CN105646362B - 3-杂芳酰基氨基-丙酸衍生物及其作为药物的用途 - Google Patents
3-杂芳酰基氨基-丙酸衍生物及其作为药物的用途 Download PDFInfo
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- CN105646362B CN105646362B CN201511021647.3A CN201511021647A CN105646362B CN 105646362 B CN105646362 B CN 105646362B CN 201511021647 A CN201511021647 A CN 201511021647A CN 105646362 B CN105646362 B CN 105646362B
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Abstract
本发明涉及式I化合物,其中Ht、G、R10、R30、R40、R50和R60具有权利要求书中所指明的含义,所述化合物是有价值的药用活性化合物。所述化合物是蛋白酶组织蛋白酶A的抑制剂,并用于如下疾病的治疗:如动脉粥样硬化、心力衰竭、肾脏病、肝病或炎性疾病。此外,本发明涉及式I化合物的制备方法、它们的用途和包含它们的药物组合物。
Description
本申请是中国申请号为201280046863.1、发明名称为“3-杂芳酰基氨基-丙酸衍生物及其作为药物的用途”且申请日为2012年7月25日的专利申请(PCT申请号为PCT/EP2012/064628)的分案申请。
技术领域
本发明涉及式I化合物,
其中Ht、G、R10、R30、R40、R50和R60具有如下指明的含义,所述化合物是有价值的药用活性化合物。所述化合物是蛋白酶组织蛋白酶A的抑制剂,并用于如下疾病的治疗:如动脉粥样硬化、心力衰竭、肾脏病、肝病或炎性疾病。此外,本发明涉及式I化合物的制备方法、它们的用途和包含它们的药物组合物。
背景技术
组织蛋白酶A(EC=3.4.16.5;基因符号CTSA)是一种蛋白酶,也称作溶酶体羧肽酶A或保护蛋白。它属于丝氨酸羧肽酶家族,该家族只包括两种其它哺乳动物的代表,即维甲酸可诱导的丝氨酸羧肽酶和卵黄羧肽酶样蛋白。在细胞内,组织蛋白酶A存在于溶酶体中,在其中所述组织蛋白酶A与β-半乳糖苷酶和神经氨酸酶形成高分子量复合物。组织蛋白酶A与这些糖苷酶的相互作用对于它们到达溶酶体的正确路径选择是必要的并保护它们使其免受溶酶体内的蛋白水解作用。由CTSA基因的各种突变引起的组织蛋白酶A的缺乏导致β-半乳糖苷酶和神经氨酸酶的继发性缺乏,其表现为常染色体隐性遗传的溶酶体贮存紊乱半乳糖唾液酸沉积症(cf.A.d'Azzo et al.,in"The Metabolic and Molecular Bases ofInherited Disease",vol.2(1995),2835-2837)。CTSA中多数已识别的突变是影响蛋白折叠或稳定性的错义突变。已经显示,这些突变均不出现在酶的活性部位(G.Rudenko etal.,Proc.Natl.Acad.Sci.USA 95(1998),621-625)。相应地,溶酶体贮存紊乱能被催化无活性的组织蛋白酶A突变体所校正(N.J.Galjart et al.,J.Biol.Chem.266(1991),14754-14762)。因此组织蛋白酶A的结构功能可与其催化活性分离。经观察还强调,与CTSA基因缺乏的小鼠相反,带有CTSA基因催化失活突变的小鼠不显现人类疾病半乳糖唾液酸沉积症的体征(R.J.Rottier et al.,Hum.Mol.Genet.7(1998),1787-1794;V.Seyrantepe et al.,Circulation 117(2008),1973-1981)。
针对各种天然存在的生物活性肽,组织蛋白酶A在酸性pH发挥羧肽酶活性并在中性pH发挥脱酰胺酶和酯酶活性。体外研究表明,组织蛋白酶A将血管紧张素I转化成血管紧张素1-9并将缓激肽转化成缓激肽1-8,其中缓激肽1-8是缓激肽B1受体的配体。它水解内皮缩血管肽-1、神经激肽和催产素及脱酰胺基物质P(cf.M.Hiraiwa,Cell.Mol.Life Sci.56(1999),894-907)。已经在尿中检出高组织蛋白酶A活性,这表明其应对肾小管缓激肽降解负责(M.Saito et al.,Int.J.Tiss.Reac.17(1995),181-190)。然而,该酶还能从血小板和淋巴细胞中释放并在抗原呈递细胞中表达,其中该酶可能与抗原加工有关(W.L.Hanna etal.,J.Immunol.153(1994),4663-4672;H.Ostrowska,Thromb.Res.86(1997),393-404;M.Reich et al.,Immunol.Lett.(online Nov.30,2009))。人类器官的免疫组织化学显示在肾小管细胞、支气管上皮细胞、睾丸的Leydig细胞和脑的大神经元中显著表达(O.Sohmaet al.,Pediatr.Neurol.20(1999),210-214)。在单核细胞向巨噬细胞分化期间它是上调的(N.M.Stamatos et al.,FEBS J.272(2005),2545-2556)。除了结构和酶功能外,已显示组织蛋白酶A与神经氨酸酶和可选的剪接β-半乳糖苷酶缔合来形成细胞表面层粘连蛋白和弹性蛋白受体复合物,该复合物在成纤维细胞、平滑肌细胞、成软骨细胞、白细胞和某些癌症细胞型上表达(A.Hinek,Biol.Chem.377(1996),471-480)。
组织蛋白酶A对于局部缓激肽水平调节的重要性已经在高血压动物模型中被证明。组织蛋白酶A活性的药理学抑制作用增加肾脏缓激肽水平并防止盐诱导的高血压的发展(H.Ito et al.,Br.J.Pharmacol.126(1999),613-620)。这也可以通过抑制组织蛋白酶A表达的反义寡核苷酸来实现(I.Hajashi et al.,Br.J.Pharmacol.131(2000),820-826)。除高血压之外,已经在各种更多的心血管疾病和其它疾病中证明了缓激肽的有益作用(cf.J.Chao et al.,Biol.Chem.387(2006),665-75;P.Madeddu et al.,Nat.Clin.Pract.Nephrol.3(2007),208-221)。组织蛋白酶A抑制剂的主要适应症由此包括动脉粥样硬化、心力衰竭、心脏梗塞、心脏肥大、血管过度生长;左心室功能障碍,具体来说是心肌梗塞后左心室功能障碍;肾脏病,如肾纤维化、肾衰竭和肾机能不全;肝病,如肝纤维化和肝硬化;糖尿病并发症,如肾病;以及如下器官的器官保护:如心脏和肾。
如上所示,组织蛋白酶A抑制剂能防止缓激肽B1受体配体缓激肽1-8的产生(M.Saito et al.,Int.J.Tiss.Reac.17(1995),181-190)。这为使用组织蛋白酶A抑制剂以治疗疼痛(具体来说是神经性疼痛)和炎症提供了机会,这已经被缓激肽B1受体拮抗剂所证实(cf.F.Marceau et al.,Nat.Rev.Drug Discov.3(2004),845-852)。组织蛋白酶A抑制剂还能用作抗血小板剂,这已经被组织蛋白酶A抑制剂抑脂酶免疫酮B(ebelactone B)(一种丙内酯衍生物)所证明,其抑制高血压动物中的血小板聚集(H.Ostrowska et al.,J.Cardiovasc.Pharmacol.45(2005),348-353)。
此外,像其它丝氨酸蛋白酶如前列腺蛋白(prostasin)、弹性蛋白酶或蛋白裂解酶(matriptase)那样,组织蛋白酶A能刺激阿米洛利敏感的上皮钠通道(ENaC)并由此与穿过上皮膜的流体体积的调节有关(cf.C.Planes et al.,Curr.Top.Dev.Biol.78(2007),23-46)。因此,通过组织蛋白酶A抑制剂的使用可改善呼吸系统疾病,如囊性纤维化、慢性支气管炎、慢性阻塞性肺病、哮喘、呼吸道感染和肺癌。肾的组织蛋白酶A调节可用来促进利尿并由此诱发降压作用。
除上述化合物抑脂酶免疫酮B之外,已经发现JP 2005/145839中所描述的某些二肽苯丙氨酸衍生物对组织蛋白酶A的抑制作用。需要抑制组织蛋白酶A并为所述疾病和其中组织蛋白酶A发挥作用的更多疾病的治疗提供机会的其它化合物。本发明通过提供以下所定义的式I的氧取代的3-杂芳酰基氨基-丙酸衍生物来满足该需要。
已经描述过3-杂芳酰基氨基-丙酸部分可存在于其中的某些化合物。例如,在WO2006/076202中,描述了调节类固醇核受体活性的胺衍生物,所述衍生物在胺官能团的氮原子上带有杂芳酰基和定义非常广泛的更多基团。在US 2004/0072802中,描述了广泛定义的β-氨基酸衍生物,所述衍生物在β-氨基上带有酰基并是基质金属蛋白酶和/或肿瘤坏死因子的抑制剂。在涉及血小板ADP受体P2Y12的拮抗剂和抑制血小板聚集的WO 2009/080226和WO 2009/080227中,描述了吡唑酰基氨基取代的羧酸衍生物,然而,所述衍生物在带有吡唑酰基氨基的碳原子上另外带有羧酸衍生物基团。其它吡唑酰基氨基取代的化合物在WO2004/056815中有描述,其中氨基的氮原子与环系相连,且所述化合物是血液凝固酶因子Xa和/或因子VIIa的抑制剂。
发明内容
本发明的一个主题是呈任意立体异构形式或任意比例的立体异构形式的混合物的式I化合物,或其生理学可接受的盐,或它们中的任何的生理学可接受的溶剂化物,
其中Ht选自
G选自R71-O-C(O)-、R72-N(R73)-C(O)-、NC-和四唑-5-基;
R1选自氢、卤素、(C1-C6)-烷基、CF3、(C3-C7)-环烷基-CsH2s-、Ar-CsH2s-、Ar-O、(C1-C6)-烷基-O-、(C1-C6)-烷基-S(O)m-和NC-;其中s为选自0、1、2和3的整数;
R2选自氢、卤素、(C1-C6)-烷基、CF3、(C1-C6)-烷基-O-、(C1-C6)-烷基-S(O)m-和NC-;
R3选自氢、(C1-C6)-烷基;
R4选自(C1-C7)-烷基、(C3-C7)-环烷基-CsH2s-和Ar-CsH2s-,其中s为选自0、1、2和3的整数;
R5选自氢、卤素、(C1-C6)-烷基、(C1-C6)-烷基-O-、(C1-C6)-烷基-S(O)m-和NC-;
R10选自R11、Het2-C(O)-、R14-C(O)-和(C1-C4)-烷基-S(O)m-;
R11选自氢、R14、(C3-C7)-环烷基、Ar和Het3;
R14为(C1-C10)-烷基,其任选被一个或者多个相同或者不同的选自下述的取代基取代:卤素、HO-、R16-O-、氧代、(C3-C7)-环烷基、Ar、Het1、Het3、NC-、H2N-C(O)-、(C1-C4)-烷基-NH-C(O)-、二((C1-C4)-烷基)N-C(O)-、Het1-C(O)-、(C1-C4)-烷基-C(O)-NH-和(C1-C4)-烷基-S(O)m-;
R16为(C1-C6)-烷基,其任选被一个或者多个相同或者不同的选自下述的取代基取代:HO-、(C1-C4)-烷基-O-和NC-;
R30选自R31、(C3-C7)-环烷基、R32-CuH2u-和Het3-CuH2u-,其中u为选自0、1、2和3的整数;
R31为(C1-C10)-烷基,其被一个或者多个相同或者不同的选自下述的取代基取代:卤素、(C3-C7)-环烷基、HO-、(C1-C6)-烷基-O-、(C1-C6)-烷基-S(O)m-和NC-;
R32选自苯基和芳族5-元或者6-元单环杂环基,所述杂环基包含一个、两个或三个相同或不同的选自氮、氧和硫的环杂原子并是经环碳原子连接的,其中所述苯基和杂环基都任选地被一个或多个相同或不同的选自下述的取代基所取代:卤素、(C1-C6)-烷基、(C3-C7)-环烷基、HO-、(C1-C6)-烷基-O-、R33-O-、R33-(C1-C4)-烷基-O-、-O-CH2-O-、-O-CF2-O-、(C1-C6)-烷基-S(O)m-、H2N-S(O)2-、(C1-C4)-烷基-NH-S(O)2-、二((C1-C4)-烷基)N-S(O)2-、H2N-、(C1-C6)-烷基-NH-、二((C1-C6)-烷基)N-、Het1、(C1-C4)-烷基-C(O)-NH-、Ar-C(O)-NH-、(C1-C4)-烷基-S(O)2-NH-和NC-;
R33选自苯基和芳族5-元或者6-元单环杂环基,所述杂环基包含一个、两个或三个相同或不同的选自氮、氧和硫的环杂原子并是经环碳原子连接的,其中所述苯基和杂环基都任选地被一个或多个相同或不同的选自下述的取代基所取代:卤素、(C1-C6)-烷基、(C3-C7)-环烷基、HO-、(C1-C6)-烷基-O-、(C1-C6)-烷基-S(O)m-、H2N-S(O)2-、(C1-C4)-烷基-NH-S(O)2-、二((C1-C4)-烷基)N-S(O)2-和NC-;
R40选自氢和(C1-C4)-烷基;
或者R30和R40一起形成(CH2)x,其任选地被一个或多个相同或不同的(C1-C4)-烷基取代基所取代,其中x为选自2、3、4和5的整数;
R50选自氢、(C1-C6)-烷基、HO-和(C1-C6)-烷基-O-;
R60选自氢和(C1-C6)-烷基;
或者R50和R60一起形成(CH2)y,其任选地被一个或多个相同或不同的(C1-C4)-烷基取代基所取代,其中y为选自2、3、4和5的整数;
或者R30和R50一起形成(CH2)z,其任选地被一个或多个相同或不同的(C1-C4)-烷基取代基所取代,其中z为选自2、3、4和5的整数;
R71选自氢和(C1-C8)-烷基,其任选被一个或者多个相同或者不同的选自下述的取代基取代:(C1-C6)-烷基-O-和(C1-C6)-烷基-C(O)-O-;
R72选自氢、(C1-C6)-烷基、(C3-C6)-环烷基、-CH2-(CH2)b-(C3-C6)-环烷基、Het4和-(CH2)b-Het4,其中烷基或者环烷基任选被一个或者多个相同或者不同的选自下述的取代基取代:卤素、HO-、HOOC-、(C1-C6)-烷基-O-和(C1-C6)-烷基-C(O)-O-、NC-、N((C1-C4)-烷基)2且b为0、1或者2;
R73选自氢、(C1-C6)-烷基;或者
R72和R73与它们所连接的氮原子一起形成饱和的4-元至7-元单环杂环基,所述杂环基任选地含有一个另外的选自氮、氧和硫的环杂原子,并且任选被一个或者多个相同或者不同的选自下述的取代基取代:卤素、(C1-C4)-烷基、HO-和(C1-C4)-烷基-O-;
Ar彼此独立地选自苯基和芳族5-元或者6-元单环杂环基,所述杂环基包含一个、两个或三个相同或不同的选自氮、氧和硫的环杂原子并是经环碳原子连接的,其中所述苯基和杂环基都任选地被一个或多个相同或不同的选自下述的取代基所取代:卤素、(C1-C6)-烷基、(C1-C6)-烷基-O-、-O-CH2-O-、-O-CH2-CH2-O-、-O-CF2-O-、(C1-C6)-烷基-S(O)m-、H2N-S(O)2-、CF3和NC-;
Het1彼此独立地是饱和的或者不饱和的4-元至8-元单环杂环基,所述杂环基包含Het1经其连接的环氮原子且任选地包含一个或两个相同或不同的选自氮、氧和硫的另外的环杂原子,并且任选被一个或者多个相同或者不同的选自下述的取代基取代:卤素、(C1-C4)-烷基、HO-、(C1-C4)-烷基-O-、氧代和NC-;
Het2是饱和的4-元至7-元单环杂环基,所述杂环基包含Het2经其连接的环氮原子且任选地包含一个另外的选自氮、氧和硫的环杂原子,并且任选被一个或者多个相同或者不同的选自下述的取代基取代:卤素、(C1-C4)-烷基、HO-、氧代和(C1-C4)-烷基-O-;
Het3彼此独立地是饱和的4-元至7-元单环杂环基,所述杂环基包含一个或两个相同或不同的选自氮、氧和硫的环杂原子并是经环碳原子连接的,并且任选被一个或者多个相同或者不同的选自下述的取代基取代:氟、(C1-C4)-烷基和氧代;
Het4彼此独立地是饱和的或者不饱和的4-元至8-元单环杂环基,所述杂环基包含一个至四个选自氮、氧和硫的环杂原子,并且任选被一个或者多个相同或者不同的选自下述的取代基取代:卤素、(C1-C4)-烷基、HO-、(C1-C4)-烷基-O-、氧代和NC-;
m彼此独立地为选自0、1和2的整数;
其中所有环烷基彼此独立地任选地被一个或多个相同或不同的选自下述的取代基所取代:氟和(C1-C4)-烷基;
其中所有烷基、CsH2s、CuH2u、(CH2)x和(CH2)y基团彼此独立且独立于任何其它取代基地任选被一个或多个氟取代基所取代。
