CN1968930A - 作为芳化酶抑制剂的双环含氮杂环 - Google Patents
作为芳化酶抑制剂的双环含氮杂环 Download PDFInfo
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- CN1968930A CN1968930A CNA2005800170603A CN200580017060A CN1968930A CN 1968930 A CN1968930 A CN 1968930A CN A2005800170603 A CNA2005800170603 A CN A2005800170603A CN 200580017060 A CN200580017060 A CN 200580017060A CN 1968930 A CN1968930 A CN 1968930A
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- Prior art keywords
- alkyl
- aryl
- compound
- halogen
- compounds
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- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
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- 229960000303 topotecan Drugs 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
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Abstract
本申请涉及新的通式(I)(I*)的杂环化合物,其中R、R1、R2、X、Y、Z和n具有在说明书中所定义的含义,涉及制备它们的方法和涉及这些化合物作为药剂,特别是作为芳化酶抑制剂的应用。
Description
本发明涉及新的杂环化合物,涉及化合物的制备方法,涉及包含它们的药品,以及涉及它们作为活性药用成分,特别是作为芳化酶抑制剂的应用。
本发明首先涉及下列通式的化合物
其中,
X为C;
Y为C或N;
Z为C;
R a)为氢;或
b)为C1-C8-烷基、C1-C8-烷氧基、卤素或三氟甲基;
R1为C1-C8-烷基、C2-C8-链烯基、C2-C8-炔基、芳基-C0-C4-烷基或不饱和的杂环基-C0-C4-烷基,所述基团为未取代的或被1-4个C1-C8-烷氧基、C1-C8-烷氧基羰基、C1-C8-烷基、C0-C8-烷基羰基、C1-C8-烷基磺酰基、芳基-C0-C4-烷氧基羰基、芳基、氰基、卤素、杂环基、氧代、三氟甲氧基、三氟甲基或三-C1-C4-烷基甲硅烷基取代;
R2 a)为氢;或
b)为C1-C8-烷基、C3-C8-环烷基、卤素、羧基-C1-C4-烷基、C1-C4-烷氧基羰基-C1-C4-烷基、C0-C4-烷基羰基、芳基-C0-C4-烷基或不饱和的杂环基-C1-C4-烷基,所述基团为未取代的或被1-4个C1-C8-烷氧基、C1-C8-烷氧基羰基、C1-C8-烷基、C0-C8-烷基羰基、C1-C8-烷基磺酰基、芳基-C0-C4-烷氧基羰基、芳基、氰基、卤素、杂环基、氧代、三氟甲氧基、三氟甲基或三-C1-C4-烷基甲硅烷基取代;
n为0、1或2的数字;
*指不对称的碳原子
和其盐,优选其药学上可用的盐,
其中,如果X、Y和Z为C时,R1不是未取代的或烷氧基-取代的苄基;或如果R为甲基时,则R1不为甲基。
术语芳基表示芳烃基团,其一般包含5-14个,优选6-10个碳原子和为,例如,苯基、茚基,例如2-或4-茚基,或萘基,例如1-或2-萘基。具有6-10个碳原子的芳基为优选的,特别是苯基或1-或2-萘基。所述基团可为未取代的或被一次或多次,例如一次或两次取代,取代基在可能的任何位置上,例如在苯基的邻、间或对位或在1-或2-萘基的3或4位上,以及还可能存在多个相同或不同的取代基。
芳基-C0-C4-烷基为例如苯基、萘基或苄基。
术语杂环基表示饱和的、部分饱和的或不饱和的4-8元,特别优选5元的单环系统,表示饱和的、部分饱和的或不饱和的7-12元,特别优选9-10元的双环系统,以及还表示饱和的、部分饱和的或不饱和的7-12元三环系统,在每种情况下,在至少一个环中包含N、O或S原子,还可能表示在一个环中存在另一个N、O或S原子。所述基团可为未被取代的或被取代一次或多次,例如一次或两次,还可能存在多个相同或不同的取代基。
不饱和的单环杂环基-C0-C4-烷基为,例如,吡咯基、噻吩基、噻唑基或唑基。未取代的吡啶基为较不优选的。
不饱和的双环杂环基-C0-C4-烷基为例如苯并呋喃基、苯并噻吩基、吲唑基、吲哚基、异喹啉基或喹啉基。
部分饱和的双环杂环基-C0-C4-烷基为例如4,5,6,7-四氢苯并呋喃基或4,5,6,7-四氢苯并噻唑基。
C3-C8-环烷基优选为3-、5-或6元环烷基、诸如环丙基、环戊基或环己基。
C1-C8-烷基可为直链或支链和/或桥连的,并且为例如甲基、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。
C2-C8-链烯基为,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-炔基为,例如,乙炔基、丙炔基、丁炔基或戊炔基、己炔基或庚炔基。
