CN102791688B - 雌激素受体配体 - Google Patents
雌激素受体配体 Download PDFInfo
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- CN102791688B CN102791688B CN201080045502.6A CN201080045502A CN102791688B CN 102791688 B CN102791688 B CN 102791688B CN 201080045502 A CN201080045502 A CN 201080045502A CN 102791688 B CN102791688 B CN 102791688B
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- hydroxyphenyl
- alkyl
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Classifications
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
本发明提供了一种式(I)的化合物或其可药用的酯、酰胺、溶剂化物或盐,包括所述酯或酰胺的盐以及所述酯、酰胺或盐的溶剂化物。本发明还提供了这类化合物用于治疗或预防与雌激素受体活性相关疾病或障碍有关的病症的用途。式(I),其中R1、R2、R3、R4、R5、R6、R7、R8、R9和R10如说明书中所定义。
Description
技术领域
本发明涉及作为雌激素受体配体(estrogen receptor ligand)且优选对β亚型雌激素受体有选择性的化合物,还涉及制备这类化合物的方法以及用该化合物治疗与雌激素受体相关的疾病的方法,所述疾病例如抑郁症(depressive disorder)、焦虑症(anxiety disorder)、阿尔兹海默氏病(Alzheimer’s disease)、认知障碍(cognitive disorder)、骨质疏松症(osteoporosis)、血液甘油三酯水平增高(elevated bloodtriglyceride level)、动脉粥样硬化(atherosclerosis)、子宫内膜异位(endometriosis)、尿失禁(urinary incontinence)、自身免疫性疾病(autoimmune disease)以及肺癌、结肠癌、乳腺癌、子宫癌和前列腺癌。
背景技术
雌激素受体(ER)是一种配体激活的参与上调和下调基因表达的哺乳动物转录因子。雌激素受体的天然激素是β-17-雌二醇(E2)和密切相关的代谢物。雌二醇与雌激素受体的结合可以引起受体二聚化,随后该二聚体又与DNA上的雌激素反应元件(ERE’s)结合。ER/DNA复合物可募集其它的转录因子,所述转录因子可负责将ERE下游DNA转录为mRNA,mRNA最终被翻译为蛋白质。或者,ER与DNA还可以通过其它转录因子——特别是fos和jun——的居间中间性(intermediacy)而间接地相互作用。由于许多基因的表达受到雌激素受体的调节,并且雌激素受体在许多细胞类型中都有表达,所以通过与天然激素或者合成ER配体的结合来对雌激素受体进行的调节可能对生物体的生理学或者病理生理学具有重要影响。
过去人们一直认为只有一种雌激素受体。但是有人已经发现了第二种亚型(ER-β)。虽然“经典”的ER-α和最近发现的ER-β广泛分布于不同的组织中,但是它们仍然显示出显著不同的细胞类型和组织分布。所以人工合成的ER-α或ER-β选择性配体既可以保留雌激素的有效作用也可以降低不想要的副作用风险。
雌激素在雌性的性发育中至关重要。另外,雌激素在保持骨密度、调节血脂水平方面有重要的作用,并且似乎还有神经保护作用。所以绝经女性的雌激素生成减少与许多疾病有关,例如骨质疏松症、动脉粥样硬化、抑郁和认知障碍。相反,某些类型的增生性疾病(如乳腺癌、子宫癌以及子宫内膜异位)是受到雌激素诱导的,所以抗雌激素(antiestrogens)(即雌激素拮抗剂)可用于预防和治疗这些类型的疾病。
而且,天然雌激素——17β-雌二醇——用于治疗各种形式的抑郁疾病的功效已被证实,并且有人已提出雌激素的抗抑郁活性可能是通过调节色氨酸羟化酶活性和随后的5-羟色胺(serotonin)的合成来介导的(参见例如,Lu N Z,Shlaes TA,Cundlah C,Dziennis S E,Lyle RE,Bethea C L,″Ovarian steroid action on tryptophan hydroxylaseprotein and serotonin compared to localization of ovarian steroidreceptors in midbrain of guinea pigs.″Endocrine 11:257-267,1999)。天然雌激素的多效性使其不能广泛和长期使用,因为这会增加乳房、子宫、卵巢组织增生的风险。雌激素受体ERβ的发现提供了一种鉴别出更多选择性雌激素试剂的方法,所述选择性雌激素试剂既具有所需的抗抑郁活性又不会发生ERα介导的增生效应。因而,证明了具有ERβ选择性的治疗药物在抑郁症治疗中有潜在的疗效。
本领域需要的是既可产生与雌激素替代疗法(estrogenreplacement therapy)同样的积极反应又没有不良副作用的化合物。同时,也需要能够对身体的不同组织发挥选择性效应的类雌激素化合物(estrogen-like compound)。
US 2003/0220377公开了一些可用作雌激素激动剂和拮抗剂的吲哚化合物以及它们在治疗雌激素介导的病症方面的潜在用途。JP 2001-122855公开了一些可用于治疗骨质疏松症的选择性作用于雌激素受体β的吲哚化合物。
本发明的化合物是雌激素受体的配体,因此可以被应用于治疗或预防多种与雌激素功能相关的病症。
发明内容
本发明提供了一种式(I)的化合物或者其可药用的酯、酰胺、溶剂合物或盐,包括所述酯或酰胺的盐以及所述酯、酰胺或盐的溶剂合物,
其中R1选自卤素、氰基、硝基、ORA、N(RB)2、-C(O)C1-4烷基、-SO2C1-4烷基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、二卤代C1-6烷基、三卤代C1-6烷基、卤代C2-6烯基、二卤代C2-6烯基、三卤代C2-6烯基、氰基C1-6烷基、C1-4烷氧基C1-6烷基、C3-8环烷基、C3-8环烷基C1-6烷基、苯基、苯甲基和5-10元杂环基,其中所述苯基、苯甲基或杂环基基团可以是未取代的或者被1-3个取代基取代的,每一个取代基独立地选自ORA、卤素、氰基、硝基、-C(O)C1-4烷基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、二卤代C1-6烷基和三卤代C1-6烷基;
R2选自氰基、硝基、N(OH)2、-CHO、-CH=N-OH、任选地被1-3个卤原子取代的-C(O)C1-4烷基、-SO2C1-4烷基、-C(O)NH-OH、-C(NH2)=N-OH、-C(CO2H)=N-OH、-C(NH2)=NH、-C(NH2)=N-NH2、-NH-C(NH2)=NH、-NH-C(O)NH2、-N=C(-NH-CH2CH2-NH-)、-S-CN、-S-C(NH2)=NH、-S-C(NH2)=N-OH、-CO2H、-CH(OH)CO2H、-C(O)N(RC)2、-SO2C1-6烷基、SO2N(RC)2、-C(O)-C(O)-NH2、-CH2NH-CONH2、-SO2ORC、-C(O)CO2H、-CH2SO3H和5-10元杂环基,其中所述杂环基基团可以是未被取代的或者被1-3个取代基取代的,每一个取代基独立地选自ORA、卤素、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、二卤代C1-6烷基和三卤代C1-6烷基;
R3、R4、R5、R6、R7、R8、R9和R10中每一个独立地选自氢、ORA、卤素、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、二卤代C1-6烷基和三卤代C1-6烷基;
每一个RA独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8环烷基C1-6烷基、苯基、苯甲基和5-10元杂环基,每一个基团任选地被1-3个卤素原子取代;以及
每一个RB独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8环烷基C1-6烷基、苯基、苯甲基和5-10元杂环基,每一个基团任选地被1-3个卤素原子取代;以及
每一个RC独立地选自氢和C1-6烷基。
本发明人意外地发现,本发明的化合物是雌激素受体的配体。所以本发明的化合物可用于治疗或预防与雌激素受体活性相关的疾病。
具体实施方式
本发明的化合物可以包含手性(不对称)中心或者整个分子是手性的。本发明的范围包括单个的立体异构体(对映异构体和非对映异构体)和它们的混合物。
本发明的一些化合物包括一个可以以(E)或(Z)型肟(oxime)异构体形式存在的肟基团。本发明的范围包括单个的(E)和(Z)型肟异构体和它们的混合物。本说明书通篇中,所示的肟结构用带有波浪线的键表示,这表明存在单一异构体但其立体化学未知,或者存在两种异构体的混合物。
本发明提供了作为雌激素受体配体的化合物。本文使用的术语“雌激素受体配体”旨在涵盖能够与雌激素受体结合的任何部分(moiety)。该配体可以作为激动剂(agonist)、部分激动剂(partial agonist)、拮抗剂(antagonist)或部分拮抗剂(antagonist)。该配体可以是ERβ选择性的或者表现出ERα和ERβ两者的混合活性。例如,该配体既可以作为ERβ的激动剂或部分激动剂,又可以作为ERα的拮抗剂或部分拮抗剂。本发明的化合物优选地为表现出ERβ选择性激动作用的雌激素受体配体。
当R1代表杂环基团的时候,该基团可以是饱和的或者不饱和的,并且可以包含一个或多个氧、氮和/或硫原子。优选5元环或6元环。在一个优选的实施方案中,其为6元环或者特别是5元环,并且优选是不饱和的,特别是芳族的。适合的杂环基基团包括呋喃基(furyl)、噻吩基(thienyl)、吡咯基(pyrrolyl)、吡咯啉基(pyrrolinyl)、吡咯烷基(pyrrolidinyl)、噁唑基(oxazolyl)、异噁唑基(isoxazolyl)、噻唑基(thiazolyl)、异噻唑基(isothiazolyl)、咪唑基(imidazolyl)、咪唑啉基(imidazolinyl)、咪唑烷基(imidazolidinyl)、吡唑基(pyrazolyl)、吡唑啉基(pyrazolinyl)、吡唑烷基(pyrazolidinyl)、吡啶基(pyridyl)、吗啉基(morpholinyl)和哌啶基(piperidyl),其中噻吩基、异噻唑基、特别是异噁唑基是特别优选的。杂环基基团优选的取代基包括1-3个,例如1或2个取代基,每一个取代基选自ORA、卤素、氰基、-C(O)C1-4烷基、C1-4烷基、C2-4烯基、C2-4炔基、卤代C1-4烷基、二卤代C1-4烷基和三卤代C1-4烷基。特别优选的取代基选自卤素、氰基、C1-4烷基(特别是甲基)、-C(O)C1-4烷基和ORA——其中RA优选地代表氢原子或C1-4烷基。更特别优选的取代基选自卤素、氰基和C1-4烷基(特别是甲基或乙基)。所以,在一个优选的实施方案中,R1是被两个甲基取代的上述基团之一,例如3,5-二甲基异噁唑-4-基、2,4-二甲基-噻吩-3-基或3,5-二甲基异噻唑-4-基。
R1为苯基时,优选的取代基包括上述R1为杂环基基团时那些取代基。
当R2代表杂环基基团时,该基团可以例如是上述R1的优选基团中的一个。
