CN102459210B - 芳基磺酰胺ccr3拮抗剂 - Google Patents
芳基磺酰胺ccr3拮抗剂 Download PDFInfo
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- CN102459210B CN102459210B CN201080027737.2A CN201080027737A CN102459210B CN 102459210 B CN102459210 B CN 102459210B CN 201080027737 A CN201080027737 A CN 201080027737A CN 102459210 B CN102459210 B CN 102459210B
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Abstract
本文提供的是用于调控CCR3活性的芳基磺酰胺及其药物组合物。本文还提供的是它们用于治疗、预防或缓解CCR3-介导的紊乱、疾病或病症的一种或多种症状的方法。
Description
相关申请的交叉参考
本申请要求2009年4月22日提交的美国临时申请No.61/171,780的优先权,在此引入该相关申请的全部公开内容作为参考。
领域
本文提供的是用于调控CCR3活性的芳基磺酰胺及其药物组合物。本文还提供的是它们用于治疗、预防或缓解CCR3-介导的紊乱、疾病或病症的一种或多种症状的方法。
背景
CC趋化因子受体3(CCR3)是一种七次跨膜G蛋白偶联受体,其与各种C-C趋化因子结合,包括嗜酸性粒细胞趋化因子(CCL11)、嗜酸性粒细胞趋化因子-3(CCL26)、MCP-3(CCL7)、MCP-4(CCL13)和RANTES(CCL5)。CCR3已知是一种在过敏性炎性细胞上表达的主要趋化因子受体,包括嗜红细胞、嗜碱细胞、肥大细胞和II型T辅助CD4+细胞(Combadiere等人,J.Biol.Chem.1995,270,16491-16494;Post等人,J.Immunol.1995,155,5299-5305)。嗜红细胞嗜红细胞牵连到多种过敏性疾病的发病机制,如支气管哮喘(Durham和Kay,Clin.Allergy 1985,15,411-418;Kroegel等人,J.Allergy Clin.Immunol.1994,93,725-734)、过敏性鼻炎(Durham,Clin.Exp.Allergy 1998,28 Suppl.2,11-16)、过敏性皮炎(Leung,J.AllergyClin.Immunol.1999,104,S99-108)和嗜酸细胞性胃肠炎(Bischoff等人,Am.J.Gastro.1999,94,3521-3529)。已经证明,活化的嗜红细胞释放主要碱性蛋白(MBP),其阻断神经上的抑制性M2胆碱受体(M2Rs),增加乙酰基胆碱释放,加强迷走神经介导的支气管狭窄(Evans等人,J.Clin.Invest.1997,100,2254-2262)。
许多报告表明,CCR3在过敏性病症起着重要作用,例如,有报道说,在过敏性和非过敏性哮喘患者中,CCR3和其配体、嗜酸性粒细胞趋化因子、嗜酸性粒细胞趋化因子-2、RANTES和MCP-4的mRNA和蛋白水平均有增加(Ying等人,J.Immunol.1999,99,6321-6329)。也已经证明,在实验性哮喘的急性模型中,CCR3基因缺失损害嗜红细胞聚集(Humbles等人,Proc.Natl.Acad.Sci.USA 2002,99,1479-1484;Ma等人,J.Clin.Invest.2002,109,621-628;Pope等人,J.Immunol.2005,175,5341-5350;Fulkerson等人,Proc.Natl.Acad.Sci.USA 2006,103,16418-16423)。此外,有研究表明,CCR3拮抗剂,如抗CCR3单克隆抗体,阻断CCR3配体结合到CCR3转染体或嗜红细胞,从而阻断C-C趋化因子诱导的嗜红细胞的趋化作用,如嗜酸性粒细胞趋化因子、RANTES或MCP-3(Heath等人,J.Clin.Invest.1997,99,178-184;Grimaldi等人,J.Leukocyte Biol.1999,65,846-853;Justice等人,Am.J.Physiol.2003,284,L168-L178)。因此,CCR3拮抗剂潜在地用于治疗炎性疾病,如过敏性鼻炎和过敏性哮喘。此外,CCR3拮抗剂也潜在地用于阻断一些微生物造成的CCR3表达细胞感染,如HIV,因为CCR3已知是一些微生物的进入共受体。
发明内容
本文提供的是一种式I的芳基磺酰胺:
或其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药;
其中:
R1、R2、R3、R4、R5和R6每一个独立地是(a)氢、卤素、氰基、硝基或胍;(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基;或(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;
R7是(a)卤素、氰基、硝基、氧代或胍;(b)C1-6烷基、C2-6烯基、C2-6炔基、环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基;或(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;
X是O或S;
RYa是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(S)NR1bR1c、-C(S)NR1aC(O)NR1bR1c、-C(NR1a)NR1bR1c、-C(NNO2)NR1bR1c、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;条件是RYa不是-C(O)O-叔丁基也不是-C(O)H;
m是0~3的整数;
n是1~3的整数;
p是0~4的整数;和
每个R1a、R1b、R1c和R1d独立地是氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、杂芳基或杂环基;或每对R1b和R1c与它们连接的氮原子一起独立地形成杂芳基或杂环基;
其中每个烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基和杂芳基任选地被一个或多个基团所取代,每一个基团独立地选自(a)氰基、卤素和硝基;(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基和杂环基,每一个任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代;和(c)-C(O)Ra、-C(O)ORa、-C(O)NRbRc、-C(NRa)NRbRc、-ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRbRc、-OC(=NRa)NRbRc、-OS(O)Ra、-OS(O)2Ra、-OS(O)NRbRc、-O S(O)2NRbRc、-NRbRc、-NRaC(O)Rd、-NRaC(O)ORd、-NRaC(O)NRbRc、-NRaC(=NRd)NRbRc、-NRaS(O)Rd、-NRaS(O)2Rd、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRbRc和-S(O)2NRbRc,其中每个Ra、Rb、Rc和Rd独立地是(i)氢;(ii)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基,每一个任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代;或(iii)Rb和Rc与它们连接的氮原子一起形成杂环基,任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代;
其中每个Q独立地选自(a)氰基、卤素和硝基;(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基和杂环基;和(c)-C(O)Re、-C(O)ORe、-C(O)NRfRg、-C(NRe)NRfRg、-ORe、-OC(O)Re、-OC(O)ORe、-OC(O)NRfRg、-OC(=NRe)NRfRg、-OS(O)Re、-OS(O)2Re、-OS(O)NRfRg、-OS(O)2NRfRg、-NRfRg、-NReC(O)Rh、-NReC(O)ORh、-NReC(O)NRfRg、-NReC(=NRh)NRfRg、-NReS(O)Rh、-NReS(O)2Rh、-NReS(O)NRfRg、-NReS(O)2NRfRg、-SRe、-S(O)Re、-S(O)2Re、-S(O)NRfRg和-S(O)2NRfRg;其中每个Re、Rf、Rg和Rh独立地是(i)氢;(ii)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基;或(iii)Rf和Rg与它们连接的氮原子一起形成杂环基。
在一个实施方案中,RYa不是-C(O)O-C1-6烷基也不是-C(O)H。
本文还提供的是含有本文公开的化合物以及一种或多种药学上可接受的载体的药物组合物,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。
本文还提供的是一种调控CCR3活性的方法,包括使CCR3与治疗有效量的本文公开的化合物接触,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。
本文还提供的是一种治疗、预防或缓解对象中CCR3-介导的紊乱、疾病或病症的一种或多种症状的方法,包括给予对象治疗有效量的本文公开的化合物,例如,式I的化合物,其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。
具体实施方式
为方便理解本文披露的内容,一些术语定义如下。
一般来说,此处使用的命名和本文所述的有机化学、药物化学和药理学的实验程序是本领域中众所周知的和常用的那些。除非另有规定,此处所用的所有技术和科学术语一般具有与本发明所属领域技术人员的通常理解相同的含义。在对于本文使用的术语存在多种定义的情况下,除非另有说明,以本部分为准。
术语“对象”是指动物,包括但不限于灵长类动物(例如,人类)、牛、猪、绵羊、山羊、马、狗、猫、兔、大鼠或小鼠。术语“对象”和“患者”互换使用,例如,用于指哺乳动物对象,如人对象。
术语“治疗”的含义包括减轻或消除紊乱、疾病或病症,或与紊乱、疾病或病症相关的一种或多种症状;或减轻或消除紊乱、疾病或病症的病灶。
术语“预防”的含义包括延缓和/或解除紊乱、疾病或病症和/或其伴随症状的发作;阻止对象获得紊乱、疾病或病症;或减少对象获得紊乱、疾病或病症的风险。
术语“治疗有效量”的含义包括当给予时足以防止正在接受治疗的紊乱、疾病或病症的一种或多种症状发展或在一定程度上减轻的化合物量。术语“治疗有效量”也指足以引起正由研究人员、兽医、医生或临床医师寻求的生物分子(例如,蛋白、酶、RNA或DNA)、细胞、组织、系统、动物或人的生物或医学响应的化合物量。
术语“药学上可接受的载体”、“药学上可接受的赋形剂”、“生理上可接受的载体”或“生理上可接受的赋形剂”是指药学上接受的材料、组合物或介质,如液体或固体填料、稀释剂、溶剂或封装材料。在一个实施方案,“药学上可接受的”每种成分是指与药剂配方的其他成分兼容,并且适用于与人和动物的组织或器官接触,而没有过多的毒性、刺激性、过敏性反应、免疫原性或其他问题或并发症,相当于合理的利益/风险比。参见,Remington:The Science and Practice of Pharmacy,21st Edition;Lippincott Williams&Wilkins:Philadelphia,PA,2005;Handbook of Pharmaceutical Excipients,第5版;Rowe等人,Eds.,The Pharmaceutical Press and the AmericanPharmaceutical Association:2005;和Handbook of Pharmaceutical Additives,3rd Edition;Ash和Ash Eds.,Gower Publishing Company:2007;Pharmaceutical Preformulation and Formulation,2nd Edition,Gibson Ed.,CRC Press LLC:Boca Raton,FL,2004。
术语“约”或“大约”是指由本领域技术人员确定的可以接受的误差,其部分取决于如何测量或确定值。在某些实施方案中,术语“约”或“大约”是指在1、2、3或4个标准偏差之内。在某些实施方案中,术语“约”或“大约”是指在给定值或范围的50%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%或0.05%之内。
术语“活性成分”和“活性物质”是指被单独给予或与一种或多种药学上可接受的赋形剂组合给予至对象以治疗、预防或缓解病症、紊乱或疾病的一种或多种症状的化合物。本文中所用的“活性成分”和“活性物质”可以是此处所述的化合物的光学活性异构体。
术语“药物”、“治疗剂”和“化疗剂”是指被给予至对象以治疗、预防或缓解病症、紊乱或疾病的一种或多种症状的化合物或其药物组合物。
术语“烷基”是指直链或支链的饱和单价烃基,其中烷基可以按本文所述的任选地被取代。在某些实施方案中,烷基是具有1~20(C1-20)、1~15(C1-15)、1~10(C1-10)或1~6(C1-6)个碳原子的直链的饱和单价烃基,或3~20(C3-20)、3~15(C3-15)、3~10(C3-10)或3~6(C3-6)个碳原子的支链的饱和单价烃基。本文中所用的直链的C1-6和支链的C3-6烷基也被称为“低级烷基”。烷基的例子包括但不限于甲基、乙基、丙基(包括所有异构体形式)、正丙基、异丙基、丁基(包括所有异构体形式)、正丁基、异丁基、仲丁基、叔丁基、戊基(包括所有异构体形式)和己基(包括所有异构体形式)。例如,C1-6烷基指1~6个碳原子的直链的饱和单价烃基或3~6个碳原子的支链的饱和单价烃基。
术语“烯基”是指含有一个或多个碳-碳双键的直链或支链的单价烃基,在一个实施方案中,含有1~5个碳-碳双键,在另一个实施方案中,含有1个碳-碳双键。烯基可以按本文所述的任选被取代。术语“烯基”还包括具有“顺式”和“反式”构型的基团,或者,“E”和“Z”构型,本领域技术人员可以理解。除非另有说明,本文中所用的术语“烯基”包括直链的和支链的烯基。例如,C2-6烯基指2~6个碳原子的直链的不饱和单价烃基或3~6个碳原子的支链的不饱和单价烃基。在某些实施方案中,烯基是2~20(C2-20)、2~15(C2-15)、2~10(C2-10)或2~6(C2-6)个碳原子的直链的单价烃基或3~20(C3-20)、3~15(C3-15)、3~10(C3-10)或3~6(C3-6)个碳原子的支链的单价烃基。烯基的例子包括但不限于乙烯基、丙烯-1-基、丙烯-2-基、烯丙基、丁烯基和4-甲基丁烯基。
术语“炔基”是指含有一个或多个碳-碳三键的直链或支链的单价烃基,在一个实施方案中,含有1~5个碳-碳三键,在另一个实施方案中,含有1个碳-碳三键。炔基可以按本文所述的任选被取代。除非另有说明,术语“炔基”还包括直链的和支链的炔基。在某些实施方案中,炔基是2~20(C2-20)、2~15(C2-15)、2~10(C2-10)或2~6(C2-6)个碳原子的直链的单价烃基或3~20(C3-20)、3~15(C3-15)、3~10(C3-10)或3~6(C3-6)个碳原子的支链的单价烃基。炔基的例子包括但不限于乙炔基(-C≡CH)和炔丙基(-CH2C≡CH)。例如,C2-6炔基指2~6个碳原子的直链的不饱和单价烃基或3~6个碳原子的支链的不饱和单价烃基。
术语“环烷基”是指环状单价烃基,可以按本文所述的任选被取代。在一个实施方案中,环烷基可以是饱和的、和/或桥接的、和/或非桥接的、和/或稠合的双环基团。在某些实施方案中,环烷基具有3~20(C3-20)、3~15(C3-15)、3~10(C3-10)或3~7(C3-7)个碳原子。环烷基的例子包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、双环[2.1.1]己基、双环[2.2.1]庚基、十氢萘基和金刚烷基。
术语“芳基”是指单价单环芳香族基团和/或含有至少一个芳香族烃环的单价多环芳香族基团。在某些实施方案中,芳基具有6~20(C6-20)、6~15(C6-15)或6~10(C6-10)个环原子。芳基的例子包括但不限于苯基、萘基、芴基、甘菊环基、蒽基、菲基、芘基、联苯基和三联苯基。芳基也指双环或三环碳环,其中一个环是芳香族的,其他的环可以是饱和的、部分饱和的或芳香族的,例如,二氢萘基、茚基、茚满基或四氢萘基(tetralinyl)。在某些实施方案中,芳基可以按本文所述的任选被取代。
术语″芳烷基″或″芳基-烷基″是指用芳基取代的单价烷基。在某些实施方案中,烷基和芳基部分按本文所述的任选被取代。