如果结构要素如基团、取代基或数字可以若干次出现在式I化合物中,则它们均彼此独立并在各个情况下可具有任何所表明的含义,且在各个情况下它们可以相同或不同于任何其它这种要素。例如,在二烷基氨基中,所述烷基可以是相同的或者不同的。
烷基,即饱和的烃残基,可以是直链的(直链)或支链的。如果这些基团是取代的或是另一基团的部分,这也适用,例如烷基-O-基团(烷基氧基、烷氧基)或HO-取代的烷基(羟基烷基)。取决于各自的定义,烷基中碳原子的数目可以是例如1个、2个、3个、4个、5个、6个、7个、8个、9个或10个,或者1个、2个、3个、4个、5个、6个、7个或8个,或者1个、2个、3个、4个、5个或6个,或者1个、2个、3个或4个,或者1个、2个或3个,或者1个或2个,或者1个。在本发明的一个实施方案中,存在于式I化合物中的(C1-C10)-烷基是(C1-C8)-烷基,在另一个实施方案中是(C1-C6)-烷基,在另一个实施方案中是(C1-C4)-烷基,在另一个实施方案中是(C1-C3)-烷基,在另一个实施方案中是(C1-C2)-烷基,在另一个实施方案中是(C2-C3)-烷基,在另一个实施方案中是甲基。在本发明的一个实施方案中,存在于式I化合物任意位置的(C1-C8)-烷基是(C1-C6)-烷基,在另一个实施方案中是(C1-C4)-烷基,在另一个实施方案中是(C1-C3)-烷基,在另一个实施方案中是(C1-C2)-烷基,在另一个实施方案中是(C2-C3)-烷基,在另一个实施方案中是甲基,其中存在于式I化合物中的任何(C1-C8)-烷基,独立于每个其它(C1-C8)-烷基,可以是任何这些实施方案的基团。在本发明的一个实施方案中,存在于式I化合物任何位置的(C1-C6)-烷基是(C1-C4)-烷基,在另一个实施方案中是(C1-C3)-烷基,在另一个实施方案中是(C1-C2)-烷基,在另一个实施方案中是(C2-C3)-烷基,在另一个实施方案中是甲基,其中存在于式I化合物中的任何(C1-C6)-烷基,独立于每个其它(C1-C6)-烷基,可以是任何这些实施方案的基团。在本发明的一个实施方案中,存在于式I化合物任何位置的(C1-C4)-烷基是(C1-C3)-烷基,在另一个实施方案中是(C1-C2)-烷基,在另一个实施方案中是(C2-C3)-烷基,在另一个实施方案中是甲基,其中存在于式I化合物中的任何(C1-C4)-烷基,独立于每个其它(C1-C4)-烷基,可以是任何这些实施方案的基团。烷基的实例是甲基、乙基;丙基,包括丙基(即正丙基)和异丙基;丁基,包括丁基(即正丁基)、仲丁基、异丁基和叔丁基;戊基,包括戊基(即正戊基)、1-甲基丁基、异戊基、新戊基和叔戊基;己基,包括己基(即正己基)、3,3-二甲基丁基和异己基;庚基,包括庚基(即正庚基);辛基,包括辛基(即正辛基);壬基,包括壬基(即正壬基);和癸基,包括癸基(即正癸基)。烷基-O-基团的实例是甲氧基、乙氧基、丙氧基(即正丙氧基)、异丙氧基、丁氧基(即正丁氧基)、异丁氧基、叔丁氧基、戊氧基(即正戊氧基)。烷基-S(O)m-的实例是甲基硫基-(CH3-S-)、甲基亚磺酰基-(CH3-S(O)-)、甲基磺酰基-(CH3-S(O)2-)、乙基硫基-(CH3-CH2-S-)、乙基亚磺酰基-(CH3-CH2-S(O)-)、乙基磺酰基-(CH3-CH2-S(O)2-)、1-甲基乙基硫基-((CH3)2CH-S-)、1-甲基乙基亚磺酰基-((CH3)2CH-S(O)-)、1-甲基乙基磺酰基-((CH3)2CH-S(O)2-)。在本发明的一个实施方案中,所述数字m选自0和2,其中所有数字m彼此独立且可以是相同的或不同的。在另一个实施方案中,数字m独立于其它出现中的其含义,任何其出现中所述数字m是0。在另一个实施方案中,数字m独立于其它出现中的其含义,任何其出现中所述数字m是2。
只要各个化合物是足够稳定的并且适于作为药用活性化合物,取代的烷基可以在任何位置被取代。所述先决条件,即具体基团和式I化合物是足够稳定的并适于作为药用活性化合物,其通常对于式I化合物中所有基团的定义适用。在本发明的一个实施方案中,式I化合物的任意烷基中的单独碳原子,以及其它基团(如环烷基和杂环基团)中的单独碳原子,独立于任何其它碳原子,不带有多于一个通过氧原子、氮原子或硫原子连接的取代基,例如,HO-、(C1-C4)-烷基-O-或(C1-C4)-烷基-S(O)m-取代基。任选地被一个或多个氟取代基所取代的烷基可以是未取代的,即不带有氟取代基,或者是取代的,例如被一个、两个、三个、四个、五个、六个、七个、八个、九个、十个或十一个氟取代基所取代,或者被一个、两个、三个、四个、五个、六个或七个氟取代基所取代,或者被一个、两个、三个、四个或五个氟取代基所取代,或者被一个、两个或三个氟取代基所取代,所述氟取代基可以位于任何位置。例如,在氟取代的烷基中,一个或多个甲基可以各自带有三个氟取代基并以三氟甲基存在,和/或一个或多个亚甲基(CH2)可以各自带有两个氟取代基并以二氟亚甲基存在。如果所述基团另外带有其它取代基和/或是另一个基团的部分,例如烷基-O-基团,则对于基团被氟的取代的解释也适用。氟取代的烷基的实例是三氟甲基、2-氟乙基、1-氟乙基、1,1-二氟乙基、2,2,2-三氟乙基、五氟乙基、3,3,3-三氟丙基、2,2,3,3,3-五氟丙基、4,4,4-三氟丁基和七氟异丙基。氟取代的烷基-O-基团的实例是三氟甲氧基、2,2,2-三氟乙氧基、五氟乙氧基和3,3,3-三氟丙氧基。氟取代的烷基-S(O)m-基团的实例是三氟甲基硫基-(CF3-S-)、三氟甲基亚磺酰基-(CF3-S(O)-)和三氟甲基磺酰基(CF3-S(O)2-)。
对于烷基的上述解释相应地适用于烷二基(二价烷基),其包括二价基团CsH2s、CuH2u、(CH2)x和(CH2)y。取代的烷基的烷基部分也可以被认为是烷二基。因此,烷二基可以是直链的或支链的,与相邻基团的键可以位于任何位置并可以从同一碳原子或不同碳原子开始,并且它们可以被氟取代基所取代。烷二基,其包括基团CsH2s和CuH2u及基团(CH2)x(关于它们构成聚亚甲基链),它们的实例是-CH2-、-CH2-CH2-、-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-、-CH(CH3)-、-C(CH3)2-、-CH(CH3)-CH2-、-CH2-CH(CH3)-、-C(CH3)2-CH2-、-CH2-C(CH3)2-。氟取代的烷二基可以包含一个、两个、三个、四个、五个或六个氟取代基,或者一个、两个、三个或四个氟取代基,或者一个或两个氟取代基,该氟取代的烷二基的实例例如是-CHF-、-CF2-、-CF2-CH2-、-CH2-CF2-、-CF2-CF2-、-CF(CH3)-、-C(CF3)2-、-C(CH3)2-CF2-、-CF2-C(CH3)2-。
(C3-C7)-环烷基中环碳原子的数目可以是三个、四个、五个、六个或七个。环烷基的实例是环丙基、环丁基、环戊基、环己基和环庚基。关于环烷基被一个或多个(C1-C4)-烷基取代基的任选取代,它们可以是未取代的,即不带有烷基取代基,或是取代的,例如被一个、两个、三个或四个相同或不同的(C1-C4)-烷基取代基所取代,或者被一个或两个相同或不同的(C1-C4)-烷基取代基所取代,例如被甲基所取代,所述取代基可以位于任何位置。这些烷基取代的环烷基的实例是1-甲基环丙基、2,2-二甲基环丙基、1-甲基环戊基、2,3-二甲基环戊基、1-甲基环己基、4-甲基环己基、4-异丙基环己基、4-叔丁基环己基和3,3,5,5-四甲基环己基。关于环烷基被一个或多个氟取代基的任选取代,它们可以是未取代的,即不带有氟取代基,或是取代的,例如被一个、两个、三个、四个、五个、六个、七个、八个、九个、十个或十一个氟取代基所取代,或者被一个、两个、三个、四个、五个或六个氟取代基所取代,或者被一个、两个、三个或四个氟取代基所取代,或者被一个或两个氟取代基所取代。所述氟取代基可以位于环烷基的任何位置且还可以位于环烷基上的烷基取代基上。这些氟取代的环烷基的实例是1-氟环丙基、2,2-二氟环丙基、3,3-二氟环丁基、1-氟环己基、4,4-二氟环己基和3,3,4,4,5,5-六氟环己基。环烷基也可以同时被氟和烷基所取代。可以表示R11或R30的(C3-C7)-环烷基取代的烷基的实例是环丙基甲基-、环丁基甲基-、环戊基甲基-、环己基甲基-、环庚基甲基-、1-环丙基乙基-、2-环丙基乙基-、1-环丁基乙基-、2-环丁基乙基-、1-环戊基乙基-、2-环戊基乙基-、1-环己基乙基-、2-环己基乙基-、1-环庚基乙基-、2-环庚基乙基-。对于环烷基的解释相应地适用于二价环烷基(环烷二基),在两个基团R30和R40一起形成(CH2)x或两个基团R50和R60一起形成(CH2)y的情况下,该基团可以出现。取代的环烷基的环烷基部分也可以被认为是环烷二基。因此,例如,环烷二基通过其与相邻基团连接的键,可以位于任何位置,且当在R30和R40一起形成(CH2)x或两个基团R50和R60一起形成(CH2)y时存在的环烷二基情况下,所述键可以从同一环碳原子开始,或者所述键可以从不同的环碳原子开始。
在取代的苯基中,所述取代基可以位于任何位置。在可存在于苯基和芳族杂环基上的二价取代基-O-CH2-O-(亚甲二氧基)、-O-CH2-CH2-O-和-O-CF2-O-(二氟亚甲二氧基)的情况下,两个氧原子与苯基或芳族杂环基的相邻环碳原子连接并代替母体系统的两个氢原子。在单取代的苯基中,所述取代基可以位于2-位、3-位或4-位。在二取代的苯基中,所述取代基可以位于2,3-位、2,4-位、2,5-位、2,6-位、3,4-位或3,5-位。在三取代的苯基中,所述取代基可以位于2,3,4-位、2,3,5-位、2,3,6-位、2,4,5-位、2,4,6-位或3,4,5-位。如果苯基带有四个取代基,其中某些可以例如是氟原子,所述取代基可以位于2,3,4,5-位、2,3,4,6-位或2,3,5,6-位。如果多取代的苯基带有不同的取代基,各取代基可以位于任何适当的位置,且本发明包括所有位置异构体。任选取代的苯基中取代基的数目可以是一个、两个、三个、四个或五个。在本发明的一个实施方案中,任选取代的苯基,独立于式I化合物中任何其它任选取代的苯基,带有一个、两个、三个或四个相同或不同的取代基,在另一个实施方案中带有一个、两个或三个相同或不同的取代基,在另一个实施方案中带有一个或两个相同或不同的取代基,在另一个实施方案中带有一个相同或不同的取代基,且在另一个实施方案中它是未取代的。
同样,在取代的杂环基团中,所述杂环基团包括可以表示R32、R33和Ar的芳族5-元和6-元单环杂环基、可以表示Het1的饱和的及不饱和的4-元至8-元单环杂环基和可以表示Het2和Het3的饱和4-元至7-元单环杂环基,所述取代基可以位于任何位置并可存在于环碳原子上和/或适当的环氮原子上。本发明包括所有位置异构体。可以存在于式I化合物的取代杂环基上取代基的数目,取决于环大小、环杂原子的数目和类型及不饱和的程度。在本发明的一个实施方案中,式I化合物的任意杂环基团上相同或不同取代基的数目,独立于该基团任何其它出现的取代基数目及式I化合物任何其它杂环基团的取代基数目,是一个、两个、三个、四个或五个,在另一个实施方案中是一个、两个、三个或四个,在另一个实施方案中是一个、两个或三个,在另一个实施方案中是一个或两个,在另一个实施方案中是一个。任选带有取代基的环氮原子,包括除这样的环经其连接的那些环氮原子之外的饱和杂环中的环氮原子,和5-元芳族杂环(如吡咯、咪唑或三唑)的环氮原子,所述环氮原子在母体杂环中带有氢原子。在本发明的一个实施方案中,在任何这些杂环基团环氮原子上的取代基,选自经碳原子连接的各个基团定义中说明的那些取代基,例如选自(C1-C6)-烷基、(C3-C7)-环烷基和R33,在另一个实施方案中,在可以表示R32的芳族杂环的情况下,选自(C1-C6)-烷基和(C3-C7)-环烷基,在可以表示R33的芳族杂环情况下,选自(C1-C6)-烷基和(C3-C7)-环烷基,并在可以表示Ar的芳族杂环情况下是(C1-C6)-烷基及在Het1、Het2和Het3的情况下是(C1-C4)-烷基。通常,除任选带有各个基团定义中表明的取代基之外,式I化合物的杂环基团中适当的环氮原子,具体来说是芳族杂环基团如可以表示R32、R33和Ar的杂环基团中适宜的环氮原子,例如吡啶基中的环氮原子,还可以带有氧化(oxido)取代基-O-并以N-氧化物存在。
式I化合物的杂环基团(包括可以表示R32、R33和Ar的芳族5-元和6-元单环杂环及表示Het1、Het2、Het3和Het4的杂环)定义中说明的环杂原子通常可以以任何组合存在并位于任何适宜的环位置,如上所述,只要所得基团和式I化合物是足够稳定的并适宜作为药用活性化合物。在本发明的一个实施方案中,式I化合物的任意杂环的两个氧原子不能存在于相邻的环位置。在另一个实施方案中,式I化合物的任意非芳族杂环的两个环杂原子不能存在于相邻的环位置。在另一个实施方案中,非芳族杂环的两个环杂原子不能存在于相邻的环位置,所述环杂原子选自带有氢原子或取代基并通过单键与相邻环原子连接的N原子以及O原子和S原子。在芳族杂环中,环杂原子及其位置的选择被所述环是芳族的先决条件所限制,即,它包含具有6个离域π电子的环系。因此,例如,芳族单环6-元杂环中,只有氮原子可以作为环杂原子出现,且在芳族单环5-元杂环中,只能存在一个选自带有氢原子或取代基的O原子、S原子和N原子的环杂原子。可以表示Het1的不饱和杂环可以是芳族的,例如在经环氮原子连接并可以表示Het1的吡咯基、咪唑基或三唑基的情况下,或者所述不饱和杂环是非芳族的,并在环内包含一个或两个可以在任何位置存在的双键。在一个实施方案中,表示Het1的4-元杂环不能是不饱和的。正如各个基团定义中所表明,杂环基团可以分别经任何环碳原子或经任何适当的环氮原子连接。所述基团Het1可以是4-元、5-元、6-元或7-元或8-元的。所述基团Het2和Het3可以是4-元、5-元、6-元或7-元的。
芳族杂环的实例是吡咯、呋喃、噻吩、咪唑、吡唑、噁唑([1,3]噁唑)、异噁唑([1,2]噁唑)、噻唑([1,3]噻唑)、异噻唑([1,2]噻唑)、[1,2,3]三唑、[1,2,4]三唑、[1,3,4]噁二唑、吡啶、哒嗪、嘧啶和吡嗪,在本发明的一个实施方案中,可以表示R32、R33及Ar和基团Het1(只要适用)的芳族5-元和6-元单环杂环选自所述实例的任意一个或多个,所述实例都可以经任何环碳原子或经任何适当的环氮原子连接,且如通常或在上述或下述任意实施方案中对式I化合物所示,所述实例都任选地被取代。芳族杂环的具体残基的实例是吡咯-1-基、吡咯-2-基、吡咯-3-基、呋喃-2-基、呋喃-3-基、噻吩-2-基(2-噻吩基)、噻吩-3-基(3-噻吩基)、咪唑-1-基、咪唑-2-基、咪唑-4-基、咪唑-5-基、吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基、噁唑-2-基、噁唑-4-基、噁唑-5-基、异噁唑-3-基、异噁唑-4-基、异噁唑-5-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、异噻唑-3-基、异噻唑-4-基、异噻唑-5-基、[1,2,3]三唑-1-基、[1,2,3]三唑-4-基、[1,2,3]三唑-5-基、[1,2,4]三唑-1-基、[1,2,4]三唑-3-基、[1,2,4]三唑-4-基、[1,3,4]噁二唑-2-基、吡啶-2-基(2-吡啶基)、吡啶-3-基(3-吡啶基)、吡啶-4-基(4-吡啶基)、哒嗪-3-基、哒嗪-4-基、嘧啶-2-基、嘧啶-4-基和吡嗪-2-基,在本发明的一个实施方案中,可以表示R32、R33或Ar和基团Het1(只要适用)的芳族5-元或6-元单环杂环残基选自所述实例的任意一个或多个,如通常或在上述或下述任一实施方案中对式I化合物所示,所述实例都任选地被取代。