除非另有说明,每一个RA优选地独立地选自氢、C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、苯基和苯甲基。优选地,每一个RA独立地代表氢或者C1-4烷基,特别是甲基。
除非另有说明,每一个RB优选地独立地选自氢和C1-4烷基,特别是甲基。
除非另有说明,每一个RC优选地独立地选自氢和C1-4烷基,特别是甲基。在一个实施方案中,每一个RC均代表氢。
优选地,R1选自C1-6烷基、C2-6烯基、C2-6炔基、苯基或5-10元杂环基,其中所述苯基或杂环基基团可以是未取代的或者如上所述被取代。更优选地,R1选自C1-6烷基、C2-6烯基、C2-6炔基、苯基或5-10元杂环基,其中所述苯基或杂环基基团可以是未取代的或者被1-2个取代基取代的,每一个取代基独立地选自氰基或C1-6烷基。最优选地,R1代表苯基或5-6元杂环基基团,其中所述苯基或杂环基基团被1-2个取代基取代,所述取代基是C1-6烷基。在另一个优选实施方案中,R1代表苯基或5元杂环基基团,其中所述苯基或杂环基基团被两个取代基取代,所述取代基是甲基。例如,R1可以是2,5-二甲基苯基、3,5-二甲基异噁唑-4-基、2,4-二甲基-噻吩-3-基或3,5-二甲基异噻唑-4-基。
本发明的一个实施方案中,R2选自氰基、-CHO、-CH=N-OH、-C(O)NH-OH、-C(NH2)=N-OH、-C(CO2H)=N-OH、-C(NH2)=NH、-C(NH2)=N-NH2、-NH-C(NH2)=NH、-NH-C(O)NH2、-S-CN、-S-C(NH2)=NH、-S-C(NH2)=N-OH、-CO2H、-CH(OH)CO2H、-C(O)N(RC)2、SO2N(RC)2、-C(O)-C(O)-NH2、-CH2NH-CONH2、-SO2C1-6烷基、-SO2ORC、-C(O)CO2H、-CH2SO3H和5-6元杂环基,其中所述杂环基基团可以是未取代的或者被1-3个取代基取代的,每一个取代基独立地选自ORA、卤素、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、二卤代C1-6烷基和三卤代C1-6烷基。在本发明的一个优选的实施方案中,R2代表氰基、-CH=N-OH、-C(O)N(RC)2、-C(NH2)=N-OH、SO2N(RC)2、-SO2C1-6烷基、-SO2ORC或者未取代或被1-3个取代基取代的5-6元杂环基团,每一个取代基独立地选自ORA、卤素、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、二卤代C1-6烷基和三卤代C1-6烷基。更优选地,R2选自氰基、-CH=N-OH、-C(O)N(RC)2、-C(NH2)=N-OH、SO2N(RC)2、-SO2C1-4烷基和-SO2ORC。
本发明的另一个实施方案中,R2选自氰基、硝基、N(OH)2、-CHO、任选被1-3个卤原子取代的-C(O)C1-4烷基、-SO2C1-4烷基、-C(O)NH-OH、-C(NH2)=N-OH、-C(CO2H)=N-OH、-C(NH2)=NH、-C(NH2)=N-NH2、-NH-C(NH2)=NH、-NH-C(O)NH2、-N=C(-NH-CH2CH2-NH-)、-S-CN、-S-C(NH2)=NH、-S-C(NH2)=N-OH、-CO2H、-CH(OH)CO2H、-C(O)N(RC)2、-SO2C1-6烷基、-C(O)-C(O)-NH2、-CH2NH-CONH2、-SO2ORC、-C(O)CO2H、-CH2SO3H和5-10元杂环基团,其中所述杂环基团可以是未取代的或者被1-3个取代基取代的,每一个取代基独立地选自ORA、卤素、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、二卤代C1-6烷基和三卤代C1-6烷基。在本实施方案中,R2优选地代表氰基、-C(O)N(RC)2、-C(NH2)=N-OH、-SO2C1-6烷基、-SO2ORC或者未取代的或被1-3个取代基取代的5-6元杂环基团,其中每个取代基独立地选自ORA、卤素、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、二卤代C1-6烷基和三卤代C1-6烷基。本实施方案中,更优选地,R2选自氰基、-C(O)N(RC)2、-C(NH2)=N-OH、-SO2C1-4烷基和-SO2ORC。
优选地,R2选自-C(NH2)=N-OH或-C(O)N(RC)2,特别是-C(NH2)=N-OH或C(O)NH2,特别是-C(NH2)=N-OH。
优选地,R3、R4、R5、R6、R7、R8、R9和R10各自选自氢、ORA、卤素、氰基、C1-4烷基例如甲基、卤代C1-4烷基例如氯代或氟代甲基、二卤代C1-4烷基例如二氯或二氟甲基,和三卤代C1-4烷基例如三氯或三氟甲基。优选地,R3、R4、R5、R6、R7、R8、R9和R10各自选自氢、OH、卤素、氰基、甲基或三氟甲基。最优选地,R3、R4、R5、R6、R7、R8、R9和R10各自独立地代表氢和/或卤素,特别是氯,或尤其是氟。在尤其优选的实施方案中,R3、R4、R5和R6各自代表氢。在另一个优选的实施方案中,R7、R8、R9和R10各自代表氢,并且R7、R8、R9和R10中的一个或两个代表卤素,特别是氟,R7、R8、R9和R10中其余的代表氢。
式(I)的化合物包括但不限于本申请实施例中具体提及的化合物。
式(I)的其他化合物包括但不限于如下化合物:
2-(2,5-二甲基-1氢-吡咯-1-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺(carboximidamide)、
2-(1,4-二甲基-1氢-吡唑-5-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺、
2-(2,5-二甲基吡咯烷-1-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺、
N′-羟基-3-(4-羟苯基)-2-(吡咯烷-1-基)-1H-吲哚-1-甲亚胺酰胺、
5-氯-2-(3,5-二甲基异噁唑-4-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺、
2-(5-氟-2,4-二甲基呋喃-3-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺、
2-(5-氯-2,4-二甲基呋喃-3-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺、
2-(1,3-二甲基-1氢-吡咯-2-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺、
2-(1,4-二甲基-1氢-咪唑-5-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺、
2-(2,5-二甲基-1氢-咪唑-1-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺、
2-(5-氟-2,4-二甲基呋喃-3-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺、
2-(5-氯-2,4-二甲基呋喃-3-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺、
2-(1,3-二甲基-1氢-吡咯-2-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺、
2-(1,4-二甲基-1氢-咪唑-5-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺、
2-(2,5-二甲基-1氢-咪唑-1-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺,
或者它们的可药用的酯、酰胺、溶剂合物或盐,包括所述酯或酰胺的盐,以及所述酯、酰胺或盐的溶剂合物。
在以上所列的化合物以及实施例的化合物中,化合物是根据IUPAC通过ACD Labs 8.0/name program(8.05版)和/或用ISISDRAW Autonom 2000和/或ChemBioDraw Ultra(11.0版)命名的。
根据式I化合物中存在的取代基不同,所述化合物可以形成酯、酰胺、氨基甲酸酯和/或盐。适合药用的式(I)化合物的盐和溶剂合物为那些其中反荷离子或相关溶剂是可药用的盐和溶剂合物。但是含有非可药用的反荷离子或相关溶剂的盐和溶剂合物也包含在本发明的范围之内,例如,用作在制备式(I)化合物以及它们的可药用盐、溶剂合物和具有生理功能的衍生物过程中的中间体。术语“具有生理功能的衍生物”是指具有与式(I)的游离化合物相同生理功能的式(I)化合物的化学衍生物,例如通过在体内转化。酯、酰胺和氨基甲酸酯均是具有生理功能衍生物的例子。
本发明中的合适盐包括与有机或无机的酸或碱形成的盐。具体而言,本发明的与酸形成的合适盐包括与无机酸、强有机羧酸或有机磺酸形成的盐,所述强有机羧酸例如未取代的或被例如卤素取代的1-4个碳原子的烷羧酸(alkanecarboxylic acid),例如饱和的或者不饱和的二羧酸(dicarboxylic acid),例如羟基羧酸,例如氨基酸;所述有机磺酸例如未被取代的或被例如卤素等取代的(C1-C4)-烷基-或芳基-磺酸。可药用的酸加成盐包括由如下酸形成的酸加成盐:盐酸、氢溴酸、硫酸、硝酸、柠檬酸、酒石酸、乙酸、磷酸、乳酸、丙酮酸、乙酸、三氟乙酸、琥珀酸、高氯酸、反丁烯二酸、马来酸、羟基乙酸、乳酸、水杨酸、草酰乙酸、甲磺酸、乙磺酸、对甲苯磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸、羟乙基磺酸、抗坏血酸、苹果酸、苯二甲酸、天冬氨酸、谷氨酸、赖氨酸和精氨酸。其它的酸例如草酸,虽然本身不可药用,但是可以作为获得本发明化合物或者它们的可药用的酸加成盐的中间体使用。
可药用的碱盐包括铵盐、碱金属盐例如钾盐和钠盐、碱土金属盐例如钙盐和镁盐,以及有机碱形成的盐例如二环己胺、N-甲基-D-葡萄糖胺(glucomine)、吗啉、硫代吗啉、哌啶、吡咯烷,单低级烷基胺、二低级烷基胺或三低级烷基胺,例如乙胺、叔丁基胺、二乙胺、二异丙胺、三乙胺、三丁胺或二甲基丙胺,或者单羟基、二羟基或三羟基低烷基胺,例如单乙醇胺、二乙醇胺或三乙醇胺。而且,还可以形成相应的内盐。
式(I)化合物可以具有可转变成为酯、酰胺或氨基甲酸酯的合适基团。因而,式(I)的化合物中由酸基团形成的典型酯和酰胺基团包括:-COORB、-CONRB 2、-SO2ORB或-SO2N(RB)2;而式I化合物中由-OH或-NHRB基团形成的的典型酯、酰胺和氨基甲酸酯基团包括:-OC(O)RB、-NRBC(O)RB、-NRBCO2RB、-OSO2RB和-NRBSO2RB,其中RB具有上文给出的含义之一。
有机化学领域的技术人员会理解,许多有机化合物能够与它们发生反应时所处其中的溶剂或者它们从其中形成沉淀或结晶的溶剂形成复合物。这种复合物称为“溶剂合物”。例如,与水形成的复合物称为“水合物”。
在给予受者后能够转化成为上述的式(I)化合物或其活性代谢物或残基的化合物称为“前药”。例如,前药可以通过例如在血液中水解等方式在体内转化成其有药效的活性形式。可药用的前药在T.Higuchi and V.Stella,Prodrugs as Novel Delivery Systems,Vol.14 ofthe A.C.S.Symposium Series(1976));“Design of Prodrugs”ed.H.Bundgaard,Elsevier,1985;以及在Edward B.Roche,ed.,BioreversibleCarriers in Drug Design,American Pharmaceutical Association andPergamon Press,1987中有所描述,所述文献以引用的方式纳入本文。