术语“杂芳基”是指单价单环芳香族基团和/或含有至少一个芳香环的多环芳香族基团,其中至少一个芳香环在环中含有独立地选自O、S和N的一个或多个杂原子。杂芳基通过芳香环与分子的其余部分结合。杂芳基的每个环可以含有一个或两个O原子、一个或两个S原子和/或一个至四个N原子,条件是每个环中的杂原子总数为四个或更少且每个环含有至少一个碳原子。在某些实施方案中,杂芳基具有5~20、5~15或5~10个环原子。单环杂芳基的例子包括但不限于呋喃基、咪唑基、异噻唑基、异噁唑基、噁二唑基、噁二唑基、噁唑基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、噻二唑基、噻唑基、噻吩基、四唑基、三嗪基和三唑基。双环杂芳基的例子包括但不限于苯并呋喃基、苯并咪唑基、苯并异噁唑基、苯并吡喃基、苯并噻二唑基、苯并噻唑基、苯并噻吩基、苯并三唑基、苯并噁唑基、呋喃并吡啶基、咪唑并吡啶基、咪唑并噻唑基、吲哚嗪基、吲哚基、吲唑基、异苯并呋喃基、异苯并噻吩基、异吲哚基、异喹啉基、异噻唑基、萘啶基、噁唑并吡啶基、酞嗪基、蝶啶基、嘌呤基、吡啶并吡啶基、吡咯并吡啶基、喹啉基、喹喔啉基、喹唑啉基、噻二唑并嘧啶基和噻吩并吡啶基。三环杂芳基的例子包括但不限于吖啶基、苯并吲哚基、咔唑基、二苯并呋喃基、萘嵌间二氮杂苯基、菲咯啉基、菲啶基、砷菲基、吩嗪基、吩噻嗪基、吩噁嗪基和氧杂蒽基。在某些实施方案中,杂芳基也可以按本文所述的任选被取代。
术语“杂环基”或“杂环”是指单价单环非芳香环系和/或含有至少一个非芳香环的多环非芳香环系,其中一个或多个非芳香环原子是独立地选自O、S或N的杂原子;和其余环原子是碳原子。在某些实施方案中,杂环基或杂环具有3~20、3~15、3~10、3~8、4~7或5~6个环原子。杂环基通过非芳香环与分子的其余部分结合。在某些实施方案中,杂环基是单环、双环、三环或四环环系,可以包括稠合或桥环环系,并且其中氮或硫原子可以任选地被氧化,氮原子可以任选地季铵化,一些环可以是部分或完全饱和的,或芳香族的。杂环基可以在任何杂原子或碳原子处与主要结构连接,生成稳定的化合物。杂环基的例子包括但不限于氮杂环庚烯基、苯并二噁烷基、苯并间二氧杂环戊烯基、苯并呋喃酮基、苯并吡喃酮基、苯并吡喃基、苯并四氢呋喃基、苯并四氢噻吩基、苯并硫代吡喃基、苯并噁嗪基、β-咔啉基、苯并二氢吡喃基、色酮基、噌啉基、香豆素基、十氢异喹啉基、二氢苯并异噻嗪基、二氢苯并异噁嗪基、二氢呋喃基、二氢异吲哚基、二氢吡喃基、二氢吡唑基、二氢吡嗪基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氧杂环己基、1,4-二噻烷基、呋喃酮基、咪唑烷基、咪唑啉基、吲哚啉基、异苯并四氢呋喃基、异苯并四氢噻吩基、异苯并二氢吡喃基、异香豆素基、异吲哚啉基、异噻唑烷基、异噁唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、噁唑烷酮基、噁唑烷基、环氧乙烷基、哌嗪基、哌啶基、4-哌啶基、吡唑烷基、吡唑啉基、吡咯烷基、吡咯啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢吡喃基、四氢噻吩基、硫代吗啉基、噻唑烷基、四氢喹啉基和1,3,5-三噻烷基。在某些实施方案中,杂环也可以按本文所述的任选地被取代。
术语“卤素”、“卤化物”或“卤代”指氟、氯、溴和/或碘。
术语“任选被取代”用于指基团,如烷基、烯基、炔基、环烷基、芳基、芳烷基、杂芳基或杂环基,可以被独立地选自例如以下的一个或多个取代基取代:(a)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基和杂环基,每一个任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代;和(b)卤素、氰基(-CN)、硝基(-NO2)、-C(O)Ra、-C(O)ORa、-C(O)NRbRc、-C(NRa)NRbRc、-ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRbRc、-OC(=NRa)NRbRc、-O S(O)Ra、-OS(O)2Ra、-OS(O)NRbRc、-OS(O)2NRbRc、-NRbRc、-NRaC(O)Rd、-NRaC(O)ORd、-NRaC(O)NRbRc、-NRaC(=NRd)NRbRc、-NRaS(O)Rd、-NRaS(O)2Rd、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRbRc和-S(O)2NRbRc,其中每个Ra、Rb、Rc和Rd独立地是(i)氢;(ii)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基,每一个任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代;或(iii)Rb和Rc与它们连接的氮原子一起形成杂芳基或杂环基,任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代。除非另有说明,本文中所用的可以被取代的所有基团均是“任选被取代”。
在一个实施方案中,每个Q独立地选自(a)氰基、卤素和硝基;和(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基和杂环基;和(c)-C(O)Re、-C(O)ORe、-C(O)NRfRg、-C(NRe)NRfRg、-ORe、-OC(O)Re、-OC(O)ORe、-OC(O)NRfRg、-OC(=NRe)NRfRg、-OS(O)Re、-OS(O)2Re、-OS(O)NRfRg、-OS(O)2NRfRg、-NRfRg、-NReC(O)Rh、-NReC(O)ORh、-NReC(O)NRfRg、-NReC(=NRh)NRfRg、-NReS(O)Rh、-NReS(O)2Rh、-NReS(O)NRfRg、-NReS(O)2NRfRg、-SRe、-S(O)Re、-S(O)2Re、-S(O)NRfRg和-S(O)2NRfRg;其中每个Re、Rf、Rg和Rh独立地是(i)氢;(ii)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基;或(iii)Rf和Rg与它们连接的氮原子一起形成杂芳基或杂环基。
在某些实施方案中,“光学活性”和“对映异构体活性”是指对映异构体过量不低于约50%、不低于约70%、不低于约80%、不低于约90%、不低于约91%、不低于约92%、不低于约93%、不低于约94%、不低于约95%、不低于约96%、不低于约97%、不低于约98%、不低于约99%、不低于约99.5%或不低于约99.8%的分子集合。在某些实施方案中,按相关外消旋物总重量计,化合物包括约95%以上的一种对映异构体和约5%以下的其他对映异构体。
在描述光学活性化合物时,前缀R和S用来表示分子绕其手性中心的绝对构型。(+)和(-)用来表示该化合物的光学旋转,即由光学活性化合物旋转的偏振光面的方向。(-)前缀表明该化合物是左旋的,即化合物使偏振光面向左或逆时针方向旋转。(+)前缀表明该化合物是右旋的,即化合物使偏振光面向右或顺时针方向旋转。然而,光学旋转的符号,(+)和(-)不涉及到分子的绝对构型,R和S。
术语“溶剂化物”指本文提供的化合物或其盐,其还包括化学计量或非化学计量量的通过非共价的分子间力结合的溶剂。如果溶剂是水,则溶剂化物是水合物。
针对诸如核酸分子、多肽、宿主细胞等生物材料使用的术语“天然发生的”或“原生的”是指在自然界中发现的并且没有人为操纵的材料。相似地,“非天然发生的”或“非原生的”是指不是在自然界中发现的或者已经人为进行结构修饰或合成的材料。
术语″CCR3″是指CC趋化因子受体3或其突变体,其能够介导针对多种趋化因子的细胞反应,包括但不限于嗜酸性粒细胞趋化因子(CCL11)、嗜酸性粒细胞趋化因子-3(CCL26)、MCP-3(CCL7)、MCP-4(CCL13)和RANTES(CCL5)。CCR3突变体包括与原生CCR3基本上同源的蛋白,即,与原生CCR3的氨基酸序列相比,具有一个或多个天然或非天然氨基酸缺失、插入或替换的蛋白(例如,CCR3衍生物、同源物和片段)。CCR3突变体的氨基酸序列与原生CCR3至少约80%相同、至少约90%相同或至少约95%相同。
术语″CCR3拮抗剂″是指例如部分或完全地阻断、减少、防止、抑制或下调CCR3活性的化合物。术语″CCR3拮抗剂″也是指与CCR3受体结合、使其延迟活化、失活或不敏感的化合物。CCR3拮抗剂可以通过干预CCR3受体与其趋化因子配体的相互作用来起作用,包括但不限于嗜酸性粒细胞趋化因子(CCL11)、嗜酸性粒细胞趋化因子-3(CCL26)、MCP-3(CCL7)、MCP-4(CCL13)和/或RANTES(CCL5)。
术语″CCR3-介导的紊乱或疾病″和″CCR3介导的病症、紊乱或疾病″是指特征在于不适宜的CCR3活性的病症、紊乱或疾病,例如,活性比正常的小或大。不适宜的CCR3功能活性可能是由于在通常不表达CCR3的细胞中CCR3表达、增加的CCR3表达或细胞内活化程度引起的,从而导致例如炎性和免疫相关的紊乱或疾病;或者减少的CCR3表达引起的。CCR3-介导的病症、紊乱或疾病可以是由不适宜的CCR3活性完全或部分介导的。特别地,CCR3-介导的病症、紊乱或疾病是指CCR3受体的调控导致对于基本病症或紊乱的一些影响,例如,CCR3拮抗剂或激动剂导致至少一些正在接受治疗的患者中的某种改善。
化合物
本文提供的是用于调控CCR3活性的芳基磺酰胺。本文还提供的是含有所述化合物的药物组合物,使用所述化合物的方法以及用于治疗CCR3-介导的紊乱、疾病或病症的组合物。
在一个实施方案中,本文提供的是一种式I的芳基磺酰胺:
或其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或者两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药;
其中:
R1、R2、R3、R4、R5和R6每一个独立地是(a)氢、卤素、氰基、硝基或胍;(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基;或(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;
R7是(a)卤素、氰基、硝基、氧代或胍;(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基;或(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;
X是O或S;
RYa是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(S)NR1bR1c、-C(S)NR1aC(O)NR1bR1c、-C(NR1a)NR1bR1c、-C(NNO2)NR1bR1c、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;
m是0~3的整数;
n是1~3的整数;
p是0~4的整数;和
每个R1a、R1b、R1c和R1d独立地是氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、杂芳基或杂环基;或每对R1b和R1c与它们连接的氮原子一起独立地形成杂芳基或杂环基;
其中每个烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基和杂芳基任选地被一个或多个基团所取代,每一个基团独立地选自(a)氰基、卤素和硝基;(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基和杂环基,每一个任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代;和(c)-C(O)Ra、-C(O)ORa、-C(O)NRbRc、-C(NRa)NRbRc、-ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRbRc、-OC(=NRa)NRbRc、-OS(O)Ra、-OS(O)2Ra、-OS(O)NRbRc、-OS(O)2NRbRc、-NRbRc、-NRaC(O)Rd、-NRaC(O)ORd、-NRaC(O)NRbRc、-NRaC(=NRd)NRbRc、-NRaS(O)Rd、-NRaS(O)2Rd、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRbRc和-S(O)2NRbRc,其中每个Ra、Rb、Rc和Rd独立地是(i)氢;(ii)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基,每一个任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代;或(iii)Rb和Rc与它们连接的氮原子一起形成杂环基,任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代;
其中每个Q独立地选自(a)氰基、卤素和硝基;(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基和杂环基;和(c)-C(O)Re、-C(O)ORe、-C(O)NRfRg、-C(NRe)NRfRg、-ORe、-OC(O)Re、-OC(O)ORe、-OC(O)NRfRg、-OC(=NRe)NRfRg、-OS(O)Re、-OS(O)2Re、-OS(O)NRfRg、-OS(O)2NRfRg、-NRfRg、-NReC(O)Rh、-NReC(O)ORh、-NReC(O)NRfRg、-NReC(=NRh)NRfRg、-NReS(O)Rh、-NReS(O)2Rh、-NReS(O)NRfRg、-NReS(O)2NRfRg、-SRe、-S(O)Re、-S(O)2Re、-S(O)NRfRg和-S(O)2NRfRg;其中每个Re、Rf、Rg和Rh独立地是(i)氢;(ii)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基;或(iii)Rf和Rg与它们连接的氮原子一起形成杂环基。
在某些实施方案中,在式I中,RYa不是-C(O)O-叔丁基也不是-C(O)H。
在某些实施方案中,在式I中,RYa不是-C(O)O-叔丁基也不是-C(O)H。在某些实施方案中,在式I中,RYa不是-C(O)O-叔丁基。在某些实施方案中,在式I中,所述化合物是4-(2-(3,5-二甲基苯氧基)-5-硝基苯基磺酰基)哌嗪-1-甲醛。
在另一个实施方案中,本文提供的是式I的芳基磺酰胺:
或其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药;
其中:
R1、R2、R3、R4、R5和R6每一个独立地是(a)氢、卤素、氰基、硝基或胍;(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基;或(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;
R7是(a)卤素、氰基、硝基、氧代或胍;(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基;或(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;
X是O或S;
RYa是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;条件是RYa不是-C(O)O-叔丁基也不是-C(O)H;
m是0~3的整数;
n是1~3的整数;
p是0~4的整数;和
每个R1a、R1b、R1c和R1d独立地是氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、杂芳基或杂环基;或每对R1b和R1c与它们连接的氮原子一起独立地形成杂芳基或杂环基;其中每个烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基和杂芳基任选地被一个或多个基团所取代,每一个基团独立地选自(a)氰基、卤素和硝基;(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基和杂环基,每一个任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代;和(c)-C(O)Ra、-C(O)ORa、-C(O)NRbRc、-C(NRa)NRbRc、-ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRbRc、-OC(=NRa)NRbRc、-O S(O)Ra、-OS(O)2Ra、-OS(O)NRbRc、-OS(O)2NRbRc、-NRbRc、-NRaC(O)Rd、-NRaC(O)ORd、-NRaC(O)NRbRc、-NRaC(=NRd)NRbRc、-NRaS(O)Rd、-NRaS(O)2Rd、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRbRc和-S(O)2NRbRc,其中每个Ra、Rb、Rc和Rd独立地是(i)氢;(ii)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基,每一个任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代;或(iii)Rb和Rc与它们连接的氮原子一起形成杂环基,任选地被一个或多个取代基Q所取代,在一个实施方案中,被1、2、3或4个取代基Q所取代;