饱和杂环与非芳族不饱和杂环的实例是氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、吡咯烷、2,5-二氢-1H-吡咯、四氢呋喃、四氢噻吩、吡唑烷、咪唑烷、4,5-二氢-1H-咪唑、[1,3]二氧戊环、噁唑烷、噻唑烷、哌啶、1,2,3,6-四氢吡啶、四氢吡喃、四氢噻喃、哌嗪、[1,3]二噁烷、[1,4]二噁烷、吗啉、硫吗啉、氮杂环庚烷、氧杂环庚烷、硫杂环庚烷、[1,3]二氮杂环庚烷、[1,4]二氮杂环庚烷、[1,4]氧杂氮杂环庚烷、[1,4]硫杂氮杂环庚烷和氮杂环辛烷(azocane),在本发明的一个实施方案中,对于环大小及饱和程度而言只要适用,所述基团Het1、Het2、Het3和Het4彼此独立地选自所述实例的任意一个或多个,如通常或在上述或下述任一实施方案中对式I化合物所示,所述实例都任选地被取代。饱和杂环与非芳族不饱和杂环的具体残基的实例是氮杂环丁烷-1-基、氧杂环丁烷-3-基、硫杂环丁烷-3-基、吡咯烷-1-基、吡咯烷-2-基、吡咯烷-3-基、2,5-二氢-1H-吡咯-1-基、四氢呋喃-2-基、四氢呋喃-3-基、四氢噻吩-2-基、四氢噻吩-3-基、吡唑烷-1-基、吡唑烷-4-基、咪唑烷-1-基、咪唑烷-2-基、咪唑烷-4-基、4,5-二氢-1H-咪唑-2-基、1,3-二氧戊环-2-基、1,3-二氧戊环-4-基、噁唑烷-2-基、噁唑烷-3-基、噁唑烷-4-基、噁唑烷-5-基、噻唑烷-2-基、噻唑烷-3-基、噻唑烷-4-基、噻唑烷-5-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、1,2,3,6-四氢吡啶-1-基、四氢吡喃-2-基、四氢吡喃-3-基、四氢吡喃-4-基、四氢噻喃-2-基、四氢噻喃-3-基、四氢噻喃-4-基、哌嗪-1-基、哌嗪-2-基、[1,3]二噁烷-2-基、[1,3]二噁烷-4-基、[1,3]二噁烷-5-基、[1,4]二噁烷-2-基、吗啉-2-基、吗啉-3-基、吗啉-4-基、硫吗啉-2-基、硫吗啉-3-基、硫吗啉-4-基、氮杂环庚烷-1-基、氮杂环庚烷-2-基、氮杂环庚烷-3-基、氮杂环庚烷-4-基、氧杂环庚烷-2-基、氧杂环庚烷-3-基、氧杂环庚烷-4-基、[1,3]二氮杂环庚烷-1-基、[1,4]二氮杂环庚烷-1-基、[1,4]氧杂氮杂环庚烷-1-基和[1,4]硫杂氮杂环庚烷-1-基,在本发明的一个实施方案中,对于环大小、饱和程度及所述残基经其连接的原子种类而言只要适用,所述基团Het1、Het2、Het3和Het4彼此独立地选自所述实例的任意一个或多个,如通常或在上述或下述任意实施方案中对式I化合物所示,所述实例都任选地被取代。
卤素是氟、氯、溴或碘。在本发明的一个实施方案中,式I化合物中任意出现的卤素,独立于所有其它出现,是氟、氯或溴,在另一个实施方案中所述卤素是氟或氯,在另一个实施方案中所述卤素是氟。
氧代取代基,即经双键连接的氧原子,当与碳原子连接时,代替与其连接的母体系统碳原子上的两个氢原子。因此,如果CH2基团被氧代所取代,它变成羰基(C(O)、C=O)。氧代取代基不能存在于芳族环的碳原子上。除了在碳原子上之外,氧代取代基还可以存在于基团Het1(具体来说如果基团Het1是饱和的)和基团Het3的环硫原子上,如果硫原子上有一个氧代取代基,得到环成员S(O)(S=O,即亚砜基团),或者如果硫原子上有两个氧代取代基,得到环成员S(O)2(S(=O)2,即砜基团)。作为可以表示Het1和Het3且在环硫原子上带有氧代取代基的杂环的实例,可能提到1,1-二氧代-四氢噻吩、1-氧代-硫吗啉和1,1-二氧代-硫吗啉,如通常或在上述或下述任意实施方案中对式I化合物所示,所述实例都任选地被更多取代基如(C1-C4)-烷基取代基所取代。
本发明包括所有式I化合物的立体异构形式,例如包括所有对映异构体和非对映异构体,包括顺式/反式异构体。本发明同样包括两种或多种立体异构形式的混合物,例如包括所有比例的对映异构体和/或非对映异构体包括顺式/反式异构体的混合物。式I化合物中包含的不对称中心,例如未取代的或取代的烷基中包含的不对称中心,都可以彼此独立地具有S构型或R构型。本发明涉及对映异构体纯形式和基本上对映异构体纯形式的左旋和右旋对映体的对映异构体,其具有例如99:1或更大的两种对映异构体的摩尔比,并涉及外消旋体形式的对映异构体及所有比例的两种对映异构体混合物形式的对映异构体。本发明同样涉及纯的和基本上纯的非对映异构体形式和所有比例的两种或多种非对映异构体混合物形式的非对映异构体。本发明还包括纯形式和基本上纯形式的式I化合物的所有顺式/反式异构体,具有例如99:1或更大的顺式/反式异构体的摩尔比,并包括所有比例的顺式异构体和反式异构体混合物形式的式I化合物的所有顺式/反式异构体。顺式/反式异构可以出现在取代的环中。如果需要,单独立体异构体的制备可以按照常用方法经混合物的拆分来进行,所述方法例如,通过色谱法或结晶法,或通过合成中立体化学均一的起始化合物的使用或通过立体选择性反应。立体异构体分离前,可以任选地进行衍生化。可以在合成过程中在式I化合物阶段或在中间体阶段进行立体异构体混合物的分离。本发明还包括所有式I化合物的互变异构形式。
式I化合物的生理学可接受的盐(包括药用盐)通常包含无毒的盐组分。它们可以含有无机盐或有机盐组分。这些盐例如可以由含有酸性基团的式I化合物和无毒的无机碱或有机碱形成,所述酸性基团例如羧酸基团(羟基羰基,HO-C(O)-)。适宜的碱是例如碱金属化合物或碱土金属化合物,如氢氧化钠、氢氧化钾、碳酸钠或碳酸氢钠、或氨、有机氨基化合物和季铵盐氢氧化物。用于制备盐的式I化合物与碱的反应,通常按照常用操作步骤在溶剂或稀释剂中进行。由此酸性基团盐的实例是钠盐、钾盐、镁盐或钙盐或铝盐,所述盐还可以在氮原子上带有一种或多种有机基团。含有碱性基团(即可质子化的基团,例如氨基或碱性杂环基)的式I化合物能以其与生理学可接受酸的酸加成盐的形式存在,例如作为与氯化氢、溴化氢、磷酸、硫酸、乙酸、苯甲酸、甲磺酸、对甲苯磺酸的盐,所述盐通常可以按照常用操作在溶剂或稀释剂中由式I化合物通过与酸的反应来制备。如果式I化合物在分子中同时含有酸性和碱性基团,则除提到的盐形式之外,本发明还包括内盐(内铵盐、两性离子)。本发明还包括所有式I化合物的盐,由于低生理学耐受性,所述盐不适于直接作为药物使用,但作为中间体适于化学反应或适于生理学可接受盐的制备,例如通过阴离子交换或阳离子交换的方式。本发明还包括所有式I化合物的溶剂化物及其盐,其包括生理学可接受的溶剂化物,如水合物,即与水的加合物和与醇如(C1-C4)-链烷醇的加合物,以及本发明还包括式I化合物的活性代谢产物和式I化合物的前药,即在体外可能未必展现药理学活性但在体内转化成药理学活性的式I化合物,例如通过代谢水解转化成式I化合物的化合物,如羧酸基团以酯化形式或以酰胺形式存在的化合物。
在由式I通过并入Ht的含义而获得的式的方面,在本发明的一个实施方案中,式I化合物为如下的任意一种或者多种化合物:式I-1至I-14例如式I-1化合物、式I-2化合物、式I-6化合物、式I-9化合物或者式I-10化合物,其为任意立体异构形式或任意比例的立体异构形式的混合物,或其生理学可接受的盐,或它们中的任一种的生理学可接受的溶剂化物,其中在式I-1至I-14的化合物中,基团Ht、R1、R2、R3、R4、R5、R10、R30、R40、R50和R60如通常或在上述或下述任意实施方案中式I化合物所定义。
在本发明的一个实施方案中,式I化合物为式I-1或者I-3化合物。
在本发明的一个实施方案中,式I化合物为式I-2或者I-4化合物。
在本发明的一个实施方案中,式I化合物为式I-5或者I-6化合物。
在本发明的一个实施方案中,式I化合物为式I-7或者I-8化合物。
在本发明的一个实施方案中,式I化合物为式I-9或者I-10化合物。
在本发明的一个实施方案中,式I化合物为式I-11或者I-12化合物。
在本发明的一个实施方案中,式I化合物为式I-13或者I-14化合物。
在本发明的一个实施方案中,基团G选自R71-O-C(O)-、R72-N(R73)-C(O)-和四唑-5-基,在另外的实施方案中,选自R71-O-C(O)-和R72-N(R73)-C(O)-,在另外的实施方案中,G为R71-O-C(O)-,且在另外的实施方案中,G为R72-N(R73)-C(O)-且在另外的实施方案中G为-C(O)OH。
在另外的实施方案中,基团R72和R73与它们所连接的氮原子一起形成饱和的5-元至6-元单环杂环基,所述杂环基不含有另外的环杂原子,并且任选被一个或者多个相同或者不同的选自下述的取代基取代:卤素、(C1-C4)-烷基、HO-和(C1-C4)-烷基-O-。
在一个实施方案中,基团R72选自氢、2,2-二甲基-丁-3-基、2,2-二甲基-丙烷-3-基、戊-3-基、丙-2-基、2-甲基-丙烷-2-基、丁-1-基、丁-2-基、2-甲基-丁-3-基、2-甲基-丁-2-基、-CH2CHF2、-CHCF3、CH2CN、-CH2CH2OCH3、-CH(CH2OH)CH(CH3)2、-CH2C(CH3)2-CH2OH、CH(C2H5)CH2OCH3、CH2CH2CH2N(CH3)2、环丙基、环丁基、环戊基、环己基和-CH2-Het4且基团R73为氢。
在另外的实施方案中,基团R72和R73与它们所连接的氮原子一起形成吡咯烷,其任选被HO-取代。
在另外的实施方案中,基团R72选自氢、(C1-C6)-烷基,其中烷基被HO-取代一次或者多次且基团R73为氢。
在本发明的一个实施方案中,基团R72和R73彼此独立地选自氢和(C1-C2)-烷基,在另外的实施方案中,选自氢和甲基。在一个实施方案中,基团R72和R73中的一个为氢且另一个选自氢和(C1-C4)-烷基,在另外的实施方案中,选自氢和(C1-C2)-烷基,在另外的实施方案中,选自氢和甲基,且在另外的实施方案中,基团R72和R73均为氢。
在本发明的一个实施方案中,基团Het4彼此独立地是饱和的或者不饱和的4-元至8-元单环杂环基,所述杂环基包含一个至四个选自氮、氧和硫的环杂原子,并且任选被一个或者多个相同或者不同的选自下述的取代基取代:卤素、(C1-C4)-烷基、HO-、(C1-C4)-烷基-O-、氧代和NC-;
在另外的实施方案中,基团Het4彼此独立地是饱和的或者不饱和的5-元至6-元单环杂环基,所述杂环基包含一个至四个选自氮、氧和硫的环杂原子,并且任选被一个或者多个相同或者不同的选自下述的取代基取代:卤素、(C1-C4)-烷基、HO-、(C1-C4)-烷基-O-、氧代和NC-;
在另外的实施方案中,基团Het4彼此独立地,是不饱和的5-元至6-元单环杂环基,所述杂环基包含一个至四个选自氮、氧和硫的环杂原子,并且任选被一个或者多个相同或者不同的选自下述的取代基取代:卤素、(C1-C4)-烷基、HO-、(C1-C4)-烷基-O-和NC-;
在另外的实施方案中,基团Het4彼此独立地选自1,2-噁二唑基、四唑基、吡唑基、呋喃基、吡啶基、嘧啶基,所述基团任选被甲基取代。
在本发明的一个实施方案中,基团Ar在式I化合物中的任意出现时彼此独立地选自苯基和芳族5-元或者6-元单环杂环基,所述杂环基包含一个或者两个相同或者不同的环杂原子,在另外的实施方案中,包含一个环杂原子,所述环杂原子选自氮、氧和硫,且所述杂环基经环碳原子连接,在另外的实施方案中,Ar选自苯基和芳族6-元杂环基,所述杂环基包含一个或者两个氮原子作为环杂原子,在另外的实施方案中,Ar选自苯基、噻吩基和吡啶基,在另外的实施方案中,选自苯基和噻吩基,在另外的实施方案中,选自苯基和吡啶基,在另外的实施方案中,基团Ar为苯基,且在另外的实施方案中,基团Ar为吡啶基,其中所述苯基和所有杂环基均任选如通常或在上述或下述任意实施方案中对式I化合物所示所取代。在一个实施方案中,任选存在于基团Ar上的取代基数目彼此独立地是一个、两个、三个或者四个,在另外的实施方案中,是一个、两个或者三个,在另外的实施方案中,是一个或者两个,在另外的实施方案中,是一个,且在另外的实施方案中,基团Ar为未取代的。在基团Ar上存在选自-O-CH2-O-和-O-CF2-O-的取代基的情况下,在一个实施方案中存在不多于两个这样的取代基,在另一个实施方案中存在不多于一个这样的取代基,或者没有任何其它取代基,或者与任何其它取代基一起存在。在一个实施方案中,任选地存在于基团Ar上的取代基彼此独立地选自卤素、(C1-C6)-烷基、(C1-C6)-烷基-O-、-O-CH2-O-、-O-CF2-O-、(C1-C6)-烷基-S(O)m-和NC-,在另一个实施方案中选自卤素、(C1-C6)-烷基、(C1-C6)-烷基-O-、(C1-C6)-烷基-S(O)m-和NC-,在另一个实施方案中选自卤素、(C1-C6)-烷基、(C1-C6)-烷基-O-和NC-,在另一个实施方案中选自卤素、(C1-C6)-烷基和(C1-C6)-烷基-O-,在另一个实施方案中选自卤素、(C1-C4)-烷基和(C1-C4)-烷基-O-,在另一个实施方案中选自卤素和(C1-C4)-烷基。
本发明的一个主题是所有的式I化合物,其中任意一个或多个结构要素如基团、取代基和数字如任意的详细说明的实施方案或所述要素的定义中所定义,或具有一个或多个作为要素实例在本申请中提到的具体含义,其中一个或多个详细说明的实施方案和/或定义和/或所述要素的具体含义的所有组合是本发明的一个主题。对于所有这样的式I化合物,所有其立体异构形式和任意比例的立体异构形式的混合物及它们的生理学可接受的盐和它们中的任一种的生理学可接受的溶剂化物,也是本发明的一个主题。
作为对于任意结构要素在本发明详细说明的实施方案或这些要素的定义中所定义的本发明化合物的实例,可提到呈任意立体异构形式或任意比例的立体异构形式的混合物的式I化合物和其生理学可接受的盐及它们中的任一种的生理学可接受的溶剂化物,其中
G为R71-O-C(O)-和R72-N(R73)-C(O)-;
R71选自氢和(C1-C8)-烷基;
R72选自氢、(C1-C6)-烷基;
R73选自氢、(C1-C6)-烷基;
且所有其它基团和数字如在式I化合物的通用定义中或在任意的本发明详细说明的实施方案中或结构要素的定义中所定义。
作为对于任意结构要素在本发明详细说明的实施方案或这些要素的定义中所定义的本发明化合物的实例,可提到呈任意立体异构形式或任意比例的立体异构形式的混合物的式I化合物和其生理学可接受的盐及它们中的任何的生理学可接受的溶剂化物,其中
R50为氢;
R60为氢;
且所有其它基团和数字如在式I化合物的通用定义中或在任意的本发明详细说明的实施方案中或结构要素的定义中所定义。
作为对于任意结构要素在本发明详细说明的实施方案或这些要素的定义中所定义的本发明化合物的实例,可提到呈任意立体异构形式或任意比例的立体异构形式的混合物的式I化合物和其生理学可接受的盐及它们中的任何的生理学可接受的溶剂化物,其中
Ht选自
R1选自氢、卤素、(C1-C6)-烷基、CF3、(C3-C7)-环烷基-CsH2s-、Ar-CsH2s-、Ar-O、(C1-C6)-烷基-O-;其中s为选自0、1、2和3的整数;
R2选自氢、卤素、(C1-C6)-烷基、CF3、(C1-C6)-烷基-O-和NC-;
R3选自氢、(C1-C6)-烷基;
R4选自(C1-C7)-烷基、(C3-C7)-环烷基-CsH2s-和Ar-CsH2s-,其中s为选自0、1、2和3的整数;
R5选自氢、卤素、(C1-C6)-烷基、(C1-C6)-烷基-O-和NC-;
且所有其它基团和数字如在式I化合物的通用定义中或在任意的本发明详细说明的实施方案中或结构要素的定义中所定义。
作为对于任意结构要素在本发明详细说明的实施方案或这些要素的定义中所定义的本发明化合物的实例,可提到呈任意立体异构形式或任意比例的立体异构形式的混合物的式I化合物和其生理学可接受的盐及它们中的任何的生理学可接受的溶剂化物,其中
R30为R32-CuH2u-,其中u为选自0和1的整数;
R32选自苯基和芳族5-元或者6-元单环杂环基,所述杂环基包含一个、两个或三个相同或不同的选自氮、氧和硫的环杂原子并是经环碳原子连接的,其中所述苯基和杂环基都任选地被一个或多个相同或不同的选自下述的取代基所取代:卤素、(C1-C6)-烷基、(C3-C7)-环烷基、HO-、(C1-C6)-烷基-O-、R33-O-、R33-(C1-C4)-烷基-O-、-O-CH2-O-、-O-CF2-O-、(C1-C6)-烷基-S(O)m-、H2N-S(O)2-、(C1-C4)-烷基-NH-S(O)2-、二((C1-C4)-烷基)N-S(O)2-、H2N-、(C1-C6)-烷基-NH-、二((C1-C6)-烷基)N-、Het1、(C1-C4)-烷基-C(O)-NH-、Ar-C(O)-NH-、(C1-C4)-烷基-S(O)2-NH-和NC-;
R33选自苯基和芳族5-元或者6-元单环杂环基,所述杂环基包含一个、两个或三个相同或不同的选自氮、氧和硫的环杂原子并是经环碳原子连接的,其中所述苯基和杂环基都任选地被一个或多个相同或不同的选自下述的取代基所取代:卤素、(C1-C6)-烷基、(C3-C7)-环烷基、HO-、(C1-C6)-烷基-O-、(C1-C6)-烷基-S(O)m-、H2N-S(O)2-、(C1-C4)-烷基-NH-S(O)2-、二((C1-C4)-烷基)N-S(O)2-和NC-;
R40为氢;
且所有其它基团和数字如在式I化合物的通用定义中或在任意的本发明详细说明的实施方案中或结构要素的定义中所定义。
作为对于任意结构要素在本发明详细说明的实施方案或这些要素的定义中所定义的本发明化合物的实例,可提到呈任意立体异构形式或任意比例的立体异构形式的混合物的式I化合物和其生理学可接受的盐及它们中的任何的生理学可接受的溶剂化物,其中