除非在具体情况下另有限定,下述定义适用于本说明书全文所用的术语。
本文所用的术语“烷基”表示直链和支链的饱和烃基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、戊基和己基。在非支链烷基中,优选甲基、乙基、正丙基、异丙基、正丁基和正戊基。在支链烷基中,可能提及的有异丙基、叔丁基、异丁基、1-乙基丙基和1-乙基丁基。
本文所用的术语“烷氧基”表示O-烷基,其中“烷基”如上所述。烷氧基的例子包括甲氧基和乙氧基。其他的例子包括丙氧基和丁氧基。
本文所用的术语“烯基”表示含有至少一个碳碳双键的直链和支链不饱和烃基。烯基的例子包括乙烯基、丙烯基、丁烯基、戊烯基和己烯基。优选的烯基包括乙烯基、1-丙烯基、2-丙烯基和丁-2-烯基。
本文所用的术语“炔基”表示含有至少一个碳碳三键的直链和支链不饱和烃基。炔基的例子包括乙炔基、丙炔基、丁炔基、戊炔基和己炔基。优选的炔基包括乙炔基、1-丙炔基和2-丙炔基。
此处所用的术语“环烷基”表示环系的饱和基团。环烷基可以是单环或者二环。二环基团可以例如为稠合或桥接的。单环的环烷基的例子包括环丙烷、环丁烷和环戊烷。单环的环烷基的其他例子有环己烷、环庚烷和环辛烷。二环的环烷基的实例包括二环[2.2.1]庚-2-基。优选环烷基是单环的环烷基。
本文所用的术语“芳基”表示单环或二环芳族碳环。芳基的例子包括苯基和萘基。萘基可以通过1位或2位连接基团。在二环芳基中,其中一个环可以例如是部分饱和的。这类基团的例子包括茚满基(indanyl)和四氢萘基。具体而言,本文所用的术语C5-10芳基表示在单环或二环芳基中含有5-10个碳原子。尤其优选的C5-10芳基是苯基。
本文所用的术语“卤素”表示氟、氯、溴或者碘。尤其优选的是氟、氯和溴。
本文所用的术语“卤代烷基”表示具有卤素取代基的烷基,术语“烷基”和“卤素”的含义应理解为具有如上所述含义。类似地,术语“二卤代烷基”表示两个卤素取代基的烷基,术语“三卤代烷基”表示有三个卤素取代基的烷基。卤代烷基的例子包括氟代甲基、氯代甲基、溴代甲基、氟代甲基、氟代丙基和氟代丁基;二卤代烷基的例子包括二氟甲基和二氟乙基;三卤代烷基的例子包括三氟甲基和三氟乙基。
此处所用的术语“杂环基”表示其中1-3个碳原子被一个或多个独立地选自氮、氧或硫的杂原子替代形成的芳族或非芳族碳环基团。杂环基团可以例如为单环或二环基团。在二环杂环基团中,每一个环或者只有其中的一个环上可以有一个或者多个杂原子。杂原子可以例如是氧原子或氮原子。含有合适的氮原子的杂环基团包括相应的氮氧化物。
单环的非芳族杂环基团(也称为单环的杂环烷基环)的实例包括吖丙啶基(aziridinyl)、氮杂环丁基(azetidinyl)、吡咯烷基(pyrrolidinyl)、咪唑烷基(imidazolidinyl)、吡唑烷基(pyrazolidinyl)、哌啶基(piperidinyl)、哌嗪基(piperazinyl)、四氢呋喃基(tetrahydrofuranyl)、四氢吡喃基(tetrahydropyranyl)、吗啉基(morpholinyl)、硫代吗啉基(thiomorpholinyl)和氮杂环庚烷基(azepanyl)。
其中一个环是非芳族环的二环杂环基团的实例包括二氢苯并呋喃基(dihydro benzofuranyl)、茚满基(indanyl)、二氢吲哚基(indolinyl)、异二氢吲哚基(isoindolinyl)、四氢异喹啉基(tetrahydroisoquinolinyl)、四氢喹啉基(tetrahydroquinolyl)和苯并氮杂环庚基(benzoazepanyl)。
单环芳族杂环基团(也称为单环杂芳基基团)的实例包括呋喃基(furanyl)、噻吩基(thienyl)、吡咯基(pyrrolyl)、噁唑基(oxazolyl)、噻唑基(thiazolyl)、咪唑基(imidazolyl)、噁二唑基(oxadiazolyl)、噻二唑基(thiadiazolyl)、吡啶基(pyridyl)、三唑基(triazolyl)、三嗪基(triazinyl)、哒嗪基(pyridazyl)、异噻唑基(isothiazolyl)、异噁唑基(isoxazolyl)、吡嗪基(pyrazinyl)、吡唑基(pyrazolyl)和嘧啶基(pyrimidinyl)。
二环芳族杂环基团(也称为双环杂芳基基团)的实例包括喹喔啉基(quinoxalinyl)、喹唑啉基(quinazolinyl)、吡啶并吡嗪基(pyridopyrazinyl)、苯并噁唑基(benzoxazolyl)、苯并苯硫基(benzothiophenyl)、苯并咪唑基(benzimidazolyl)、1,5-二氮杂萘基(naphthyridinyl)、喹啉基(quinolinyl)、苯并呋喃基(benzofuranyl)、吲哚基(indolyl)、苯并噻唑(benzothiazolyl)、噁唑基[4,5-b]吡啶基(oxazolyl[4,5-b]pyridiyl)、吡啶并嘧啶基(pyridopyrimidinyl)、异喹啉基(isoquinolinyl)和苯并二噁唑(benzodroxazole)。
优选的杂环基团的实例包括哌啶基(piperidinyl)、四氢呋喃基(tetrahydrofuranyl)、四氢吡喃基(tetrahydropyranyl)、吡啶基(pyridyl)、嘧啶基(pyrimidinyl)和吲哚基。优选的杂环基团还包括噻吩基(thienyl)、噻唑基(thiazolyl)、呋喃基(furanyl)、吡唑基(pyrazolyl)、吡咯基(pyrrolyl)、异噁唑基(isoxazolyl)和咪唑基(imidazolyl)。
本文所用的术语“环烷基烷基”表示通过烷基相连接的环烷基-烷基-,其中“环烷基”和“烷基”应理解为具有如上所述的含义。
如上所述,本发明的化合物具有雌激素受体配体活性。本发明的化合物具有雌激素受体调节剂活性,可以是雌激素受体的激动剂、部分激动剂、拮抗剂或部分拮抗剂。尤其优选的本发明化合物具有ERβ的激动剂或部分激动剂活性。优选的此类化合物为雌激素受体β(ERβ)的选择性激动剂。
由此,本发明中的化合物可以用于治疗雌激素受体活性相关的疾病或病症。具体而言,作为雌激素受体激动剂或部分激动剂的本发明化合物可用于治疗选择性雌激素受体激动剂或部分激动剂被指明可用的疾病或病症。作为雌激素受体的拮抗剂或部分拮抗剂的本发明化合物可用于治疗选择性雌激素受体拮抗剂或部分拮抗剂被指明可用的疾病或病症。
激动剂或部分激动剂被指明可用的临床病症包括但不限于:骨丢失(bone loss)、骨折(bone fracture)、骨质疏松、软骨退变(cartilagedegeneration)、子宫内膜异位(endometriosis)、子宫平滑肌瘤(uterinefibroid disease)、热潮红(hot flush)、LDL胆固醇水平升高(increasedlevels of LDL cholesterol)、心血管疾病(cardiovascular disease)、认知功能损害(impairment of cognitive functioning)、脑变性疾病(cerebral degenerative disorder)、再狭窄(restenosis)、男子乳腺发育(gynecomastia)、血管平滑肌细胞增生(vascular smooth musclecell proliferation)、肥胖症(obesity)、失禁(incontinence)、焦虑(anxiety)、抑郁(depression)、自身免疫性疾病、炎症(inflammation)、炎性肠病(IBD)、肠应激综合征(IBS)、性功能障碍(sexualdysfunction)、高血压(hypertension)、视网膜变性(retinaldegeneration)、以及肺、结肠、乳房、子宫和前列腺癌症,和/或雌激素功能相关的病症。
本发明中的化合物可具体用于预防或治疗下述病症:骨丢失、骨折、骨质疏松、软骨退变、子宫内膜异位、子宫平滑肌瘤、热潮红、LDL胆固醇水平升高、心血管疾病、认知功能损害、年龄相关的轻度认知功能损害、脑变性疾病、再狭窄、男子乳腺发育、血管平滑肌细胞增生、肥胖症、失禁、焦虑、抑郁、围绝经期抑郁(perimenopausaldepression)、产后抑郁(post-partum depression)、月经前期综合症(premenstrual syndrome)、狂躁抑郁(manic depression)、痴呆(dementia)、强迫行为(obsessive compulsive behavior)、注意力缺陷障碍(attention deficit disorder)、伴多动注意力缺陷障碍(attention deficit hyperactivity disorder)、睡眠障碍(sleepdisorders)、易激惹(irritability)、冲动(impulsivity)、愤怒管理(anger management)、听力障碍(hearing disorder)、多发性硬化症(multiple sclerosis)、帕金森氏病(Parkinson’s disease)、阿尔兹海默氏病(Alzheimer’s disease)、亨廷顿氏病(Huntington’s disease)、肌萎缩侧索硬化(amyotrophic lateral sclerosis)、脊髓损伤(spinal cordinjury)、中风(stroke)、自身免疫性疾病、炎症、IBD、IBS、性功能障碍、高血压、视网膜变性、以及肺癌、结肠癌、乳腺癌、子宫癌、前列腺癌以及被称为胆管癌(cholangiocarcinoma)的胆管癌症形式。本发明的化合物也可还具体用于治疗或预防下述病症:良性前列腺增生症(benign prostatic hyperplasia)、下泌尿道综合症(lower urinarytract symptom)、膀胱活动过度(overactive bladder)、间质性膀胱炎(interstitial cystitis)、膀胱疼痛综合症(painful bladder symptom)、阴道萎缩(vaginal atrophy)、伤口愈合(wound healing)、慢性疼痛(chronic pain)、脓毒症(sepsis)、炎性神经痛(inflammatory andneuropathic pain)、卵巢癌(ovarian cancer)、黑色素瘤(melanoma)和淋巴瘤(lymphoma)(B细胞淋巴瘤、T细胞淋巴瘤)。
本发明的药物也可以与已知能够诱导血管舒缩(vasomotor)症状的药物联合使用,用于如下用途:与选择性雌激素受体调节剂(SERM)例如他莫西芬(tamoxifen)联合用于治疗乳腺癌,与雷洛昔芬联合用于治疗和/或预防骨质疏松症,从而缓解SERM诱导的血管舒缩症状;与芳香酶抑制剂联合用于治疗乳腺癌或子宫内膜异位,以缓解芳香酶抑制剂诱导的血管舒缩症状;以及用于进行了雄激素去势治疗(androgen deprivation)的男性前列腺癌患者。
本发明的一个实施方案中,本发明的化合物可用于治疗或预防抑郁症、围绝经期抑郁症、产后抑郁症、月经前期综合征和狂躁抑郁症。
对男性热潮红的治疗或预防优选用于因前列腺癌症治疗而导致雄激素缺失的患者。
术语“抑郁症”包括但不限于严重的抑郁性障碍、心境恶劣障碍、双向型障碍、循环情感性精神障碍、一般医疗状况引起的心境障碍、物质诱导的心境障碍、季节性情感障碍(SAD)、产后精神抑郁和月经前焦虑障碍。
本发明还提供了在哺乳动物中治疗或预防雌激素受体介导的病症的方法,所述方法包括给予所述哺乳动物治疗有效量的本发明的化合物。可通过本发明方法治疗的雌激素受体介导的临床病症优选上文所列的那些病症。
本发明还提供了本发明的化合物用于制造治疗或预防雌激素受体介导病症的药剂的用途。可通过本发明方法治疗的雌激素受体介导的临床病症优选上文所列的那些病症。