其中每个Q独立地选自(a)氰基、卤素和硝基;(b)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基和杂环基;和(c)-C(O)Re、-C(O)ORe、-C(O)NRfRg、-C(NRe)NRfRg、-ORe、-OC(O)Re、-OC(O)ORe、-OC(O)NRfRg、-OC(=NRe)NRfRg、-OS(O)Re、-OS(O)2Re、-OS(O)NRfRg、-OS(O)2NRfRg、-NRfRg、-NReC(O)Rh、-NReC(O)ORh、-NReC(O)NRfRg、-NReC(=NRh)NRfRg、-NReS(O)Rh、-NReS(O)2Rh、-NReS(O)NRfRg、-NReS(O)2NRfRg、-SRe、-S(O)Re、-S(O)2Re、-S(O)NRfRg和-S(O)2NRfRg;其中每个Re、Rf、Rg和Rh独立地是(i)氢;(ii)C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基;或(iii)Rf和Rg与它们连接的氮原子一起形成杂环基。
在一个实施方案中,RYa不是-C(O)O-C1-6烷基也不是-C(O)H。在另一个实施方案中,RYa是-C(O)O-C1-6烷基,但不是-C(O)O-叔丁基。
在一个实施方案中,在式I中,
R1、R2、R3、R4和R5每一个独立地是氢、卤素或C1-6烷基;
R6是氰基或硝基;
R7是C1-6烷基;
X是O或S;
m是0、1或2;
n是1或2;
p是0、1、2、3或4;和
RYa是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(S)NR1bR1c、-C(S)NR1aC(O)NR1bR1c、-C(NNO2)NR1bR1c、-S(O)2R1a或-S(O)2NR1bR1c;其中每个R1a和R1c独立地是(a)氢;(b)C1-6烷基,任选地被1、2或3个取代基所取代,每个取代基独立地选自氰基、卤素、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-C(O)Ra、-C(O)ORa和-SRa,其中环烷基、芳基、杂芳基和杂环基每一个进一步任选地被1、2或3个取代基所取代,每个取代基独立地是卤素或C1-6烷基;(c)C1-6烯基,任选地被C6-14芳基所取代;(d)C3-7环烷基,任选地被1或2个C6-14芳基所取代;(e)C6-14芳基,任选地被1、2或3个取代基所取代,每个取代基独立地选自卤素、硝基、氰基、-ORa、-C(O)Ra和C1-6烷基,其中烷基进一步任选地被1、2或3个卤素所取代;(f)杂芳基,任选地被1、2或3个取代基所取代,每个取代基独立地是卤素或C1-6烷基;或(g)杂环基;和R1b是氢或C1-6烷基。
在另一个实施方案中,在式I中,
R1、R2、R3、R4和R5每一个独立地是氢、卤素或C1-6烷基;
R6是氰基或硝基;
R7是C1-6烷基;
X是O或S;
m是0、1或2;
n是1或2;
p是0、1、2、3或4;和
RYa是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(S)NR1bR1c、-C(S)NR1aC(O)NR1bR1c、-C(NNO2)NR1bR1c、-S(O)2R1a或-S(O)2NR1bR1c;其中每个R1a和R1c独立地是(a)氢;或(b)C1-6烷基、C2-6烯基、C3-7环烷基、C6-14芳基、杂芳基或杂环基,每一个任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基;和R1b是氢或C1-6烷基。
在另一个实施方案中,在式I中,
R1、R2、R3、R4和R5每一个独立地是氢、卤素或C1-6烷基;
R6是氰基或硝基;
R7是C1-6烷基;
X是O或S;
m是0、1或2;
n是1或2;
p是0、1、2、3或4;和
RYa是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(S)NR1bR1c、-C(S)NR1aC(O)NR1bR1c、-C(NNO2)NR1bR1c、-S(O)2R1a或-S(O)2NR1bR1c;其中每个R1a和R1c独立地是(a)氢;或(b)C1-6烷基、C2-6烯基、C3-7环烷基、C6-14芳基、杂芳基或杂环基,每一个任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基;和R1b是氢或C1-6烷基。
在另一个实施方案中,在式I中,
R1、R2、R3、R4和R5每一个独立地是氢、卤素或C1-6烷基;
R6是氰基或硝基;
R7是C1-6烷基;
X是O或S;
m是0、1或2;
n是1或2;
p是0、1、2、3或4;和
RYa是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(S)NR1bR1c、-C(S)NR1aC(O)NR1bR1c、-C(NNO2)NR1bR1c、-S(O)2R1a或-S(O)2NR1bR1c;其中R1a和R1c每一个独立地是(a)氢;(b)C1-6烷基,任选地被取代基所取代,所述取代基选自氯、氰基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、丙酰基和乙氧基羰基;(c)C2-6烯基,任选地被苯基所取代;(d)C3-7环烷基;(e)C6-14芳基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基和乙酰基;(f)杂芳基,任选地被1或2个甲基所取代;或(g)杂环基;和R1b是氢或C1-6烷基。
在另一个实施方案中,在式I中,
R1、R2、R3、R4和R5每一个独立地是氢、氯或甲基;
R6是氰基或硝基;
X是O或S;
m是0、1或2;
n是1或2;
p是0;和
RYa是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(S)NR1bR1c、-C(S)NR1aC(O)NR1bR1c、-C(NNO2)NR1bR1c、-S(O)2R1a或-S(O)2NR1bR1c;其中R1a和R1c每一个独立地是(a)氢;(b)甲基、乙基、丙基(例如,正丙基或异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基),每一个任选地被取代基所取代,所述取代基选自氯、氰基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、丙酰基和乙氧基羰基;(c)乙烯基或烯丙基,每一个任选地被苯基所取代;(d)环丁基、环戊基或环己基;(e)苯基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基和乙酰基;(f)呋喃基、噻吩基、异噁唑基、吡唑基、1,2,3-噻二唑基、吡啶基、吡嗪基、苯并呋喃基、苯并[c][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基,每一个任选地被1或2个甲基所取代;或(g)吗啉基;和R1b是氢、甲基或乙基。
在另一个实施方案中,在式I中,
R1、R2、R3、R4和R5每一个独立地是氢、氯或甲基;
R6是氰基或硝基;
X是O或S;
m是0、1或2;
n是1或2;
p是0;和
RYa是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(S)NR1bR1c、-C(S)NR1aC(O)NR1bR1c、-C(NNO2)NR1bR1c、-S(O)2R1a或-S(O)2NR1bR1c;其中每个R1a和R1c独立地是氢、甲基、乙基、丙基(例如,正丙基或异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)、氯乙基、氯丙基、氯丁基、乙氧基羰基乙基、甲硫基丙基、氰基甲基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基甲基、苄基、氯苄基、呋喃基甲基、吗啉基乙基、丙酰基乙基、乙烯基、烯丙基、苯基乙烯基、环丁基、环戊基、环己基、苯基、氯苯基(例如,2-氯苯基、3-氯苯基或4-氯苯基)、氟苯基(例如,2-氟苯基、3-氟苯基或4-氟苯基)、氰基苯基(例如,2-氰基苯基、3-氰基苯基或4-氰基苯基)、硝基苯基(例如,2-硝基苯基、3-硝基苯基或4-硝基苯基)、甲基苯基(例如,2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如,2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)、乙基苯基(例如,2-乙基苯基、3-乙基苯基或4-乙基苯基)、甲氧基苯基(例如,2-甲氧基苯基、3-甲氧基苯基或4-甲氧基苯基)、乙酰基苯基(例如,2-乙酰基苯基、3-乙酰基苯基或4-乙酰基苯基)、二氯苯基(例如,2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基、2,6-二氯苯基、3,4-二氯苯基或3,5-二氯苯基)、呋喃基(例如,呋喃-2-基或呋喃-3-基)、噻吩基(例如,噻吩-2-基或噻吩-3-基)、甲基-噻吩基、异噁唑基、二甲基吡唑基、甲基-1,2,3-噻二唑基、吡啶基(例如,吡啶-2-基、吡啶-3-基或吡啶-4-基)、吡嗪基(例如,2-吡嗪基或3-吡嗪基)、苯并呋喃基、苯并[c][1,2,5]噁二唑基、苯并噻吩基、苯并噻唑基或吗啉基;和每个R1b独立地是氢、甲基或乙基。
在另一个实施方案中,在式I中,
R1是氢;
R2是氯或甲基;
R3是氢;
R4是氯或甲基;
R5是氢;
R6是氰基;
X是O或S;
m是1;
n是1;
p是0;和
RYa是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(S)NR1bR1c、-C(S)NR1aC(O)NR1bR1c、-C(NNO2)NR1bR1c、-S(O)2R1a或-S(O)2NR1bR1c;其中每个R1a和R1c独立地是氢、甲基、乙基、异丙基、异丁基、叔丁基、1,1-二甲基丙基、2,2-二甲基丙基、2-氯乙基、3-氯丙基、4-氯丁基、2-乙氧基羰基乙基、3-甲硫基丙基、1-氰基甲基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基甲基、苄基、3-氯苄基、呋喃-2-基甲基、2-吗啉-4-基乙基、2-丙酰基乙基、乙烯基、烯丙基、2-苯基乙烯基、环丁基、环戊基、环己基、苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、4-氰基苯基、4-硝基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、4-三氟甲基苯基、4-乙基苯基、4-甲氧基苯基、3-乙酰基苯基、3,4-二氯苯基、呋喃-2-基、噻吩-2-基、3-甲基-噻吩-2-基、异噁唑-5-基、2,5-二甲基吡唑-3-基、4-甲基-1,2,3-噻二唑-5-基、吡啶-2-基、2-吡嗪基、苯并呋喃-2-基、苯并[c][1,2,5]噁二唑-5-基、苯并噻吩-2-基、苯并噻唑-2-基或吗啉-4-基;和每个R1b独立地是氢、甲基或乙基。
在一个实施方案中,在式I中,
R1、R2、R3、R4和R5每一个独立地是氢、卤素或C1-6烷基;
R6是氰基或硝基;
R7是C1-6烷基;
X是O或S;
m是0、1或2;
n是1或2;
p是0、1、2、3或4;和
RYa是-C(O)R1a、-C(O)NR1bR1c或-S(O)2R1a;其中R1a和R1c每一个独立地是C1-6烷基;C3-7环烷基,任选地被1或2个C6-14芳基所取代;或C6-14芳基,任选地被一个或多个卤素或C1-6烷基所取代,其中烷基进一步任选地被1、2或3个卤素所取代;和R1b是氢。
在另一个实施方案中,在式I中,
R1、R2、R3、R4和R5每一个独立地是氢、卤素或C1-6烷基;
R6是氰基或硝基;
R7是C1-6烷基;
X是O或S;
m是0、1或2;
n是1或2;
p是0、1、2、3或4;和
RYa是-C(O)R1a、-C(O)NR1bR1c或-S(O)2R1a;其中R1a和R1c每一个独立地是C1-6烷基;C3-7环烷基,任选地被2个甲基所取代;或C6-14芳基,任选地被氟、氯、甲基、三氟甲基或乙基所取代;和R1b是氢。
在另一个实施方案中,在式I中,
R1、R2、R3、R4和R5每一个独立地是氢、氯或甲基;
R6是氰基或硝基;
X是O或S;
m是0、1或2;
n是1或2;
p是0;和
RYa是-C(O)R1a、-C(O)NR1bR1c或-S(O)2R1a;其中R1a和R1c每一个独立地是甲基、乙基、丙基(例如,正丙基或异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)、戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)、环丁基、环戊基、环己基、二甲基双环[2.2.1]庚基(例如,7,7-二甲基双环[2.2.1]-庚基)、苯基,氟苯基(例如,2-氟苯基、3-氟苯基或4-氟苯基)、氯苯基(例如,2-氯苯基、3-氯苯基或4-氯苯基)、甲基苯基(例如,2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如,2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)或乙基苯基(例如,2-乙基苯基、3-乙基苯基或4-乙基苯基);和R1b是氢。
在另一个实施方案中,在式I中,
R1是氢;
R2是氯或甲基;
R2是氢;
R4是氯或甲基;
R5是氢;
R6是氰基;
X是O或S;
m是1;
n是1;
P是0;和
RYa是-C(O)R1a、-C(O)NR1bR1c或-S(O)2R1a;其中R1a和R1c每一个独立地是甲基、乙基、异丙基、异丁基、叔丁基、1,1-二甲基丙基、2,2-二甲基丙基、环丁基、环戊基、环己基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、2-氯苯基、4-氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、4-三氟甲基苯基或4-乙基苯基;和R1b是氢。
式I中的基团R1、R2、R3、R4、R5、R6、R7、R1a、R1b、R1c、R1d、RYa、X、m、n和p在本文所述的实施方案进一步限定。对于这些基团,本文提供的实施方案的所有组合都在本发明的范围内。
在某些实施方案中,R1是氢、卤素、氰基、硝基或胍。在某些实施方案中,R1是氢。在某些实施方案中,R1是卤素。在某些实施方案中,R1是氟或氯。在某些实施方案中,R1是C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R1是C1-6烷基,任选地被1、2或3个卤素所取代。在某些实施方案中,R1是甲基、乙基、丙基{例如,正丙基和异丙基)、丁基{例如,正丁基、2-丁基、异丁基或叔丁基)或戊基{例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些实施方案中,R1是甲基。在某些实施方案中,R1是C1-6烷氧基,任选地按本文所述被取代。在某些实施方案中,R1是C1-6烷氧基,任选地被1、2或3个卤素所取代。在某些实施方案中,R1是C2-6烷硫基,任选地按本文所述被取代。在某些实施方案中,R1是C1-6烷硫基,任选地被1、2或3个卤素所取代。在某些实施方案中,R1是C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基,每一个任选地按本文所述被取代。在某些实施方案中,R1是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;其中R1a、R1b、R1c和R1d每一个是按本文定义的。
在某些实施方案中,R2是氢、卤素、氰基、硝基或胍。在某些实施方案中,R2是氢。在某些实施方案中,R2是卤素。在某些实施方案中,R2是氟或氯。在某些实施方案中,R2是C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R2是C1-6烷基,任选地被1、2或3个卤素所取代。在某些实施方案中,R2是甲基、乙基、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些实施方案中,R2是甲基。在某些实施方案中,R是C1-6烷氧基,任选地按本文所述被取代。在某些实施方案中,R2是C1-6烷氧基,任选地被1、2或3个卤素所取代。在某些实施方案中,R2是C2-6烷硫基,任选地按本文所述被取代。在某些实施方案中,R2是C1-6烷硫基,任选地被1、2或3个卤素所取代。在某些实施方案中,R2是C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基,每一个任选地按本文所述被取代。在某些实施方案中,R2是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;其中R1a、R1b、R1c和R1d每一个是按本文定义的。