R30为R32-CuH2u-,其中u为整数0;
R40为氢;
且所有其它基团和数字如在式I化合物的通用定义中或在任意的本发明详细说明的实施方案中或结构要素的定义中所定义。
本发明的一个主题还是式I化合物,所述化合物选自本申请所公开的任意的具体式I化合物或是本申请所公开的具体式I化合物中的任意一个,不管其是否作为游离化合物和/或作为具体的盐或其生理学可接受的盐或它们中的任一种的生理学可接受的溶剂化物被公开,其中呈任意立体异构形式或任意比例的立体异构形式的混合物的式I化合物是本发明的一个主题。例如,本发明的一个主题是选自如下的式I化合物:
(S)-3-[(2-苯基-1H-咪唑-4-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-[(5-苯基-异噁唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
3-环己基-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-4-苯基-丁酸
(S)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-[(1-异丙基-1H-吲唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-(2-氟-苯基)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(3-氟-苯基)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(4-氟-苯基)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-3-苯基-丙酸
(R)-3-{[3-(2-氟-苯基)-[1,2,4]噁二唑-5-羰基]-氨基}-4-苯基-丁酸
(S)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(R)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-4-苯基-丁酸
(S)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-苯基-丁酸
(S)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-间甲苯基-丙酸
(S)-3-(2-氟-苯基)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-丙酸
(S)-3-(3-氟-苯基)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-丙酸
(S)-3-(4-氟-苯基)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-苯基-丙酸
(S)-3-[(1-乙基-5-苯基-1H-吡唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-[(5-异丙基-2-苯基-噁唑-4-羰基)-氨基]-3-苯基-丙酸
(S)-3-(4-甲氧基-苯基)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(3-甲氧基-苯基)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[5-(4-氯-苯基)-异噁唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-3-间甲苯基-丙酸
(S)-3-(3-氯-苯基)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(R)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-4-苯基-丁酸
(S)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-3-苯基-丁酸
(S)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-3-苯基-丙酸
(S)-3-(2-氯-苯基)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-{[1-(2-氯-苯基)-5-甲基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-苯基-丙酸
3-环己基-3-[(5-异丙基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(2-氟-苯基)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-丙酸
(S)-3-(3-氟-苯基)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-丙酸
(S)-3-(4-氟-苯基)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-间甲苯基-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-苯基-丁酸
(R)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-4-苯基-丁酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-(2-氟-苯基)-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-(4-氟-苯基)-丙酸
3-[(5-异丙基-2-苯基-噁唑-4-羰基)-氨基]-4-苯基-丁酸
(S)-3-[(5-二甲基氨磺酰基-2-甲基-呋喃-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-(2-氟-苯基)-3-[(5-异丙基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(4-氟-苯基)-3-[(5-异丙基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(R)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-4-苯基-丁酸
(S)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-3-间甲苯基-丙酸
(S)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-3-苯基-丁酸
(S)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-3-对甲苯基-丙酸
(S)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-3-邻甲苯基-丙酸
(S)-环己基-{[5-(4-三氟甲基-吡啶-3-基)-[1,2,4]噁二唑-3-羰基]-氨基}-乙酸
(S)-3-{[1-(2-氯-苯基)-5-甲基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-乙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-甲基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-(4-氟-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸
(S)-3-(2-氟-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸
(S)-3-(3-氟-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸
(S)-3-(3-氯-苯基)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-丙酸
3-(2-氯-苯基)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-丙酸
(S)-3-(4-氯-苯基)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-丙酸
(S)-3-{[1-甲基-4-(丙烷-1-磺酰基氨基)-1H-吡唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-[(5-异丙基-2-苯基-噁唑-4-羰基)-氨基]-3-(3-甲氧基-苯基)-丙酸
(S)-3-(2,3-二甲氧基-苯基)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(2-氯-苯基)-3-[(5-异丙基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
3-环己基-3-[(2-苯基-5-三氟甲基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-3-苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-乙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-乙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-[(1-苄基-1H-吲唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-3-(4-甲氧基-苯基)-丙酸
(S)-3-(3-氯-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸
(S)-3-(2,4-二氯-苯基)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(2,3-二氯-苯基)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-[(2-苯基-5-三氟甲基-噁唑-4-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-3-(2-三氟甲基-苯基)-丙酸
(S)-3-(3-氟-苯基)-3-[(2-苯基-5-三氟甲基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-(2-三氟甲基-苯基)-丙酸
(S)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-(3-三氟甲基-苯基)-丙酸
(S)-3-{[1-(2-氯-苯基)-5-环丙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-环丙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-异丙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-对甲苯基-丙酸
3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-4-苯基-丁酸
(S)-3-{[1-(2-氯-苯基)-5-异丙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-丙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-丙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-3-(2-氟-苯基)-丙酸
(S)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-3-(4-氟-苯基)-丙酸
(S)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-3-(3-三氟甲基-苯基)-丙酸
(S)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-3-(4-三氟甲基-苯基)-丙酸
(S)-3-(2,3-二氯-苯基)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-丙酸
(S)-3-{[4-(2,2-二甲基-丙烷-1-磺酰基氨基)-1-甲基-1H-吡唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-(3-氯-苯基)-3-[(2-苯基-5-三氟甲基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(2-氯-苯基)-3-[(2-苯基-5-三氟甲基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-[(1-苄基-5-苯基-1H-吡唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-(4-氯-苯基)-2-{[5-(4-三氟甲基-吡啶-3-基)-[1,2,4]噁二唑-3-羰基]-氨基}-丙酸
(S)-3-{[1-乙基-5-(2-丙基-哌啶-1-羰基)-1H-吡唑-3-羰基]-氨基}-3-苯基-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-(2-三氟甲基-苯基)-丙酸
(S)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-3-(3-甲氧基-苯基)-丙酸
(S)-3-(2,3-二氯-苯基)-3-[(5-异丙基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(3-氯-苯基)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-丙酸
(S)-3-(2,4-二氯-苯基)-3-[(5-异丙基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(2-氯-苯基)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-丙酸
(S)-3-{[1-(2,6-二氯-苯基)-5-乙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-{[1-(2,6-二氯-苯基)-5-乙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-[(4-环己基甲磺酰基氨基-1-甲基-1H-吡唑-3-羰基)-氨基]-3-苯基-丙酸
(S)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-3-(2-三氟甲基-苯基)-丙酸
(S)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-3-(4-三氟甲基-苯基)-丙酸
(S)-3-(2,3-二氯-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸
(S)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-3-(3-三氟甲基-苯基)-丙酸
(S)-3-{[1-乙基-5-(2-丙基-哌啶-1-羰基)-1H-吡唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[1-乙基-5-(2-丙基-哌啶-1-羰基)-1H-吡唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-{[1-乙基-5-(2-丙基-哌啶-1-羰基)-1H-吡唑-3-羰基]-氨基}-3-间甲苯基-丙酸