要达到治疗效果的活性成分的量当然会随着具体化合物、给药途径、正在治疗的受试者(包括体型、物种、年龄、体重、性别,受试者的医疗状况以及受试者的肝肾功能),以及所治疗的具体病症或疾病及其严重程度而变化。具有普通技术水平的内科医生、兽医或者临床医生可以容易地确定需要预防、对抗或阻止病症进程的药物有效量并开出处方。
当用于产生上述作用时,本发明的成人口服剂量应介于每天每千克体重约0.01mg(mg/kg/日)至大约100mg/kg/日,优选0.01-10mg/kg/日,最优选0.1-5.0mg/kg/日。口服时,所述组合物优选以片剂形式提供,或以含0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100和500毫克活性成分的离散单位提供,用于对给予待治疗患者的剂量进行症状调节。药剂通常含有约0.01mg至约500mg活性成分,优选约1mg至约100mg活性成分。静脉注射时,最优选的剂量范围为在恒定速率输注时约0.1至大约10mg/kg/min。本发明化合物可有利地以每日单剂量给药,或者每日总剂量可以分成每日两次、三次或四次的剂量给药。另外,本发明的优选化合物可以通过局部应用合适的鼻内运送工具以鼻内形式给药或者应用本领域普通技术人员所熟知的透皮贴剂形式通过经皮途径给药。以经皮送递系统形式给药时,所述剂量给药当然应在整个剂量方案中为持续给药,而不是间断性给药。
虽然可以单独给予活性成分,但是优选其存在于药物制剂或组合物中。相应地,本发明提供了一种含有本发明化合物和可药用的稀释剂、赋形剂或载体(此处通称作“载体”材料)的药物制剂。本发明的药物组合物可以采用下述药物制剂的形式。
本发明的药物制剂包括适合于口服、肠胃外(包括皮下注射、真皮内注射、肌内注射、静脉注射(推注或输注)和关节内注射)、吸入(包括微小颗粒粉剂或可由各种类型的定量剂量加压气雾剂产生的气雾)、喷雾器或吹入器、直肠、腹膜内或局部(包括皮肤、含服、舌下和眼内)给药,但最适合的途径可依据例如受者的疾病或病症确定。
所述制剂可方便地以单位剂量形式存在,也可通过药学领域中公知的方法制备。所有的方法都包括将活性成分与构成一种或多种辅助成分的载体混合。总的说来,通过将活性成分与液态载体和/或粉末固体载体直接均一混合,并且,如果必要将产品制成所需要的制剂形状。
适合口服给药的本发明制剂可以如下形式存在:分散单位,例如胶囊、扁胶囊、丸剂或片剂,每个单位含有预定量的活性成分;粉末或颗粒;水性或非水性液体中的溶液或悬浮液,例如酏剂(elixir)、酊剂(tincture)、悬液或糖浆;或水包油液体乳剂或油包水液体乳剂。所述活性成分也可以是大丸剂、药糖剂或膏剂形式。
片剂可以通过压制或模塑制成,任选地使用一种或多种辅助成分。压制片可以通过在合适的机器中将自由流动形式(例如粉末或颗粒形式)的活性成分进行压制而制备而成,任选的与粘合剂、润滑剂、惰性稀释剂、润滑剂、表面活性剂或者分散剂混合。模印片可以通过在合适的机器中将以惰性液体稀释剂湿润的粉末状化合物的混合物进行模塑制成。片剂可任选地进行包衣或者刻印,并且可以配制成缓慢释放或可控地释放活性成分的形式。本发明的化合物可以例如以适于速效释放或延长释放的形式给药。速效释放或延长释放可以通过使用合适的含有本发明化合物的药物组合物实现,或者具体地就延长释放而言,可以通过使用诸如皮下植入物或渗透泵等装置实现。本发明的化合物也可以脂质体形式给药。
用于口服的示例组合物包括可含如下成分的悬液,例如用于填充体积的微晶纤维素、作为助悬剂的海藻酸或海藻酸钠、作为增粘剂的甲基纤维素,以及增甜剂或调味剂例如本领域中已知的那些;以及可含如下成分的速释片,例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁、硫酸钙、山梨醇、葡萄糖和/或乳糖和/或其它的赋形剂、粘合剂、增容剂、崩解剂、稀释剂和润滑剂,例如本领域已知的那些。合适的粘合剂包括淀粉、明胶、天然糖例如葡萄糖或β-乳糖、玉米增甜剂、天然或合成胶如阿拉伯胶(acacia)、西黄芪树胶(tragacanth)或海藻酸钠、羧甲基纤维素、聚乙二醇和蜡类等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土(bentonite)和黄胞胶(xanthan gum)等。式(I)的化合物也可以以舌下和/或含服方式通过口腔给药。模制片、压制片或冷冻干燥片均为可以使用的示例形式。示例的组合物还包括以速溶稀释剂(例如甘露醇、乳糖、蔗糖和/或环糊精)配制本发明化合物的组合物。这类制剂还可含有高分子量赋形剂,例如纤维素(微晶粉末纤维素)或聚乙二醇(PEG)。这类制剂还可含有帮助增加粘膜附着能力的赋形剂,例如羟丙基纤维素(HPC)、羟丙甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)、马来酸酐共聚物(例如Gantrez等),以及能够控制释放的试剂,例如聚丙烯酸共聚物(例如卡波姆934等)。为制造和使用方便,也可以加入润滑剂、助流剂、调味剂、增色剂和稳定剂。用于这些剂型中的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、醋酸钠和氯化钠等。对于液体形式的口服给药,口服药物成分可以与任何口服的、无毒性的、可药用的惰性载体(例如乙醇、甘油和水等)联合使用。
本发明中的化合物也可以脂质体送递系统给药,例如小单室囊泡、大单室囊泡和多室囊泡。脂质体可以由多种磷酯——1,2-二棕榈酰磷脂酰胆碱、磷脂酰乙醇胺(脑磷脂)或磷脂酰胆碱(卵磷酯)——形成。
肠胃外给药的制剂包括可含有如下成分的水性或非水性无菌注射液:抗氧化剂、缓冲剂、抑菌剂和使制剂与目标受体血液等渗的溶质;以及可含悬浮剂和增稠剂的水性或非水性无菌悬浮液。所述制剂可以是单剂量或多剂量容器形式,例如封口的安剖和小瓶,并且可以在冷冻干燥(冻干)条件下储存,只需要在临用前加入诸如盐水或注射用水等无菌液体载体。临时注射溶液和悬浮液可以用无菌的粉末、颗粒和前文所述种类的片剂制成。肠胃外给药的示例组合物包括可以含有如下组分的可注射溶液或悬浮液:例如合适的无毒肠胃外可用的稀释剂或溶剂,例如甘露醇、1,3-丁二醇、水、林格氏液、等渗氯化钠溶液或其它适合的分散剂或湿润剂和助悬剂,包括合成的甘油单酯或甘油二酯,和脂肪酸包括油酸或Cremaphor。
用于鼻腔给药、气雾给药或吸入给药的示例组合物包括盐水形式的溶液,其可含有例如苯甲醇或其它适合的防腐剂、增强生物利用度的吸收促进剂和/或其它增溶剂或分散剂,例如本领域已知的那些。
直肠给药制剂可以是含常用载体的栓剂形式,所述常用载体例如可可脂、合成甘油酯或聚乙二醇。此类载体通常在常温下是固体,但是在肠腔内会液化和/或溶解从而释放出所述药物。
口腔局部给药(例如含服或舌下)的制剂包括在(诸如蔗糖和阿拉伯胶或西黄芪树胶)调味剂基质中含活性成分的糖锭剂和在(诸如明胶、甘油或蔗糖和阿拉伯胶)基质中含活性成分的软锭剂。局部给药的示例性组合物包括诸如Plastibase(以聚乙烯胶化的矿物油)的局部给药载体。
优选的单位剂量制剂为含有如上所述有效剂量或其合适部分量的活性成分的制剂。
应理解,除了上述具体提到的组分外,本发明的制剂还可以包含与目的制剂类型有关的本领域常用的其它试剂,例如适合口服的其他试剂可包括调味剂。
本发明的化合物既可以作为药剂中唯一的活性成分,也可以与一种或多种其它活性药剂联合使用。所述其它活性药剂可以是本发明的其它化合物,或者它们可以是不同的治疗药剂,例如抗抑郁药、抗焦虑药、抗精神病药、可用于预防或治疗骨质疏松的药物、可用于预防或治疗癌症的药物或其它药物活性物质。例如,本发明的化合物可以与有效量的其他药剂有效地联合给药,所述其他药剂例如抗抑郁药、抗焦虑药、抗精神病药、有机二膦酸盐或组织蛋白酶K(cathepsin K)抑制剂。在一个优选的实施方案中,本发明的化合物可以与有效量的抗抑郁药有效地联合给药。抗抑郁药的非限制性实例包括去甲肾上腺素再吸收抑制剂(noradrenaline reuptake inhibitor,NRI)、选择性5-羟色胺再吸收抑制剂(selective serotonin reuptake inhibitor)、单胺氧化酶抑制剂(monoamine oxidase inhibitor)、三环抗抑郁药(tricyclicantidepressant,TCA)、多巴胺再吸收抑制剂(dopamine reuptakeinhibitor,DRI)、阿片样物质(opioid)、选择性5-羟色胺再吸收增强剂(selective seretonic reuptake enhancer)、四环类抗抑郁剂(tetracyclic antidepressant)、单胺氧化酶可逆抑制剂(reversibleinhibitor of monoamine oxidase)、退黑激素激动剂(melatoninagonist)、5-羟色胺和去甲肾上腺素再吸收抑制剂(serotonin andnoradrenaline reuptake inhibitor,SNRI)、促肾上腺皮质激素释放因子拮抗剂(corticotropin releasing factor antagonist)、α-肾上腺素能受体拮抗剂(α-adrenoreceptor antagonist)、5HT1α受体激动剂和拮抗剂(5HT1α receptor agonist and antagonist)、锂和非典型抗精神病药(atypical anti-psychotics)。SSRI类抗抑郁剂的例子包括氟西汀(Fluoxetine)和舍曲林(Sertraline);SNRI类抗抑郁剂的例子包括文拉法辛(Venlafaxine)、西酞普兰(Citalopram)、帕罗西汀(Paroxetine)、依他普仑(Escitalopram)、氟伏沙明(Fluvoxamine);SNRI类抗抑郁剂的例子包括度洛西汀(Duloxetine);DRI和NRI类抗抑郁剂的例子包括丁氨苯丙酮(Bupropion);TCA类抗抑郁剂的例子包括阿米替林(Amitriptyline)和二苯噻庚英(Dothiepin)(度硫平(Dosulepin))。非典型抗精神病药的例子包括:氯氮平(Clozapine)、奥氮平(Olanzapine)、利培酮(Risperidone)、喹硫平(Quetiapine)、齐拉西酮(Ziprasidone)和多巴胺部分激动剂。抗焦虑药的非限制性例子包括苯并二氮卓类(benzodiazepine)和非苯(并)二氮卓类(non-benzodiazapine)。苯并二氮卓类的例子包括劳拉西泮(lorazepam)、阿普唑仑(alprazolam)和地西泮(diazepam)。非苯并二氮卓类的例子包括丁螺环酮(Buspirone)(Buspar)、巴比妥类(barbiturate)和甲丙氨酯(meprobamate)。可以联合使用一种或多种那些其他的抗抑郁药。
抗癌药的实例包括治疗乳腺癌时使用的他莫昔芬(tamoxifene)或芳香酶抑制剂。
当具体治疗诱导热潮红时,本发明的化合物可与该治疗的药剂联合使用。这类联合治疗疗法的非限制性实例包括:本发明的化合物与治疗乳腺癌的他莫昔芬联合、本发明的化合物与治疗乳腺癌的芳香酶抑制剂联合或本发明的化合物与治疗骨质疏松症的雷洛昔芬联合。
上述有机二膦酸盐的非限制性实例包括:阿仑膦酸盐(adendronate)、氯膦酸盐(clodronate)、依替膦酸盐(etidronate)、伊班膦酸盐(ibandronate)、伊卡膦酸盐(incadronate)、米诺膦酸盐(minodronate)、奈立磷酸盐(neridronate)、利塞膦酸盐(risedronate)、吡利膦酸盐(piridronate)、帕米膦酸盐(pamidronate)、替鲁膦酸盐(tiludronate)、唑来膦酸盐(zoledronate)和其可药用的盐或酯或其混合物。优选的有机二膦酸盐包括阿仑膦酸盐(alendronate)和其可药用的盐和混合物。最优选的是阿仑膦酸单钠三水合物(alendronate monosodium trihydrate)。
