因子抑制活性者;例如为诸如阿法依泊汀、沙格司亭、非格司亭、培格非格司亭、oprelvekin、干扰素α2b所述的有生长激素活性者;例如为诸如pemetrexed、达卡巴嗪、丙卡巴肼、奥沙利铂、门冬酰胺酶、培门冬酶、altetamine、gemtuzumab、长春瑞滨、米托蒽醌、denileukin、利妥希玛、alitretinoin、三氧化砷、bortezomib、维A酸、多西他赛所述的有各种各样抗肿瘤活性者;例如为诸如多拉司琼、帕洛诺司琼、aprepitant、ganisetron、屈大麻酚、odansetron所述的有止吞活性者。
本发明中所述化合物可以使用如下:
-作为呈一种制剂或一种由各单一组分组成的试剂盒的形式的治疗组合,其中包括本文中所述式(I)化合物及其医药上可用盐和至少一种可以要么同时要么顺序给药的、有抗肿瘤活性的药剂。该制剂或试剂盒可以含有使用说明。
剂量可以在广阔区间内变化,而且当然必须适应于每一种个别情况下的个体状况。一般来说,为了经口给药,每位成人(70kg)的日剂量为约0.3mg~约3g、较好约1mg~约1g、例如约10mg,可以分成1~3个分剂量,这些分剂量可以有诸如相等大小,这样的成人经口日剂量可能是适当的,尽管当发现适当时也可以超过所规定的上限;典型地,儿童按照其年龄和体重接受更低的剂量。
实施例
以下实施例说明本发明。温度都以摄氏度表示,压力都以mbar表示。除非另有提示,否则反应在室温下进行。“Rf=xx(A)”这一缩略语系指,例如,在溶剂系统A中实测Rf有数值xx。各溶剂彼此的比例总是以体积分数表述。终端产物和中间体的化学名称是借助于AutoNom2000(自动命名法)程序产生的。
在Hypersil BDSC-18(5μm)上的HPLC梯度;柱:4×125mm:
(I)90%水*/10%乙腈*至0%水*/100%乙腈*,5分钟+2.5分钟(1.5mL/min)
(II)99%水*/1%乙腈*至0%水*/100%乙腈*,10分钟+2分钟(1.5mL/min)
在Synergi4μm POLAR-RP80A上的HPLC梯度;柱4.60×100mm:
(III)90%水*/10%乙腈*至0%水*/100%乙腈*,5分钟+2.5分钟(1.5mL/min)
*含有0.1%三氟乙酸
所使用的缩略语如下:
Rf 在薄层色谱法中一种物质从起始点移动的距离与洗脱剂从起始点移动的距离之比
Rt 在HPLC中一种物质的保留时间(分钟)
m.p.熔点(温度)
实施例1
4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-5-基)苄腈
将1.00mmol甲磺酸1-(4-氰基苯基)-2-(1-三苯甲基-1H-咪唑-4-基甲氧基)乙酯在5mL N,N-二甲基甲酰胺中的溶液与2.50mmol碳酸铯混合、在80℃加热6小时。将反应混合物冷却到室温、用水稀释、用乙酸乙酯萃取(2x)。合并的有机相用硫酸钠干燥、蒸发。用闪急色谱法(SiO260F)从残渣中得到黄色结晶状标题化合物。Rf=0.61(二氯甲烷-甲醇-25%氨水溶液=200:10:1),Rt=3.54(梯度II)。
起始原料制备如下:
a)甲磺酸1-(4-氰基苯基)-2-(1-三苯甲基-1H-咪唑-4-基甲氧基) 乙酯
在0℃将4mmol三乙胺和2.00mmol甲磺酰氯添加到1.00mmol4-[1-羟基-2-(1-三苯甲基-1H-咪唑-4-基甲氧基)乙基]苄腈在10mL二氯甲烷中的溶液中。反应混合物在0℃搅拌1小时,用二氯甲烷稀释,用1N NCl洗涤,用硫酸钠干燥,蒸发。粗标题化合物不进一步精制就用于下一阶段。Rf=0.43(二氯甲烷-甲醇=95:5);Rt=4.46(梯度I)。
b1)4-[1-羟基-2-(1-三苯甲基-1H-咪唑-4-基甲氧基)乙基]苄腈
在0℃将硼氢化钠分批添加到1mmol4-[2-(1-三苯甲基-1H-咪唑-4-基甲氧基)乙酰基]苄腈在12mL乙醇中的溶液中。反应溶液在室温搅拌12小时,然后倾入冰水中并搅拌15分钟。该混合物通过添加冰乙酸调整到pH 5,用叔丁基·甲基醚萃取(2x)。合并的有机相用水和食盐水洗涤、用硫酸钠干燥、蒸发。用闪急色谱法(SiO260F)根据Rf从残渣中鉴定出标题化合物。
c1)4-[2-(1-三苯甲基-1H-咪唑-4-基甲氧基)乙酰基]苄腈