(S)-3-[(1-甲基-4-苯基甲磺酰基氨基-1H-吡唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-{[1-(4-氟-苄基)-5-苯基-1H-吡唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-[(4-环己基甲磺酰基氨基-1-甲基-1H-吡唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-(2,3-二甲氧基-苯基)-3-[(2-苯基-5-三氟甲基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-{[1-甲基-4-(2-苯基-乙磺酰基氨基)-1H-吡唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-(2,3-二氯-苯基)-3-[(2-苯基-5-三氟甲基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(2,4-二氯-苯基)-3-[(2-苯基-5-三氟甲基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(2,3-二氯-苯基)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-丙酸
(S)-3-(2,4-二氯-苯基)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-丙酸
或者所述化合物是这些化合物中的任意一个,或其生理学可接受的盐或它们中的任一种的生理学可接受的溶剂化物,其中呈任意立体异构形式或任意比例的立体异构形式的混合物的式I化合物是本发明的一个主题,除非具体立体异构形式对于各个化合物中任意碳原子是详细说明的。
例如,本发明的另外的主题为选自下述的式I化合物:
(S)-3-[(2-苯基-1H-咪唑-4-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-[(1-异丙基-1H-吲唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(R)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-4-苯基-丁酸
(S)-3-[(1-乙基-5-苯基-1H-吡唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-3-邻甲苯基-丙酸
(R)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-4-苯基-丁酸
(S)-3-(3-氟-苯基)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-(2-氟-苯基)-丙酸
(S)-3-{[1-(2-氯-苯基)-5-甲基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-甲基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-(2-氟-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸
(S)-3-(3-氯-苯基)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-丙酸
(S)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-3-苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-乙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-乙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-[(1-苄基-1H-吲唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-(3-氯-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸
(S)-3-(2,3-二氯-苯基)-3-[(5-甲基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-异丙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-异丙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-丙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-{[1-(2-氯-苯基)-5-丙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-3-(2-氟-苯基)-丙酸
(S)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-3-(4-氟-苯基)-丙酸
(S)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-3-(4-三氟甲基-苯基)-丙酸
(S)-3-(2,3-二氯-苯基)-3-{[2-(2-氟-苯基)-5-甲基-噁唑-4-羰基]-氨基}-丙酸
(S)-3-[(1-苄基-5-苯基-1H-吡唑-3-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-3-(3-甲氧基-苯基)-丙酸
(S)-3-(2,3-二氯-苯基)-3-[(5-异丙基-2-苯基-噁唑-4-羰基)-氨基]-丙酸
(S)-3-(3-氯-苯基)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-丙酸
(S)-3-(2-氯-苯基)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-丙酸
(S)-3-{[1-(2,6-二氯-苯基)-5-乙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-{[1-(2,6-二氯-苯基)-5-乙基-1H-[1,2,4]三唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[1-乙基-5-(2-丙基-哌啶-1-羰基)-1H-吡唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-(2,3-二氯-苯基)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-丙酸
(S)-3-(2,4-二氯-苯基)-3-[(1,5-二苯基-1H-[1,2,4]三唑-3-羰基)-氨基]-丙酸。
本发明的另一个主题是式I化合物的制备方法,所述方法概述如下并且通过该方法可获得所述化合物。例如,式I化合物的制备可以通过使式II化合物与式III化合物反应形成酰胺键来进行。酰胺键形成的各种合成方法在如下文献中有描述,例如C.A.G.N.Montalbetti et al.,Tetrahedron 61(2005),10827-10852。
式II和III化合物中基团R10、R30、R40、R50和R60如式I化合物中所定义,并且官能团可以另外以保护的形式或以前体基团的形式存在,所述形式稍后被转化成最终的基团。式II化合物中基团J可以是HO-(羟基),即式II化合物由此可以是羧酸,或是在取代反应中可以被式III化合物中的基团NH所代替的另一基团,例如,芳氧基如任选取代的苯氧基;或烷基氧基,如(C1-C4)-烷基-O-基团,例如(C1-C3)-烷基-O-基团如甲氧基或乙氧基;或卤素,例如氯或溴,并且式II化合物由此可以是各个羧酸的反应性酯(reactive ester)如芳基酯或烷基酯,例如甲酯或乙酯;或各个羧酸的酰基卤,例如酰基氯或酰基溴。式II和III化合物还可以以盐的形式来采用,且式I化合物可以以盐的形式来获得,例如式III化合物的酸加成盐如氢卤化物,例如盐酸盐,和/或其中J是HO-的式II化合物的碱金属盐,例如钠盐。同样,在式I化合物制备的所有其它反应中,包括起始化合物制备的所有其它反应中,化合物还可以以盐形式来采用和/或产物以盐形式来获得。
在使用其中J是HO-的式II化合物的情况下,羧酸基团HO-C(O)-通常以常用的酰胺偶联试剂原位活化或转化成可以原位制备或分离的反应性羧酸衍生物。例如,通过用亚硫酰氯、五氯化磷、三溴化磷或草酰氯处理,其中J是HO-的式II化合物可以被转化成酰基卤,如其中J是氯或溴的式II化合物,或用氯甲酸烷基酯如氯甲酸乙酯或氯甲酸异丁酯处理得到混合酸酐。在向酰基卤转化的有利方法中,在催化量的酰胺如N,N-二甲基甲酰胺存在下,在约0℃至约60℃温度例如室温,在惰性溶剂如烃或氯化烃或醚中,将酸用草酰氯处理。可以使用的常用酰胺偶联试剂是丙基膦酸酐;N,N'-羰基二唑,如N,N'-羰基二咪唑(CDI);碳二亚胺,如1,3-二异丙基碳二亚胺(DIC)、1,3-二环己基碳二亚胺(DCC)或1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC);与添加物一起的碳二亚胺,所述添加物如1-羟基-苯并三唑(HOBT)或1-羟基-7-氮杂苯并三唑(HOAT);基于脲鎓的偶联试剂,如O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(HATU)、O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(HBTU)或O-(氰基(乙氧基羰基)亚甲基氨基)-N,N,N',N'-四甲基脲鎓四氟硼酸盐(TOTU);和基于鏻的偶联试剂如(苯并三唑-1-基氧基)三(二甲基氨基)鏻六氟磷酸盐(BOP)、(苯并三唑-1-基氧基)三吡咯烷子基鏻六氟磷酸盐(PyBOP)或溴代三吡咯烷子基鏻六氟磷酸盐(PyBroP)。
由式II和III化合物制备式I化合物的反应条件取决于具体情况的详细说明,且对于本领域技术人员而言在该领域的常识的基础上是熟悉的,所述具体情况例如基团J的含义或所用的偶联试剂。例如,在式II化合物(其中J是烷基-O-,如甲氧基或乙氧基)与式III化合物反应的情况下,所述反应通常在惰性溶剂中在升高的温度进行,所述惰性溶剂例如烃或氯化烃如苯、甲苯、二甲苯、氯苯、二氯甲烷、氯仿或二氯乙烷,醚如四氢呋喃(THF)、2-甲基四氢呋喃、二噁烷、二丁醚、二异丙醚或二甲氧基乙烷(DME),或溶剂的混合物,所述温度例如在约40℃至约140℃的温度,具体来说在约50℃至约120℃的温度,例如在大约溶剂的沸点温度。在式II化合物(其中J是卤素,如氯或溴)与式III化合物反应的情况下,所述反应通常同样在惰性溶剂中在一定温度进行,所述惰性溶剂例如烃或氯化烃或醚如上提及的那些,酯如乙酸乙酯或乙酸丁酯,腈如乙腈,或水,或溶剂的混合物包括水和与水混溶或不混溶的有机溶剂的混合物,所述温度是在约-10℃至约100℃的温度,具体来说在约0℃至约80℃的温度,例如在大约室温。有利地,式II化合物(其中J是卤素)与式III化合物的反应在碱存在下进行,所述碱如叔胺,如三乙胺、N-乙基-二异丙基胺(EDIA)、N-甲基吗啉、N-乙基吗啉或吡啶,或无机碱如碱金属氢氧化物、碳酸盐或碳酸氢盐,如氢氧化钠、氢氧化钾、碳酸钠或碳酸氢钠。
在式II化合物(其中J是HO-)与式III化合物反应并以酰胺偶联试剂如碳二亚胺或TOTU活化所述羧酸基团的情况下,所述反应通常在无水条件下在惰性非质子溶剂中在一定温度在碱的存在下进行,所述惰性非质子溶剂例如醚如THF、二噁烷或DME,酰胺如N,N-二甲基甲酰胺(DMF)或N-甲基吡咯烷酮(NMP),所述温度在约-10℃至约40℃的温度,具体来说在约0℃至约30℃的温度,例如在室温,所述碱如叔胺,如三乙胺、EDIA、N-甲基吗啉或N-乙基吗啉。在与式II化合物的反应中以酸加成盐的形式使用式III化合物的情况下,通常加入足量的碱以便释放游离的式III化合物。
如上面所指出,在式II化合物和式III化合物间酰胺键形成期间,式II和式III化合物中的官能团可以以保护的形式或以前体基团的形式存在。取决于具体情况的详细说明,为避免所述反应的不期望过程或副反应,可能是必要的或可取的是暂时以保护基来封闭任意官能团并稍后将其除去,或使官能团以前体基团的形式存在且稍后将其转化成期望的最终基团。这相应地用于包括中间体、起始化合物和结构单元合成的式I化合物合成中的所有反应。相应的合成策略是本领域中常用的。有关保护基及其引入和除去的详情,例如,在P.G.M.Wuts and T.W.Greene,Greene's Protective Groups in Organic Synthesis,4.ed.(2007),John Wiley&Sons中有描述。可能提到的保护基的实例是苄基保护基、叔丁基保护基、酰基保护基和烷基氧基羰基保护基,所述苄基保护基可以以羟基的苄基醚和羧酸基团苄酯的形式出现,苄基可以在钯催化剂存在下通过催化氢化从其中除去;叔丁基保护基可以以羧酸基团的叔丁酯的形式出现,叔丁基可以通过用三氟乙酸处理从其中除去;酰基保护基可以以酯和酰胺的形式用来保护羟基和氨基,且可以通过酸性水解或碱性水解而被解离;烷基氧基羰基保护基可以以氨基的叔丁氧基羰基衍生物的形式出现,其可以通过用三氟乙酸处理而被解离。羧酸基团的不期望反应,例如,在期望的式I化合物中G是羧酸基团的情况下存在于式III化合物中的羧酸基团的不期望反应,还可以通过在与式II化合物的反应中以其它酯的形式使用它们来避免,所述其它酯的形式例如烷基酯如甲酯或乙酯的形式,所述烷基酯可通过水解被解离,例如通过碱金属氢氧化物如氢氧化钠或氢氧化锂被解离。作为前体基团的实例,可能提到氰基(NC-,N≡C-)和硝基,氰基可以在水解条件下转化成羧酸基团、羧酸酯基团和羧酰胺基团或通过还原转化成氨基甲基,硝基可以通过还原转化成氨基,例如通过催化氢化或通过用连二亚硫酸钠还原。前体基团的再一个实例是氧代基团,氧代基团最初可以存在于含羟基的式I化合物合成过程中,并可以例如用配位氢化物如硼氢化钠还原,或与有机金属化合物例如Grignard化合物反应。如果式II和式III化合物中存在任何保护基或前体基团并且反应的直接产物仍不是期望的最终化合物,则通常还在原位进行保护基的除去或向期望化合物的转化。
用于式I化合物合成的起始化合物通常可以按照文献中所描述的操作或与这些操作类似的操作来制备,或是可商购的。
式III的β-氨基酸及衍生物是可商购的或可以从易得的起始化合物通过众所周知的标准方法或与这些方法类似的方法来合成。例如,对于其中R50和R60是氢的式III的β-氨基酸及其烷基酯的制备,式R30-C(O)-R40的羰基化合物具体来说是式R32-C(O)-H的醛,如V.M.Rodionov et al.,Izv.Akad.Nauk SSSR,Ser.Khim.(1952),696-702(Chem.Abstr.47(1953),abstr.no.61888)中所描述,在碱存在下可以与丙二酸单乙酯和氨在溶剂中反应,所述碱如碱金属氢氧化物如氢氧化钾,所述溶剂如醇如乙醇;或如V.Scudi,J.Am.Chem.Soc.57(1935),1279;or M.K.Tse et al.,Chem.Eur.J.12(2006),1855-1874中所描述,将氨加成到羰基化合物与丙二酸或丙二酸二乙酯的缩合产物中的双键中,并就与丙二酸二乙酯的缩合产物来说,用酸如盐酸处理所述反应产物;并且如上面所期望和所概述,在所获得的产物中,分别是酯基团水解成羧酸或羧酸基团酯化。对映体纯的这些式III化合物,例如,可以通过盐的结晶作用从外消旋化合物获得,所述结晶作用使用光学活性的酸如酒石酸,例如,如在M.K.Tse等提到的论文或在J.Mano et al.,Bioscience,Biotechnology and Biochemistry 70(2006),1941-1946.中所描述,通过立体选择性的酶降解或微生物降解获得。在这些化合物合成的另一个策略中,具体来说是其中R40、R50和R60是氢且R30是R32的化合物,将可以从相应的醛获得的各个3-取代丙烯酸转化成酰基卤,例如用草酰氯;再用醇将酰基氯转化成酯,例如用叔丁醇转化成叔丁酯;然后通过与光学活性胺的锂盐的反应而引入氨基,例如(R)-(+)-N-苄基-N-(1-苯基乙基)胺的锂盐;并在所获得的3-取代的3-(N-苄基-N-(1-苯乙基)氨基)丙酸叔丁酯中,以催化氢化将苄基和苯基乙基解离掉(cf.S.G.Davies et al.,Tetrahedron:Asymmetry 2(1991),183-186);S.G.Davieset al.,J.Chem.Soc.Perkin Trans.1(1994),1129-1139)。