所述二膦酸盐的精确剂量依据给药方案、具体所选二膦酸的口服效能、哺乳动物或人的年龄、体型、性别和身体状况、待治疗疾病的性质和严重程度以及其它相关的医学或生理因素等确定。所以,精确的药学有效量无法预先规定,但其可由护理员或临床医师容易地确定。可以通过常规的动物模型试验和人类临床研究确定合适的量。总体来说,所选择的二膦酸盐的合适量使得可以达到抑制骨再吸收的作用,也就是说可以给予抑制骨再吸收的量的二膦酸盐。对人类来说,二膦酸盐的有效口服剂量通常为约1.5至约6000μg/kg体重,优选约10至约2000μg/kg体重。
对于含阿仑膦酸盐、其可药用盐或其可药用衍生物的人口服组合物,单位剂量一般包含以阿仑膦酸有效重量计(即以相应的酸计)约8.75mg-约140mg阿仑膦酸盐。
本发明的化合物可以与其它用于治疗雌激素介导病症的药物联合使用。这类联合药物形式的各组分可以在治疗过程中的不同时间分别给药或者在以分散的或单一的联合形式同时给药。所以本发明应理解为包括所有的同时或者交替治疗的这类方案,术语“给药(administering)”也相应地按此理解。应理解,本发明的化合物与其它用于治疗雌激素介导病症的药物的联合形式的范围涵盖了原则上任何与任何用于治疗雌激素功能相关疾病的药物组合物联合的形式。
当与本发明的化合物联合使用时,上述其他治疗试剂可以例如按照Physicians′Desk Reference(PDR)中所述的用量或者由本领域普通技术人员确定的量使用。
当本发明的化合物与一种或多种其它治疗试剂联合使用时,无论同时或者惯序给药,都优选下述混合比例和剂量范围:
当与抗抑郁药、抗焦虑药、抗精神病药、有机二膦酸盐或组织蛋白酶K抑制剂联合使用时,式(I)的化合物可以与所述另一试剂以约10:1至约1:10的比例使用。
上述本发明的化合物也可以任选地以标记的形式用作诊断与雌激素受体功能障碍相关的疾病的诊断药物。例如该化合物可以是放射性标记的形式。
上述本发明的化合物也可以任选地以标记的形式在用于找寻其他雌激素受体激动剂、部分激动剂、拮抗剂或部分拮抗剂的方法中用作参比化合物。因此,本发明提供了一种发现雌激素受体配体的方法,其包括使用本发明的化合物或经标记形式的本发明化合物作为参比化合物。例如,该方法可包括一个竞争性结合试验,其中本发明中的化合物与雌激素受体结合作用因存在另一种具有雌激素受体结合特征的化合物而下降,例如所述具有雌激素受体结合特征的另一种化合物具有比本发明的目标化合物更强的雌激素受体结合特征。
本领域的技术人员可以设计许多本发明化合物的合成路线,本发明并不受下述可能的合成路线的限制。文献中有许多用于合成吲哚化合物的方法,例如:Indoles Part One,W.J.Houlihan(ed.),1972;Indoles,Sundberg,R.J.,1996;Heterocyclic Chemistry,Joule,J.A.;Mills,K.2000;Chem.Rev.,2005,105,2873-2920;Org.Lett.2006,8,5919-5922;Bioorg.Med.Chem.Lett.,2007,17,902-906;US 2003/0220377;JP 2001-122855;和Chem.Pharm.Bull.,2007,55(2),328-333。下文示例性地示出了一些可能的合成路线。如果合适,任何初始生成的本发明化合物都可以通过已知的方法转化成另一种本发明的化合物。
通用方法I
下述通用方法可以用于制备R2为氰基、-C(NH2)=NOH或-C(O)NH2的式(I)的化合物。
(a)4-甲氧苯基硼酸,Pd(PPh3)4,碳酸氢钠,DME/H2O;
(b)碳酸钾,甲醇;
(c)NBS,二氯甲烷;
(d)R1-硼酸,Pd(PPh3)4,碳酸氢钠,DME/H2O;
(e)2,2-双-(4-氰酰苯基)丙烷,Et3N,二甲亚砜;
(f)NaH,2,2-双-(4-氰酰苯基)丙烷,THF;
(g)BBr3,二氯甲烷;
(h)盐酸羟胺,NaOMe,甲醇;
(i)NH2OH,二甲亚砜;
(j)NH2OH,DCM;
(k)NH2OH,甲醇
上述反应方案所示的通用方法I已用于实施例1、2、3、5、7、10-12和16-23的合成。适用于合成这些实施例中最终化合物的通用方法中各步骤的全部试验细节在实施例1-3中有描述。
通用方法II
下述通用方法可以用于制备R2为-SO2N(RC)2的式(I)化合物。
(a)(Rc)2NSO2Cl,NaH,DMF;(b)BF3·SMe2,DCM
上述反应方案所示的通用方法II已用于实施例4和6的合成。适用于合成这些实施例中最终化合物的通用方法中各步骤的全部试验细节在实施例4中有描述。
通用方法III
下述通用方法可以用于制备R2为CHO或-CH=NOH的式(I)化合物。
(a)DIBAH,DCM;
(b)盐酸羟胺,吡啶,甲醇;
上述反应方案中所示的通用方法III用于实施例5的合成。适用于合成该实施例中最终化合物的通用方法中各步骤的全部试验细节都在实施例5中有描述。
通用方法IV
下述通用方法可以用于制备R2为-C(O)NH(RC)的式(I)化合物。
(a)NCORc,DMF;(b)BF3·SMe2,CH2Cl2
上述反应方案所示的通用方法IV用于实施例8、9、13、14和15的合成。适用于合成这些实施例中最终化合物的通用方法中各步骤的全部试验细节在实施例8中有描述。
通用方法V
下述通用方法可以被用于制备R2为氰基、-C(NH2)=NOH或-C(O)NH2的式(I)中的化合物。
(a)NaH,2,2-双-(4-氰酰苯基)丙烷,THF;
(b)R1-硼酸,Pd(PPh3)4,碳酸氢钠,DME/H2O;
(c)BF3.SMe2;二氯甲烷;
(d)NH2OH,甲醇;
上述反应式所示的通用方法V已用于实施例24和25的合成。适用于合成这些实施例中最终化合物的通用方法中各步骤的全部试验细节在实施例24和25中有描述。
通过下述实施例对本发明进行举例说明。
实施例1
2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲腈
(a)4-甲氧苯基硼酸,Pd(PPh3)4,碳酸氢钠,DME/H2O;
(b)碳酸钾,甲醇;
(c)NBS,二氯甲烷;
(d)3,5-二甲基异噁唑-4-硼酸,Pd(PPh3)4,碳酸氢钠,DME/H2O;
(e)2,2-双-(4-氰酰苯基)丙烷,Et3N,二甲亚砜;
(f)BBr3,二氯甲烷;
方案1
步骤(a):将3-溴-1-(苯磺酰)-1H-吲哚(500mg,1.49mmol)和5mol%四(三苯基膦)钯(tetrakis(triphenylphosphine)palladium)在9ml脱气的DME中混合。将所得混合物在氮气条件下搅拌5分钟然后加热到85℃。在85℃下,在5分钟内同时滴加溶解于3ml DME中的4-甲氧基苯基硼酸(1.2eq)和5.95ml碳酸氢钠(1M)。在85℃搅拌反应物10分钟,然后冷却至室温。将DME浓缩后加入水,剩余的混合水溶液用DCM萃取。将合并的有机层浓缩并以EtOAc/正庚烷(1:9至2:8)为洗脱液用二氧化硅将粗产物纯化。得到363毫克白色结晶状的3-(4-甲氧基苯基)-1-(苯磺酰基)-1H-吲哚。
步骤(b):将3-(4-甲氧基苯基)-1-(苯磺酰基)-1H-吲哚(200mg,0.55mmol)和15eq碳酸钾在氮气条件下溶于40ml甲醇中。将所得混合物回流加热16小时,然后冷却至室温,并浓缩干燥。加入DCM和盐水,并用2M HCl将所述混合物酸化(pH 2-4)。将水层用DCM提取,将合并的有机层浓缩。以EtOAc/n-庚烷(1:1)为洗脱液用二氧化硅将粗产物纯化。得到121.1毫克白色固体状的3-(4-甲氧基苯基)-1H-吲哚。
步骤(c):将3-(4-甲氧基苯基)-1H-吲哚溶解到4ml DCM中。在2分钟内分多次少量加入NBS(0.9eq)。将所述溶剂浓缩,粗产物用HPLC(MeCN/H2O梯度)方法进行纯化。得到103.3毫克白色固体状的2-溴-3-(4-甲氧基苯基)-1H-吲哚。
步骤(d):将2-溴-3-(4-甲氧基苯基)-1H-吲哚(93mg,0.31mmol)、3mol%四(三苯基膦)钯和3,5-二甲基异噁唑-4-基硼酸(3eq)在氮气条件下混合于1.5ml脱气的DME中。在5分钟内滴加1.24ml碳酸氢钠(1M)。所得混合物在90℃下搅拌45分钟后冷却至室温。在氮气流环境下蒸发所述溶剂,并将残余物溶于DCM中。经一个短二氧化硅塞过滤得到粗产物,该粗产物用二氧化硅(EtOAc/n-庚烷1:9-3:7)进行再次纯化。得到40.5mg黄色固体状4-(3-(4-甲氧基苯基)-1H-吲哚-2-基)-3,5-二甲基异噁唑。
步骤(e):将4-(3-(4-甲氧基苯基)-1H-吲哚-2-基)-3,5-二甲基异噁唑(37mg,0.12mmol)和2,2-双-(4-氰酰苯基)丙烷(2,2-bis-(4-cyanatophenyl)propane)(0.6eq)在玻璃瓶中混合。加入1.8ml DMSO和Et3N(3eq),所得混合物在120℃下微波加热。加入2,2-双-(4-氰酰苯基)丙烷(5.7eq)和Et3N(40eq),所得混合物在150℃下微波加热25分钟。加入盐水,并将水层用EtOAc萃取6次。合并的有机层用硫酸钠干燥后浓缩。所得粗产物溶于DCM中,并用脱脂棉进行过滤,然后用二氧化硅(EtOAc/n-庚烷1:9-2:8)纯化。得到25.7mg浅黄色固体状的2-(3,5-二甲基异噁唑-4-基)-3-(4-甲氧基苯基)-1H-吲哚-1-甲腈。
步骤(f):2-(3,5-二甲基异噁唑-4-基)-3-(4-甲氧基苯基)-1H-吲哚-1-甲腈溶解于3ml DCM中,将所得混合物冷却至-50℃。加入BBr3(5eq),在-50℃下搅拌反应4.5小时,然后在-20℃下搅拌16小时。将所得混合物冷却至-78℃,先后加入甲醇(90μl)和水。水层用DCM萃取3次,浓缩合并的有机层。粗产物用二氧化硅(EtOAc/n-庚烷2:8-3:7)进行纯化。得到4.9毫克白色固体状的2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲腈。ES/MS m/z:330.2(M+H),328.3(M-H);1HNMR(CDCl3,500MHz):7.75(m,1H),7.67(m,1H),7.51(m,1H),7.41(m,1H),7.20(m,2H),6.88(m,2H),2.28(s,3H)和2.05(s,3H)。
实施例2和3
2-(3,5-二甲基异噁唑-4-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺(E2)
2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺(E3)
方案2
在氮气条件下将1毫升无水甲醇加入到2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲腈(实施例1,4.5mg,0.01mmol)中,然后加入10eq盐酸羟胺。加入10eq NaOMe,将所得混合物搅拌4小时。将溶剂浓缩,粗产物以CH2Cl2/MeOH(97:3至96:4)为洗脱液用二氧化硅进行纯化。得到2.10毫克白色固体状的2-(3,5-二甲基异噁唑-4-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺(E2)ES/MS m/z:363.5(M+H),361.6(M-H);1H NMR(MeOD,500MHz):7.65(m 1H),7.60(m,1H),7.29(m,1H),7.18(m,1H),7.12(m,2H),6.79(m,2H),2.12(s,3H),1.99(s,3H)和1.90mg白色固体状的2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺(E3)ES/MS m/z:348.2(M+H),346.3(M-H);1H NMR(MeOD,500MHz):7.93(m 1H),7.61(m,1H),7.35(m,1H),7.23(m,1H),7.08(m,2H),6.81(m,2H),2.07(s,3H),2.03(s,3H)。就实施例2而言,题述化合物用1H-NMR进行鉴定,其显示该肟(oxime)产物为单一异构体,但并不确定得到的是(E)型还是(Z)型肟异构体。