C1-C8-烷氧基为,例如,C1-C5-烷氧基诸如甲氧基、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,但也可为己氧基或庚氧基。
C1-C8-烷氧基羰基优选为C1-C4-烷氧基羰基诸如甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、丁氧基羰基、异丁氧基羰基、仲丁氧基羰基或叔丁氧基羰基。
C0-C8-烷基羰基为,例如,甲酰基、乙酰基、丙酰基、丙基羰基、异丙基羰基、丁基羰基、异丁基羰基、仲丁基羰基或叔丁基羰基。
C1-C4-烷氧基羰基-C1-C4-烷基为,例如,甲氧基羰基-或乙氧基羰基甲基、2-甲氧基羰基-或2-乙氧基羰基乙基、3-甲氧基羰基-或3-乙氧基羰基丙基或4-乙氧基羰基丁基。
卤素为,例如,氟、氯、溴或碘。
羧基-C1-C4-烷基为,例如,羧基甲基、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、特别是羧基甲基。
以下提及的化合物基团不被认为是封闭的;相反,这些化合物基团的部分可相互被替代或被以上给出的定义替代,或被省略,以有意义的方式,例如通常被更具体的定义替代。
优选的式(I)或(I*)化合物为下列通式的化合物
其中R、R1、R2和n的含义如同对于式(I)或(I*)化合物所指定的含义。
R优选为氢或C1-C8-烷基、特别优选氢或甲基。
R1优选为芳基或不饱和的杂环基、尤其特别优选为任选单-或二取代的苯并呋喃基、苯并噻吩基、吲唑基、吲哚基、苯基、吡咯基、噻唑基、噻吩基或唑基。
R2优选为氢、卤素、C1-C8-烷基或芳基-C1-C4-烷基。
n优选0或1的数字。对于式(I*)化合物,n特别优选数字1。
对于芳基或不饱和的杂环基的优选的取代基为卤素、氰基、三氟甲基、杂环基或C1-C8-烷基羰基。对于芳基或不饱和的杂环基的尤其特别优选的取代基为溴、氰基、噻吩基、噻唑基、唑基或乙酰基。
特别优选的式(I)或(I*)化合物为通式(Ia)、(Ib)、(Ic)或(1*)的化合物,其中R1为芳基,优选单-或二取代的苯基,或不饱和的杂环基,优选单-或二取代的苯并呋喃基、苯并噻吩基、吲唑基或吲哚基。
至于式(I*)化合物本身(但不涉及它们的应用或含所述化合物的任何组合物),其中R和R2为H、R1为对氰基苯基和n为1的化合物为较不优选的。
具有至少一个不对称的碳原子的式(I)化合物,可以光学纯对映体、对映体的混合物的形式或作为外消旋物存在。具有第二个不对称的碳原子的化合物可以光学纯非对映异构体、非对映异构体的混合物、非对映异构的外消旋物、非对映异构的外消旋物的混合物的形式或作为内消旋化合物存在。本发明包括所有这些形式。对映体的混合物、外消旋物、非对映异构体的混合物、非对映异构的外消旋物或非对映异构的外消旋物的混合物可用常规的方法例如使外消旋物拆分、柱层析法、薄层层析法、HPLC等分馏。
式(I*)化合物具有至少一个指示为*的不对称的碳原子。所述化合物应理解为所述不对称的碳原子上具有特殊构型的单一化合物。在制备产生外消旋化合物的方法中,对映体的分离采用常规的方法,例如用手性HPLC-柱进行。详细内容见于实施例中。依据本发明的式(I*)化合物显示显著的芳化酶抑制活性。所述活性可采用如此后描述的市售的Cyp19酶抑制试剂盒,优选Cyp19/甲氧基-4-三氟甲基-香豆素(MFC)高产量抑制试剂盒(Becton Dickinson Biosciences,San Jose,CA,USA)方便地测定。在指示为*的不对称的碳原子上具有相对构型的式(I*)化合物,在此测试系统中显示活性比现在的式(I*)化合物低至少20倍,优选低40倍。″
术语“药学上可用的盐”包括与无机或有机酸形成的盐,所述酸有例如盐酸、氢溴酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、顺丁烯二酸、乙酸、丁二酸、酒石酸、甲烷磺酸、对甲苯磺酸等。具有盐形成基团的化合物的盐为,特别是、酸加成盐、与碱形成的盐,或如果存在多个盐形成基团,也任选混合盐或内盐。
式(I)或(I*)化合物可以以类似于在文献(流程图)中公开的制备方法制备。
具体制备变化的细节可见于实施例中。
式(I)化合物也可以光学纯形式制备。通过本领域已知的方法分离成对映体是可能的,所述方法的进行或者优选在合成的早期阶段,通过与光学活性酸例如,(+)-或(-)-扁桃酸形成盐和通过分级结晶分离非对映异构体的盐,或者优选在相当晚的阶段通过用手性辅助成分例如,(+)-或(-)-莰基氯(camphanyl chloride)衍生化,和通过层析法和/或结晶以及随后的对连接至手性辅助剂的键的裂解方法分离非对映异构体的产物。使用常规的分光镜的方法(特别适当的方法为单晶X-射线光谱法)可分析纯非对映异构体的盐和衍生物以确定的所含的化合物的绝对构型。