将14mmol 4-碘苄腈[3058-39-7]/20mL四氢呋喃溶液冷却到-30℃,添加14.80mmol氯化异丙基镁(四氢呋喃中2M)。该混合物在-30℃搅拌60min,添加预冷却到-30℃的、10.0mmol N-甲氧基-N-甲基-2-(1-三苯甲基-1H-咪唑-4-基甲氧基)乙酰胺/30mL四氢呋喃溶液。该混合物在-30℃搅拌30min,然后让该反应混合物回升到室温,用饱和氯化铵水溶液终止反应。将各相分离,水相用乙酸乙酯萃取(3x)。合并的有机相用食盐水洗涤、用硫酸镁干燥、蒸发。用闪急色谱法(SiO2 60F)根据Rf从残渣中鉴定出标题化合物。
d1)N-甲氧基-N-甲基-2-(1-三苯甲基-1H-咪唑-4-基甲氧基)乙酰胺
将4.03mmol(1-三苯甲基-1H-咪唑-4-基甲氧基)乙酸和4.44mmolN,O-二甲基羟胺盐酸盐在100mL二氯甲烷中的溶液与20.2mmol三乙胺和4.44mmol丙烷膦酸环酐[68957-94-8](乙酸乙酯中50%)混合。反应混合物在室温搅拌3小时,用二氯甲烷稀释。将各相分离,有机相用1M HCl和食盐水洗涤、用硫酸钠干燥、蒸发。用闪急色谱法(SiO2 60F)从残渣得到淡黄色固体状标题化合物。Rf=0.45(二氯甲烷-甲醇=95:5);Rt=4.11(梯度I)。
e1)(1-三苯甲基-1H-咪唑-4-基甲氧基)乙酸
1.0mmol(1-三苯甲基-1H-咪唑-4-基甲氧基)乙酸乙酯/16mL四氢呋喃与16mL 2N NaOH的混合物在回流下搅拌18小时。将反应混合物冷却并将四氢呋喃蒸出。将20mL 2NHCl添加到残留水溶液中,所得到的悬浮液用叔丁基·甲基醚稀释。将固体滤出、滤饼用水和叔丁基·甲基醚洗涤、干燥。得到黄色固体状标题化合物。Rf=0.02(乙酸乙酯-庚烷=2:1);Rt=3.86(梯度I)。
f)(1-三苯甲基-1H-咪唑-4-基甲氧基)乙酸乙酯
在20℃将58.0mmol氢化钠(石蜡中60%分散液)分批添加到30.0mmol(1-三苯甲基-1H-咪唑-4-基)甲醇[33769-07-2]/300mL N,N-二甲基甲酰胺溶液中。该混合物在20℃搅拌1.5小时。添加50.0mmol溴乙酸乙酯[105-36-2]和6.00mmol碘化钾,该混合物在室温下搅拌16小时。添加进一步58.0mmol氢化钠和50mmol溴乙酸乙酯,该混合物再搅拌16小时。将反应混合物倾入水中、用叔丁基·甲基醚萃取(2x)。合并的有机相用水和食盐水洗涤、用硫酸镁干燥、蒸发。用闪急色谱法(SiO260F)从残渣得到褐色油状标题化合物。Rf=0.20(乙酸乙酯-庚烷=2:1),Rt=4.32(梯度I)。
4-[1-羟基-2-(1-三苯甲基-1H-咪唑-4-基甲氧基)乙基]苄腈的替代合成:
b2)4-[1-羟基-2-(1-三苯甲基-1H-咪唑-4-基甲氧基)乙基]苄腈
将1.5mmol氟化四丁铵(四氢呋喃中1M溶液)添加到1mmol4-[1-(叔丁基二甲基甲硅烷氧基)-2-(1-三苯甲基-1H-咪唑-4-基甲氧基)乙基]苄腈/5mL四氢呋喃溶液中,该溶液在室温搅拌1小时。然后,该反应溶液用水稀释、用叔丁基·甲基醚萃取(2x)。合并的有机相用硫酸钠干燥、蒸发。用闪急色谱法(SiO2 60F)根据Rf从残渣鉴定出标题化合物。
c2)4-[1-(叔丁基二甲基甲硅烷氧基)-2-(1-三苯甲基-1H-咪唑-4- 基甲氧基)乙基]苄腈
在0℃将1.27mmol四氯化钛/1.5mL二氯甲烷溶液添加到2.61mmol三氟甲磺酸三甲基甲硅烷酯/1mL二氯甲烷溶液中。该混合物在室温下搅拌4小时、然后冷却到0℃。添加0.83mmol(叔丁基二甲基甲硅烷氧基)(4-氰基苯基)乙酸1-三苯甲基-1H-咪唑-4-基甲酯和4.17mmol三乙基甲硅烷在2mL二氯甲烷中的溶液,反应混合物在室温下搅拌20小时。将反应混合物倾入冰水中、用乙酸乙酯萃取(2x)。合并的有机相用水和食盐水洗涤、用硫酸钠干燥、蒸发。用闪急色谱法(SiO2 60F)根据Rf从该残渣鉴定出标题化合物。
d2)(叔丁基二甲基甲硅烷氧基)(4-氰基苯基)乙酸1-三苯甲基 -1H-咪唑-4-基甲酯
将5.0mmol三乙胺和1.0mmol丙烷膦酸环酐[68957-94-8](乙酸乙酯中50%)添加到1.0mmol(1-三苯甲基-1H-咪唑-4-基)甲醇[33769-07-2]和1.0mmol(叔丁基二甲基甲硅烷氧基)(4-氰基苯基)乙酸在20mL二氯甲烷中的溶液中。该反应混合物在室温下搅拌3小时、用二氯甲烷稀释。将各相分离,有机相用1M HCl和食盐水洗涤、用硫酸钠干燥、蒸发。用闪急色谱法(SiO2 60F)根据Rf从残渣中鉴定出标题化合物。