在某些实施方案中,R3是氢、卤素、氰基、硝基或胍。在某些实施方案中,R3是氢。在某些实施方案中,R3是卤素。在某些实施方案中,R3是氟或氯。在某些实施方案中,R3是C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R3是C1-6烷基,任选地被1、2或3个卤素所取代。在某些实施方案中,R3是甲基、乙基、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些实施方案中,R3是甲基。在某些实施方案中,R3是C1-6烷氧基,任选地按本文所述被取代。在某些实施方案中,R3是C1-6烷氧基,任选地被1、2或3个卤素所取代。在某些实施方案中,R3是C2-6烷硫基,任选地按本文所述被取代。在某些实施方案中,R3是C1-6烷硫基,任选地被1、2或3个卤素所取代。在某些实施方案中,R3是C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基,每一个任选地按本文所述被取代。在某些实施方案中,R3是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;其中R1a、R1b、R1c和R1d每一个是按本文定义的。
在某些实施方案中,R4是氢、卤素、氰基、硝基或胍。在某些实施方案中,R4是氢。在某些实施方案中,R4是卤素。在某些实施方案中,R4是氟或氯。在某些实施方案中,R4是C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R4是C1-6烷基,任选地被1、2或3个卤素所取代。在某些实施方案中,R4是甲基、乙基、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些实施方案中,R4是甲基。在某些实施方案中,R4是C1-6烷氧基,任选地按本文所述被取代。在某些实施方案中,R4是C1-6烷氧基,任选地被1、2或3个卤素所取代。在某些实施方案中,R4是C2-6烷硫基,任选地按本文所述被取代。在某些实施方案中,R4是C1-6烷硫基,任选地被1、2或3个卤素所取代。在某些实施方案中,R4是C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基,每一个任选地按本文所述被取代。在某些实施方案中,R4是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;其中R1a、R1b、R1c和R1d每一个是按本文定义的。
在某些实施方案中,R5是氢、卤素、氰基、硝基或胍。在某些实施方案中,R5是氢。在某些实施方案中,R5是卤素。在某些实施方案中,R5是氟或氯。在某些实施方案中,R5是C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R5是C1-6烷基,任选地被1、2或3个卤素所取代。在某些实施方案中,R5是甲基、乙基、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些实施方案中,R5是甲基。在某些实施方案中,R5是C1-6烷氧基,任选地按本文所述被取代。在某些实施方案中,R5是C1-6烷氧基,任选地被1、2或3个卤素所取代。在某些实施方案中,R5是C2-6烷硫基,任选地按本文所述被取代。在某些实施方案中,R5是C1-6烷硫基,任选地被1、2或3个卤素所取代。在某些实施方案中,R5是C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基,每一个任选地按本文所述被取代。在某些实施方案中,R5是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;其中R1a、R1b、R1c和R1d每一个是按本文定义的。
在某些实施方案中,R1、R2、R3、R4和R5中的两个是卤素或C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R1、R2、R3、R4和R5中的两个是卤素或C1-6烷基,任选地按本文所述被取代,其余三个是氢。在某些实施方案中,R1、R2、R3、R4和R5中的两个是氯或甲基。在某些实施方案中,R1、R2、R3、R4和R5中的两个是氯或甲基,其余三个是氢。在某些实施方案中,R1、R3和R5是氢,R2和R4是卤素或C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R1、R3和R5是氢,R2和R4是氯或甲基。在某些实施方案中,R1、R3和R5是氢,R2和R4是氯。在某些实施方案中,R1、R3和R5是氢,R2和R4是是甲基。在某些实施方案中,R1、R3和R5是氢,R2和R4是卤素或C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R2、R3和R5是氢,R1和R4是氯或甲基。在某些实施方案中,R2、R3和R5是氢,R1和R4是氯。在某些实施方案中,R2、R3和R5是氢,R1和R4是甲基。
在某些实施方案中,R6是氢、卤素、氰基、硝基或胍。在某些实施方案中,R6是氢。在某些实施方案中,R6是卤素。在某些实施方案中,R6是氟或氯。在某些实施方案中,R6是氰基。在某些实施方案中,R6是硝基。在某些实施方案中,R6是C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R6是C1-6烷基,任选地被1、2或3个卤素所取代。在某些实施方案中,R6是甲基、乙基、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些实施方案中,R6是甲基。在某些实施方案中,R6是C1-6烷氧基,任选地按本文所述被取代。在某些实施方案中,R6是C1-6烷氧基,任选地被1、2或3个卤素所取代。在某些实施方案中,R6是C2-6烷硫基,任选地按本文所述被取代。在某些实施方案中,R6是C1-6烷硫基,任选地被1、2或3个卤素所取代。在某些实施方案中,R6是C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基,每一个任选地按本文所述被取代。在某些实施方案中,R6是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;其中R1a、R1b、R1c和R1d每一个是按本文定义的。
在某些实施方案中,R7是卤素、氰基、硝基、氧代或胍。在某些实施方案中,R7是卤素。在某些实施方案中,R7是氟或氯。在某些实施方案中,R7是氰基。在某些实施方案中,R7是硝基。在某些实施方案中,R7是氧代。在某些实施方案中,R7是C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R7是C1-6烷基,任选地被1、2或3个卤素所取代。在某些实施方案中,R7是甲基、乙基、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些实施方案中,R7是甲基。在某些实施方案中,R7是C1-6烷氧基,任选地按本文所述被取代。在某些实施方案中,R7是C1-6烷氧基,任选地被1、2或3个卤素所取代。在某些实施方案中,R7是C2-6烷硫基,任选地按本文所述被取代。在某些实施方案中,R7是C1-6烷硫基,任选地被1、2或3个卤素所取代。在某些实施方案中,R7是C2-6烯基、C2-6炔基、C3-7环烷基、C6-14芳基、C7-15芳烷基、杂芳基或杂环基,每一个任选地按本文所述被取代。在某些实施方案中,R7是-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1′、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c或-S(O)2NR1bR1c;其中R1a、R1b、R1c和R1d每一个是按本文定义的。
在某些实施方案中,X是O。在某些实施方案中,X是S。
在某些实施方案中,RYa是-C(O)R1a,其中R1a是按本文定义的。在某些实施方案中,RYa不是-C(O)H。在某些实施方案中,RYa是-C(O)OR1a,其中R1a是按本文定义的。在某些实施方案中,RYa是-C(O)OR1a,其中R1a是按本文定义的,条件是R1a不是叔丁基、9-芴基甲基或苄基。在某些实施方案中,RYa是-C(O)O-乙基。在某些实施方案中,RYa是-C(O)NR1bR1c,其中R1b和R1c每一个是按本文定义的。在某些实施方案中,RYa是-C(S)NR1bR1c,其中R1b和R1c每一个是按本文定义的。在某些实施方案中,RYa是-C(S)NR1aC(O)NR1bR1c,其中R1a,R1b,和R1c每一个是按本文定义的。在某些实施方案中,RYa是-C(NR1a)NR1bR1c,其中R1a、R1b和R1c每一个是按本文定义的。在某些实施方案中,RYa是-C(NNO2)NR1bR1c,其中R1b和R1c每一个是按本文定义的。在某些实施方案中,RYa是-S(O)R1a,其中R1a是按本文定义的。在某些实施方案中,RYa是-S(O)2R1a,其中R1a是按本文定义的。在某些实施方案中,RYa是-S(O)NR1bR1c,其中R1b和R1c每一个是按本文定义的。在某些实施方案中,RYa是-S(O)2NR1bR1c,其中R1a和R1d每一个是按本文定义的。
在某些实施方案中,m是0。在某些实施方案中,m是1。在某些实施方案中,m是2。在某些实施方案中,m是3。
在某些实施方案中,n是1。在某些实施方案中,n是2。在某些实施方案中,n是3。
在某些实施方案中,m是1和n是1。在某些实施方案中,m是1和n是2。
在某些实施方案中,p是0。在某些实施方案中,p是1。在某些实施方案中,p是2。在某些实施方案中,p是3。在某些实施方案中,p是4。
在某些实施方案中,R1a是氢。在某些实施方案中,R1a是C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R1a是C1-6烷基,任选地被1、2或3个取代基所取代,每个取代基独立地选自氰基、卤素、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-C(O)Ra、-C(O)ORa和-SRa,其中环烷基、芳基、杂芳基和杂环基每一个进一步任选地被1、2或3个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1a是C1-6烷基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1a是C1-6烷基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1a是C1-6烷基,任选地被一个取代基所取代,所述取代基选自氯、氰基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、丙酰基和乙氧基羰基。在某些实施方案中,R1a是甲基、乙基、丙基(例如,正丙基或异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些实施方案中,R1a是甲基、乙基、异丙基、异丁基、叔丁基、1,1-二甲基丙基或2,2-二甲基丙基。在某些实施方案中,R1a是C1-6烷基、甲基、乙基、丙基(例如,正丙基或异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基),每一个任选地被取代基所取代,所述取代基选自氯、氰基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、丙酰基和乙氧基羰基。在某些实施方案中,R1a是甲基、乙基、丙基(例如,正丙基或异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)、戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)、氯乙基、氯丙基、氯丁基、乙氧基羰基乙基、甲硫基丙基、氰基甲基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基甲基、苄基、氯苄基、呋喃基甲基、吗啉基乙基或丙酰基乙基。在某些实施方案中,R1a是甲基、乙基、异丙基、异丁基、叔丁基、1,1-二甲基丙基、2,2-二甲基丙基、2-氯乙基、3-氯丙基、4-氯丁基、2-乙氧基羰基乙基、3-甲硫基丙基、1-氰基甲基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基甲基、苄基、3-氯苄基、呋喃-2-基甲基、2-吗啉-4-基乙基或2-丙酰基乙基。
在某些实施方案中,R1a是C2-6烯基,任选地按本文所述被取代。在某些实施方案中,R1a是C1-6烯基,任选地被C6-14芳基所取代。在某些实施方案中,R1a是C2-6烯基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1a是C2-6烯基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1a是C2-6烯基,任选地被C6-14芳基所取代。在某些实施方案中,R1a是C2-6烯基,任选地被苯基所取代。在某些实施方案中,R1a是乙烯基或烯丙基,每一个任选地被苯基所取代。在某些实施方案中,R1a是乙烯基、烯丙基,或苯基乙烯基。在某些实施方案中,R1a是乙烯基、烯丙基或2-苯基乙烯基。
在某些实施方案中,R1a是C2-6炔基,任选地按本文所述被取代。在某些实施方案中,R1a是C3-7环烷基,任选地按本文所述被取代。在某些实施方案中,R1a是C3-7环烷基,任选地被1或2个C6-14芳基所取代。在某些实施方案中,R1a是C3-7环烷基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1a是C3-7环烷基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)--7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1a是C3-7环烷基,任选地被1或2个C6-14芳基所取代。在某些实施方案中,R1a是C3-7环烷基,任选地被2个甲基所取代。在某些实施方案中,R1a是环丁基、环戊基、环己基或二甲基双环[2.2.1]庚基{例如,7,7-二甲基双环[2.2.1]-庚基)。在某些实施方案中,R1a是环丁基、环戊基或环己基。在某些实施方案中,R1a是环丁基、环戊基、环己基或(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基。
在某些实施方案中,R1a是C6-14芳基,任选地按本文所述被取代。在某些实施方案中,R1a是C6-14芳基,任选地被1、2或3个取代基所取代,每个取代基独立地选自卤素、硝基、氰基、-ORa、-C(O)Ra和C1-6烷基,其中烷基进一步任选地被1、2或3个卤素所取代。在某些实施方案中,R1a是C6-14芳基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1a是C6-14芳基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1a是C6-14芳基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基和乙酰基。在某些实施方案中,R1a是苯基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基和乙酰基。在某些实施方案中,R1a是C6-14芳基,任选地被一个或多个卤素或C1-6烷基所取代,其中烷基任选地被1、2或3个卤素所取代。在某些实施方案中,R1a是C6-14芳基,任选地被氟、氯、甲基、三氟甲基或乙基所取代。在某些实施方案中,R1a是苯基,氟苯基{例如,2-氟苯基、3-氟苯基或4-氟苯基)、氯苯基(例如,2-氯苯基、3-氯苯基或4-氯苯基)、甲基苯基(例如,2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如,2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)或乙基苯基(例如,2-乙基苯基、3-乙基苯基或4-乙基苯基)。在某些实施方案中,R1a是苯基、3-氟苯基、3-甲基苯基、4-氯苯基、4-甲基苯基、4-三氟甲基苯基或4-乙基苯基。在某些实施方案中,R1a是苯基、氯苯基(例如,2-氯苯基、3-氯苯基或4-氯苯基)、氟苯基(例如,2-氟苯基、3-氟苯基或4-氟苯基)、氰基苯基(例如,2-氰基苯基、3-氰基苯基或4-氰基苯基)、硝基苯基(例如,2-硝基苯基、3-硝基苯基或4-硝基苯基)、甲基苯基(例如,2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如,2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)、乙基苯基(例如,2-乙基苯基、3-乙基苯基或4-乙基苯基)、甲氧基苯基(例如,2-甲氧基苯基、3-甲氧基苯基或4-甲氧基苯基)、乙酰基苯基(例如,2-乙酰基苯基、3-乙酰基苯基或4-乙酰基苯基)、二氯苯基(例如,2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基、2,6-二氯苯基、3,4-二氯苯基或3,5-二氯苯基)。在某些实施方案中,R1a是苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、4-氰基苯基、4-硝基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、4-三氟甲基苯基、4-乙基苯基、4-甲氧基苯基、3-乙酰基苯基或3,4-二氯苯基。