本发明另外的主题为存在于呈任意立体异构形式或任意比例的立体异构形式的混合物的式I化合物及其盐和它们中的任意溶剂化物的合成中出现的新的起始化合物和中间体,以及它们作为合成中间体或者起始化合物的用途。如上关于式I化合物给出的所有一般解释、实施方案的具体说明以及数目和基团的定义相应地适用于所述中间体和起始化合物中。本发明的一个主题具体来说是本申请所描述的新型具体起始化合物和中间体。其独立地不论它们被描述为游离化合物和/或被描述为具体的盐,它们以游离化合物的形式和以其盐的形式都是本发明的一个主题,且如果描述了具体的盐,另外以该具体盐的形式是本发明的一个主题。
式I化合物抑制蛋白酶组织蛋白酶A,这在下面所描述的药理学测试中并在本领域技术人员已知的其它测试中可被证明。因此式I化合物和其生理学可接受的盐及溶剂化物是有价值的药用活性化合物。例如,式I化合物和其生理学可接受的盐及其溶剂化物可用于如下心血管疾病的治疗:如心力衰竭,其包括收缩期心力衰竭、舒张期心力衰竭、糖尿病性心力衰竭和射血分数正常的心力衰竭;心肌病;心肌梗塞;左心室功能障碍,其包括心肌梗塞后左心室功能障碍、心脏肥大;心肌重塑,其包括梗塞后心肌重塑或心脏手术后心肌重塑;瓣膜性心脏病;血管过度生长;血管重塑,其包括血管硬化(vascular stiffness);高血压,其包括肺动脉高血压、门静脉高血压和收缩期高血压;动脉粥样硬化;周围动脉闭塞性疾病(PAOD);再狭窄;血栓形成和血管渗透性障碍(vascular permeability disorders);缺血和/或再灌注损伤,其包括心脏的缺血和/或再灌注损伤和视网膜的缺血和/或再灌注损伤;炎症和炎性疾病,如类风湿性关节炎和骨关节炎;肾脏病,如肾乳头坏死和肾衰竭,其包括缺血/再灌注后肾衰竭;肺病,如囊性纤维化、慢性支气管炎、慢性阻塞性肺病(COPD)、哮喘、急性呼吸窘迫综合征(ARDS)、呼吸道感染和肺癌;免疫性疾病;糖尿病并发症,其包括糖尿病性肾病和糖尿病性心肌病;纤维化疾病,如包括特发性肺纤维化的肺纤维化、心脏纤维化、血管纤维化、血管周围纤维化、包括肾小管间质纤维化的肾纤维化、包括瘤样瘢痕(keloid)形成、胶原病和硬皮病的纤维化皮肤病(fibrosing skin conditions)及肝纤维化;肝病,如肝硬化;疼痛,如神经性疼痛、糖尿病性疼痛和炎性疼痛;黄斑变性;神经变性疾病或精神病(psychiatric disorders);或用于心脏保护,其包括心肌梗塞后心脏保护和心脏手术后心脏保护;或用于肾脏保护。式I化合物及其生理学可接受的盐和溶剂化物可用作利尿剂(单独(stand-alone)治疗或与确定的利尿剂组合)。疾病的治疗应被理解为如下两种含义:为了缓解、减轻或治愈的目的,现有病理变化或生物体机能障碍或现有症状的治疗;和为了预防或抑制其发生或在其发生情况下的减弱的目的,病理变化或生物体机能障碍或人或动物中症状的预防或防治,所述人或动物对其易感并需要这样的预防或防治。例如,在由于其病史而易患心肌梗塞的患者中,通过预防性或防治性药物疗法,可防止心肌梗塞发生或再发生或降低其程度和后遗症;或在易患哮喘发作的患者中,通过预防性或防治性药物疗法,可防止这样的发作或降低其严重度。疾病的治疗在急性病例和慢性病例中均可发生。式I化合物的功效在下面所描述的药理学测试中并在本领域技术人员已知的其它测试中可被证明。其中G选自R72-N(R73)-C(O)-的式I化合物及其生理学可接受的盐和溶剂化物还可作为前药使用。
因此式I化合物及其生理学可接受的盐和溶剂化物,可自身单独作为药物或药剂、以相互的混合物或以药物组合物的形式用在动物中,具体来说是用在哺乳动物中且具体是用在人类中。本发明的一个主题还是作为药物使用的式I化合物及其生理学可接受的盐和溶剂化物,以及包含有效剂量的至少一种作为活性成分的式I化合物和/或其生理学可接受的盐和/或其溶剂化物和药用载体(即一种或多种药学上无毒或无害的媒介物和/或赋形剂)和任选的一种或多种其它药用活性化合物的药物组合物和药物。此外本发明的一个主题是用在上述或下述疾病的治疗中或用于心脏保护的式I化合物及其生理学可接受的盐和溶剂化物,所述治疗包括任意一种所提到疾病的治疗,例如如下疾病的治疗:心力衰竭、心肌梗塞、心脏肥大、糖尿病性肾病、糖尿病性心肌病、心脏纤维化或缺血和/或再灌注损伤;式I化合物及其生理学可接受的盐和溶剂化物在制备用于上述或下述疾病的治疗或用于心脏保护的药物中的用途,所述治疗包括任意一种所提到疾病的治疗,例如如下疾病的治疗:心力衰竭、心肌梗塞、心脏肥大、糖尿病性肾病、糖尿病性心肌病、心脏纤维化或缺血和/或再灌注损伤,其中疾病的治疗包括如上所述的疾病治疗和预防;以及它们在制备用于组织蛋白酶A抑制的药物中的用途。本发明的一个主题还是用于上述或下述疾病的治疗或心脏保护的方法,所述治疗包括任意一种所提到疾病的治疗,例如如下疾病的治疗:心力衰竭、心肌梗塞、心脏肥大、糖尿病性肾病、糖尿病性心肌病、心脏纤维化或缺血和/或再灌注损伤,所述方法包括对有其需要的人或动物给予有效剂量的至少一种式I化合物和/或其生理学可接受的盐和/或其溶剂化物。式I化合物及包含它们的药物组合物和药物可肠内给药,例如通过口服、舌下或直肠给药;或肠胃外给药,例如通过静脉内、肌内、皮下或腹膜内注射或输注;或通过其它类型的给药,如局部(topical)、经皮(percutaneous)、透皮(transdermal)、关节内或眼内给药。
式I化合物及其生理学可接受的盐和溶剂化物还可以与其它药用活性化合物组合来使用,其中在这样的组合使用中,式I化合物和/或其生理学可接受的盐和/或其溶剂化物和一种或多种其它药用活性化合物可以存在于一种且同一药物组合物中或存在于用于分开、同时或先后给药的两种或更多种药物组合物中。这些其它药用活性化合物的实例是利尿剂、促排水剂(aquaretics)、血管紧张素转化酶(ACE)抑制剂、血管紧张素受体阻滞剂、肾素抑制剂、β阻滞剂、地高辛、醛固酮拮抗剂、NO供体、硝酸盐、肼苯哒嗪、ionotropes、加压素受体拮抗剂、可溶性鸟苷酸环化酶活化剂、他汀类、过氧化物酶体增殖物活化受体-α(PPAR-α)活化剂、过氧化物酶体增殖物活化受体-γ(PPAR-γ)活化剂、罗格列酮、匹格列酮、二甲双胍、磺酰脲类、胰高血糖素样肽1(GLP-1)激动剂、二肽基肽酶IV(DPPIV)抑制剂、胰岛素、抗心律失常药、内皮缩血管肽受体拮抗剂、钙拮抗剂、磷酸二酯酶抑制剂、5型磷酸二酯酶(PDE5)抑制剂、因子II/因子IIa抑制剂、因子IX/因子IXa抑制剂、因子X/因子Xa抑制剂、因子XIII/因子XIIIa抑制剂、肝素、糖蛋白IIb/IIIa拮抗剂、P2Y12受体拮抗剂、氯吡格雷、香豆素、环氧合酶抑制剂、乙酰水杨酸、RAF激酶抑制剂和p38丝裂原活化蛋白激酶抑制剂。本发明的一个主题还是任意一种或多种本申请所公开的式I化合物及其生理学可接受的盐和溶剂化物与一种或多种(例如一种或两种)所提到的其它药用活性化合物的组合使用。
本发明的药物组合物和药物通常含有约0.5wt%至约90wt%(重量百分数)的式I化合物和/或其生理学可接受的盐和/或溶剂化物,和适量的式I活性成分和/或其生理学可接受的盐和/或溶剂化物,其通常是每单位剂量约0.2mg至约1.5g,具体来说是每单位剂量约0.2mg至约1g,更具体来说是每单位剂量约0.5mg至约0.5g,例如每单位剂量约1mg至约0.3g。取决于药物组合物的类型和其它具体状况的详细说明,所述量可能偏离指明的量。药物组合物和药物的生产可以以本身已知的方式来进行。对此,式I化合物和/或其生理学可接受的盐和/或溶剂化物与一种或多种固态或液态媒介物和/或赋形剂一起混合,如果有需要还可与一种或多种其它药用活性化合物如上述那些化合物组合来混合,并使其形成用于配药(dosage)和给药的适当形式,然后该形式可用在人用药或兽用药中。
作为媒介物和赋形剂,可使用适当的有机物和无机物,所述物质不与式I化合物以不期望的方式反应,所述媒介物还可以看作是稀释剂或填充剂。作为药物组合物和药物中可含有的赋形剂或添加物类型的实例,可能提到润滑剂、防腐剂、增稠剂、稳定剂、崩解剂、湿润剂、达到储存效果的试剂、乳化剂、盐例如影响渗透压的盐、缓冲物质、着色剂、调味剂和芳族物质。媒介物和赋形剂的实例是水;植物油;蜡;醇如乙醇、异丙醇、1,2-丙二醇、苄醇、甘油、多元醇、聚乙二醇或聚丙二醇;甘油三醋酸酯;聚乙烯吡咯烷酮;明胶;纤维素;糖类如乳糖或淀粉如玉米淀粉;氯化钠;硬脂酸及其盐如硬脂酸镁;滑石;羊毛脂;凡士林(petroleum jelly);或其混合物,例如盐水或水与一种或多种有机溶剂的混合物如水与醇的混合物。对于口服和直肠用途,可使用药物形式如片剂、薄膜包衣片剂、糖衣片剂、颗粒剂、硬明胶胶囊剂和软明胶胶囊剂、栓剂、包括含油(oily)、含醇或含水的溶液剂、糖浆剂、汁液(juices)或滴剂,此外还有混悬剂或乳剂。对于肠胃外用途,例如通过注射或输注,可使用药物形式如溶液剂,例如含水溶液。对于局部用途,可使用药物形式如软膏剂(ointments)、乳膏剂(creams)、糊剂、洗剂、凝胶剂、喷雾剂、泡沫剂、气溶胶剂、溶液剂或粉末剂。更多适宜的药物形式是,例如,埋植剂和贴片剂和适合吸入的形式。还可将式I化合物及其生理学可接受的盐冻干并使用所获得冻干物,例如,用于可注射组合物的生产。具体来说对于局部施用,脂质体组合物也是适合的。药物组合物和药物还可含有一种或多种其它活性成分和/或,例如,一种或多种维生素。
照例,式I化合物的剂量取决于具体病例的情况并由医师按照惯例和操作来调整。例如,其取决于所给予的式I化合物及其效力和作用持续时间,取决于个体综合征的性质和严重度,取决于所要治疗的人或动物的性别、年龄、体重和个体应答性,取决于治疗是急性的还是慢性的还是预防性的,或取决于除式I化合物之外是否给予另外的药用活性化合物。通常,在对体重约75kg的成人给药的情况下,给予约0.1mg至约100mg/kg/天的剂量,具体来说是约1mg至约20mg/kg/天的剂量,例如约1mg至约10mg/kg/天(在各病例中以mg/kg体重为单位)的剂量。每日剂量可以以单一剂量给药或分成若干单独剂量,例如两个、三个或四个单独剂量。还可以连续进行给药,例如通过连续注射或输注。取决于具体病例中的个体行为,可能有必要向上或向下偏离指明的剂量。
此外,作为人用药和兽用药中的药用活性化合物,如果组织蛋白酶A的抑制作用是预期的,则式I化合物还可用作生物化学研究的辅助剂或用作科学工具或用于诊断目的,例如在生物学样品的体外诊断中。式I化合物及其盐还可用作中间体,例如用于进一步药用活性物质制备的中间体。
具体实施方式
下列实施例示例说明本发明。
缩写
ACN 乙腈
DCM 二氯甲烷
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
EA 乙酸乙酯
EDIA N-乙基-二异丙基胺
FA 甲酸
MOH 甲醇
NEM N-乙基-吗啉
TFA 三氟乙酸
THF 四氢呋喃
TOTU O-(氰基(乙氧基羰基)亚甲基氨基)-N,N,N',N'-四甲基脲鎓四氟硼酸盐
当通过反相(RP)柱材料上的制备性高压液相色谱(HPLC)纯化含碱性基团的实施例化合物且洗脱剂照例是含三氟乙酸的水和乙腈的梯度混合物时,取决于后处理的详情如蒸发或冻干条件,它们部分以其与三氟乙酸的酸加成盐形式获得。在实施例化合物的名称和结构式中对这种实施例化合物含三氟乙酸不作说明。同样,以酸加成盐形式获得的实施例化合物的其它酸组分在名称和式中通常不作说明。
制备的化合物通常以光谱数据和色谱数据来表征,具体来说是通过组合分析性HPLC/MS表征(LC/MS)获得的质谱(MS)和HPLC保留时间(Rt,以分钟为单位),和/或核磁共振(NMR)谱。除非另有说明,在298K以D6-DMSO作为溶剂在500MHz记录1H-NMR谱。在NMR表征中,给出从图示描述的光谱中确定的峰的化学位移δ(以ppm为单位)、氢原子数(H)和多重性(s:单峰,d:二重峰,dd:双二重峰,t:三重峰,q:四重峰,m:多重峰)。在MS表征中,通常给出分子离子[M],例如[M+];或相关离子如离子[M+1],例如[(M+1)+],即质子化的分子离子[(M+H)+];或离子[M-1],例如[(M-1) ̄],即脱质子化的分子离子[(M-H) ̄]的峰的质量数(m/z),其是取决于所用的离子化方法来形成的。通常,所述离子化方法是电喷雾离子化(ES)。所用LC/MS方法的详细说明如下。
方法LC1
柱:Waters UPLC BEH C18,50x 2.1mm,1.7μm;流速:0.9ml/min;55℃;洗脱剂A:水+0.05%FA;洗脱剂B:ACN+0.035%FA;梯度:历时2.0分钟从98%A+2%B至5%A+95%B,然后在5%A+95%B保持0.6分钟,然后历时0.1分钟至95%A+5%B,然后在95%A+5%B保持0.3分钟;MS电离法:ES+
方法LC2
柱:Waters XBridge C18,50x 4.6mm,2.5μm;洗脱剂A:水+0.05%TFA;洗脱剂B:ACN+0.05%TFA;梯度:在95%A+5%B保持0.3分钟,然后历时3.2分钟至5%A+95%B,然后在5%A+95%B保持0.5分钟;MS电离法:ES+
方法LC3
柱:Waters UPLC BEH C18,50x 2.1mm,1.7μm;流速:0.9ml/min;55℃;洗脱剂A:水+0.05%FA;洗脱剂B:ACN+0.035%FA;梯度:在95%A+5%B保持1.1分钟,历时0.6分钟从95%A+5%B至5%A+95%B,然后在95%A+5%B保持0.1分钟,然后历时0.2分钟至95%A+5%B;MS电离法:ES+
方法LC4
柱:Jsphere 33x 2mm,4μm,洗脱剂A:水+0.05%TFA;洗脱剂B:ACN+0.05%TFA;梯度:在98%A:2%B保持1分钟,然后历时4分钟至5%A:95%B,然后历时1.25分钟至5%A:95%B
方法LC5
柱:Waters XBridge C18,50x 4.6mm,2.5μm;流速:1.7ml/min;40℃;洗脱剂A:水+0.05%TFA;洗脱剂B:ACN+0.05%TFA;梯度:在95%A+5%B保持0.2分钟,然后历时2.2分钟至5%A+95%B,然后在5%A+95%B保持0.8分钟,然后历时0.1分钟至95%A+5%B,然后在95%A+5%B保持0.7分钟;MS电离法:ES+
实验
通式:
一般而言,描述于该专利的化合物根据以下一般方案来合成:
羧酸可为芳族或者杂芳族羧酸,其为可商购得到的或者根据例如在Houben-Weyl“Methods of Organic Chemistry”中所述的操作合成。
1-苯基-1-H-吡唑-3-羧酸的合成描述于Justus Liebigs Annalen der Chemie,1894.295。且1,5-二芳基-吡唑-3-羧酸的合成的一般操作可在JACS,1955,1205中找到。
合成2-芳基氨基-噻唑-4-羧酸的典型的方法可在Chemical&PharmaceuticalBulletin 2005,437中找到。
1-苯基-4,5,6,7-四氢-1H-吲唑-3-羧酸根据Carbohydrate Research,1988,1合成。
羧酸和β-氨基酸之间的酰胺键的形成可通过偶联剂的使用来完成,所述偶联剂为本领域的技术人员所熟知并在如下文献中有描述,例如Tetrahedron(2005),61(46),10827-10852。代替羧酸的羧酸酰氯和代替β-氨基酸的β-氨基酸酯尤其是甲酯或乙酯,可以作为替换物使用。
本操作中所用的β-氨基酸要么是可商购的要么是通过如下文献中所描述方法制备的,例如JACS 1935,1279或Rhodionow的Chem.Abstr.1953,1051。Rhodionow方案描述如下:
对映体纯的β-氨基酸要么可以商业购得要么可以通过如下文献中所描述的操作从外消旋的物质制备:Bioscience,Biotechnology and Biochemistry,2006,1941。