盐主要为式(I)或(I*)化合物的药学上可用的或无毒的盐。这样的盐是例如通过具有酸性基团例如羧基或磺基的式(I)或(I*)化合物形成的,是,例如,其与适合的碱所成的盐,诸如衍生自元素周期表的Ia、Ib、IIa和IIb族的金属,例如碱金属,特别是锂、钠或钾的盐,碱土金属盐,例如镁或钙盐,还有锌盐或铵盐的无毒的金属盐,和那些与有机胺形成的盐,所述有机胺有例如任选羟基-取代的单-、二-或三烷基胺,特别是单-、二-或三-低级-烷基胺,或与季铵碱,例如甲基-、乙基-、二乙基-或三乙基胺,单-、二-或三(2-羟基-低级-烷基)胺诸如乙醇-、二乙醇-或三乙醇胺、三(羟基甲基)甲基胺或2-羟基-叔-丁基胺、N,N-二-低级-烷基-N-(羟基-低级-烷基)胺,诸如N,N-二甲基-N-(2-羟基乙基)胺或N-甲基-D-葡糖胺,或季铵氢氧化物诸如四丁基氢氧化铵。具有碱基,例如氨基的式(I)或(I*)化合物,可例如与适合的无机酸,例如氢卤酸如盐酸、氢溴酸、置换一个或两个质子的硫酸、置换一个或多个质子的磷酸,例如正磷酸或偏磷酸,或置换一个或多个质子的焦磷酸,或与有机羧酸、磺酸或磷酸或N-取代的氨基磺酸(sulphamic acid),例如乙酸、丙酸、乙二醇酸、丁二酸、顺丁烯二酸、羟基顺丁烯二酸、甲基顺丁烯二酸、反丁烯二酸、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-乙酸基苯甲酸、扑酸、烟酸、异烟酸,还有氨基酸例如,上面所提到的α-氨基酸,和甲烷磺酸、乙烷磺酸、2-羟基乙烷磺酸、乙烷-1,2-二磺酸、苯磺酸、4-甲苯磺酸、萘-2-磺酸、2-或3-磷酸甘油酸盐(phosphoglycerate)、葡萄糖6-磷酸盐、N-环己基氨基磺酸(形成环磺酸盐)或与其它的酸性有机化合物诸如抗坏血酸,形成酸加成盐。具有酸性和碱性基团的式(I)或(I*)化合物也可形成内盐。
药学上不适合的盐也可用于分离和纯化。
式(I)或(I*)化合物还包括其中一个或多个原子被它们的稳定的、非放射性同位素置换(例如被氘置换的氢原子)的化合物。
以上描述的化合物的前药衍生物,是在使用时通过化学的或生理学的过程在体内释放原化合物的衍生物。例如当达到生理pH或通过酶的转化作用,前药可被转化为原化合物。前药衍生物的可能的实例为游离可用的羧酸酯、硫醇、醇或酚的S-和O-酰基衍生物,其中酰基为如上定义。优选药学上可用的酯衍生物,其通过在生理介质中的溶剂分解作用转化为原羧酸,例如,低级烷基酯、环烷基酯、低级链烯基酯、苄基酯、单-或二取代的低级烷基酯,诸如低级ω-(氨基、单-或二烷基氨基、羧基、低级烷氧基羰基)-烷基酯或诸如低级α-(烷酰基氧基、烷氧基羰基或二烷基氨基羰基)-烷基酯;也可按相同方法常规应用新戊酰氧基甲酯和类似的酯。
由于游离化合物、前药衍生物和盐化合物之间的紧密关系,本发明中所定义的化合物还包括其可能的和适当的前药衍生物和盐形式。
天然存在的雌激素17β-雌二醇(E2)、雌酮(E1)和雌三醇(E3)为衍生自胆固醇的C18类固醇。与脂蛋白受体结合后,胆固醇被类固醇生成细胞摄取,贮存和运送至类固醇合成之处。在类固醇架构中的A-环的芳构化为雌激素形成的最后步骤。该反应由存在于平滑内质网中、且作为去甲基酶(demethylase)功能的P450芳化酶单氧合酶的酶复合物(Cyp19)催化。在三个连续的羟化反应中,雌酮和雌二醇分别由它们的必需的前体雄烯二酮和睾丸激素形成。
女性中的雌二醇的主要来源为卵巢的卵泡膜细胞和粒细胞和这些细胞的黄体衍生物。依据雌激素合成的“两-细胞”学说,卵泡膜细胞分泌雄激素,后者扩散至粒细胞中被芳构化形成雌激素。然而,有证据显示,两种细胞类型均能够形成雄激素和雌激素。雌酮和雌三醇主要在肝脏中由雌二醇形成。在肌肉、脂肪、神经组织和睾丸的Leydig细胞中也检测到芳化酶活性。作为年龄和体重的函数,性腺外组织中的雌激素合成水平提高。
血清中,雌二醇可逆地结合于性激素结合的球蛋白,一种β-球蛋白,而与白蛋白结合的亲合力较低;约2-3%未结合。雌激素通过硫酸化作用或葡糖苷酸化作用(glucuronidation)代谢,轭合物由胆汁或尿排泄。通过肠道菌丛使这些轭合物水解,随后对雌激素的再吸收导致肠肝循环。
雌激素在性器官中刺激生长、血流和水的潴留,并且还与引起乳腺癌和子宫内膜肿瘤有关。在肝脏,雌激素增加脂蛋白受体的表达,引起低密度脂蛋白胆固醇血清浓度的下降。雌激素还通过刺激肝脏中产生凝结因子而增加凝结效能。在骨骼中,破骨细胞和成骨细胞均为雌激素的直接标靶,但是在卵巢,雌激素被类分为抗再吸收剂。
在乳腺中,雌激素刺激管腺上皮细胞的生长和分化,引起管腺柱状细胞的有丝分裂活性和刺激结缔组织的生长。雌激素刺激乳腺癌细胞的生长。在患乳腺癌的绝经后的妇女中,尽管存在低血清雌二醇浓度,由原位的芳构化而导致肿瘤中的雌二醇高浓度。
本发明中描述的化合物具有有用的药理学特性,它们选择性地抑制哺乳动物,包括人中的芳化酶(Cyp19)。作为结果,雄激素转化为雌激素的代谢被抑制。因此,化合物适合例如,用于治疗雌激素依赖的疾病,包括雌激素依赖的乳腺癌,特别是在绝经后的妇女中。它们还可用于,例如男子女性型乳房,即男性乳房发育的治疗,因为类固醇的芳构化可被所述化合物抑制。
这些功效可在使用无细胞和细胞系统的体外分析试验中得到证实。
本发明化合物的体外抑制芳化酶活性,可通过采用市售的Cyp19酶抑制试剂盒证实。Cyp19/甲氧基-4-三氟甲基-香豆素(MFC)高产量抑制试剂盒(Becton Dickinson Biosciences,San Jose,CA,USA),例如,被预期用于在96-孔格式板上筛选Cyp19催化活性的有效抑制剂。试剂盒包括以supersomes的形式的重组人Cyp19酶、荧光P450底物、NADPH再生系统、反应缓冲剂和终止试剂。通过Cyp19 supersomes迅速将MFC,荧光底物转化为高度的荧光产物7-羟基-4-三氟甲基香豆素(7-HFC)。在从0.2毫微摩尔至20毫摩尔的范围的多种浓度的抑制剂化合物的存在下,依据制造厂商的说明书进行分析。
通过采用最小二乘方法(the least squares approach),对样本的原始数据进行4-参数对数函数的拟合,产生抑制曲线。函数描述如下:
Y=(d-a)/((1+(x/c)-b))+a
其中:
a=最小数据值
b=斜率
C=IC50
d=最大数据值
x=抑制剂浓度
本发明中描述的化合物,在10-3至10-10mol/l的最小浓度显示Cyp19抑制特性。
本发明中描述的化合物的Cyp19抑制特性,还可在细胞分析中得到证实。NCI-H295R人肾上腺皮质肿瘤细胞系已在文献中被详细描述和显示表达大多数胆固醇产生必须的关键酶。这些酶包括Cyp11A(胆固醇侧链裂解酶)、Cyp11B1(类固醇11-β-羟化酶)、Cyp11B2(醛固酮合成酶)、Cyp17(类固醇17-α-羟化酶和/或17,20裂合酶)、Cyp19(芳化酶aromatase)、Cyp21B2(类固醇21-羟化酶)和3-β-HSD(羟基类固醇脱氢酶)。所述细胞具有带状的未分化的人类胚胎肾上腺细胞的生理学特征,具有产生在成人肾上腺皮质发现的三个表型清楚的带的每一种的类固醇激素的能力。
在75cm2细胞培养瓶中,温度37℃,95%空气和5%CO2湿润空气下,将所述NCI-295R细胞(美国典型培养物保藏中心,ATCC,Rockville,MD,美国)培养于Dulbecco’s Modified Eagle’Ham(达氏改良依格氏)F-12培养基(DME/F 12)中,所述培养基中补充有Ultroser SF血清(Soprachem,Cergy-Saint-Christophe,法国)以及胰岛素、转铁蛋白、亚硒酸盐(selenit)(I-T-S,Becton Dickinson Biosiences,FranklinLakes,NJ,美国)和抗生素。随后将所述细胞转种到含有DME/F 12培养基的24孔培养板中,所述培养基补充了代替Ultroser SF血清的0.1%牛血清白蛋白。所述实验从在DME/F 12培养基中孵育细胞72小时开始,所述培养基补充有0.1%牛血清白蛋白和细胞刺激剂存在或缺乏下的测试化合物。被加入的测试化合物的浓度范围为0.2纳摩尔到20毫摩尔。作为细胞刺激剂,使用血管紧缩素-II(于10或100毫微摩尔浓度)、钾离子(16毫摩尔)、弗司扣林(10微摩尔)或两种试剂的组合。进入细胞培养基的雌酮、雌二醇、二氢表雄酮、醛固酮、皮质酮和/或皮质醇的细胞分泌,可用商业上可得的免疫测定和特异性单克隆抗体,依据制造厂商的说明书进行定量分析。选择性类固醇的分泌程度用作在有或无测试化合物存在下的酶活性、各种酶抑制的测度。化合物的剂量依赖的酶抑制活性反映在以IC50值为特征的抑制曲线中。
通过采用最小二乘方法,对样本的原始数据进行4-参数对数函数的拟合,产生抑制曲线。函数描述如下:
Y=(d-a)/((1+(x/c)-b))+a
其中:
a=最小值
b=斜率
C=IC50
d=最大值
x=抑制剂浓度
本发明中描述的化合物,在10-3至10-10mol/l的最小浓度显示Cyp19抑制特性。
所述化合物的芳化酶抑制作用,也可使用有利的哺乳动物模型诸如,例如豚鼠、小鼠、大鼠、猫、狗或猴子在体内证实。
化合物介导的芳化酶活性的体内抑制,可通过以下描述的方案,监测血浆类固醇水平变化进行测试:生理周期内的雌性大鼠隔天皮下注射100IU的孕马血清促性腺激素(PMSG,Sigma)的0.1ml无菌盐水5次。最后一次注射后的24小时,给动物口饲剂量范围为0.01至10mg/kg的测试化合物处理。处理后24小时,使动物末端放血。将肝素化血浆贮存于-20℃直至分析。用商业上可得的放射免疫测定试剂盒,依据制造厂商的说明书,测定类固醇(17β-雌二醇、雌酮、雌三醇、孕酮、睾丸激素、醛固酮和皮质酮)的血浆水平。纯化和浓缩步骤对于测量在雌性大鼠中的睾丸激素是需要的:将四体积的乙醚加至样本中,经轻轻地倒置15分钟混合,然后于2000rpm离心5分钟。水相于干冰中冷冻,回收有机相并于氮气流下蒸发至干。干燥的提取物用实验缓冲液再生。
化合物介导的芳化酶活性的体内抑制,可如下监测卵巢雌激素含量测试:二十一天龄的雌性大鼠皮下注射10IU的孕马血清促性腺激素(PMSG,Sigma)。2天后,给相同的大鼠皮下注射30IU人绒毛膜促性腺激素(hCG,Sigma)。在用hCG处理的次日,大鼠皮下注射或者丙二醇(0.2ml)或者不同剂量的测试化合物。一个小时后,所有大鼠经用在0.1ml油中的2.25mg 4-雄烯-3,17-二酮皮下注射处理。注射雄烯二酮四个小时后,处死大鼠并切取它们的卵巢,剔除附着的组织,成对贮存于-50℃。为了测定卵巢的总雌激素含量,加入1.5ml的0.05M含水磷酸钾缓冲液(pH7.4)和0.2ml的0.1N NaOH溶液至其后匀浆的组织中。匀浆用15ml乙醚萃取-5ml等分试样用具有与雌酮、雌二醇和雌三醇有100%交叉反应的抗血清进行放射性免疫测定。结果用ng雌激素/每对卵巢表示。
抗肿瘤,特别是抗雌激素依赖的肿瘤的活性,可在体内例如在二甲基苯并蒽(DMBA)诱导的雌性Sprague-Dawley大鼠的乳腺肿瘤(见Proc.Soc.Exp.Biol.Med.160,296-301,1979)中证实。本发明化合物在每天约1至约20mg/kg或更少的口饲的剂量下,引起现有的肿瘤退化和抑制新的肿瘤的出现。
为使所治疗的患者达到所预期的效果,本发明化合物可口服给予或肠内给予,例如静脉内、腹膜内、肌肉内、直肠、皮下或任何将活性物质直接局部注射到组织或肿瘤内的方法。术语患者包括恒温动物和哺乳动物如人类、灵长类、牛、狗、猫、马、绵羊、小鼠、大鼠和猪。所述化合物可以作为药品给予或将其加入到确保可持续释放所述化合物的给药装置中。所给予的药物的量可在一个宽的范围内变动并且每一个剂量都表现为有效剂量。根据所治疗的患者或所治疗的疾病以及给药模式,每天有效药物的剂量可在每公斤体重约0.005到50mg之间,但优选在每天每公斤体重约0.05到5mg之间。