在某些实施方案中,R1a是杂芳基,任选地按本文所述被取代。在某些实施方案中,R1a是杂芳基,任选地被1、2或3个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1a是杂芳基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1a是杂芳基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1a是杂芳基,任选地被1或2个甲基所取代。在某些实施方案中,R1a是呋喃基、噻吩基、异噁唑基、吡唑基、1,2,3-噻二唑基、吡啶基、吡嗪基、苯并呋喃基、苯并[c][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基,每一个任选地被1或2个甲基所取代。在某些实施方案中,R1a是呋喃基(例如,呋喃-2-基或呋喃-3-基)、噻吩基(例如,噻吩-2-基或噻吩-3-基)、甲基-噻吩基、异噁唑基、二甲基吡唑基、甲基-1,2,3-噻二唑基、吡啶基(例如,吡啶-2-基、吡啶-3-基或吡啶-4-基)、吡嗪基(例如,2-吡嗪基或3-吡嗪基)、苯并呋喃基、苯并[c][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基。在某些实施方案中,R1a是呋喃-2-基、噻吩-2-基、3-甲基-噻吩-2-基、异噁唑-5-基、2,5-二甲基吡唑-3-基、4-甲基-1,2,3-噻二唑-5-基、吡啶-2-基、2-吡嗪基、苯并呋喃-2-基、苯并[c][1,2,5]噁二唑-5-基、苯并噻吩-2-基或苯并噻唑-2-基。
在某些实施方案中,R1a是杂环基。在某些实施方案中,R1a是杂环基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1a是杂环基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1a是吗啉基。在某些实施方案中,R1a是吗啉-4-基。
在某些实施方案中,R1b是氢。在某些实施方案中,R1b是C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R1b是甲基或乙基。在某些实施方案中,R1b是C2-6烯基,任选地按本文所述被取代。在某些实施方案中,R1b是C2-6炔基,任选地按本文所述被取代。在某些实施方案中,R1b是C3-7环烷基,任选地按本文所述被取代。在某些实施方案中,R1b是C6-14芳基,任选地按本文所述被取代。在某些实施方案中,R1b是杂芳基,任选地按本文所述被取代。在某些实施方案中,R1b是杂环基,按本文所述的任选被取代。
在某些实施方案中,R1c是氢。在某些实施方案中,R1c是C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R1c是C1-6烷基,任选地被1、2或3个取代基所取代,每个取代基独立地选自氰基、卤素、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-C(O)Ra、-C(O)ORa和-SRa,其中环烷基、芳基、杂芳基和杂环基每一个进一步任选地被1、2或3个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1c是C1-6烷基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1c是C1-6烷基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1c是C1-6烷基,任选地被一个取代基所取代,所述取代基选自氯、氰基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、丙酰基和乙氧基羰基。在某些实施方案中,R1c是甲基、乙基、丙基(例如,正丙基或异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些实施方案中,R1c是甲基、乙基、异丙基、异丁基、叔丁基、1,1-二甲基丙基或2,2-二甲基丙基。在某些实施方案中,R1c是C1-6烷基、甲基、乙基、丙基(例如,正丙基或异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)或戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基),每一个任选地被取代基所取代,所述取代基选自氯、氰基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、丙酰基和乙氧基羰基。在某些实施方案中,R1c是甲基、乙基、丙基(例如,正丙基或异丙基)、丁基(例如,正丁基、2-丁基、异丁基或叔丁基)、戊基(例如,正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)、氯乙基、氯丙基、氯丁基、乙氧基羰基乙基、甲硫基丙基、氰基甲基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基甲基、苄基、氯苄基、呋喃基甲基、吗啉基乙基或丙酰基乙基。在某些实施方案中,R1c是甲基、乙基、异丙基、异丁基、叔丁基、1,1-二甲基丙基、2,2-二甲基丙基、2-氯乙基、3-氯丙基、4-氯丁基、2-乙氧基羰基乙基、3-甲硫基丙基、1-氰基甲基、(1S,2S,4R)-二甲基双环[2.2.1]-庚基甲基、苄基、3-氯苄基、呋喃-2-基甲基、2-吗啉-4-基乙基或2-丙酰基乙基。
在某些实施方案中,R1c是C2-6烯基,任选地按本文所述被取代。在某些实施方案中,R1c是C1-6烯基,任选地被C6-14芳基所取代。在某些实施方案中,R1c是C2-6烯基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1c是C2-6烯基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1c是C2-6烯基,任选地被C6-14芳基所取代-在某些实施方案中,R1c是C2-6烯基,任选地被苯基所取代。在某些实施方案中,R1c是乙烯基或烯丙基,每一个任选地被苯基所取代。在某些实施方案中,R1c是乙烯基、烯丙基,或苯基乙烯基。在某些实施方案中,R1c是乙烯基、烯丙基或2-苯基乙烯基。
在某些实施方案中,R1c是C2-6炔基,任选地按本文所述被取代。在某些实施方案中,R1c是C3-7环烷基,任选地按本文所述被取代。在某些实施方案中,R1c是C3-7环烷基,任选地被1或2个C6-14芳基所取代。在某些实施方案中,R1c是C3-7环烷基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1c是C3-7环烷基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1c是C3-7环烷基,任选地被1或2个C6-14芳基所取代。在某些实施方案中,R1c是C3-7环烷基,任选地被2个甲基所取代。在某些实施方案中,R1c是环丁基、环戊基、环己基或二甲基双环[2.2.1]庚基(例如,7,7-二甲基双环[2.2.1]-庚基)。在某些实施方案中,R1c是环丁基、环戊基或环己基。在某些实施方案中,R1c是环丁基、环戊基、环己基或(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基。
在某些实施方案中,R1c是C6-14芳基,任选地按本文所述被取代。在某些实施方案中,R1c是C6-14芳基,任选地被1、2或3个取代基所取代,每个取代基独立地选自卤素、硝基、氰基、-ORa、-C(O)Ra和C1-6烷基,其中烷基进一步任选地被1、2或3个卤素所取代。在某些实施方案中,R1c是C6-14芳基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1c是C6-14芳基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1c是C6-14芳基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基和乙酰基。在某些实施方案中,R1c是苯基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基和乙酰基。在某些实施方案中,R1c是C6-14芳基,任选地被一个或多个卤素或C1-6烷基所取代,其中烷基任选地被1、2或3个卤素所取代。在某些实施方案中,R1c是C6-14芳基,任选地被氟、氯、甲基、三氟甲基或乙基所取代。在某些实施方案中,R1c是苯基,氟苯基(例如,2-氟苯基、3-氟苯基或4-氟苯基)、氯苯基(例如,2-氯苯基、3-氯苯基或4-氯苯基)、甲基苯基(例如,2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如,2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)或乙基苯基(例如,2-乙基苯基、3-乙基苯基或4-乙基苯基)。在某些实施方案中,R1c是苯基、3-氟苯基、3-甲基苯基、4-氯苯基、4-甲基苯基、4-三氟甲基苯基或4-乙基苯基。在某些实施方案中,R1c是苯基、氯苯基(例如,2-氯苯基、3-氯苯基或4-氯苯基)、氟苯基(例如,2-氟苯基、3-氟苯基或4-氟苯基)、氰基苯基(例如,2-氰基苯基、3-氰基苯基或4-氰基苯基)、硝基苯基(例如,2-硝基苯基、3-硝基苯基或4-硝基苯基)、甲基苯基(例如,2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如,2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)、乙基苯基(例如,2-乙基苯基、3-乙基苯基或4-乙基苯基)、甲氧基苯基(例如,2-甲氧基苯基、3-甲氧基苯基或4-甲氧基苯基)、乙酰基苯基(例如,2-乙酰基苯基、3-乙酰基苯基或4-乙酰基苯基)、二氯苯基(例如,2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基、2,6-二氯苯基、3,4-二氯苯基或3,5-二氯苯基)。在某些实施方案中,R1c是苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、4-氰基苯基、4-硝基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、4-三氟甲基苯基、4-乙基苯基、4-甲氧基苯基、3-乙酰基苯基或3,4-二氯苯基。
在某些实施方案中,R1c是杂芳基,任选地按本文所述被取代。在某些实施方案中,R1c是杂芳基,任选地被1、2或3个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1c是杂芳基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1c是杂芳基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1c是杂芳基,任选地被1或2个甲基所取代。在某些实施方案中,R1c是呋喃基、噻吩基、异噁唑基、吡唑基、1,2,3-噻二唑基、吡啶基、吡嗪基、苯并呋喃基、苯并[c][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基,每一个任选地被1或2个甲基所取代。在某些实施方案中,R1c是呋喃基(例如,呋喃-2-基或呋喃-3-基)、噻吩基(例如,噻吩-2-基或噻吩-3-基)、甲基-噻吩基、异噁唑基、二甲基吡唑基、甲基-1,2,3-噻二唑基、吡啶基(例如,吡啶-2-基、吡啶-3-基或吡啶-4-基)、吡嗪基(例如,2-吡嗪基或3-吡嗪基)、苯并呋喃基、苯并[c][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基。在某些实施方案中,R1c是呋喃-2-基、噻吩-2-基、3-甲基-噻吩-2-基、异噁唑-5-基、2,5-二甲基吡唑-3-基、4-甲基-1,2,3-噻二唑-5-基、吡啶-2-基、2-吡嗪基、苯并呋喃-2-基、苯并[c][1,2,5]噁二唑-5-基、苯并噻吩-2-基或苯并噻唑-2-基。
在某些实施方案中,R1c是杂环基。在某些实施方案中,R1c是杂环基,任选地被1或2个取代基所取代,每个取代基独立地选自卤素、氰基、硝基、C1-6烷基、C3-7环烷基、C6-14芳基、杂芳基、杂环基、-ORa、-SRa和-C(O)Ra,其中Ra是按本文定义的并且烷基、环烷基、芳基、杂芳基和杂环基每一个任选地进一步被1或2个取代基所取代,每个取代基独立地是卤素或C1-6烷基。在某些实施方案中,R1c是杂环基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S,2S,4R)-7,7-二甲基双环[2.2.1]-庚基、苯基、氯苯基、呋喃基、吗啉基、乙酰基、丙酰基和乙氧基羰基。在某些实施方案中,R1c是吗啉基。在某些实施方案中,R1c是吗啉-4-基。
在某些实施方案中,R1b和R1c与它们连接的氮原子一起独立地形成杂芳基,任选地按本文所述被取代。在某些实施方案中,R1b和R1c与它们连接的氮原子一起独立地形成杂环基,按本文所述的任选被取代。
在某些实施方案中,R1d是氢。在某些实施方案中,R1d是C1-6烷基,任选地按本文所述被取代。在某些实施方案中,R1d是C2-6烯基,任选地按本文所述被取代。在某些实施方案中,R1d是C2-6炔基,任选地按本文所述被取代。在某些实施方案中,R1d是C3-7环烷基,任选地按本文所述被取代。在某些实施方案中,R1d是C6-14芳基,任选地按本文所述被取代。在某些实施方案中,R1d是杂芳基,任选地按本文所述被取代。在某些实施方案中,R1d是杂环基,按本文所述的任选被取代。
在一个实施方案中,本文提供的是选自以下的化合物:
和其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体和两种或两种以上的互变异构体的混合物;和其药学上可接受的盐、溶剂化物、水合物和前药。
除非指定特殊的立体化学,本文提供的化合物意图包括所有可能的立体异构体。如果本文提供的化合物含有烯基或亚烯基,则该化合物可以作为一种几何顺式/反式(或Z/E)异构体或它们的混合物存在。如果结构异构体可以相互转换,则该化合物可以作为单一互变异构体或互变异构体的混合物存在。这可以在含有例如亚氨基、酮基或肟基的化合物中采用质子互变异构形式;或在含有芳香族部分的化合物中采用所谓的价态互变异构形式。因此,单一化合物可以出现出一种以上的异构形式。
本文提供的化合物可以是对映异构体纯的,如单一对映异构体或单一非对映异构体,或可以是立体异构的混合物,如对映异构体的混合物、两种对映异构体的外消旋混合物或两种非对映异构体的混合物。因此,本领域技术人员会认识到,对于体内发生差向立体异构化作用的化合物,给予(R)形式的化合物相当于给予(S)形式的化合物。制备/分离各对映异构体的常规技术包括从合适的光学纯前体合成、从非手性原料不对称合成或对映异构体混合物的拆分,例如,手性色谱法、重结晶、拆分、非对映异构体盐形成或分离之后衍生成非对映异构体加合物。
当本文提供的化合物含有含有酸性或碱性部分时,也可能作为药学上可接受的盐提供(参见,Berge等人,J.Pharm.Sci.1977,66,1-19;和“Handbook of Pharmaceutical Salts,Properties,and Use”,Stahl和Wermuth,Ed.;Wiley-VCH和VHCA,Zurich,2002)。
制备药学上可接受的盐中使用的适合酸包括但不限于乙酸、2,2-二氯乙酸、酰基化的氨基酸、己二酸、褐藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、硼酸、(+)-樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、环己基氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基-乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、D-葡萄糖醛酸、L-谷氨酸、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、(+)-1-乳酸、(±)-DL-乳酸、乳糖酸、月桂酸、马来酸、(-)-1-苹果酸、丙二酸、(±)-DL-扁桃酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、扑酸、高氯酸、磷酸、L-焦谷氨酸、葡萄糖二酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、单宁酸、(+)-1-酒石酸、硫氰酸、对甲苯磺酸、十一烯酸和戊酸。