e2)(叔丁基二甲基甲硅烷氧基)(4-氰基苯基)乙酸
将1.0mmol(叔丁基二甲基甲硅烷氧基)(4-氰基苯基)乙酸甲酯[435344-67-5]在12mL四氢呋喃、12mL甲醇和12mL水中的混合物与4mmol氢氧化锂混合并在0℃搅拌2小时。将20mL 2N HCl添加到该反应混合物中,用叔丁基·甲基醚萃取(3x)。合并的有机相用水和食盐水相继洗涤、用硫酸钠干燥、过滤和蒸发,根据Rf鉴定出粗标题化合物。该粗标题化合物不进一步精制就用于下一阶段。
b3)4-[1-羟基-2-(1-三苯甲基-1H-咪唑-4-基甲氧基)乙基]苄腈
在氩气下将20.0mmol氢化钠(石蜡中60%分散液)添加到20.0mmol(1-三苯甲基-1H-咪唑-4-基)甲醇[33769-07-02]在120mL无水N,N-二甲基甲酰胺中的溶液中。该混合物在100℃加热1小时、然后冷却到40℃。在35~40℃滴加20.0mmol4-环氧乙烷基苄腈[52695-39-3]在10mL无水N,N-二甲基甲酰胺中的溶液,该反应混合物在40℃搅拌15min。将该反应混合物冷却到室温、倾入冰水中、用乙酸乙酯萃取。合并的有机相用水和食盐水洗涤、用硫酸钠干燥、蒸发。用闪急色谱法(SiO2 60F)从残渣中得到白色固体状标题化合物。Rf=0.29(二氯甲烷-甲醇=95:5);Rt=4.26(梯度I)。用手性制备HPLC将外消旋化合物分级成各对映体以提供标题化合物。将标题化合物分离为对映体,后者洗脱验证。Rt*=13.55min。
*HPLC方法:
柱:250×50mm CHIRALPAKADμm
移动相:CO2/甲醇80:20
流量率:240mL/min
检测:UV 250nm
温度:25℃
压力:150bar
以类似于实施例1中所述的方法制备下列化合物:
2 4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-5-基)-2-氟苄腈
从2-氟-4-碘苄腈[137553-42-5]出发。
3 5-(4-硝基苯基)-5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪
从1-碘-4-硝基苯[636-98-6]出发。
4 5-(4-甲磺酰苯基)-5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪
从1-碘-4-甲磺酰苯[64984-08-3]出发。
5 4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-5-基)-2,6-二氟苄腈
从2,6-二氟-4-碘苄腈[14743-50-3]出发。
6 5-(3,4-二氟苯基)-5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪
从2-(3,4-二氟苯基)环氧乙烷[111991-13-0]出发。Rf=0.31(二氯甲烷-甲醇=95:5);Rt=4.20(梯度II)。
8 4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-5-基)邻苯二甲腈
从4-碘邻苯二甲腈[69518-17-8]出发。
实施例7
1-[4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-5-基)苯基]乙酮
将0.47mmol溴化甲基镁溶液(二乙醚中3M)添加到0.47mmol 4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-5-基)苄腈(实施例1)在5mL无水甲苯中的悬浮液中。将反应混合物加热回流16小时、冷却并与稀碳酸氢钠水溶液混合。该混合物用乙酸乙酯-二氯甲烷(4:1)萃取、合并的有机相用食盐水洗涤、用硫酸钠干燥、蒸发。用闪急色谱法(SiO260F)从残渣中得到淡白色固体状标题化合物。Rf=0.34(二氯甲烷-甲醇=95:5);Rt=3.54(梯度II)。
外消旋化合物用手性制备HPLC分级成各对映体,给出标题化合物。
Claims (9)