对于口服给药,可将所述化合物制备成固体或液体的药物剂型,如胶囊剂、丸剂、片剂、包衣片剂、颗粒剂、粉剂、溶液、悬浮液或乳剂。所述固体药物形式的剂量可以是一个常规的硬明胶胶囊,所述胶囊可装填活性成份和赋形剂如润滑剂和填料如乳糖、蔗糖和玉米淀粉。另一种给药剂型可以为本发明所述活性物质的片剂。所述片剂可加入常规的制备片剂的赋形剂如乳糖、蔗糖、玉米淀粉,与粘合剂如阿拉伯树胶、玉米淀粉或明胶的结合、崩解剂如马铃薯淀粉或交联的聚乙烯吡咯烷酮(PVPP)和润滑剂如硬脂酸或硬脂酸镁。
用于软明胶胶囊的合适的赋形剂的实例是蔬菜油、蜡、脂肪、半固体和液体的多元醇等。
用于制备溶液和糖浆剂的赋形剂的实例为水、多元醇、蔗糖、转化糖、葡萄糖等。
对于直肠给药,可将所述化合物配制为固体或液体药物形式,例如栓剂。适用于栓剂的赋形剂的实例为天然油或硬化油、蜡、脂肪、半固体和液体的多元醇等。
对于胃肠外给药,可将所述化合物制备成含有活性成份的可注射剂型的液体或悬浮液。所述制剂通常含有生理上可耐受的无菌溶剂(所述溶剂可含有油-包-水乳剂、加入或不加入表面活性剂),以及其它药学上可接受的赋形剂。可用于这类制剂的油是石蜡和蔬菜、动物或合成来源的甘油三酯,如花生油、豆油和矿物油。可注射溶液通常含有液体载体如,优选水、生理盐水、葡萄糖或相关的糖溶液、乙醇和二醇类如丙二醇和聚乙二醇。
如果所述剂型使得所述活性成份的持续释放成为可能,那么该物质可以作为经皮贴剂的系统、作为贮库注射剂或植入物给予。可将所述活性物质压缩成颗粒或狭窄的圆柱体并且通过皮下或肌肉内作为贮库注射剂或植入物给予。
所述药品也可另外含有防腐剂、加溶剂、增稠剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、芳香剂、改变渗透压的盐、缓冲液、包衣剂或抗氧化剂。它们还可以含有其它有治疗价值的物质。
本发明还提供式(I)或(I*)化合物及其药学上可用的盐在以下疾病或病症的治疗或预防上的应用,所述疾病或病症是对芳化酶抑制有反应的,特别是增殖性疾病诸如乳腺癌或类似的软组织内分泌敏感的癌症,最优选雌激素依赖的病症如男子女性型乳房、乳房和子宫内膜肿瘤、子宫内膜异位症和早产。所述化合物还用于治疗或预防在激素受体阳性或未知的、绝经期后妇女中的局部晚期或转移性乳腺癌。
式(I)或(I*)化合物及其药学上可用的盐也可与一个或多个具有抗肿瘤作用的药物联合给药,所述抗肿瘤作用包括例如抗雌激素活性(如对于依西美坦(exemestane)、托瑞米芬(toremifene)、氟维司群(fulvestrant)、他莫昔芬所述);如骨再吸收抑制活性(如对于帕米磷酸盐(pamidronate)、唑来膦酸(zoledronic acid)所述);烷基化活性(如对于白消胺(busulfan)、替莫唑胺(temozolomide)、美法仑、苯丁酸氮芥、氮芥(mechlorethalamine)所述);核苷酸碱嵌入(intercalating)活性(例如对于阿霉素、道诺霉素、放线菌素D(dactinomcyin)、多柔比星、表柔比星(epirubicin)、依达比星(idarubicin)所述);抗代谢物活性(例如对于阿糖胞苷、氟达拉滨、克拉屈滨(cladrbine)、巯基嘌呤、硫鸟嘌呤、卡培他滨(capecitabine)所述);抗雄激素活性(例如对于阿巴瑞克(abarelix)、比卡鲁胺(bicalutamide)所述);雄激素性活性(例如对于尼鲁米特(nilutamide)、甲基睾丸激素所述);促性腺激素释放激素活性(例如对于亮丙瑞林、曲普瑞林(triptorelin)、戈舍瑞林(goserelin)所述);孕激素性活性(例如对于甲孕酮所述);核苷类似物活性(例如对于吉西他滨(gemcitarabine)描述;I型拓扑异构酶抑制活性(例如对于托泊替康(topotecan)、依立替康(Irinotecan)所述);激酶抑制剂活性(例如对于伊马替尼(imatinib)所述);生长因子抑制活性(例如对于吉非替尼(gefitinib)、曲妥珠单抗(trastuzumab)所述);生长激素活性(例如对于阿法依泊汀、沙莫司亭(sargramostim)、非格司亭(filgastrim)、聚乙二醇化非格司亭(pegfilgastrim)、奥普瑞白介素(oprelvekin)、干扰素α2b所述);其它抗肿瘤活性(例如对于培美曲唑(pemetrexed)、达卡巴嗪、甲基苄肼、奥沙利铂(oxaliplatin)、天冬酰胺酶、培门冬酶(pegaspargase)、altetamine、吉妥珠单抗(gemtuzumab)、长春瑞滨(vinorelbine)、米托蒽醌、地尼白介素-2(denileukin)、利妥昔单抗(rituximab)、9-顺式视黄酸(alitretinoin)、三氧化砷、硼替佐米(bortezomib)、维甲酸(tretinoin)、多烯紫杉醇(docetaxel)所述);止吐活性(例如对于多拉司琼(dolasetron)、洛诺司琼(palonosetron)、阿瑞吡坦(aprepitant)、格拉司琼(ganisetron)、屈大麻酚(dronabinol)、昂丹司琼(odansetron)所述)。
本发明中描述的化合物可应用如下:
-以含有各组分的制剂或药剂盒的形式作为组合药物,所述组包括此处描述的式(I)或(I*)化合物及其药学上可用的盐和至少一种可或者同时给药或者顺序给药的具抗肿瘤活性的药物。制剂或药剂盒可包括使用说明书。
剂量可在宽范围界限内变化,当然必须适合于每一个体病例中的个体状况。通常,对于口服给药,每天剂量为约0.3mg至约3g,优选约1mg至约1g,例如每成人(70kg)约10mg,优选分成1-3个单次剂量,所述剂量可,例如具有相同的大小,可为适当的,虽然指定的上限也可突破(如果这发现应是适当的话);典型地,儿童依据它们的年龄和体重给予较低剂量。
以下的实施例阐述本发明。所有温度以摄氏度、压力用毫巴(mbar)表示。除非另有所指,反应在室温进行。缩写“Rf=xx(A)”意指例如在溶剂系统A中发现Rf的值为xx。溶剂之间的配比量总是以体积之比表示的。最终产物和中间体的化学名借助于AutoNom 2000(Automatic Nomenclature)程序产生。
HPLC梯度于Hypersil BDS C-18(5μm)上;柱:4×125mm95%水*/5%乙腈*至0%水*/100%乙腈*,于10分钟+2分钟(1ml/min)内。
*含0.1%三氟乙酸
用到以下的缩写:
Rf 在薄层层析中,从起始点起由某物质的移动的距离与溶剂移动的距离之比
Rt 物质在HPLC中的保留时间(以分钟表示)
m.p.熔点(温度)
实施例1:
4-(6,7-二氧-5H-[2]吡啶-2-基)苄腈盐酸盐
回流下,使1.240mmol的N-叔-丁基-4-(6,7-二氢-5H-[2]吡啶-7-基)苯甲酰胺溶液和1.0ml的亚硫酰氯于30ml的氯仿中搅拌6个小时。使反应混合物冷却至室温,并蒸发。用二氯甲烷提取残余物,用饱和的碳酸氢钠水溶液混合。分离掉有机相,且水相用用二氯甲烷(2x)萃取。合并的有机相经硫酸钠干燥,蒸发。使残余物溶于乙醚,经加入乙醚的HCl溶液(2N)将标题化合物转化为盐酸盐。固体于乙醚/丙酮(1∶1)中搅拌,过滤和干燥。得到深灰色固体样标题化合物。Rf(游离碱)=0.36(EtOAc);Rt=4.98。
起始原料制备如下:
a)N-叔-丁基-4-(6,7-二氢-5H-[2]吡啶-7-基)苯甲酰胺
使1.250mmol的N-叔-丁基-4-(5H-[2]吡啶-7-基)苯甲酰胺的10ml的乙醇溶液与360mg的10%Pd/C混合,然后将反应混合物于20-25℃,在大气压下氢化6个小时。经过滤使反应混合物澄清,蒸发滤液。从残余物得到棕色油样粗标题化合物。
b)N-叔-丁基-4-(5H-[2]吡啶-7-基)苯甲酰胺
于50℃,使1.260mmol的N-叔-丁基-4-(7-羟基-6,7-二氢-5H-[2]吡啶-7-基)苯甲酰胺溶液于20ml的4M HCl中搅拌20个小时。反应混合物冷却至室温,用饱和的碳酸氢钠水溶液小心地调节至pH8。水相用二氯甲烷(3x)萃取-合并的有机相经硫酸钠干燥,蒸发。从残余物得到黄色油样粗标题化合物。Rt=5.47。
c)N-叔-丁基-4-(7-羟基-6,7-二氢-5H-[2]吡啶-7-基)苯甲酰胺
于-78℃,将5.3ml的正丁基锂(1.6M的己烷)逐滴加至4.250mmol的4-溴-N-叔-丁基苯甲酰胺于70ml的四氢呋喃溶液中。30分钟后,逐滴加入3.270mmol的5,6-二氢-[2]吡啶-7-酮[51907-18-7]的10ml的四氢呋喃溶液。反应混合物于-78℃搅拌1个小时和于室温下搅拌2个小时,然后用饱和的氯化铵水溶液猝灭。分离掉有机相,水相用乙酸乙酯(2x)萃取。合并的有机相经硫酸钠干燥,蒸发。从残余物经快速层析法(SiO2 60F)得到白色泡沫样标题化合物。Rf=0.29(甲苯∶甲醇=85∶15),Rt=5.00。
实施例2:
4-(5,6,7,8-四氢喹唑啉-5-基)苄腈
使0.480mmol的4-(7,8-二氢喹唑啉-5-基)苄腈的12ml的乙醇溶液与33mg的10%Pd/C混合,然后使反应混合物于20-25℃,在大气压下氢化50个小时。经过滤使反应混合物澄清,蒸发滤液。经快速层析法(SiO2 60F)从残余物得到棕色油样标题化合物。Rf=0.26(二氯甲烷∶甲醇=95.5);Rt=5.92。
起始原料制备如下:
a)4-(7,8-二氢喹唑啉-5-基)苄腈
于50℃,0.500mmol的4-(5-羟基-5,6,7,8-四氢喹唑啉-5-基)苄腈的1.25ml的2M HCl溶液搅拌8个小时。使反应混合物冷却至室温,用饱和的碳酸氢钠水溶液小心地调节至pH8。水相用乙酸乙酯(3x)萃取,合并的有机相经硫酸钠干燥,蒸发。从残余物得到黄色油样粗标题化合物。Rf=0.20(甲苯∶甲醇=85∶15),Rt=6.21。
b)4-(5-羟基-5,6,7,8-四氢喹唑啉-5-基)苄腈
于-20℃,将1.0ml的异丙基氯化镁(2.0M在四氢呋喃中)逐滴加至2.000mmol的4-碘苄腈的5ml四氢呋喃溶液中。30分钟后,逐滴加入1.000mmol的7,8-二氢-6H-喹唑啉-5-酮[21599-28-0]的2ml的四氢呋喃溶液。反应混合物于-20℃搅拌30分钟和室温下搅拌1个小时,然后用0.1M HCl猝灭。分离掉有机相,水相用二氯甲烷(2x)萃取。合并的有机相经硫酸钠干燥,蒸发。经快速层析法(SiO2 60F)从残余物得到棕色油样标题化合物。Rf=0.16(甲苯∶甲醇=85∶15),Rt=5.15。
实施例3:
(S或R)-4-(5,6,7,8-四氢-咪唑并[1,5-a]吡啶-8-基)-苄腈