使用可商购得到的杂环和β-氨基酸的偶联法的一般操作在下面给出:
合成方法并未具体提及的所有化合物均根据一般操作A来合成。
一般操作A
将0.25mmol羧酸称重于反应小瓶中,加入1.25mmol N-乙基吗啉在1ml DMF中的溶液,接着加入0.245mmol TOTU在0.5ml DMF中的溶液。使得该混合物在RT反应30分钟。加入混悬于0.5ml DMF中的0.275mmol氨基酸,将小瓶盖上螺旋盖并在RT振摇过夜。加入0.2mlTFA,将该溶液经过注射器式滤器过滤并直接进行制备性HPLC。
产物收率:5%-80%
一般操作B:
如下对于2-溴-噻唑-4-羧酸所述的反应顺序也可通过由下述杂环开始来进行:
2-溴-噁唑-4-羧酸
4-溴-噁唑-2-羧酸
3-溴-[1,2,4]噁二唑-5-羧酸
步骤1
步骤2
步骤3
步骤1:
3-[(2-溴-噻唑-4-羰基)-氨基]-3-邻甲苯基-丙酸甲酯
将100mg(0.48mmol)2-溴-1,3-噻唑-4-羧酸溶于10ml DMF中,加入N-乙基吗啉(122mg,2.2当量)和TOTU(174mg,1.1当量)并将混合物在RT搅拌5分钟。然后加入93mg(1当量)3-氨基-3-(2-甲基苯基)丙酸甲酯并将混合物搅拌过夜。将溶剂真空除去并将残留物进行制备性HPLC纯化,得到3-[(2-溴-噻唑-4-羰基)-氨基]-3-邻甲苯基-丙酸甲酯,收率低于80%。
步骤2:
3-[(2-溴-噻唑-4-羰基)-氨基]-3-邻甲苯基-丙酸
将100mg(0.26mmol)3-[(2-溴-噻唑-4-羰基)-氨基]-3-邻甲苯基-丙酸甲酯溶于10ml MeOH中,加入0.55ml 1N NaOH溶液(2.1当量NaOH)并将所得的混合物搅拌1小时。加入10ml水并通过加入10%HCl将所得的混合物的pH调节至5.5并将MeOH真空除去。将所得的水相用10ml CH2Cl2萃取三次,收集有机层,经Na2SO4干燥并将溶剂真空除去,得到3-[(2-溴-噻唑-4-羰基)-氨基]-3-邻甲苯基-丙酸,其收率低于90%。
步骤3:
3-[(2-苯基-噻唑-4-羰基)-氨基]-3-邻甲苯基-丙酸
将100mg(0.27mmol)3-[(2-溴-噻唑-4-羰基)-氨基]-3-邻甲苯基-丙酸溶于5mlDMF中,加入49.6mg(1.5当量)苯基硼酸、350mg Cs2CO3(1.08mmol,4当量)和27mg(0.1当量)二(三苯基膦)二氯化钯(II)作为催化剂。加入2ml水后,将残留的混合物加热至100℃过夜,将溶剂真空除去并将残留物在HPLC系统上进行制备性色谱法纯化,得到产物3-[(2-苯基-噻唑-4-羰基)-氨基]-3-邻甲苯基-丙酸,收率低于80%。
如上对于2-溴-噻唑-4-羧酸所述的反应顺序也可通过由如下杂环开始来进行:
下述化合物可根据一般操作B来合成:
所述化合物可为对映异构体的混合物、外消旋物或者纯的立体异构形式:
(S)-3-{[2-(2-氟-苯基)-噁唑-4-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[2-(3-氟-吡啶-4-基)-噁唑-4-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[2-(2-氟-3-甲基-苯基)-噁唑-4-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[2-(2-甲基-呋喃-3-基)-噁唑-4-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-[(2-苯基-噁唑-4-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-{[4-(2-氟-苯基)-噁唑-2-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[4-(3-氟-吡啶-4-基)-噁唑-2-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[4-(2-氟-3-甲基-苯基)-噁唑-2-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[4-(2-甲基-呋喃-3-基)-噁唑-2-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-[(4-苯基-噁唑-2-羰基)-氨基]-3-邻甲苯基-丙酸
(S)-3-{[3-(2-氟-苯基)-[1,2,4]噁二唑-5-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[3-(3-氟-吡啶-4-基)-[1,2,4]噁二唑-5-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[3-(2-氟-3-甲基-苯基)-[1,2,4]噁二唑-5-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-{[3-(2-甲基-呋喃-3-基)-[1,2,4]噁二唑-5-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-[(3-苯基-[1,2,4]噁二唑-5-羰基)-氨基]-3-邻甲苯基-丙酸
与在合成实施例中所述类似地制备表1中所列的式I的实施例化合物。
表1.式I的实施例化合物
(1)质谱表征;除非另有说明,离子[(M+H)+]的实测质量数
(2)在下述药理学测试“组织蛋白酶A抑制活性”中所确定的组织蛋白酶A抑制活性。
药理学测试
a)组织蛋白酶A抑制活性
将重组人组织蛋白酶A(残基29-480,具有C-末端10-His标记;R&D Systems,#1049-SE)用重组人组织蛋白酶L(R&D Systems,#952-CY)来进行蛋白水解活化。简单来说,将10μg/ml组织蛋白酶A在活化缓冲液(25mM 2-(吗啉-4-基)-乙磺酸(MES),pH 6.0,其含5mM二硫苏糖醇(DTT))中与1μg/ml组织蛋白酶L在37℃孵育15分钟。然后通过加入半胱氨酸蛋白酶抑制剂E-64(N-(反式-环氧琥珀酰)-L-亮氨酸-4-胍基丁酰胺;Sigma-Aldrich,#E3132;溶于活化缓冲液/DMSO中)至10μM的终浓度,终止组织蛋白酶L活性。
将活化的组织蛋白酶A在测定缓冲液(25mM MES,pH 5.5,其含5mM DTT)中稀释并与测试化合物(溶于含(v/v)3%DMSO的测定缓冲液中)混合,或在对照实验中,在多重测定板中与媒介物混合。室温孵育15分钟后,接着向所述混合物中加入作为底物的带Bodipy FL(4,4-二氟-5,7-二甲基-4-硼杂-3a,4a-二氮杂-对称-二环戊二烯并苯(s-indacene)-3-丙酰基)标记(JPT Peptide Technologies GmbH;溶于测定缓冲液中)的缓激肽。组织蛋白酶A的终浓度是833ng/ml而标记缓激肽的终浓度是2μM。室温孵育15分钟后,通过加入终止缓冲液(130mM 2-(4-(2-羟基-乙基)-哌嗪-1-基)-乙磺酸,pH 7.4,其含(v/v)Triton X-100,0.13%Coating Reagent 3(Caliper Life Sciences)、6.5%DMSO和20μM抑脂酶免疫酮B(Sigma,#E0886))来终止反应。
然后通过3000Drug Discovery System(12-Sipper-Chip;CaliperLife Sciences)上的微流控毛细管电泳来分离未解离的底物和产物并通过各峰面积的测定来定量。通过将产物峰面积除以底物和产物峰面积的总和来计算底物转换(Substrateturnover),并由此定量酶活性和测试化合物的抑制作用。由用数个浓度的测试化合物观察到的组织蛋白酶A活性抑制百分数,计算抑制浓度IC50,即产生50%酶活性抑制的浓度。各种实施例化合物的IC50值在表1给出。
B)体内抗肥大(antihypertrophic)和肾脏保护活性
可以在例如DOCA-盐敏感的单侧肾切除大鼠模型中研究本发明化合物的体内药理学活性。简单来说,在该模型中对150g至200g体重的Sprague Dawley大鼠进行左肾的单侧肾切除(UNX)。手术后以及在接下来的几周每周开始时,通过皮下注射对大鼠给予30mg/kg体重的DOCA(醋酸去氧皮质酮)。对以DOCA处理的肾切除大鼠提供含1%氯化钠的饮用水(UNX/DOCA大鼠)。UNX/DOCA大鼠患上高血压、内皮机能障碍、心肌肥大和纤维化以及肾功能不全。在由随机UNX/DOCA大鼠组成的测试组(UNX/DOCA测试)和安慰剂组(UNX/DOCA安慰剂)中,用每日剂量测试化合物(例如溶于媒介物的10mg/kg体重的剂量)或仅用媒介物分别在6a.m.和6p.m.以两部分给药通过灌胃对大鼠进行口服处理。在由尚未进行UNX和DOCA给药的动物组成的对照组(对照)中,所述动物接受正常饮用水并仅用媒介物来处理。处理五周后,经尾套法(tail cuff method)非侵入地测量收缩压(SBP)和心率(HR)。对于蛋白尿和肌酐的测定,通过代谢笼收集24h尿。内皮功能在如以前所描述的离体的胸主动脉环中进行评估(W.Linz et al.,JRAAS(Journal of the renin-angiotensin-aldosterone system)7(2006),155-161)。作为心肌肥大和纤维化的度量标准(measure),在离体的心脏中确定心脏重量、左心室重量和羟基脯氨酸与脯氨酸的关系。
Claims (9)
1.式I化合物或其生理学可接受的盐:
其中Ht选自
G选自R71-O-C(O)-;
R10为R11;
R11为Ar;
R30选自(C3-C7)-环烷基和R32-CuH2u-,其中u为选自0和1的整数;
R32为苯基,其中所述苯基任选地被一个或多个相同或不同的选自下述的取代基所取代:卤素、(C1-C6)-烷基、(C1-C6)-烷基-O-和NC-;
R40选自氢和(C1-C4)-烷基;
R50选自氢和(C1-C6)-烷基;
R60选自氢和(C1-C6)-烷基;
R71为氢;
Ar彼此独立地为苯基,其中所述苯基任选地被一个或多个相同或不同的选自下述的取代基所取代:卤素、(C1-C6)-烷基、(C1-C6)-烷基-O-、CF3和NC-;
m彼此独立地为选自0、1和2的整数。
2.权利要求1的式I化合物或其生理学可接受的盐,其中
R30为R32-CuH2u-,其中u为选自0和1的整数;
R40为氢。
3.权利要求1的式I化合物或其生理学可接受的盐,其中
R50为氢;
R60为氢。
4.权利要求1的式I化合物或其生理学可接受的盐,其中
R30为R32-CuH2u-,其中u为整数0;
R40为氢。
5.权利要求1的式I化合物或其生理学可接受的盐,其中所述化合物选自
(R)-3-{[3-(2-氟-苯基)-[1,2,4]噁二唑-5-羰基]-氨基}-4-苯基-丁酸
(R)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-4-苯基-丁酸
(S)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-苯基-丁酸
(S)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-邻甲苯基-丙酸
(S)-3-(4-氟-苯基)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-苯基-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-对甲苯基-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-间甲苯基-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-苯基-丁酸
(R)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-4-苯基-丁酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-(2-氟-苯基)-丙酸
(S)-3-{[5-(2,3-二氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-(4-氟-苯基)-丙酸
(S)-3-(4-氟-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸
(S)-3-(2-氟-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸
(S)-3-(3-氟-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸
(S)-3-(3-氯-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸
(S)-3-{[5-(2-氟-苯基)-[1,2,4]噁二唑-3-羰基]-氨基}-3-(2-三氟甲基-苯基)-丙酸
(S)-3-(2,3-二氯-苯基)-3-{3-[3-(2-氟-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-丙酸。
6.权利要求1的式I化合物或其生理学可接受的盐的制备方法,其包括使式II化合物与式III化合物反应:
其中式II及III化合物中基团Ht、G、R10、R11、R30、R40、R50和R60如式I化合物中所定义,且此外官能团可以按保护的形式或按前体基团的形式存在,且式II化合物中基团J是HO-、(C1-C4)-烷基-O-或卤素。
7.权利要求1的式I化合物或其生理学可接受的盐,其用作药物。
8.药物组合物,其包含至少一种权利要求1至5中任意一项的式I化合物或其生理学可接受的盐和药用载体。
9.权利要求1至5中任意一项的式I化合物或其生理学可接受的盐在制备用于治疗以下疾病或用于心脏保护或肾脏保护或用作利尿剂的药物中的用途,所述疾病为充血性心力衰竭、心肌梗塞、左心室功能障碍、心脏肥大、瓣膜性心脏病、高血压、动脉粥样硬化、周围动脉闭塞性疾病、再狭窄、血管渗透性障碍、水肿治疗、血栓形成、类风湿性关节炎、骨关节炎、肾衰竭、囊性纤维化、慢性支气管炎、慢性阻塞性肺病、哮喘、糖尿病并发症、纤维化疾病、疼痛、缺血或再灌注损伤或神经变性疾病。
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MY162786A (en) * | 2011-07-26 | 2017-07-14 | Sanofi Sa | Substituted 3-thiazoloamino-propionic acid derivatives and their use as pharmaceuticals |
NZ702539A (en) | 2012-05-31 | 2016-11-25 | Phenex Pharmaceuticals Ag | Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor ror[gamma] |
JO3215B1 (ar) | 2012-08-09 | 2018-03-08 | Phenex Pharmaceuticals Ag | حلقات غير متجانسة بها 5 ذرات تحتوي على النيتروجين بها استبدال بكربوكساميد أو سلفوناميد كمعدلات لمستقبل نووي غير محمي RORy |
WO2014053533A1 (en) | 2012-10-05 | 2014-04-10 | Sanofi | Use of substituted 3-heteroaroylamino-propionic acid derivatives as pharmaceuticals for prevention/treatment of atrial fibrillation |
MX2015013800A (es) * | 2013-03-28 | 2016-06-02 | Sanofi Sa | Derivados de acido-biaril-propionico y su uso como productos farmaceuticos. |