在一个实施方案中,本文提供的化合物是盐酸盐。
制备药学上可接受的盐中使用的适合碱包括但不限于无机碱,如氢氧化镁、氢氧化钙、氢氧化钾、氢氧化锌或氢氧化钠;和有机碱,如伯、仲、叔和季、脂肪族和芳香族胺,包括L-精氨酸、苯乙苄胺、苄星、胆碱、二甲基乙醇胺、乙醇胺、二乙胺、二甲胺、二丙胺、二异丙胺、2-(二乙基氨基)-乙醇、乙醇胺、乙胺、乙二胺、异丙胺、N-甲基-葡萄糖胺、哈胺、1H-咪唑、L-赖氨酸、吗啉、4-(2-羟乙基)吗啉、甲胺、哌啶、哌嗪、丙胺、吡咯烷、1-(2-羟乙基)吡咯烷、吡啶、奎宁环、喹啉、异喹啉、仲胺、三乙醇胺、三甲胺、三乙胺、N-甲基-D-葡萄糖胺、2-氨基-2-(羟甲基)-1,3-丙二醇和氨基丁三醇。
本文提供的化合物也可作为前药提供,其是例如式I的化合物的功能衍生物,并且很容易体内转化成母体化合物。前药往往是有用的,因为在某些情况下它们可能会比母体化合物更易于给予。它们可以例如被口服生物利用,而母体化合物不能口服。前药药物组合物也可以比母体化合物具有更高的溶解度。前药可以通过各种机制转化为母体药物,包括酶解过程和新陈代谢水解。参见Harper,Progress in Drug Research 1962,4,221-294;Morozowich等人,“Design of Biopharmaceutical Properties through Prodrugsand Analogs”,Roche Ed.,APHA Acad.Pharm.Sci.1977;“BioreversibleCarriers in Drug in Drug Design,Theory and Application”,Roche Ed.,APHAAcad.Pharm.Sci.1987;“Design of Prodrugs”,Bundgaard,Elsevier,1985;Wang等人,Curr.Pharm.Design 1999,5,265-287;Pauletti等人,Adv.Drug.Delivery Rev.1997,27,235-256;Mizen等人,Pharm.Biotech.1998,11,345-365;Gaignault等人,Pract.Med.Chem.1996,671-696;Asgharnejad,“Transport Processes in Pharmaceutical Systems”,Amidon等人,Ed.,MarcellDekker,185-218,2000;Balant等人,Eur.J.Drug Metab.Pharmacokinet.1990,15,143-53;Balimane和Smko,Adv.Drug Delivery Rev.1999,39,183-209;Browne,Clin.Neuropharmacol.1997,20,1-12;Bundgaard,Arch.Pharm.Chem.1979,86,1-39;Bundgaard,Controlled Drug Delivery 1987,17,179-96;Bundgaard,Adv.Drug Delivery Rev.1992,8,1-38;Fleisher等人,Adv.DrugDelivery Rev.1996,19,115-130;Fleisher等人,Methods Enzymol.1985,112,360-381;Farquhar等人,J.Pharm.Sci.1983,72,324-325;Freeman等人,JChem.Soc,Chem.Commun.1991,875-877;Friis和Bundgaard,Eur.J.Pharm.Sci.1996,4,49-59;Gangwar等人,Des.Biopharm.Prop.Prodrugs Analogs,1977,409-421;Nathwani和Wood,Drugs 1993,45,866-94;Sinhababu和Thakker,Adv.Drug Delivery Rev.1996,19,241-273;Stella等人,Drugs 1985,29,455-73;Tan等人,Adv.Drug Delivery Rev.1999,39,117-151;Taylor,Adv.Drug Delivery Rev.1996,19,131-148;Valentino和Borchardt,Drug DiscoveryToday 1997,2,148-155;Wiebe和Knaus,Adv.Drug Delivery Rev.1999,39,63-80;和Waller等人,Br.J.Clin.Pharmac.1989,28,497-507。
合成方法
本文提供的化合物可以通过本领域技术人员已知的任何方法制备、分离或获得。例如,式I的化合物可以按方案1所示制备,其中P1是氢或氨基保护基,例如,Boc、Cbz或Fmoc;和X1是离去基团,例如,氯、溴、碘、咪唑或甲酸酯。
化合物1通过芳香族取代反应与化合物2反应,形成化合物3,同时释放盐酸。使用还原剂,例如,亚硫酸氢钠或氯化锡(II),将化合物3的硝基还原成氨基,形成苯胺4,随后通过Sandmeyer反应转化成磺酰氯5。然后,化合物5与胺6偶联,其中氨基保护基P1在一些实施方案中是任选的。除去保护基P1生成化合物7,与RYaX1反应,形成式I的化合物。
药物组合物
本文提供的是含有本文提供的化合物作为活性成分以及药学上可接受的介质、载体、稀释剂或赋形剂或其混合物的药物组合物,例如式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。
本发明提供的化合物可以单独给予,或与本发明提供的一种或多种其他化合物组合给予。含有本发明提供的化合物例如式I的化合物的药物组合物可以配制成各种剂型,用于口服、胃肠外和局部给予。药物组合物也可以配制成为改变的释放剂型,包括延时的-、扩展的-、延长的-、持续的-、脉冲的、控制的、加速的和快速的、靶向的、程序释放和胃滞留剂型。这些剂型可以根据本领域技术人员已知的常规方法和技术制备(参见,Remington:The Science and Practice of Pharmacy,同上;Modified-ReleaseDrug Deliver Technology,第2版,Rathbone等人,Eds.,Marcel Dekker,Inc.:New York,NY,2008)。
方案1
在一个实施方案中,药物组合物以口服给予剂型提供,其含有本发明提供的化合物和一种或多种药学上可接受的赋形剂或载体,例如式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。
在另一个实施方案中,药物组合物以胃肠外给予剂型提供,其含有本发明提供的化合物和一种或多种药学上可接受的赋形剂或载体,例如式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。
在另一个实施方案中,药物组合物以局部给予剂型提供,其含有本文提供的化合物和一种或多种药学上可接受的赋形剂或载体,例如式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。
本文提供的药物组合物可以单位-剂型或多个-剂型提供。本文中所用的单位-剂型指物理上分散的单位,适于给予至人和动物对象,并按本领域已知的独立包装。每个单位-剂量含有足以产生所需治疗效果的预定量的活性成分以及所需的药物载体或赋形剂。单位-剂型的例子包括安瓿、注射剂和单独包装的片剂和胶囊。单位-剂型可以分次或多次给予。多个-剂型是在一个容器中包装的多个相同单位-剂型,以隔离的单位-剂型给予。多个-剂型的例子包括小瓶、片剂或胶囊瓶、或者品脱或加仑瓶。
本文提供的药物组合物可以一次给予,或在时间间隔多次给予。应该理解,精确剂量和治疗时间可以随正在接受治疗的患者的年龄、体重和病症变化,并且可以利用已知的试验协议或者从体内或体外试验或诊断数据外推来经验确定。应该进一步理解,对于任何特定的个人,具体给药方案应该根据个人的需要和给予或监督制剂给予的人员的专业判断随时间调整。
A.口服给予
本文提供的口服给予的药物组合物可以固体、半固体或液体的口服给予剂型提供。本文中所用的口服给予还包括口腔、舌和舌下给予。适合的口服剂型包括但不限于片剂、速溶片、咀嚼片、胶囊剂、丸剂、条剂、药片、止咳糖、锭剂、药包、小药丸、药用口香糖、颗粒剂、散装粉、泡腾或非泡腾粉末或颗粒、口服雾、溶液、乳剂、悬浮液、圆圆、喷剂、酏剂和糖浆。除了活性成分之外,药物组合物可以含有一种或多种药学上可接受的载体或赋形剂,包括但不限于粘结剂、填料、稀释剂、崩解剂、润湿剂、润滑剂、滑动剂、着色剂、染料迁移抑制剂、甜味剂、调味剂、乳化剂、悬浮和分散剂、防腐剂、溶剂、非水性液体、有机酸和二氧化碳的来源。
粘结剂或制粒剂赋予片剂凝聚力,以确保片剂在压缩后完好无损。适合的粘结剂或制粒剂包括但不限于淀粉,如玉米淀粉、马铃著淀粉和预糊化淀粉(例如,STARCH 1500);明胶;糖类,如蔗糖、葡萄糖、右旋糖、糖蜜和乳糖;天然和合成树胶,如洋槐、藻酸、藻、爱尔兰苔提取、潘瓦尔胶、盖提胶、依莎贝果外皮的粘液、羧甲基纤维素、甲基纤维素、聚乙烯吡咯烷酮(PVP胶)、Veegum、落叶松阿拉伯半乳聚糖、粉状黄氏胶和瓜尔豆胶;纤维素类,如乙基纤维素、醋酸纤维素、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC);微晶纤维素,如VICEL-PH-101、AVICEL-PH-103、AVICEL RC-581、AVICEL-PH-105(FMC Corp.,Marcus Hook,PA);和其混合物。适合的填料包括但不限于滑石粉、碳酸钙、微晶纤维素、粉状纤维素、dextrates、高岭土、甘露醇、硅酸、山梨醇、淀粉、预糊化淀粉和其混合物。本文提供的药物组合物中的粘结剂或填料量随制剂类型变化,并可以由本领域技术人员容易地确定。粘结剂或填料在本文提供的药物组合物中可以为约50~约99重量%。
适合的稀释剂包括但不限于磷酸氢钙、硫酸钙、乳糖、山梨醇、蔗糖、肌醇、纤维素、高岭土、甘露醇、氯化钠、干淀粉和粉状糖。某些稀释剂,如甘露醇、乳糖、山梨醇、蔗糖和肌醇,当有足够量时,可以赋予一些压缩片剂各种性能,允许通过咀嚼在嘴中崩解。这种压缩片剂可以用作咀嚼片。本文提供的药物组合物中的稀释剂量随制剂类型变化,并可以由本领域技术人员容易地确定。
适合的崩解剂包括但不限于琼脂;膨润土;纤维素类,如甲基纤维素和羧甲基纤维素;木制品;天然海绵;阳离子交换树脂;藻酸;树胶类,如瓜尔豆胶和Veegum HV;柑橘纸浆;交联纤维素类,如交联羧甲基纤维素;交联聚合物,如交联吡咯烷酮;交联淀粉;碳酸钙;微晶纤维素,如淀粉乙醇酸钠;波拉克林钾、淀粉;如玉米淀粉、马铃著淀粉、木著淀粉和预糊化淀粉;粘土;aligns;其混合物。崩解剂在本文提供的药物组合物中的量随制剂类型变化,并可以由本领域技术人员容易地确定。本文提供的药物组合物中的崩解剂量随制剂类型变化,并可以由本领域技术人员容易地确定。本文提供的药物组合物可以含有约0.5~约15%或约1~约5重量%的崩解剂。
适合的润滑剂包括但不限于硬脂酸钙;硬脂酸镁;矿物油;轻质矿物油;甘油;山梨醇;甘露醇;二醇类,如甘油山嵛酸酯和聚乙二醇(PEG);硬脂酸;十二烷基硫酸钠;滑石;氢化植物油;包括花生油、棉籽油、葵花籽油、芝麻油、橄榄油、玉米油和豆油;硬脂酸锌;油酸乙酯;月桂酸乙酯;琼脂;淀粉;石松;硅石或硅胶,如200(W.R.Grace Co.,Baltimore,MD)和CAB-O-(Cabot Co.of Boston,MA);和其混合物。本文提供的药物组合物可以含有约0.1~约5重量%的润滑剂。
适合的滑动剂包括但不限于胶体二氧化硅、CAB-O-(Cabot Co.ofBoston,MA)和无石棉滑石粉。适合的着色剂包括但不限于任何经批准认证的溶于水的FD&C染料和在氧化铝水合物上悬浮的不溶于水的FD&C染料和色淀和其混合物。色淀是由水溶性染料吸附到重金属水合氧化物上组合,导致不溶性的染料形式。适合的调味剂包括但不限于从诸如水果等植物中提取的天然香料,并产生愉快味觉的化合物的合成混合物,如薄荷油和水杨酸甲酯。适合的甜味剂包括但不限于蔗糖、乳糖、甘露醇、糖浆、甘油和诸如糖精和天冬氨酰苯丙氨酸甲酯等人造甜味剂。适合的乳化剂包括但不限于明胶、刺槐、黄氏胶、膨润土和表面活性剂,如聚氧乙烯失水山梨醇单油酸酯(20)、聚氧乙烯失水山梨醇单油酸酯80(80)和三乙醇胺油酸酯。适合的悬浮和分散剂包括但不限于羧甲基纤维素钠、果胶、黄氏胶、Veegum、刺槐、羧甲基纤维素钠、羟丙基甲基纤维素和聚乙烯吡咯烷酮。适合的防腐剂包括但不限于甘油、羟基苯甲酸甲酯和丙酯、苯甲酸、苯甲酸钠和醇。适合的润湿剂包括但不限于丙二醇单硬脂酸酯、失水山梨醇单油酸酯、二甘醇单月桂酸酯和月桂醇聚氧乙烯醚。适合的溶剂包括但不限于甘油、山梨醇、乙醇和糖浆。乳液中使用的适合的非水性液体包括但不限于矿物油和棉籽油。适合的有机酸包括但不限于柠檬酸和酒石酸。适合的二氧化碳的来源包括但不限于碳酸氢钠和碳酸钠。
应该理解,许多载体和赋形剂可以发挥多种功能,即使在同一制剂中。
本文提供的口服给予的药物组合物可以作为压缩片剂、片剂粉碎物、咀嚼止咳糖、迅速溶解片剂、多压缩片剂、肠包衣片剂、糖衣或膜衣片剂提供。肠包衣片是用抵抗胃酸作用但在肠道内溶解或崩解的物质涂布的压缩片剂,从而在胃部的酸性环境中保护活性成分。肠包衣包括但不限于脂肪酸、脂肪、水杨酸苯酯、蜡、虫胶、氨化虫胶和醋酸纤维素邻苯二甲酸酯。糖衣片剂是用糖衣包围的压缩片剂,可用于盖住味道或气味和保护片剂不被氧化。膜衣片剂是用水溶性物质的薄层或膜覆盖的压缩片剂。膜衣包括但不限于羟乙基纤维素、羧甲基纤维素钠、聚乙二醇4000和醋酸纤维素邻苯二甲酸酯。膜包衣赋予与糖衣相同的一般特性。多压缩片剂是由超过一个的压缩周期形成的压缩片剂,包括分层片剂和压涂或干涂的片剂。
片剂剂型可以从粉末、结晶或颗粒状形式的活性成分单独或与一种或多种本发明所述的载体或赋形剂(包括粘结剂、崩解剂、控释聚合物、润滑剂、稀释剂和/或着色剂)组合来制备。调味剂和甜味剂特别用于形成咀嚼片和止咳糖。
本文提供的口服给予的药物组合物可作为软或硬胶囊提供,可从明胶、甲基纤维素、淀粉或藻酸钙制造。硬明胶胶囊,也被称作干填充胶囊(DFC),由两部分组成,一部分比另一部分更滑动,从而完全封闭活性成分。软弹性胶囊(SEC)是一种柔软、球状壳,如明胶壳,通过加入甘油、山梨醇或类似的多元醇塑化。软明胶壳可以含有防腐剂以防止微生物生长。适合的防腐剂是如本文所述的那些,包括对甲苯甲酸甲酯和丙酯和山梨酸。本发明提供的液体、半固体、固体剂型可以封装在胶囊中。适合的液体和半固体剂型包括在碳酸亚丙酯、植物油或甘油三酯中的溶液和悬浮液。含有此类溶液的胶囊可以根据美国专利No.4,328,245、4,409,239和4,410,545描述的制备。本领域技术人员已知的是,胶囊也可以被涂布,从而改变或维持活性成分的溶解。
本文提供的口服给予的药物组合物可以液体和半固体剂型提供,包括乳液、溶液、悬浮液、酏剂和糖浆。乳液是一种两相体系,其中一种液体以小球的形式分散在另一种液体中,可以是水包油型或油包水型。乳液可以包括药学上可接受的非水液体或溶剂、乳化剂和防腐剂。悬浮液可以包括药学上可接受的悬浮剂和防腐剂。水性醇溶液可以包括药学上可接受的乙缩醛,如低级烷基醛的二(低级烷基),例如,乙醛二乙基缩醛;和具有一个或多个羟基的水混溶性溶剂,如丙二醇和乙醇。酏剂是透明的、有甜味的水醇溶液。糖浆是糖的浓水溶液,例如蔗糖,也可以含有防腐剂。对于液体剂型,例如,聚乙二醇中的溶液可以用足够量的药学上可接受的液体载体(例如,水)稀释,以方便给予。
其他有用的液体和半固体剂型包括但不限于含有本发明提供的活性成分和二烷基化的单或聚烷撑二醇的那些,包括1,2-二甲氧基甲烷、二甘醇二甲醚、三甘醇二甲醚、四甘醇二甲醚、聚乙二醇-350-二甲醚、聚乙二醇-550-二甲醚、聚乙二醇-750-二甲醚,其中350、550和750指聚乙二醇的近似平均分子量。这些制剂可以进一步包括一种或多种抗氧化剂,如丁基化的羟基甲苯(BHT)、丁基化的羟基茴香醚(BHA)、没食子酸、维生素E、对苯二酚、羟基香豆素、乙醇胺、卵磷脂、脑磷脂、抗坏血酸、苹果酸、山梨糖醇、磷酸、酸性亚硫酸盐、偏亚硫酸氢钠、硫代二丙酸及其酯和二硫代氨基甲酸酯。
口服给予的本文提供的药物组合物也可以脂质体、胶束、微球或纳米系统的形式提供。胶束剂型可以根据美国专利No.6,350,458所述的制备。
本文提供的口服给予的药物组合物可以作为非泡腾片或泡腾片、颗粒和粉末提供,将重构为液体剂型。非泡腾颗粒或粉末中使用的药学上可接受的载体和赋形剂可以包括稀释剂、甜味剂和润湿剂。泡腾颗粒或粉末中使用的药学上可接受的载体和赋形剂可以包括有机酸和二氧化碳的来源。
着色剂和调味剂可用于上述所有剂型中。
本文提供的口服给予的药物组合物可以配制为立即或改变的释放剂型,包括延时的、持续的、脉冲的、控制的、靶向的和程序释放形式。
B.胃肠外给予
本文提供的药物组合物可给予的以通过注射、输液或植入而胃肠外给予,从而局部或全身给予。本文中所使用的胃肠外给予包括静脉、动脉、腹腔、鞘内、心室内、尿道内、胸骨内、颅内、肌肉、滑膜内和皮下给予。
本文提供的胃肠外给予的药物组合物可以配制成适合于胃肠外给予的任何剂型,包括溶液、悬浮液、乳液、胶束、脂质体、微球面三角形、纳米系统以及在注射之前适合于溶液或悬浮液的固体形式。这种剂型可以根据药物科学领域技术人员已知的常规方法制备(参见,Remington:TheScience and Practice of Pharmacy,同上)。