实施例4
2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-N,N-二甲基-1H-吲哚-1-磺酰胺(E4)
(a)(CH3)2NSO2Cl,NaH,DMF;(b)BF3.SMe2,DCM
方案3
步骤(a):在0℃在氮气条件下将4-(3-(4-甲氧基苯基)-1H-吲哚-2-基)-3,5-二甲基异噁唑(实施例1中步骤(d)的中间产物,35mg,0.11mmol)加入到NaH(25mg,60%庚烷溶液)的DMF(无水,0.7ml)悬浮液中。所得混合物在室温下搅拌30分钟,然后再次冷却至0℃。滴加二甲基氨磺酰氯(2eq)。所得混合物在室温下搅拌2小时,冷却至0℃,加水终止反应。使用Isolute相分离器用DCM进行萃取,将合并的有机层浓缩得到定量产量的2-(3,5-二甲基异噁唑-4-基)-3-(4-甲氧基苯基)-N,N-二甲基-1H-吲哚-1-磺酰胺。
步骤(b):将2-(3,5-二甲基异噁唑-4-基)-3-(4-甲氧基苯基)-N,N-二甲基-1H-吲哚-1-磺酰胺(23mg,0.05mmol)溶于DCM中,所得混合物冷却至0℃。滴加BF3·SMe2(0.7ml),将反应混合物在冰箱中搅拌16小时。向冷的混合物中加入几滴甲醇。然后用Isolute相分离器以H2O/DCM对所述混合物进行萃取。浓缩后得到粗产物,其用HPLC(40-70%AcN,25min梯度)纯化。得到5.6毫克2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-N,N-二甲基-1H-吲哚-1-磺酰胺。ES/MS m/z:412.06(M+H),410.16(M-H);1H NMR(丙酮-d6,500MHz):8.18(m,1H),7.60(m,1H),7.43(m,1H),7.34(m,1H),7.12(m,2H),6.88(m,2H),2.70(s,6H),2.10(s,3H)和2.09(s,3H)。
实施例5
2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲醛肟(E5)
(a)DIBAH,DCM;
(b)盐酸羟胺,吡啶,甲醇;
方案4
步骤(a):将2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲腈(24mg,0.07mmol)在氮气条件下溶于5ml DCM中,并将所得混合物冷却至-60℃。在-60℃条件下滴加5eq DIBAH(1M溶于己烷)。移走冷浴后于室温下搅拌所述反应物16小时。先加入2ml HCl终止反应(1M),再加入50ml EtOAc。将所得到的混合物进行过滤并用盐水洗涤3次。有机层用硫酸钠干燥,并浓缩溶剂。得到18毫克2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲醛。
步骤(b):2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲醛(18mg,0.05mmol)溶解于5ml甲醇中。加入5eq盐酸羟胺和6eq吡啶。将所得混合物回流加热1.5小时,然后使其冷却至室温。加入50mlEtOAc,得到的混合物用盐水洗涤3次后用硫酸钠干燥。浓缩溶剂,粗产物用制备型HPLC进行纯化。得到3.5毫克2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲醛肟。用1H-NMR鉴定题述化合物,其显示该肟产物是单一异构体,但不能确定得到的是(E)型还是(Z)型肟异构体。ES/MS m/z:348.01(M+H),346.18(M-H);1H NMR(MeOD,500MHz):8.38(s,1H),8.26(m,1H),7.66(m,1H),7.35(m,1H),7.25(m,1H),7.11(m,2H),6.80(m,2H),2.13(s,3H)和1.99(s,3H)。
实施例6和7
使用类似于上述合成实施例4中所用方法制备实施例6,按照上述通用方法I制备实施例7。所述通用方法中各步骤的所有实验细节在上述实施例中有描述。对于实施例6,题述化合物的1H-NMR鉴定结果表明,该肟产物是单一异构体,但不确定所得的是(E)型还是(Z)型肟异构体。
实施例8
2-(3,5-二甲基异噁唑-4-基)-N-乙基-3-(4-羟苯基)-1H-吲哚-1-甲酰胺(E8)
(a)EtNCO,DMF;(b)BF3·SMe2,CH2Cl2
方案5
步骤(a):将4-(3-(4-甲氧基苯基)-1H-吲哚-2-基)-3,5-二甲基异噁唑(15mg,0.06mmol)和异氰酰乙烷(40μl)在氮气条件下混合于1ml无水DMF中。将所得混合物在70℃下加热3小时。加入100μl异氰酰乙烷,继续在70℃下加热过夜。将粗反应混合物用制备型HPLC纯化。得到8.0mg 2-(3,5-二甲基异噁唑-4-基)-N-乙基-3-(4-甲氧基苯基)-1H-吲哚-1-甲酰胺。
步骤(b):将2-(3,5-二甲基异噁唑-4-基)-N-乙基-3-(4-甲氧基苯基)-1H-吲哚-1-甲酰胺(8mg,0.02mmol)溶解于8ml DCM,使所得混合物经冰浴冷却。滴加BF3·SMe2(0.40ml),将所得混合物在0-2℃下搅拌16小时。加入几滴甲醇,然后加水。分离各层,浓缩有机层。粗产物用制备型HPLC进行纯化。得到3.4毫克2-(3,5-二甲基异噁唑-4-基)-N-乙基-3-(4-羟苯基)-1H-吲哚-1-甲酰胺。ES/MS m/z:376.1(pos.M+H),374.2(neg.M-H);1H NMR(丙酮-d6,500MHz):7.90(m,1H),7.63(m,1H),7.33(m,1H),7.23(m,1H),7.14(m,2H),6.88(m,2H),3.38(m,2H),2.04(s,3H),2.03(s,3H)和1.16(t,3H,J=7.3Hz)。
实施例9-15
按照上述通用方法IV制备实施例9、13、14和15,按照上述通用方法I制备实施例10-12。通用方法中各步骤的所有实验细节如上述实施例中所述。对于实施例10和12,题述化合物的1H-NMR鉴定结果表明,该肟产物是单一异构体,但不确定所得的是(E)型还是(Z)型肟异构体。
实施例16-20
按照上述通用方法I制备实施例16-20。所述通用方法中各步骤的所有实验细节如上述实施例所述。对于实施例16-20中的每个实施例,题述化合物的1H-NMR鉴定结果表明,该肟产物是单一异构体,但不确定所得的是(E)型还是(Z)型肟异构体。
实施例21
5-氯-2-(2,4-二甲基噻吩-3-基)-N′-羟基-3-(4-羟苯基)-1氢-吲哚-1-甲亚胺酰胺(E21)
根据方案1获得
(a)NaH,2,2-双-(4-氰酰苯基)丙烷,THF;
(b)BF3.SMe2;DCM;
(c)NH2OH,DCM
方案6
步骤(a):在0℃下将NaH(6.11mg,0.25mmol)加入到无水THF(1ml)中并搅拌,滴加溶于无水THF(2ml)中的5-氯-2-(2,4-二甲基噻吩-3-基)-3-(4-甲氧基苯基)-1H-吲哚(72mg,0.20mmol),所得混合物在0℃下搅拌5分钟。滴加溶于无水THF(2ml)中的2,2-双-(4-氰酰苯基)丙烷(70.8mg,0.25mmol),所得混合物在室温下搅拌9小时。先后加入NH4Cl(aq,sat)和盐水,所得水性混合物用DCM萃取。浓缩溶剂,粗产物用二氧化硅(EtOAc/正庚烷1:9)进行纯化。得到72毫克5-氯-2-(2,4-二甲基噻吩-3-基)-3-(4-甲氧基苯基)-1H-吲哚-1-甲腈。
步骤(b):将5-氯-2-(2,4-二甲基噻吩-3-基)-3-(4-甲氧基苯基)-1H-吲哚-1-甲腈(75mg,0.19mmol)溶于4ml DCM中,所得混合物经冰浴冷却。滴加BF3.SMe2(0.20ml,1.91mmol),所得混合物在室温下搅拌24小时。在0℃下先加入几滴甲醇、再加入NaHCO3(aq,sat)和盐水。分离各层,并将有机层浓缩。粗产物用二氧化硅(MeOH/DCM 1:99)纯化。得到42.0毫克5-氯-2-(2,4-二甲基噻吩-3-基)-3-(4-羟苯基)-1H-吲哚-1-甲腈。
步骤(c):在0℃下将羟胺(16.3M水溶液,0.69ml,11.0mmol)加入到溶于DCM(5ml)的5-氯-2-(2,4-二甲基噻吩-3-基)-3-(4-羟苯基)-1H-吲哚-1-甲腈(42mg,0.11mmol)溶液中,并在0℃下搅拌反应物65小时。加入盐水,并将所得水性混合物用DCM萃取。浓缩溶剂,粗产物用制备型HPLC纯化得到5-氯-2-(2,4-二甲基噻吩-3-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺(7.0mg,35%)。题述化合物的1H-NMR鉴定结果表明,该肟产物是单一异构体,但不确定所得的是(E)型还是(Z)型肟异构体。ES/MS m/z:414.5;412.4(M+H),412.3;409.9(M-H);1HNMR(丙酮-d6,500MHz):7.65(d,1H,J=2.1Hz),7.58(d,1H,J=8.8Hz),7.25(dd,1H,J=8.8,2.1Hz),7.10(m,2H),6.83-6.80(m,3H),2.18(s,3H)和1.95(d,3H,J=1.1Hz)。
实施例22和23
按照上述通用方法I制备实施例22和23。所述通用方法中各步骤的所有实验细节在上述实施例1和21中有所描述。对于实施例22和23中的每个实施例,题述化合物的1H-NMR鉴定结构表明,该肟产物是单一异构体,但不确定所得的是(E)型还是(Z)型肟异构体。
实施例24和25
2-(3,5-二甲基异噻唑-4-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺(E24)
2-(3,5-二甲基异噻唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺(E25)
按照方案1获得
(a)NaH,2,2-双-(4-氰酰苯基)丙烷,THF;
(b)3,5-二甲基异噻唑-4-基硼酸,Pd(PPh3)4,碳酸氢钠,DME/H2O;
(c)BF3.SMe2;二氯甲烷;
(d)NH2OH,甲醇;
方案7
步骤(a):在0℃下将NaH(18.35mg,0.76mmol)溶于无水THF(1ml)中并搅拌,滴加溶于无水THF(4.5ml)中的2-溴-3-(4-甲氧基苯基)-1H-吲哚(210mg,0.69mmol)。所得混合物在0℃下搅拌5分钟,然后滴加溶于无水THF(4.5ml)中的2,2-双-(4-氰酰苯基)丙烷(251mg,0.90mmol)。加水后将所得混合物搅拌30分钟。加入盐水并用DCM萃取所得水性混合物。浓缩溶剂,粗产物用二氧化硅(EtOAc/正庚烷1:4)纯化。得到198毫克2-溴-3-(4-甲氧基苯基)-1H-吲哚-1-甲腈。
步骤(b):在氮气条件下,将2-溴-3-(4-甲氧基苯基)-1H-吲哚-1-腈(70.0mg,0.21mmol),四(三苯基膦)钯(24.7mg,0.21mmol)和3,5-二甲基异噻唑-4-基硼酸(102.3mg,0.43mmol)混合于3.5ml DME和0.86ml碳酸氢钠(1M)中。将所得的混合物在120℃下微波加热20分钟。蒸发溶剂,将残余物溶于DCM中。用短的二氧化硅塞过滤得到粗提物,该粗产物用二氧化硅(EtOAc/正庚烷1:4)进行纯化。得到38.0mg2-(3,5-二甲基异噻唑-4-基)-3-(4-甲氧基苯基)-1H-吲哚-1-甲腈。