TW201522318A (zh) | 2013-03-28 | 2015-06-16 | Sanofi Sa | 聯芳基丙酸及其作為醫藥品之用途 |
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AU2017343638B2 (en) | 2016-10-12 | 2021-12-09 | Research Triangle Institute | Heterocyclic apelin receptor (APJ) agonists and uses thereof |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999023063A1 (en) * | 1997-10-31 | 1999-05-14 | Aventis Pharma Limited | Substituted anilides |
WO2000035285A1 (de) * | 1998-12-17 | 2000-06-22 | Aventis Cropscience Gmbh | 4-haloalkyl-3-heterocyclylpyridine und 4-haloalkyl-5-heterocyclyl-pyrimidine und ihre verwendung als repellentien |
WO2000020358A3 (en) * | 1998-08-20 | 2000-11-16 | Agouron Pharma | NON-PEPTIDE GnRH AGENTS, METHODS AND INTERMEDIATES FOR THEIR PREPARATION |
JP2002326980A (ja) * | 2001-04-27 | 2002-11-15 | Nippon Nohyaku Co Ltd | ジアミド誘導体及び農園芸用薬剤並びにその使用方法 |
WO2008124838A1 (en) * | 2007-04-10 | 2008-10-16 | University Of Maryland, Baltimore | Compounds that inhibit human dna ligases and methods of treating cancer |
WO2010136493A1 (en) * | 2009-05-28 | 2010-12-02 | Novartis Ag | Substituted aminopropionic derivatives as neprilysin inhibitors |
WO2011011232A1 (en) * | 2009-07-22 | 2011-01-27 | Theravance, Inc. | Dual-acting oxazole antihypertensive agents |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6080767A (en) * | 1996-01-02 | 2000-06-27 | Aventis Pharmaceuticals Products Inc. | Substituted n-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides |
AR011515A1 (es) * | 1996-12-25 | 2000-08-30 | Agrogene Ltd | Derivado del acido aminobutirico para la proteccion de plantas de enfermedades fungosas y un metodo para proteger un cultivo contra enfermedadesfungosas por ejemplo tomates y papas contra el tizon tardio o temprano, cereales contra el mildiu polvoroso, y pepino, vides, melones contra el mildiu |
US6468977B1 (en) * | 1998-03-02 | 2002-10-22 | Apotex Inc. | Thiadiazole compounds useful as inhibitors of cysteine activity dependent enzymes |
US6462076B2 (en) * | 2000-06-14 | 2002-10-08 | Hoffmann-La Roche Inc. | Beta-amino acid nitrile derivatives as cathepsin K inhibitors |
IL161992A0 (en) * | 2001-12-04 | 2005-11-20 | Hoffmann La Roche | Substituted 2-amino-cycloalkanecarboxamides and t heir use as cysteine protease inhibitors |
US20040072802A1 (en) | 2002-10-09 | 2004-04-15 | Jingwu Duan | Beta-amino acid derivatives as inhibitors of matrix metalloproteases and TNF-alpha |
EP1581523B1 (en) | 2002-12-23 | 2009-09-30 | Sanofi-Aventis Deutschland GmbH | Pyrazole-derivatives as factor xa inhibitors |
JP4591347B2 (ja) * | 2003-03-17 | 2010-12-01 | 宇部興産株式会社 | 3−アミノ−3−アリールプロピオン酸n−アルキルエステル及びその製造方法並びに光学活性3−アミノ−3−アリールプロピオン酸及びその対掌エステルの製造方法 |
EP1493740A1 (fr) * | 2003-07-03 | 2005-01-05 | Warner-Lambert Company LLC | Dérivés de 5-fluoro-thiophene, leur procédé de preparation, les compositions pharmaceutiques les contenant et leur utilisation comme inhibiteurs de métalloprotéinases |
EP1493739A1 (fr) | 2003-07-03 | 2005-01-05 | Warner-Lambert Company LLC | Dérivés thiophényliques d'aminoacides, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent |
US7115646B2 (en) * | 2003-10-08 | 2006-10-03 | Bristol Myers Squibb, Co. | Cyclic diamines and derivatives as factor Xa inhibitors |
JP2005145839A (ja) | 2003-11-12 | 2005-06-09 | Japan Science & Technology Agency | 新規なカテプシンa阻害剤 |
TW200526641A (en) | 2003-12-26 | 2005-08-16 | Daiichi Seiyaku Co | Amidopyrazole derivatives |
EP1844020B1 (en) | 2005-01-10 | 2017-09-06 | Exelixis, Inc. | Heterocyclic carboxamide compounds as steroid nuclear receptor ligands |
ATE538650T1 (de) * | 2006-03-10 | 2012-01-15 | Jenrin Discovery | Cannabinoid-rezeptor-antagonisten / inverse agonisten zur behandlung von übergewicht |
JPWO2009028280A1 (ja) * | 2007-08-29 | 2010-11-25 | 三井化学アグロ株式会社 | ピラゾールカルボン酸誘導体及びその製造方法、並びに殺菌剤 |
US8133904B2 (en) * | 2007-09-07 | 2012-03-13 | Jenrin Discovery, Inc. | Cannabinoid receptor antagonists/inverse agonists useful for treating obesity |
CA2709784A1 (en) * | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
WO2009080227A2 (en) | 2007-12-26 | 2009-07-02 | Sanofi-Aventis | Pyrazole-carboxamide derivatives as p2y12 antagonists |
EP2238128B1 (en) | 2007-12-26 | 2012-08-22 | Sanofi | Heterocyclic pyrazole-carboxamides as p2y12 antagonists |
WO2009137338A1 (en) * | 2008-05-06 | 2009-11-12 | Boehringer Ingelheim International Gmbh | Pyrazole compounds as ccr1 antagonists |
EP2334651A2 (en) * | 2008-07-24 | 2011-06-22 | Theravance, Inc. | Dual-acting antihypertensive agents |
US7956054B2 (en) * | 2009-07-07 | 2011-06-07 | Theravance, Inc. | Dual-acting pyrazole antihypertensive agents |
UY33200A (es) * | 2010-01-26 | 2011-08-31 | Sanofi Aventis | Derivados de ácido 3-heteroaroilamino-propiónico sustituidos con oxígeno y su uso como productos farmacéuticos |
EP2893812B1 (en) * | 2011-05-17 | 2016-08-24 | WaterDiam Sàrl | Method for post-harvest treating citrus fruit |
JP5959074B2 (ja) * | 2011-05-31 | 2016-08-02 | セラヴァンス バイオファーマ アール&ディー アイピー, エルエルシー | ネプリライシン阻害剤 |
CN105646362B (zh) | 2011-07-26 | 2019-07-05 | 赛诺菲 | 3-杂芳酰基氨基-丙酸衍生物及其作为药物的用途 |
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- 2012-07-26 US US13/559,401 patent/US9353068B2/en not_active Expired - Fee Related
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2013
- 2013-12-23 IL IL230126A patent/IL230126A/en not_active IP Right Cessation
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2014
- 2014-06-19 HK HK14105865.5A patent/HK1192559A1/zh not_active IP Right Cessation
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2016
- 2016-01-15 HR HRP20160047TT patent/HRP20160047T1/hr unknown
- 2016-02-03 CY CY20161100093T patent/CY1117397T1/el unknown
- 2016-04-27 US US15/140,350 patent/US9751858B2/en not_active Expired - Fee Related
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2017
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999023063A1 (en) * | 1997-10-31 | 1999-05-14 | Aventis Pharma Limited | Substituted anilides |
WO2000020358A3 (en) * | 1998-08-20 | 2000-11-16 | Agouron Pharma | NON-PEPTIDE GnRH AGENTS, METHODS AND INTERMEDIATES FOR THEIR PREPARATION |
WO2000035285A1 (de) * | 1998-12-17 | 2000-06-22 | Aventis Cropscience Gmbh | 4-haloalkyl-3-heterocyclylpyridine und 4-haloalkyl-5-heterocyclyl-pyrimidine und ihre verwendung als repellentien |
JP2002326980A (ja) * | 2001-04-27 | 2002-11-15 | Nippon Nohyaku Co Ltd | ジアミド誘導体及び農園芸用薬剤並びにその使用方法 |
WO2008124838A1 (en) * | 2007-04-10 | 2008-10-16 | University Of Maryland, Baltimore | Compounds that inhibit human dna ligases and methods of treating cancer |
WO2010136493A1 (en) * | 2009-05-28 | 2010-12-02 | Novartis Ag | Substituted aminopropionic derivatives as neprilysin inhibitors |
WO2011011232A1 (en) * | 2009-07-22 | 2011-01-27 | Theravance, Inc. | Dual-acting oxazole antihypertensive agents |
Non-Patent Citations (2)
Title |
---|
Database Registry;(STN);《CA on Web》;20110513;第4-9、11-12页对应化合物 |
Thiophene and bioisostere derivatives as new MMP12 inhibitors;Matthew Badland等;《Bioorganic & Medicinal Chemistry Letters》;20101109;第21卷(第11期);第530页表2第1和2个化合物 |
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