用于胃肠外给予的药物组合物可以包括一种或多种药学上可接受的载体和赋形剂,包括但不限于水性介质、水混溶性介质、非水性介质、抵抗微生物生长的抗菌剂或防腐剂、稳定剂、溶解度促进剂、等渗剂、缓冲剂、抗氧化剂、局部麻醉剂、悬浮和分散剂、润湿或乳化剂、络合剂、隐蔽或螯合剂、抗冻剂、冻干保护剂、增稠剂、pH调节剂和惰性气体。
适合的水性介质包括但不限于水、盐水、生理盐水或磷酸盐缓冲盐水(PBS)、氯化钠注射液、林格氏注射液、等渗葡萄糖注射液、无菌水注射液、葡萄糖和乳酸化的林格氏注射液。适合的非水性介质包括但不限于蔬菜源的固定油、蓖麻油、玉米油、棉籽油、橄榄油、花生油、薄荷油、红花油、芝麻油、大豆油、氢化植物油、氢化大豆油、椰子油的中链甘油三酯和棕榈籽油。适合的水混溶性介质包括但不限于乙醇、1,3-丁二醇、液体聚乙二醇(例如,聚乙二醇300和聚乙二醇400)、丙二醇、甘油、N-甲基-2-吡咯烷酮、N,N-二甲基乙酰胺和二甲亚砜。
适合的抗菌剂或防腐剂包括但不限于苯酚、甲酚、汞制剂、苯甲醇、氯丁醇、对羟基苯甲酸甲酯和丙酯、噻汞撒、苯扎氯铵(例如,氯化苄索)、对甲苯甲酸甲酯和丙酯和山梨酸。适合的等渗剂包括但不限于氯化钠、甘油和葡萄糖。适合的缓冲剂包括但不限于磷酸盐和柠檬酸盐。适合的抗氧化剂是如本文所述的那些,包括酸性亚硫酸盐和偏亚硫酸氢钠。适合的局部麻醉剂包括但不限于盐酸普鲁卡因。适合的悬浮和分散剂是如本文所述的那些,包括羧甲基纤维素钠、羟丙基甲基纤维素和聚乙烯吡咯烷酮。适合的乳化剂是如本文所述的那些,包括聚氧乙烯失水山梨醇单月桂酸酯、聚氧乙烯失水山梨醇单油酸酯80和三乙醇胺油酸酯。适合的隐蔽或螯合剂包括但不限于EDTA。合适的pH调节剂包括但不限于氢氧化钠、盐酸、柠檬酸和乳酸。适合的络合剂包括但不限于环糊精,包括α-环糊精、β-环糊精、羟丙基-β-环糊精、磺丁基醚-β-环糊精和磺丁基醚7-β-环糊精(CyDex,Lenexa,KS)。
当本文提供的药物组合物配制成用于多剂量给予时,多剂量胃肠外制剂必须含有抑菌或抑真菌浓度的抗菌剂。所有胃肠外制剂必须消毒,这是本领域中已知的并被实践。
在一个实施方案,胃肠外给予的药物组合物以易于使用的无菌溶液提供。在另一种实施方案中,药物组合物以无菌干的可溶性产品提供,包括冻干粉和皮下注射片剂,在使用之前用介质重构。在另一个实施方案中,药物组合物以易于使用的无菌悬浮液提供。在另一个实施方案中,药物组合物以无菌干的不可溶性产品提供,在使用之前用介质重构。在另一个实施方案中,药物组合物以易于使用的无菌乳液提供。
本文提供的胃肠外给予的药物组合物可以配制为立即或改变的释放剂型,包括延时的、持续的、脉冲的、控制的、靶向的和程序释放形式。
药物组合物可以配制为悬浮液、固体、半固体或触变液体,作为植入的储器给予。在一个实施方案中,本文提供的胃肠外给予的药物组合物分散在固体内部基质中,被不溶于体液中但允许药物组合物中的活性成分扩散通过的外部聚合物膜包围。
适合的内部基质包括但不限于聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯或增塑或未塑化的聚氯乙烯、塑化的尼龙、塑化的聚对苯二甲酸乙二醇酯、天然橡胶、聚异戊二烯、聚异丁烯、聚丁二烯、聚乙烯、乙烯乙酸乙烯酯共聚物、硅橡胶、聚二甲基硅氧烷、硅酮碳酸酯共聚物、亲水性聚合物(如丙烯酸和甲基丙烯酸的水凝胶)、胶原蛋白、交联的聚乙烯醇和交联的部分水解的聚乙酸乙烯酯。
适合的外部聚合物膜包括但不限于聚乙烯、聚丙烯、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、乙烯/乙酸乙烯酯共聚物、硅橡胶、聚二甲基硅氧烷、氯丁橡胶、氯化聚乙烯、聚氯乙烯、氯乙烯、偏二氯乙烯、乙烯和丙烯与乙酸乙烯酯的共聚物、离聚物聚对苯二甲酸乙二醇酯、丁基橡胶表氯醇橡胶、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇共聚物和乙烯/乙烯氧基乙醇共聚物。
C.局部给予
本文提供的药物组合物可以局部给予至皮肤、口或粘膜。本文中所使用的局部给予包括:真皮(内)、结膜、角膜内、眼内、眼、耳、透皮、鼻、阴道、尿道、呼吸系统和直肠给予。
本文提供的药物组合物可以配制成适于用于局部或全身效果的局部给予的任何剂型,包括乳液、溶液、悬浮液、霜剂、凝胶、水凝胶、药膏、尘粉、敷料、酏剂、洗液、悬浮液、酊剂、糊剂、泡沫、膜剂、气雾剂、灌注剂、喷雾剂、栓剂、绷带、真皮贴。本文提供的药物组合物的局部制剂还可以包括脂质体、胶束、微球、纳米系统和其混合物。
适用于本发明提供的局部制剂的药学上可接受的载体和赋形剂包括但不限于水性介质、水混溶性介质、非水性介质、抵抗微生物生长的抗菌剂或防腐剂、稳定剂、溶解度促进剂、等渗剂、缓冲剂、抗氧化剂、局部麻醉剂、悬浮和分散剂、润湿或乳化剂、络合剂、隐蔽或螯合剂、渗透促进剂、抗冻剂、冻干保护剂、增稠剂和惰性气体。
药物组合物也可以通过电击、离子导入、声透入、超音波导入或微针或无针注射而局部给予,如粉末JECTTM(Chiron Corp.,Emeryville,CA)和BIOJECTTM(Bioject Medical Technologies Inc.,Tualatin,OR)。
本文提供的药物组合物可以药膏、霜剂和凝胶的形式提供。适合的药膏介质包括油质或烃介质,包括猪油、安息香化猪油、橄榄油、棉籽油和其他油、白凡士林;可乳化或吸收的介质,如亲水性凡士林、羟基硬脂硫酸酯和无水羊毛脂;可除水的介质,如亲水性药膏;水溶性药膏介质,包括不同分子量的聚乙二醇;乳液介质,油包水(W/O型)乳剂或水包油(O/W型)乳液,包括十六烷醇、单硬脂酸甘油酯、羊毛脂和硬脂酸(参见,Remington:The Science and Practice of Pharmacy,同上)。这些介质是润肤的,但一般需要加入抗氧化剂和防腐剂。
适合的霜剂可以是水包油或油包水型的。适合的霜剂介质可以是可水洗的,并含有油相(乳化剂)和水相。油相也被称为“内部”相,一般由凡士林和诸如十六烷基或硬脂基醇等脂肪醇构成。水相的量一般但不一定超过油相,并一般含有保温剂。霜剂中的乳化剂可以是非离子、阴离子、阳离子或两性表面活性剂。
凝胶是半固体的悬浮型系统。单相凝胶含有在液体载体内基本上均匀分布的有机大分子。适合的胶凝剂但不限于包括交联的丙烯酸聚合物,如卡波姆、羧基聚烷撑和亲水性聚合物,如聚环氧乙烷、环氧乙烷-环氧丙烷共聚物和聚乙烯醇;纤维素聚合物,如羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯和甲基纤维素;树胶,如黄氏胶和黄原胶;藻酸钠;和明胶。为了制备均匀的凝胶,可以加入诸如醇或甘油等分散剂,或可以通过滴定、机械混合和/或搅拌分散胶凝剂。
本文提供的药物组合物可以直肠、尿道、阴道、阴道前庭给予,以栓剂、阴道栓剂、探针、药膏或糊剂、糊剂、粉剂、敷料、霜剂、橡皮膏、避孕药、药膏、溶液、乳液、悬浮液、止血垫、凝胶、泡沫、喷雾剂或灌肠剂的形式。这些制剂可以使用Remington:The Science and Practice ofPharmacy,同上中所述的常规方法制造。
直肠、尿道和阴道栓剂是用于插入身体口的固体,在常温下固体但在体温下熔化或软化而在口内释放活性成分。当配制本文提供的药物组合物时直肠和阴道栓剂中使用的药学上可接受的载体包括基材或介质,如硬化剂,在接近体温时产生熔点;和如本文所述的抗氧化剂,包括酸性亚硫酸盐和偏亚硫酸氢钠。适合的介质包括但不限于可可脂(可可油)、甘油-明胶、聚乙二醇(聚氧乙烯乙二醇)、鲸蜡、石蜡、白和黄蜡以及脂肪酸的甘油单、二和三酸脂的适宜混合物和水凝胶,如聚乙烯醇、甲基丙烯酸羟乙酯和聚丙烯酸。也可以使用各种介质的组合。直肠和阴道栓剂可以通过压缩或成型来制备。直肠和阴道栓剂的典型重量为约2~约3g。
本文提供的药物组合物可以眼内给予,以溶液、悬浮液、药膏、乳液、凝胶形成溶液、溶解用粉末、凝胶、眼插入物和植入物的形式。
本文提供的药物组合物可以鼻内或通过吸入呼吸道给予。药物组合物可以气溶胶或溶液的形式提供,使用压力容器、泵、喷射器、雾化器(如使用电水动力学以产生薄雾的雾化器)或喷雾器单独或与诸如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷等适合的推进剂组合输送。药物组合物还可以作为喷射用的干粉单独或与惰性载体(如乳糖或磷脂)组合和滴鼻液提供。对于鼻内使用,粉末可以含有生物粘附剂,包括壳聚糖或环糊精。
压力容器、泵、喷射器、雾化器或喷雾器中使用的溶液或悬浮液可以配制成含有乙醇、水性乙醇或适合替代剂,用于分散、增溶或延长本发明提供的活性成分的释放,作为溶剂的推进剂;和/或表面活性剂,如失水山梨醇三油酸酯、油酸或低聚乳酸。
本文提供的药物组合物可以微粉化至适于吸入输送的尺寸,如约50微米或更小,约10微米或更小。这种粒径的粒子可以使用本领域技术人员已知的粉碎方法制备,如螺旋气流磨、流化床气流磨、超临界流体加工形成纳米粒子、高压均质化或喷雾干燥。
吸入器或吹入器中使用的胶囊、泡罩和药筒可以配制成含有本文提供的药物组合物的混合粉末;适合的粉末基材,如乳糖或淀粉;及性能改善剂,如L-亮氨酸、甘露醇或硬脂酸镁。乳糖可以是无水或一水合物的形式。其他适合的赋形剂或载体包括但不限于右旋糖酐、葡萄糖、麦芽糖、山梨醇、木糖醇、果糖、蔗糖和藻糖。吸入/鼻内给予的本文提供的药物组合物可以进一步包括适合的风味剂,如薄荷醇和左旋薄荷脑;和/或甜味剂,如糖精和糖精钠。
用于局部给予的本文提供的药物组合物可以配制为立即或改变的释放剂型,包括延时的、持续的、脉冲的、控制的、靶向的和程序释放形式。
D.改变的释放
本文提供的药物组合物可以配制为改变的释放剂型。本文中所用的,术语″改变的释放″指当通过相同的路径给予时,活性成分的释放速率和位置不同于立即剂型的剂型。改变的释放剂型包括但不限于延时的-、扩展的-、延长的-、持续的-、脉冲的、控制的、加速的和快速的、靶向的、程序释放和胃滞留剂型。可以使用本领域技术人员已知的各种改变的释放装置和方法制备改变的释放剂型中的药物组合物,包括但不限于基质控释装置、渗透控释装置、多粒子控释装置、离子交换树脂、肠包衣、多层包衣、微球、脂质体以及它们的组合。活性成分的释放速率也可以通过改变活性成分的粒子大小和多晶型来改变。
改变的释放的例子包括但不限于美国专利No.:3,845,770;3,916,899;3,536,809;3,598,123;4,008,719;5,674,533;5,059,595;5,591,767;5,120,548;5,073,543;5,639,476;5,354,556;5,639,480;5,733,566;5,739,108;5,891,474;5,922,356;5,972,891;5,980,945;5,993,855;6,045,830;6,087,324;6,113,943;6,197,350;6,248,363;6,264,970;6,267,981;6,376,461;6,419,961;6,589,548;6,613,358;和6,699,500中所述的那些。
1.基质控释装置
改变的释放剂型中的本文提供的药物组合物可以使用本领域技术人员已知的基质控释装置制造(参见,Takada等人,″Encyclopedia of ControlledDrug Delivery″,Vol.2,Mathiowitz Ed.,Wiley,1999)。
在某些实施方案中,使用侵蚀基质装置配制改变的释放剂型中的本文提供的药物组合物,它是水可溶胀的、可侵蚀的或可溶解的聚合物,包括但不限于合成聚合物和天然聚合物及其衍生物,如多糖和蛋白。
形成侵蚀基质的材料包括但不限于甲壳素、壳聚糖、葡聚糖和茁霉多糖、胶琼脂、阿拉伯树胶、梧桐胶、刺槐豆胶、胶黄氏、卡拉胶、胶盖提、瓜尔豆胶、黄原胶和硬葡聚糖;淀粉,如糊精和麦芽糊精;亲水性胶体,如果胶;磷脂,如卵磷脂;藻酸盐;藻酸丙二醇酯;明胶;胶原蛋白;纤维素,如乙基纤维素(EC)、甲基乙基纤维素(MEC)、羧甲基纤维素(CMC)、CMEC、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、醋酸纤维素(CA)、丙酸纤维素(CP)、丁酸纤维素(CB)、醋酸丁酸纤维素(CAB)、CAP、CAT、羟丙基甲基纤维素(HPMC)、HPMCP、HPMCAS、醋酸羟丙基甲基纤维素偏苯三酸(HPMCAT)和乙基羟基乙基纤维素(EHEC);聚乙烯吡咯烷酮;聚乙烯醇;聚乙酸乙烯酯;甘油脂肪酸酯;聚丙烯酰胺;聚丙烯酸;乙基丙烯酸或甲基丙烯酸的共聚物(Rohm America,Inc.,Piscataway,NJ);聚(2-羟乙基甲基丙烯酸酯);聚乳酸;L-谷氨酸和乙基-1-谷氨酸的共聚物;可降解的乳酸-乙醇酸共聚物;聚D-(-)-3-羟丁酸;和其他丙烯酸衍生物,如甲基丙烯酸丁酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯、丙烯酸乙酯、(2-二甲基氨基乙基)甲基丙烯酸酯和(三甲基氨基乙基)甲基丙烯酸氯化物均聚物和共聚物。
在某些实施方案中,使用非侵蚀基质装置配制药物组合物。活性成分溶解或分散在惰性基质中,并主要通过在给予后扩散进惰性基质中释放出来。适用作非侵蚀基质装置的材料包括但不限于不溶性塑料,如聚乙烯、聚丙烯、聚异戊二烯、聚异丁烯、聚丁二烯、聚甲基丙烯酸甲酯、聚甲基丙烯酸本酯、氯化的聚乙烯、聚氯乙烯、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、乙烯-乙酸乙烯酯共聚物、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、氯乙烯、偏二氯乙烯、乙烯和丙烯与乙酸乙烯酯的共聚物、离聚物聚对苯二甲酸乙二醇酯、丁基橡胶表氯醇橡胶、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三元共聚物、乙烯/乙烯氧基乙醇共聚物、聚氯乙烯、塑化的尼龙、塑化的聚对苯二甲酸乙二醇酯、天然橡胶、硅橡胶、聚二甲基硅氧烷和硅树脂碳酸酯共聚物;亲水性聚合物,如乙基纤维素、醋酸纤维素、交聚维酮和交联的部分水解的聚乙酸乙烯酯;和脂肪化合物,如巴西棕榈蜡、微晶蜡和甘油三酸酯。
在基质控释系统,可以控制所需的释放动力学,例如,通过采用的聚合物类型、聚合物粘度、聚合物和/或活性成分的粒子大小、活性成分与聚合物的比例以及组合物中的其他赋形剂或载体。
改变的释放剂型中的本文提供的药物组合物可以通过本领域技术人员已知的方法制备,包括直接压缩、干或湿造粒然后压缩和熔化-造粒,然后压缩。
2.渗透控释装置
可以使用渗透控释装置制造改变的释放剂型中的本文提供的药物组合物,包括但不限于一室系统、二室系统、非对称膜技术(AMT)和挤出核心系统(ECS)。一般来说,这种装置具有至少两个组成部分:(a)含有活性成分的核心;和(b)带有至少一个输送端口并封装核心的半透膜。半透膜控制水从使用的环境到核心的流入,从而通过输送端口挤出而药物释放。
除了活性成分之外,渗透装置的核心任选地包括渗透剂,产生水从使用的环境输送进装置的核心的驱动力。一类渗透剂是水可溶胀的亲水性聚合物,也被称为“渗透聚合物”和“水凝胶”。适合的作为渗透剂的水可溶胀的亲水性聚合物包括但不限于亲水性乙烯基和丙烯酸类聚合物、多糖(藻酸钙)、聚环氧乙烷(PEO)、聚乙二醇(PEG)、聚丙二醇(PPG)、聚(甲基丙烯酸2-羟乙酯)、聚丙烯酸、聚甲基丙烯酸、聚乙烯吡咯烷酮(PVP)、交联的PVP、聚乙烯醇(PVA)、PVA/PVP共聚物、PVA/PVP与疏水性单体如甲基丙烯酸甲酯和乙酸乙烯酯的共聚物、含有大的PEO嵌段的聚氨酯、交联羧甲基纤维素钠、卡拉胶、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素(CMC)和羧乙基纤维素(CEC)、藻酸钠、聚卡波非、明胶、黄原胶和淀粉乙醇酸钠。
另一类渗透剂是osmogens,其能够吸收水而影响周围涂层阻挡的渗透压梯度。适合的osmogens包括但不限于无机盐,如硫酸镁、氯化镁、氯化钙、氯化钠、氯化锂、硫酸钾、磷酸钾、碳酸钠、亚硫酸钠、硫酸锂、氯化钾、和硫酸钠;糖类,如右旋糖、果糖、葡萄糖、肌醇、乳糖、麦芽糖、甘露醇、棉子糖、山梨醇、蔗糖、藻糖和木糖醇;有机酸,如抗坏血酸、苯甲酸、富马酸、柠檬酸、马来酸、癸二酸、山梨酸、己二酸、依地酸、谷氨酸、对甲苯磺酸、琥珀酸和酒石酸;尿素;和其混合物。
不同溶出度的渗透剂可被用来影响活性成分最初从剂量输送有多迅速。例如,无定形糖如MANNOGEMTM EZ(SPI Pharma,Lewes,DE)可用于提供在最初几个小时的快速输送,以迅速产生所需的治疗效果,并逐步和连续释放其余量以在较长时期内保持治疗或预防效果的理想水平。在这种情况下,在这样的速率下释放活性成分,以代替代谢和分泌的活性成分的量。
核心还可以包括如本文所述的各种其他赋形剂和载体,以提高剂型的性能或促进稳定性或加工。
形成半透膜时使用的材料包括各种等级的丙烯酸酯类、乙烯类、醚类、聚酰胺类、聚酯类和纤维素衍生物,它们在生理上有关的pH下是水可渗透的和水不溶性的,或容易通过化学改变变成水不溶性的,如交联。形成包衣中使用的适合聚合物的例子包括塑化的、未塑化的和加强的醋酸纤维素(CA)、二醋酸纤维素、三醋酸纤维素、丙酸CA、硝酸纤维素、醋酸丁酸纤维素(CAB)、CA乙基氨基甲酸酯、CA甲基氨基甲酸酯、CA琥珀酸酯、醋酸纤维素偏苯三酸(CAT)、CA二甲基氨基醋酸酯、CA乙基碳酸酯、CA氯乙酸酯、CA乙基草酸酯、CA甲基磺酸酯、CA丁基磺酸酯、CA对甲苯磺酸酯、醋酸琼脂、直链淀粉三醋酸酯、β-葡聚糖醋酸酯、β-葡聚糖三醋酸酯、乙醛二甲基醋酸酯、刺槐豆胶的三醋酸酯、羟基化的乙烯-乙酸乙烯酯、EC、PEG、PPG、PEG/PPG共聚物、PVP、HEC、HPC、CMC、CMEC、HPMC、HPMCP、HPMCAS、HPMCAT、聚丙烯酸和酯及聚甲基丙烯酸和酯及其共聚物段、淀粉、葡聚糖、糊精、壳聚糖、胶原、明胶、聚烯烃、聚醚、聚砜、聚醚砜、聚苯乙烯、聚乙烯卤化物、聚乙烯酯和醚、天然蜡和合成蜡。