用Chiralpak AD-H柱(5μm,250×20mm),采用70∶30∶0.1庚烷/乙醇/二乙胺作为流动相,于50ml/min的流速下,对(外消旋的)-4-(5,6,7,8-四氢-咪唑并[1,5-a]吡啶-8-基)-苄腈的对映体进行制备性分离。为了进行光学纯度的分析测定,使用Chiralpak AD-H柱(5μm,250×4.6mm),采用70∶30∶0.1庚烷/乙醇/二乙胺作为流动相,流速1ml/min。第一洗脱的对映体经真空浓缩,提供白色固体样标题化合物。Rt=10.6。
起始原料制备如下:
a)(外消旋的)-4-(5,6,7,8-四氢-咪唑并[1,5-a]吡啶-8-基)-苄腈
类似于实施例1,使1.74mmol的N-叔-丁基-4-(5,6,7,8-四氢-咪唑并[1,5-a]吡啶-8-基)-苯甲酰胺盐酸盐反应。得到奶油色固体样标题化合物。Rf=0.37(甲苯∶甲醇=85∶15);Rt=4.88
b)N-叔-丁基-4-(5,6,7,8-四氢-咪唑并[1,5-a]吡啶-8-基)-苯甲酰胺盐酸盐
类似于实施例1a,使1.79mmol的N-叔-丁基-4-(5,6-二氢-咪唑并[1,5-a]吡啶-8-基)-苯甲酰胺盐酸盐反应。得到棕色固体样粗标题化合物。Rf=0.35(甲苯∶甲醇=85∶15),Rt=5.54
c)N-叔-丁基-4-(5,6-二氢-咪唑并[1,5-a]吡啶-8-基)-苯甲酰胺盐酸盐
类似于实施例1b,使1.85mmol的N-叔-丁基-4-(8-羟基-5,6,7,8-四氢-咪唑并[1,5-a]吡啶-8-基)-苯甲酰胺反应。得到灰色固体样粗标题化合物。Rt=5.54
d)N-叔-丁基-4-(8-羟基-5,6,7,8-四氢-咪唑并[1,5-a]吡啶-8-基)-苯甲酰胺
类似于实施例1c,使6.00mmol的6,7-二氢-5H-咪唑并[1,5-a]吡啶-8-酮[51907-18-7]反应。得到黄色固体样标题化合物。Rf=0.16(二氯甲烷∶甲醇=95∶5),Rt=4.96
以下的化合物以类似于在实施例1-3中描述的方法的方式制备。
实施例
4 4-(5,6,7,8-四氢异喹啉-8-基)苄腈
从6,7-二氢-5H-异喹啉-8-酮[21917-88-4]开始
Claims (11)
1.下列通式的化合物
其中,
X为C;
Y为C或N;
Z为C;
Ra)为氢;或
b)为C1-C8-烷基、C1-C8-烷氧基、卤素或三氟甲基;
R1为C1-C8-烷基、C2-C8-链烯基、C2-C8-炔基、芳基-C0-C4-烷基或不饱和的杂环基-C0-C4-烷基,所述基团为未取代的或被1-4个C1-C8-烷氧基、C1-C8-烷氧基羰基、C1-C8-烷基、C0-C8-烷基羰基、C1-C8-烷基磺酰基、芳基-C0-C4-烷氧基羰基、芳基、氰基、卤素、杂环基、氧代、三氟甲氧基、三氟甲基或三-C1-C4-烷基甲硅烷基取代;
R2a)为氢;或
b)为C1-C8-烷基、C3-C8-环烷基、卤素、羧基-C1-C4-烷基、C1-C4-烷氧基羰基-C1-C4-烷基、C0-C4-烷基羰基、芳基-C0-C4-烷基或不饱和的杂环基-C1-C4-烷基,所述基团为未取代的或被1-4个C1-C8-烷氧基、C1-C8-烷氧基羰基、C1-C8-烷基、C0-C8-烷基羰基、C1-C8-烷基磺酰基、芳基-C0-C4-烷氧基羰基、芳基、氰基、卤素、杂环基、氧代、三氟甲氧基、三氟甲基或三-C1-C4-烷基甲硅烷基取代;
n为0、1或2的数字;
*指不对称的碳原子
及其盐、前药或其中一个或多个原子被它们的稳定的、非放射性同位素置换的化合物,特别是药学上可用的盐,
其中,如果X、Y和Z为C时,R1不是未取代的或烷氧基-取代的苄基;或如果R为甲基,则R1不为甲基。
2.依据权利要求1的化合物,其特征为其对应于以下通式
其中R、R1、R2和n的含义如同依据权利要求1对式(I)或(I*)化合物的表述。
3.依据权利要求1或2的化合物,其中R为氢或C1-C8-烷基、特别优选氢或甲基。
4.依据权利要求1至3中任一项的化合物,其中R1为芳基或不饱和的杂环基、尤其特别优选任选单-或二取代的苯并呋喃基、苯并噻吩基、吲唑基、吲哚基、苯基、吡咯基、噻唑基、噻吩基或唑基。
5.依据权利要求1至4中任一项的化合物,其中R2为氢、卤素、C1-C8-烷基或芳基-C1-C4-烷基。
6.依据权利要求1的化合物,其中n为数字0或1。
7.依据权利要求2的化合物,其中
R为氢或C1-C8-烷基;
R1为芳基或不饱和的杂环基,在每种情况中,任选被卤素、氰基、三氟甲基、杂环基或C1-C8-烷基羰基取代;和R2为氢、卤素、C1-C8-烷基或芳基-C1-C4-烷基。
8.依据权利要求1至7中任一项的通式(I)或(I*)化合物在制备药物中的应用。
9.依据权利要求1至7中任一项的通式(I)或(I*)化合物在制备人用药物中的应用,所述药物用于对芳化酶抑制有反应的疾病或病症,特别是增殖性疾病的预防、治疗,或延迟所述疾病的进展。
10.对芳化酶抑制有反应的疾病或病症,特别是增殖性疾病的预防、治疗,或延迟所述疾病的进展的方法,所述方法使用有效治疗量的依据权利要求1至7中任一项的通式(I)或(I*)化合物。
11.包含依据权利要求1至7中任一项的通式(I)或(I*)化合物和常规赋形剂的药品。
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TW200804378A (en) * | 2005-12-09 | 2008-01-16 | Speedel Experimenta Ag | Organic compounds |