1.通式(I)化合物
式中
R是氘、卤素或氢;
R1是芳基C0-C4烷基或杂环基C0-C4烷基,这些基团可以有1~4个以下基团取代:C1-C8烷氧基、C1-C8烷氧羰基、C1-C8烷基、C0-C8烷羰基、C1-C8烷磺酰基、任选地有取代芳基、芳基C0-C4烷氧羰基、氰基、卤素、任选地有取代杂环基、羟基、硝基、氧化物、氧代基、三C1-C4烷基甲硅烷基、三氟甲氧基或三氟甲基;
R2是a)氘、卤素、羟基、氰基或氢;或
b)C2-C8烯基、C2-C8炔基、C1-C8烷氧基、C1-C4烷氧羰基C1-C4烷基、C1-C8烷基、C0-C4烷羰基、芳基C0-C4烷基、羧C1-C4烷基、C3-C8环烷基、或杂环基C0-C4烷基,这些基团可以有1~4个下列基团取代:C1-C8烷氧基、C1-C8烷氧羰基、C1-C8烷基、C0-C8烷羰基、C1-C8烷磺酰基、任选地有取代芳基、芳基C0-C4烷氧羰基、氰基、卤素、任选地有取代杂环基、羟基、硝基、氧化物、氧代基、三C1-C4烷基甲硅烷基、三氟甲氧基或三氟甲基;
Q是氧或硫;
m是数字0、1或2;
n是数字0、1或2;且
*表示不对称碳原子;且
其中
m和n不同时为0;
或其盐、较好其医药上可接受盐,
且该化合物显示出比有关于标“*”不对称碳原子的相反构型的式(I)化合物高至少10倍、但较好20倍、或更好40倍的芳香酶抑制活性。
2.按照权利要求1的化合物,式中R是氘或氢。
3.按照权利要求1或2的化合物,式中R1是任选地有一、二或三取代的苯基或任选地有一、二或三取代的苯并呋喃基、苯并[b]噻吩基、苯并咪唑基、苯并[d]异噻唑基、苯并[d]异噁唑基、苯并[b]噻吩基、咪唑基、吲唑基、噁唑基、吡啶基、吡咯基、噻唑基或噻吩基。
4.按照权利要求1~3中任何一项的化合物,式中R2是C1-C8烷氧基、羟基、C1-C8烷基、芳基-C0-C4烷基、氘、卤素、氰基或氢。
5.按照权利要求1~4中任何一项的化合物,式中Q是氧。
6.按照权利要求1~5中任何一项的通式(I)化合物或其医药上可接受盐用于制药的用途。
7.按照权利要求1~5中任何一项的通式(I)化合物或其医药上可接受盐用于生产人用药物的用途,该药物可用于预防对芳香酶抑制作出反应的疾病或病情、尤其增生型疾病、用于延缓该疾病进展、或用于治疗该疾病。
8.用于预防对芳香酶抑制作出反应的疾病或病情、尤其增生型疾病、用于延缓该疾病进展、或用于治疗该疾病的方法,其中使用了治疗有效量的、按照权利要求1~5中任何一项的通式(I)化合物或其医药上可接受盐。
9.药品,其包含按照权利要求1~5中任何一项的通式(I)化合物或其医药上可接受盐,以及惯常赋形剂。
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WO2005118540A2 (en) * | 2004-05-28 | 2005-12-15 | Speedel Experimenta Ag | Bicyclic, nitrogen-containing heterocycles as aromatase inhibitors |
TW200804378A (en) * | 2005-12-09 | 2008-01-16 | Speedel Experimenta Ag | Organic compounds |
TW200808812A (en) * | 2006-04-12 | 2008-02-16 | Speedel Experimenta Ag | Imidazo compounds |
TW200808813A (en) * | 2006-04-12 | 2008-02-16 | Speedel Experimenta Ag | Imidazo compounds |
AU2010251948A1 (en) | 2009-05-28 | 2011-12-01 | Novartis Ag | Substituted aminobutyric derivatives as neprilysin inhibitors |
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US8877815B2 (en) | 2010-11-16 | 2014-11-04 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as NEP |