步骤(c):2-(3,5-二甲基异噻唑-4-基)-3-(4-甲氧基苯基)-1H-吲哚-1-甲腈(38mg,0.11mmol)溶于10ml DCM中,将所得混合物冰浴冷却。滴加BF3·SMe2(0.56ml,5.29mmol),所得混合物在0-2℃下搅拌16小时。滴入几滴甲醇,再加入碳酸氢钠饱和水溶液。分离各层,将有机层浓缩。粗产物用制备型HPLC进行纯化。得到18.0毫克2-(3,5-二甲基异噻唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲腈。
步骤(d):将羟胺(16.3M水溶液,0.33ml,5.21mmol)加入到溶于甲醇(2mL)的2-(3,5-二甲基异噻唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲腈(18mg,0.05mmol)中,在130℃下微波搅拌反应物20分钟。所得混合物用制备型HPLC纯化得到E24:2-(3,5-二甲基异噻唑-4-基)-N′-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺(7.0mg,35%):ES/MS m/z 379.11(M+H),377.14(M-H);1H NMR(丙酮-d6,500MHz):7.70(dd,1H,J=7.9,1.0Hz),7.59(dd,1H,J=9.0,0.9Hz),7.29(m,1H),7.20(m,1H),7.09(m,2H),6.81(m,2H),2.30(s,3H)和2.16(s,3H),和E25 2-(3,5-二甲基异噻唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺(5mg,26%):ES/MS m/z 364.11(M+H),362.14(M-H);1H NMR(丙酮-d6,500MHz):8.12(d,1H,J=8.4Hz),7.67(d,1H,J=7.9Hz),7.36(m,1H),7.26(m,1H),7.05(m,2H),6.83(m,2H)和2.21(s,6H)。对于每个题述化合物,1H-NMR鉴定结果表明,该酰胺肟产物为单一异构体,但不确定所得到的是(E)型还是(Z)型肟异构体。
结合活性分析1:雌激素受体结合活性测定
雌激素受体配体结合测定被设计为闪烁迫近测定法(scintillationproximity assay,SPA)的形式,其使用了氚标记的雌二醇(3H-E2)和重组表达的生物素化的雌激素受体结合结构域。人ERα(ERα-LBD,pET-N-AT #1,aa 301-595)和ERβ(ERβ-LBD,pET-N-AT #1,aa255-530)蛋白的结合结构域由在22℃下于添加有50μM生物素的2xLB培养基中的大肠杆菌(BL21,DE3,pBirA)产生。IPTG(0.55mM)诱导3小时后,以7300g离心15分钟收集细胞并将细胞沉淀冻存在-20℃。通过将5g细胞用50ml提取缓冲液(50mM Tris,pH 8.0,100mMKCl,4mM EDTA,4mM DDT和0.1mM PMSF)悬浮后提取ERα和ERβ。所述细胞悬液经过两次微流均质仪(Microfluidizer M-110L,Microfluidics)后以15,000g离心60分钟。将上清液分装保存在-70℃。
用测定缓冲液(18mM K2HPO4,2mM KH2PO4,20mM NasMoO4,1mM EDTA,1mM TCEP)分别按照1:676和1:517的比例稀释ERα-LBD和ERβ-LBD提取物。稀释的受体浓度应为900fmol/l。将所述提取物与抗生蛋白链菌素包被的聚乙烯基甲苯(polyvinyltoluene)SPA珠(RPNQ0007,GE Healthcare)以0.43mg/ml的浓度在室温下预孵育1小时。
测试化合物的浓度范围为37.5pM至157μM。测试化合物储液是以100%DMSO制成,浓度为测试分析所需终浓度的5倍。在384孔板的测试孔中DMSO的量占20%。往测定板中先后加入18μl测试化合物的等分试样和35μl预孵育的受体/SPA珠混合物,最后加入35μl浓度为3nM的3H-E2。用塑料封膜住所述板,1000rpm下离心1分钟,然后于室温下在振荡器上平衡过夜。第二天上午将所述板以2000rpm离心5分钟,然后用例如PerkinElmer Microbeta 1450Trilux的平板闪烁记数仪器进行测试。
对于能从受体上置换3[H]-E2的化合物,应用非线性四参数逻辑模型(non-linear four parameter logistic model)计算IC50-值(抑制50%的3[H]-E2结合所需的浓度);b=((bmax-bmin)/(1+(I/IC50)S))+bmin,I是加入的结合抑制剂的浓度、IC50是最大结合一半时的抑制剂浓度、S是斜率因子(slope factor)。所述Microbeta-设备生成平均cpm(每分钟计数)值/分钟,并且针对检测器之间的个体差异进行校正,从而生成经校正的cpm值
转活(tansactivation)测定1:以pERE-ALP和人类雌激素受体α稳定转染的人类胚肾293细胞的转活测定
表达载体pMThERα含有缺失了先导序列的野生型人类雌激素受体α的插入序列。pERE-ALP报告构建体含有分泌形式的胎盘碱性磷酸酶(placental alkaline phosphatase,ALP)和卵黄蛋白雌激素反应元件(ERE)的基因。人类胚肾293细胞的转染分为两个步骤。首先,获得以pERE-ALP报告构建体和用于筛选的pSV2-Neo转染的稳定克隆混合物用于筛选。第二步,用pMThERα和用于筛选的pKSV-Hyg抗性载体转染该稳定的克隆混合物用于筛选。所有的转染都应用Lipofectamine(Invitrogen)并根据制造商的说明书操作。选取同时含有pERE-ALP和pMThERα的克隆用于转活测定。
将所述细胞以每孔12500个细胞的浓度接种在384孔板的含有10%以葡聚糖包被的炭末(DCC)处理的胎牛血清(FBS)、2mM L-谷氨酰胺和50μg/ml庆大霉素的Ham’s F12 Coon’s改良培养基(不含酚红)中。孵育24小时后(37℃,5% CO2)弃掉接种培养基,替换为含有1.5% DCC-FCS、2mM L-谷氨酰胺并添加有100U/ml青霉素和100μg/ml链霉素的20μl Ham’s F12Coon’s改良培养基(不含酚红)。将选出的化合物以范围在3.3pM至33μM内的12个浓度加入到孔中。将所述化合物溶解于100%二甲基亚砜(DMSO)中,DMSO在测定液中的终浓度为0.1%。孵育72小时(37℃,5%CO2)后,将所述培养基用化学发光(chemiluminescence)分析法测定ALP活性;将10μl所述细胞培养基的等分试样与100μl测定缓冲液(0.1M二乙醇胺,1mM氯化镁)和0.5mM 3-(4-甲氧螺1,2-二氧杂环丁烷-3,2′-(5′-氯)-三环[3.3.1.13,7]癸-4-基)苯基磷酸二钠(CSPD)(Tropix,Applied Biosystems)混合,在37℃下孵育20分钟,再于室温下孵育15分钟,然后用WallacMicrobeta Trilux 1450-028(PerkinElmer)进行化学发光信号测量(每孔一秒)。根据用XLfit软件2.0版(IDBS)或更高版本以四参数逻辑模型对浓度-反应数据拟合的曲线计算最大有效浓度一半(EC50)的数值。
转活测定2:以pERE2-ALP和人类雌激素受体β稳定转染的人类胚肾293细胞的转活测定
表达报告载体pERE2-ALP和人类雌激素受体β(hERβ530)的HEK293稳定细胞系(CRL-1573;American Type Culture Collection)的获得方法已有记载(Mol Pharmacol 1998,54,105-112;Endocrinology2002,143,1558-1561)。
将所述细胞以每孔12500个细胞的浓度接种在384孔板的含有10%以葡聚糖包被的炭末(DCC)处理的胎牛血清(FBS)、2mM L-谷氨酰胺和50μg/ml庆大霉素的Ham’s F12 Coon’s改良培养基(不含酚红)中。孵育24小时后(37℃,5%二氧化碳)弃掉接种培养基,替换为含有1.5%DCC-FCS、2mM L-谷氨酰胺并添加有100U/ml青霉素和100μg/ml链霉素的20μl Ham’s F12 Coon’s改良培养基(不含酚红)。将选出的化合物以范围在3.3pM至33μM内的12个浓度加入到孔中。将所述化合物溶解于100%二甲基亚砜(DMSO)中,DMSO在测定液中的终浓度为0.1%。孵育72小时(37℃,5%CO2)后,将所述培养基用化学发光分析法测定ALP活性。将10μl所述条件培养基的等分试样与100μl测定缓冲液(0.1M二乙醇胺,1mM氯化镁)和0.5mM 3-(4-甲氧螺1,2-二氧杂环丁烷-3,2′-(5′-氯)-三环[3.3.1.13,7]癸-4-基)苯基磷酸二钠(CSPD)(Tropix,Applied Biosystems)混合,然后在37℃下孵育20分钟,再于室温下孵育15分钟,然后用WallacMicrobeta Trilux 1450-028(PerkinElmer)进行化学发光信号测量(每孔一秒)。LCPS中表达的ALP活性与细胞的ALP表达水平成正比。根据用XLfit软件2.0版(IDBS)或更高版本以四参数逻辑模型对浓度-反应数据拟合的曲线计算最大有效浓度一半(EC50)的数值。
实施例1-24的化合物在结合测定1以及转活测定1和2中进行了测试。
实施例1-24的化合物显示出以下一种或几种活性:
(i)在结合测定1中,与α亚型雌激素受体的结合亲和力IC50范围为:1至10,000nM;
(ii)在结合测定1中,与β亚型雌激素受体的结合亲和力IC50范围为:1至10,000nM;
(iii)在转活测定1中,对α亚型雌激素受体的效力EC50范围为:1至10,000nM;
(iv)在转活测定2中,对β亚型雌激素受体的效力EC50范围为:1至10,000nM;
本发明优选的实施例化合物为在上述IC50范围内较低浓度下显示出对β亚型雌激素受体的结合亲和力的那些化合物。例如,结合测定1中实施例1-3、5-8、10-12、15-18和20-24的化合物在IC50为1到200nM的范围内显示出对β亚型雌激素受体的结合亲和力。
本发明优选的实施例化合物为那些在结合测定1中对于β亚型雌激素受体的选择性高于α亚型雌激素受体的化合物。例如,实施例1-3,6-8,10-12,15-18和20-24的化合物在结合测定中显示出对β亚型雌激素受体的选择性为50或者更高。
本发明优选的实施例化合物为那些在上述EC50范围内较低浓度下显示出对β亚型雌激素受体的效力的化合物。例如,转活测定2中实施例1-13和15-24在EC50为0.1至200nM的范围内显示出对β亚型雌激素受体的效力;实施例2-3,5-8,10-12和16-24的化合物在EC50为0.1至10nM的范围内显示出效力。
本发明优选的实施例化合物为那些在转活测定1和2中对β亚型雌激素受体的选择性高于α亚型雌激素受体的化合物。例如,在转活测定中实施例1-3和6、8、10-13、15-20和22-24的化合物显示出对β亚型雌激素受体的选择性为50或者更高。
Claims (21)
1.式(I)中的化合物或其可药用的盐,
其中,R1选自C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、卤代C2-6烯基、苯基和5-10元杂环基,其中所述苯基或杂环基基团可以是未取代的或者被1-3个取代基取代的,每一个取代基独立地选自卤素、氰基、硝基和C1-6烷基;