AR060225A1 (es) * | 2006-03-31 | 2008-06-04 | Speedel Experimenta Ag | Proceso para preparar 6,7- dihidro-5h-imidazo (1,5-a) piridin -8- ona |
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2005
- 2005-05-27 TW TW094117477A patent/TW200612947A/zh unknown
- 2005-05-27 WO PCT/EP2005/052419 patent/WO2005118581A1/en not_active Application Discontinuation
- 2005-05-27 EP EP05752767A patent/EP1749005A1/en not_active Withdrawn
- 2005-05-27 WO PCT/EP2005/052416 patent/WO2005118540A2/en not_active Application Discontinuation
- 2005-05-27 US US11/597,623 patent/US8680079B2/en not_active Expired - Fee Related
- 2005-05-27 EP EP05747969A patent/EP1765777A2/en not_active Withdrawn
- 2005-05-27 US US11/597,585 patent/US20080076784A1/en not_active Abandoned
- 2005-05-27 CA CA002568163A patent/CA2568163A1/en not_active Abandoned
- 2005-05-27 CN CNA2005800170603A patent/CN1968930A/zh active Pending
- 2005-05-27 CN CNA2005800173175A patent/CN1960991A/zh active Pending
- 2005-05-27 JP JP2007513939A patent/JP2008500997A/ja active Pending
- 2005-05-27 AR ARP050102196A patent/AR049125A1/es unknown
- 2005-05-27 TW TW094117480A patent/TW200616623A/zh unknown
- 2005-05-27 CA CA002568159A patent/CA2568159A1/en not_active Abandoned
- 2005-05-27 AR ARP050102199A patent/AR049126A1/es unknown
- 2005-05-27 BR BRPI0511621-0A patent/BRPI0511621A/pt not_active IP Right Cessation
- 2005-05-27 JP JP2007513942A patent/JP5179174B2/ja not_active Expired - Fee Related
- 2005-05-27 BR BRPI0510409-2A patent/BRPI0510409A/pt not_active IP Right Cessation
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WO2005118581A1 (en) | 2005-12-15 |
IL179408A0 (en) | 2007-05-15 |
WO2005118540A3 (en) | 2006-02-02 |
CN1960991A (zh) | 2007-05-09 |
BRPI0511621A (pt) | 2008-01-02 |
IL179406A0 (en) | 2007-05-15 |
JP2008501000A (ja) | 2008-01-17 |
US8680079B2 (en) | 2014-03-25 |
EP1765777A2 (en) | 2007-03-28 |
TW200616623A (en) | 2006-06-01 |
AR049126A1 (es) | 2006-06-28 |
WO2005118540A2 (en) | 2005-12-15 |
CA2568163A1 (en) | 2005-12-15 |
US20070225232A1 (en) | 2007-09-27 |
AR049125A1 (es) | 2006-06-28 |
US20080076784A1 (en) | 2008-03-27 |
JP5179174B2 (ja) | 2013-04-10 |
EP1749005A1 (en) | 2007-02-07 |
BRPI0510409A (pt) | 2007-10-23 |
JP2008500997A (ja) | 2008-01-17 |
CA2568159A1 (en) | 2005-12-15 |
TW200612947A (en) | 2006-05-01 |
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