US8673974B2 (en) | 2010-11-16 | 2014-03-18 | Novartis Ag | Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors |
AU2012282109B2 (en) | 2011-07-08 | 2016-06-23 | Novartis Ag | Method of treating atherosclerosis in high triglyceride subjects |
UY35144A (es) | 2012-11-20 | 2014-06-30 | Novartis Ag | Miméticos lineales sintéticos de apelina para el tratamiento de insuficiencia cardiaca |
PL2956464T3 (pl) | 2013-02-14 | 2018-08-31 | Novartis Ag | Podstawione pochodne bisfenylowe kwasu butanowofosfonowego jako inhibitory nep (neutralnej endopeptydazy) |
UY35671A (es) | 2013-07-25 | 2015-02-27 | Novartis Ag | Bioconjugados de polipéptidos de apelina sintética |
TW201536814A (zh) | 2013-07-25 | 2015-10-01 | Novartis Ag | 用於治療心臟衰竭之合成環狀多肽 |
EP3172212B1 (en) * | 2014-07-24 | 2018-06-13 | Boehringer Ingelheim International GmbH | Aldosterone synthase inhibitors |
PE20171328A1 (es) | 2015-01-23 | 2017-09-12 | Novartis Ag | Conjugados de acidos grasos y apelina sintetica con mayor vida media |
JOP20190086A1 (ar) | 2016-10-21 | 2019-04-18 | Novartis Ag | مشتقات نافثيريدينون جديدة واستخدامها في معالجة عدم انتظام ضربات القلب |
UY38072A (es) | 2018-02-07 | 2019-10-01 | Novartis Ag | Compuestos derivados de éster butanoico sustituido con bisfenilo como inhibidores de nep, composiciones y combinaciones de los mismos |
UY38485A (es) | 2018-11-27 | 2020-06-30 | Novartis Ag | Compuestos tetrámeros cíclicos como inhibidores de proproteína convertasa subtilisina/kexina tipo 9 (pcsk9), método de tratamiento, uso y su preparación |
CN113166204A (zh) | 2018-11-27 | 2021-07-23 | 诺华股份有限公司 | 作为治疗代谢障碍的蛋白质原转换酶枯草杆菌蛋白酶/kexin 9型(PCSK9)抑制剂的环状肽 |
CN113166101A (zh) | 2018-11-27 | 2021-07-23 | 诺华股份有限公司 | 作为治疗代谢障碍的蛋白质原转换酶枯草杆菌蛋白酶/kexin 9型(PCSK9)抑制剂的环状五聚体化合物 |