R2选自氰基、-CHO、-CH=N-OH、-SO2C1-4烷基、-C(NH2)=N-OH、-C(O)N(RC)2和SO2N(RC)2;
R3、R4、R5、R6、R7、R8、R9和R10中的每一个独立地选自氢或卤素;
每一个RC独立地选自氢和C1-6烷基。
2.权利要求1中要求保护的化合物,其中所述卤代C1-6烷基为二卤代C1-6烷基或三卤代C1-6烷基。
3.权利要求1中要求保护的化合物,其中所述卤代C2-6烯基为二卤代C2-6烯基或三卤代C2-6烯基。
4.权利要求1中要求保护的化合物,其中R1选自C2-6烯基、苯基和5-6元杂环基,
其中所述苯基或杂环基可以是未取代的或者被1-3个取代基取代的,每一个取代基独立地选自氰基和C1-6烷基;和
R2选自氰基、-CH=N-OH、-SO2C1-4烷基、-C(NH2)=N-OH、-C(O)N(RC)2和SO2N(RC)2。
5.权利要求1-4中任一项要求保护的化合物,其中R2代表氰基、-CH=N-OH、-C(O)N(RC)2或-C(NH2)=N-OH。
6.权利要求5中要求保护的化合物,其中R2代表-CH=N-OH或-CONH2。
7.权利要求1-4中任一项要求保护的化合物,其中R1代表C2-6烯基、苯基或5元杂环基,其中所述苯基或杂环基基团可以是未取代的或被1-2个取代基取代的,每一个取代基独立地选自C1-6烷基。
8.权利要求7中要求保护的化合物,其中R1代表苯基或5元杂环基,其中所述苯基或杂环基基团被1-2个取代基取代,所述取代基为C1-6烷基。
9.权利要求8中要求保护的化合物,其中R1代表苯基或5元杂环,其中所述苯基或杂环基基团被2个取代基取代,所述取代基为甲基。
10.权利要求9中要求保护的化合物,其中R1代表2,6-二甲基苯基、3,5-二甲基异噁唑-4-基、2,4-二甲基-噻吩-3-基或3,5-二甲基异噻唑-4-基。
11.权利要求1-4中任一项中要求保护的化合物,其中R3、R4、R5、R6、R7、R8、R9和R10中每一个独立地选自氢、Cl和F。
12.权利要求11中要求保护的化合物,其中R3、R4、R5和R6中的每一个代表氢;R7、R8、R9和R10中的一个或两个代表氟,其余的代表氢。
13.权利要求1中要求保护的化合物,其为以下化合物中的任意一个或其可药用的盐:
2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲腈;
2-(3,5-二甲基异噁唑-4-基)-N'-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺;
2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺;
2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-N,N-二甲基-1H-吲哚-磺酰胺;
2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲醛肟;
4-(2-(3,5-二甲基异噁唑-4-基)-1-(甲基磺酰基)-1H-吲哚-3-基)苯酚;
2-((Z)-丁-2-烯-2-基)-N'-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺;
2-(3,5-二甲基异噁唑-4-基)-N-乙基-3-(4-羟苯基)-1H-吲哚-1-甲酰胺;
2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-N-甲基-1H-吲哚-1-甲酰胺;
2-(2,4-二甲基噻吩-3-基)-N'-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺;
2-(2,4-二甲基噻吩-3-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺;
2-(2,6-二甲基苯基)-N'-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺;
2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-N-异丙基-1H-吲哚-1-甲酰胺;
2-(3,5-二甲基异噁唑-4-基)-3-(4-羟苯基)-N-戊基-1H-吲哚-1-甲酰胺;
2-(2,4-二甲基噻吩-3-基)-N-乙基-3-(4-羟苯基)-1H-吲哚-1-甲酰胺;
3-(3,5-二氟-4-羟苯基)-2-(3,5-二甲基异噁唑-4-基)-N'-羟基-1H-吲哚-1-甲亚胺酰胺;
3-(2,3-二氟-4-羟苯基)-2-(3,5-二甲基异噁唑-4-基)-N'-羟基-1H-吲哚-1-甲亚胺酰胺;
2-(3,5-二甲基异噁唑-4-基)-3-(2-氟-4-羟苯基)-N'-羟基-1H-吲哚-1-甲亚胺酰胺;
3-(2,5-二氟-4-羟苯基)-2-(3,5-二甲基异噁唑-4-基)-N'-羟基-1H-吲哚-1-甲亚胺酰胺;
2-(3,5-二甲基异噁唑-4-基)-3-(3-氟-4-羟苯基)-N'-羟基-1H-吲哚-1-甲亚胺酰胺;
5-氯-2-(3,5-二甲基异噁唑-4-基)-N'-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺;
2-(2,4-二甲基呋喃-3-基)-N'-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺;
2-(3,5-二甲基异噻唑-4-基)-N'-羟基-3-(4-羟苯基)-1H-吲哚-1-甲亚胺酰胺;
2-(3,5-二甲基异噻唑-4-基)-3-(4-羟苯基)-1H-吲哚-1-甲酰胺。
14.一种药物组合物,其含有前述权利要求中任一项要求保护的化合物和一种可药用载体。
15.权利要求1至13中任一项要求保护的化合物用于制备治疗或预防与雌激素受体活性相关疾病或障碍有关的病症的药剂的用途。
16.权利要求14要求保护的组合物用于制备治疗或预防与雌激素受体活性相关的疾病或障碍的药剂的用途。
17.权利要求1至13中任一项要求保护的化合物以经标记的形式用于制备用以诊断与雌激素受体活性相关的疾病或障碍有关的病症的诊断剂的用途,或者权利要求1至13中任一项要求保护的化合物或该化合物的经标记形式用于制备在用于鉴别雌激素受体配体的方法中用作参比化合物的试剂的用途。
18.权利要求15至16中任一项要求保护的用途,其中所述与雌激素受体活性相关的疾病或障碍有关的病症选自骨丢失、骨折、软骨退变、热潮红、LDL胆固醇水平增高、心血管疾病、认知功能损害、脑变性疾病、血管平滑肌细胞增生、肥胖症、失禁、焦虑症、抑郁症、睡眠障碍、易激惹、冲动、愤怒管理、听力障碍、脊髓损伤、自身免疫性疾病、炎症、性功能障碍、高血压、视网膜变性、下泌尿道综合征、膀胱活动过度、膀胱疼痛综合征、伤口愈合、慢性疼痛、炎性神经痛和注意力缺陷。
19.权利要求15至16中任一项要求保护的用途,其中所述与雌激素受体活性相关的疾病或障碍有关的病症选自骨质疏松、子宫内膜异位、子宫平滑肌瘤、年龄相关轻度认知功能损害、再狭窄、男性乳腺发育、围绝经期抑郁症、产后抑郁症、月经前期综合征、狂躁抑郁症、痴呆、强迫行为、伴多动注意力缺陷障碍、多发性硬化症、帕金森氏病、阿尔兹海默氏病(Alzheimer’s disease)、亨廷顿氏病、肌萎缩侧索硬化、中风、IBD、IBS、肺癌、结肠癌、乳腺癌、子宫癌、前列腺癌、被称为胆管癌的胆管癌症形式、良性前列腺增生、间质性膀胱炎、阴道萎缩、脓毒症、卵巢癌、黑色素瘤和淋巴瘤。
20.权利要求17要求保护的用途,其中所述与雌激素受体活性相关的疾病或障碍有关的病症选自骨丢失、骨折、软骨退变、热潮红、LDL胆固醇水平增高、心血管疾病、认知功能损害、脑变性疾病、血管平滑肌细胞增生、肥胖症、失禁、焦虑症、抑郁症、睡眠障碍、易激惹、冲动、愤怒管理、听力障碍、脊髓损伤、自身免疫性疾病、炎症、性功能障碍、高血压、视网膜变性、下泌尿道综合征、膀胱活动过度、膀胱疼痛综合征、伤口愈合、慢性疼痛、炎性神经痛和注意力缺陷。
21.权利要求17要求保护的用途,其中所述与雌激素受体活性相关的疾病或障碍有关的病症选自骨质疏松、子宫内膜异位、子宫平滑肌瘤、年龄相关轻度认知功能损害、再狭窄、男性乳腺发育、围绝经期抑郁症、产后抑郁症、月经前期综合征、狂躁抑郁症、痴呆、强迫行为、伴多动注意力缺陷障碍、多发性硬化症、帕金森氏病、阿尔兹海默氏病(Alzheimer’s disease)、亨廷顿氏病、肌萎缩侧索硬化、中风、IBD、IBS、肺癌、结肠癌、乳腺癌、子宫癌、前列腺癌、被称为胆管癌的胆管癌症形式、良性前列腺增生、间质性膀胱炎、阴道萎缩、脓毒症、卵巢癌、黑色素瘤和淋巴瘤。
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JP2001122855A (ja) * | 1999-10-27 | 2001-05-08 | Japan Tobacco Inc | インドール化合物及びその医薬用途 |
US20030220377A1 (en) * | 2002-05-08 | 2003-11-27 | Richard Chesworth | Indole compounds and their use as estrogen agonists/antagonists |
FR2868779B1 (fr) * | 2004-04-09 | 2008-08-22 | Pierre Fabre Medicament Sa | Procede de synthese et intermediaires de benzoxathiepines |
ITMI20040874A1 (it) | 2004-04-30 | 2004-07-30 | Ist Naz Stud Cura Dei Tumori | Derivati indolici ed azaindolici con azione antitumorale |
EP1779848A1 (en) | 2005-10-28 | 2007-05-02 | Nikem Research S.R.L. | V-ATPase inhibitors for the treatment of inflammatory and autoimmune diseases |
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2010
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Also Published As
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DK2486010T3 (da) | 2019-09-23 |
CN102791688A (zh) | 2012-11-21 |
AR078537A1 (es) | 2011-11-16 |
EP2486010B1 (en) | 2019-06-12 |
US20120202861A1 (en) | 2012-08-09 |
EP2486010A2 (en) | 2012-08-15 |
TW201124404A (en) | 2011-07-16 |
JP2013507335A (ja) | 2013-03-04 |
WO2011042473A2 (en) | 2011-04-14 |
ES2744219T3 (es) | 2020-02-24 |
JP5687704B2 (ja) | 2015-03-18 |
WO2011042473A3 (en) | 2011-06-03 |
IN2012DN02555A (zh) | 2015-08-28 |
US8710243B2 (en) | 2014-04-29 |
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