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WO2023084449A1 (en) | 2021-11-12 | 2023-05-19 | Novartis Ag | Diaminocyclopentylpyridine derivatives for the treatment of a disease or disorder |
AR127698A1 (es) | 2021-11-23 | 2024-02-21 | Novartis Ag | Derivados de naftiridinona para el tratamiento de una enfermedad o un trastorno |
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JPH0670064B2 (ja) * | 1986-12-08 | 1994-09-07 | 三井石油化学工業株式会社 | 二環性イミダゾ−ル誘導体 |
AU6015796A (en) * | 1995-06-14 | 1997-01-15 | Yamanouchi Pharmaceutical Co., Ltd. | Fused imidazole derivatives and medicinal composition thereof |
JPH0971586A (ja) * | 1995-09-07 | 1997-03-18 | Yamanouchi Pharmaceut Co Ltd | 新規な二環性縮合イミダゾール誘導体 |
CN1422152A (zh) * | 2000-04-12 | 2003-06-04 | 诺瓦提斯公司 | 有机化合物的联合形式 |
BR0313293A (pt) * | 2002-08-07 | 2005-06-14 | Novartis Ag | Compostos orgânicos |
EP2261225A1 (en) * | 2004-05-28 | 2010-12-15 | Novartis AG | Heterocyclic compounds and their use as aldosterone synthase inhibitors |
WO2005118540A2 (en) * | 2004-05-28 | 2005-12-15 | Speedel Experimenta Ag | Bicyclic, nitrogen-containing heterocycles as aromatase inhibitors |
TW200608978A (en) * | 2004-05-28 | 2006-03-16 | Speedel Experimenta Ag | Organic compounds |
AR049711A1 (es) * | 2004-07-09 | 2006-08-30 | Speedel Experimenta Ag | Compuestos heterociclicos condensados como inhibidores de la aldosterona sintasa; composiciones farmaceuticas que los contienen y su uso en la preparacion de un medicamento para el tratamiento o prevencion de enfermedades relacionadas con el hiperaldosterismo y por una liberacion excesiva de cortiso |
TW200804378A (en) * | 2005-12-09 | 2008-01-16 | Speedel Experimenta Ag | Organic compounds |
TW200808812A (en) * | 2006-04-12 | 2008-02-16 | Speedel Experimenta Ag | Imidazo compounds |
TW200808813A (en) * | 2006-04-12 | 2008-02-16 | Speedel Experimenta Ag | Imidazo compounds |
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