半透膜也可以是疏水性微孔膜,其中孔基本上充满了气体,没有被水性介质浸湿,但水蒸汽可透过,如美国专利No.5,798,119中披露的。这种疏水性但水蒸汽可透过的膜通常由疏水性聚合物构成,如聚烯烃、聚乙烯、聚丙烯、聚四氟乙烯、聚丙烯酸衍生物、聚醚、聚砜、聚醚砜、聚苯乙烯、聚乙烯卤化物、聚偏二氟乙烯、聚乙烯酯和醚、天然蜡和合成蜡。
半透膜上的输送端口可以通过机械或激光钻孔在涂布后形成。输送端口也可以通过侵蚀水溶性材料的塞子或通过在核心的缩进上使膜的较薄部分破裂而原位形成。此外,输送端口可以在涂布过程中形成,如同在美国专利No.5,612,059和5,698,220披露的非对称膜涂层类型。
活性成分的释放总量和释放速率基本上可以通过半透膜的厚度和孔隙度、核心的组成以及输送端口的数量、大小和位置来调节。
渗透控释剂型中的药物组合物可以进一步包括如本文所述的额外的常规赋形剂或载体,以促进制剂的性能或加工。
渗透控释剂型可以根据本领域技术人员已知的常规方法和技术制备(参见,Remington :The Science and Practice of Pharmacy,同上;Santus和Baker,J.Controlled Release 1995,35,1-21;Verma等人,Drug Development andIndustrial Pharmacy 2000,26,695-708;Verma等人,J.Controlled Release2002,79,7-27)。
在某些实施方案中,本文提供的药物组合物配制为AMT控释剂型,其包括涂布含有活性成分和其他药学上可接受的赋形剂或载体的核心的非对称渗透膜。参见,美国专利No.5,612,059和WO2002/17918。AMT控释剂型可以根据本领域技术人员已知的常规方法和技术制备,包括直接压缩、干燥造粒、湿造粒以及浸涂法。
在某些实施方案中,本文提供的药物组合物配制为ESC控释剂型,其包括涂布含有活性成分、羟乙基纤维素和其他药学上可接受的赋形剂或载体的核心的渗透膜。
3.多粒子控释装置
改变的释放剂型中的本文提供的药物组合物可以配制成多粒子控释装置,其包括多个粒子、颗粒剂或小球,直径约10μm~约3mm、约50μm~约2.5mm或约100μm~约1mm。可以通过本领域技术人员已知的方法制备这种多粒子,包括干湿造粒、挤出/滚圆、辊-压实、熔融-凝固和喷涂种子核心。参见,例如,Multiparticulate Oral Drug Delivery;Marcel Dekker:1994;和Pharmaceutical Pelletization Technology,Marcel Dekker:1989。
如本文所述的其他赋形剂或载体可以与药物组合物共混,以有助于加工和形成多粒子。由此产生的粒子本身可以构成多粒子装置或可以通过各种甩膜材料涂布,如肠衣聚合物、水可溶胀的和水溶性聚合物。多粒子可以被进一步处理成胶囊或片剂。
4.靶向输送
本文提供的药物组合物可以被配制成靶向特定组织、受体或将要治疗的对象的身体其他区域,包括脂质体-、加封红细胞-及抗体-基输送系统。其例子包括但不限于美国专利No.6,316,652;6,274,552;6,271,359;6,253,872;6,139,865;6,131,570;6,120,751;6,071,495;6,060,082;6,048,736;6,039,975;6,004,534;5,985,307;5,972,366;5,900,252;5,840,674;5,759,542;和5,709,874中公开的那些。
使用方法
在一个实施方案中,提供一种治疗、预防或缓解对象中与CCR3相关的紊乱、疾病或病症的一种或多种症状的方法,包括给予对象治疗有效量的本文提供的化合物,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。在一个实施方案中,对象是哺乳动物。在另一个实施方案中,对象是人。
在另一个实施方案中,提供一种治疗、预防或缓解对象中响应于CCR3活性调控的紊乱、疾病或病症的一种或多种症状的方法,包括给予对象治疗有效量的本发明提供的化合物,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。在一个实施方案中,对象是哺乳动物。在另一个实施方案中,对象是人。
在另一个实施方案中,提供一种治疗、预防或缓解对象中由CCR3受体介导的紊乱、疾病或病症的一种或多种症状的方法,包括给予对象治疗有效量的本发明提供的化合物,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。在一个实施方案中,对象是哺乳动物。在另一个实施方案中,对象是人。
在另一个实施方案中,提供一种治疗、预防或缓解对象中嗜红细胞相关的紊乱、疾病或病症的一种或多种症状的方法,包括给予对象治疗有效量的本发明提供的化合物,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。在一个实施方案中,对象是哺乳动物。在另一个实施方案中,对象是人。
在另一个实施方案中,提供一种治疗、预防或缓解对象中嗜碱细胞相关的紊乱、疾病或病症的一种或多种症状的方法,包括给予对象治疗有效量的本发明提供的化合物,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。在一个实施方案中,对象是哺乳动物。在另一个实施方案中,对象是人。
在另一个实施方案中,提供一种治疗、预防或缓解对象中肥大细胞相关的紊乱、疾病或病症的一种或多种症状的方法,包括给予对象治疗有效量的本发明提供的化合物,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。在一个实施方案中,对象是哺乳动物。在另一个实施方案中,对象是人。
在另一个实施方案中,提供一种治疗、预防或缓解对象中炎性疾病的一种或多种症状的方法,包括给予对象治疗有效量的本发明提供的化合物,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。在一个实施方案中,对象是哺乳动物。在另一个实施方案中,对象是人。
可以用本文提供的化合物治疗的紊乱、疾病或病症,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药,包括但不限于(1)炎症或过敏性疾病,包括全身过敏反应和过敏性紊乱、过敏性皮炎、荨麻疹、药物过敏、昆虫蜇过敏、食物过敏(包括腹腔疾病等)和肥大细胞增多症;(2)炎症性肠道疾病,包括克罗恩病、溃疡性结肠炎、回肠炎和肠炎;(3)血管炎和白塞病综合征;(4)牛皮癣和炎症性皮肤病,包括皮炎、湿疹、过敏性皮炎、过敏性接触性皮炎、荨麻疹、病毒性皮肤疾病(包括源于人类乳头状瘤病毒的那些)、HIV或RLV感染、细菌性、真菌性和其他寄生性皮肤疾病和皮肤红斑狼疮;(5)哮喘和呼吸道过敏疾病,包括过敏性哮喘、运动诱发哮喘、过敏性鼻炎、中耳炎、过敏性结膜炎、过敏性肺部疾病和慢性阻塞性肺疾病;(6)自身免疫性疾病,包括关节炎(包括风湿性关节炎和牛皮癣)、系统性红斑狼疮、I型糖尿病、重症肌无力、多发性硬化症、Grave病和肾小球肾炎;(7)移植排斥(包括移植免疫排斥反应和移植物抗宿主病),例如,皮肤移植排斥、固体器官移植排斥、骨髓移植排斥;(8)发热;(9)心血管紊乱,包括急性心脏衰竭、低血压、高血压、心绞痛、心肌梗死、心肌病、充血性心脏衰竭、动脉粥样硬化、冠状动脉疾病、再狭窄和血管狭窄;(10)脑血管紊乱,包括脑外伤、中风、缺血再灌注损伤和动脉瘤;(11)乳腺、皮肤、前列腺、宫颈、子宫、卵巢、睾丸、膀胱、肺、肝、喉、口腔、结肠和胃肠道(例如,食道、胃、胰腺)、脑、甲状腺、血液和淋巴系统的癌症;(12)纤维化、结缔组织病和结节病;(13)生殖器和生殖病症,包括勃起功能障碍;(14)胃肠功能紊乱,包括胃炎、溃疡、恶心、胰腺炎和呕吐;(15)神经紊乱,包括老年痴呆症;(16)睡眠紊乱,包括失眠、嗜睡症、睡眠呼吸暂停综合征和Pickwick综合征;(17)疼痛;(18)肾功能紊乱;(19)眼疾,包括青光眼;和(20)传染病,包括HIV。
在某些实施方案中,所述紊乱、疾病或病症选自哮喘、过敏性哮喘、运动诱发哮喘、过敏性鼻炎、永久性过敏性鼻炎、季节性过敏性鼻炎、过敏性皮炎、接触过敏、接触性皮炎、结膜炎、过敏性结膜炎、嗜酸细胞性支气管炎、食物过敏、嗜酸细胞性胃肠炎、炎症性肠道疾病、溃疡性结肠炎、克罗恩病、肥大细胞增多症、超IgE综合征、系统性红斑狼疮、牛皮癣、痤疮、多发性硬化症、移植排斥、再灌注损伤、慢性阻塞性肺疾病、Churg-Strauss综合征、鼻窦炎、嗜碱性白血病、慢性荨麻疹、嗜碱性白细胞增多、牛皮癣、湿疹、COPD(慢性阻塞性肺紊乱)、关节炎、类风湿关节炎、银屑病关节炎和骨关节炎。
在某些实施方案中,所述紊乱、疾病或病症是哮喘、运动诱发哮喘、过敏性鼻炎、过敏性皮炎、慢性阻寒性肺疾病或过敏性结膜炎。
取决于将要治疗的紊乱、疾病或病症和对象的病症,本文提供的化合物或药物组合物可以通过口服、胃肠外(例如,肌肉、腹腔、静脉、ICV、脑池内注射或输液、皮下注射或植入)、吸入、鼻、阴道、直肠、舌下或局部(例如,透皮或局部)的给予途径给予,并可以单独或组合地与适于各种给予途径的药学上可接受的赋形剂、载体、佐剂和介质配制成适合的剂量单位。还提供以储存制剂形式给予本文提供的化合物或药物组合物,其中活性成分在预定时间段内释放。
在治疗、预防或缓解哮喘、过敏性鼻炎、湿疹、牛皮癣、过敏性皮炎、发烧、败血症、系统性红斑狼疮、糖尿病、类风湿关节炎、多发性硬化症、动脉粥样硬化症、移植排斥反应、炎症性肠道疾病、癌症或者与CCR3受体相关的其他病症、紊乱或疾病的一种或多种症状时,适宜的剂量水平通常为约0.001~100mg/kg对象体重/天(mg/kg/天)、约0.01~约75mg/kg/天、约0.1~约50mg/kg/天、约0.5~约25mg/kg/天或约1~约20mg/kg/天,可以单个或多个剂量给予。在这个范围内,剂量可以为约0.005~约0.05、约0.05~约0.5、约0.5~约5.0、约1~约15、约1~约20或约1~约50mg/kg/天。在某些实施方案中,剂量水平为约0.001~约100mg/kg/天。在某些实施方案中,剂量水平为约0.01~约75mg/kg/天。在某些实施方案中,剂量水平为约0.1~约50mg/kg/天。在某些实施方案中,剂量水平为约0.5~约25mg/kg/天。在某些实施方案中,剂量水平为约1~约20mg/kg/天。
对于口服给予,本文提供的药物组合物可以被配制成含有约1.0~约1,000mg的活性成分的片剂形式,在一个实施方案中,约1、约5、约10、约15、约20、约25、约50、约75、约100、约150、约200、约250、约300、约400、约500、约600、约750、约800、约900和约1,000mg活性成分,用于针对待治疗的患者进行症状性调节。药物组合物可以1~4次/天的方案给予,包括一次、二次、三次和四次/天。
然而,应该理解,对于任何特定患者的具体剂量水平和给予频率可以变化,并将取决于多种因素,包括使用的具体化合物的活性、代谢稳定性和化合物的作用长度、年龄、体重、一般健康状况、性别、饮食、给予模式和时间、排泄率、药物组合、特定病症的严重程度和接受治疗的主体。
本文还提供的是调控CCR3活性的方法,包括使CCR3受体与本文提供的化合物接触,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药。在一个实施方案中,CCR3受体由细胞表达。
本文提供的化合物,例如,式I的化合物,包括其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐、溶剂化物、水合物或前药,可以与用于治疗、预防或缓解本文提供的化合物适用的紊乱、疾病或病症的一种或多种症状的其他药剂或疗法组合或联合使用,包括哮喘、过敏性鼻炎、湿疹、牛皮癣、过敏性皮炎、发烧、败血症、系统性红斑狼疮、糖尿病、类风湿关节炎、多发性硬化症、动脉粥样硬化症、移植排斥反应、炎症性肠道疾病、癌症、传染病和本文提及的那些病态。
在某些实施方案中,本发明提供的化合物可以与本领域中已知的一种或多种类固醇药物组合,包括但不限于醛固酮、倍氯米松、倍他米松、醋酸去氧皮质酮、氟氢可的松、氢化可的松(皮质醇)、泼尼松龙、泼尼松、甲泼尼龙、地塞米松和去炎松。
在某些实施方案中,本发明提供的化合物可以与本领域中已知的一种或多种抗菌剂组合,包括但不限于氨基羟丁基卡那霉素、阿莫西林、氨苄青霉素、胂凡纳明、阿奇霉素、氨曲南、阿洛西林、杆菌肽、羧苄青霉素、头孢克罗、头孢羟氨苄、头孢孟多、头孢唑啉、头孢氨苄、头孢地尼、头孢托仑酯、头孢吡肟、头孢克肟、头孢哌酮、头孢噻肟、头孢西丁、头孢泊肟、头孢丙烯、头孢他啶、头孢布烯、头孢唑肟、头孢曲松、头孢呋辛、氯霉素、西司他丁、环丙沙星、克拉霉素、克林霉素、氯唑西林、粘菌素、达福普汀、美环素、双氯西林、地红霉素、强力霉素、红霉素、恩诺沙星、艾他培南、乙胺丁醇、氟氯西林、磷霉素、呋喃唑酮、加替沙星、格尔德霉素、庆大霉素、除莠霉素、亚胺培南、异烟肼、卡那霉素、左氧氟沙星、利奈唑胺、洛美沙星、氯碳头孢、磺胺米隆、莫西沙星、美罗培南、甲硝唑、美洛西林、米诺环素、莫匹罗星、萘夫西林、新霉素、奈替米星、呋喃妥因、诺氟沙星、氧氟沙星、土霉素、青霉素、哌拉西林、平板霉素、多粘菌素B、prontocil、吡嗪酰胺、奎奴普丁、利福平、罗红霉素、大观霉素、链霉素、磺乙酰胺、磺胺甲噻二唑、磺胺甲噁唑、替考拉宁、泰利霉素、四环素、替卡西林、妥布霉素、甲氧苄啶、竹桃霉素、曲氟沙星和万古霉素。
在某些实施方案中,本发明提供的化合物可以与本领域中已知的一种或多种抗真菌剂组合,包括但不限于阿莫罗芬、两性霉素B、阿尼芬净、联苯苄唑、布替萘芬、布康唑、卡泊芬净、环哟酮胺、克霉唑、益康唑、芬替康唑、菲利平、氟康唑、异康唑、伊曲康唑、酮康唑、米卡芬净、咪康唑、萘替芬、纳他霉素、制霉菌素、奥昔康唑、福康唑、泊沙康唑、利福霉素、舍他康唑、硫康唑、特比萘芬、特康唑、噻康唑和伏立康唑。
在某些实施方案中,本发明提供的化合物可以与本领域中已知的一种或多种抗凝血剂组合,包括但不限于醋硝香豆素、阿加曲班、比伐卢定、来匹卢定、磺达肝素、肝素、苯茚二酮、华法林和希美加群。
在某些实施方案中,本发明提供的化合物可以与本领域中已知的一种或多种溶栓剂组合,包括但不限于阿尼普酶、瑞替普酶、t-PA(阿替普酶活化酶)、链激酶、替奈普酶和尿激酶。
在某些实施方案中,本发明提供的化合物可以与本领域中已知的一种或多种非甾体抗炎剂组合,包括但不限于醋氯芬酸、阿西美、amoxiprin、阿司匹林、阿扎丙宗、贝诺酯、溴芬酸、卡洛芬、塞来昔布、水杨酸胆碱镁、双氯芬酸、二氟尼柳、依托度酸、依托考昔、faislamine、芬布芬、非诺洛芬、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮咯酸、氯诺昔康、洛索洛芬、鲁米昔布、甲氯芬那酸、甲芬那酸、美洛昔康、安乃近、甲基水杨酸、水杨酸镁、萘丁美酮、萘普生、尼美舒利、羟布宗、帕瑞昔布、保泰松、炎痛喜康、水杨基水杨酸、舒林酸、苯磺唑酮、舒洛芬、替诺昔康、噻洛芬酸和托美汀。
在某些实施方案中,本发明提供的化合物可以与本领域中已知的一种或多种抗血小板剂组合,包括但不限于阿昔单抗、西洛他唑、氯吡格雷、潘生丁、噻氯匹定和替罗非班。
本发明提供的化合物也可以与其他类化合物组合给予,包括但不限于(1)α-肾上腺素能剂;(2)抗心律失常药物;(3)抗动脉粥样硬化剂,如ACAT抑制剂;(4)抗生素,如蒽环类抗生素、博来霉素、丝裂霉素、更生霉素和普卡霉素;(5)抗癌药和细胞毒素药物,例如,烷化剂,如氮芥、烷基磺酸盐、亚硝基脲、环乙亚胺和三氮烯;(6)抗凝血剂,如醋硝香豆素、阿加曲班、比伐卢定、来匹卢定、磺达肝素、肝素、苯茚二酮、华法林和希美加群;(7)抗糖尿病药物,如双胍类(例如,二甲双胍)、葡萄糖苷酶抑制剂(例如,阿卡波糖)、胰岛素、格列奈类(例如,瑞格列奈)、磺脲类(例如,格列美脲、格列苯和格列吡嗪)、噻唑烷二酮类(例如,曲格列酮、罗格列酮和吡格列酮)和PPAR-γ激动剂;(8)抗真菌剂,如阿莫罗芬、两性霉素B、阿尼芬净、联苯苄唑、布替萘芬、布康唑、卡泊芬净、环哟酮胺、克霉唑、益康唑、芬替康唑、菲利平、氟康唑、异康唑、伊曲康唑、酮康唑、米卡芬净、咪康唑、萘替芬、纳他霉素、制霉菌素、奥昔康唑、福康唑、泊沙康唑、利福霉素、舍他康唑、硫康唑、特比萘芬、特康唑、噻康唑和伏立康唑;(9)抗炎药,例如,非甾体抗炎剂,如醋氯芬酸、阿西美、amoxiprin、阿司匹林、阿扎丙宗、贝诺酯、溴芬酸、卡洛芬、塞来昔布、水杨酸胆碱镁、双氯芬酸、二氟尼柳、依托度酸、依托考昔、faislamine、芬布芬、非诺洛芬、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮咯酸、氯诺昔康、洛索洛芬、鲁米昔布、甲氯芬那酸、甲芬那酸、美洛昔康、安乃近、甲基水杨酸、水杨酸镁、萘丁美酮、萘普生、尼美舒利、羟布宗、帕瑞昔布、保泰松、炎痛喜康、水杨基水杨酸、舒林酸、苯磺唑酮、舒洛芬、替诺昔康、噻洛芬酸和托美汀;(10)抗代谢药物,如叶酸拮抗剂、嘌呤类似物和嘧啶类似物;(11)抗血小板剂,如GPIIb/IIIa阻滞剂(例如,阿昔单抗、依替巴肽和替罗非班)、P2Y(AC)拮抗剂(例如,氯吡格雷、噻氯匹定和CS-747)、西洛他唑、潘生丁和阿司匹林;(12)抗增生药,如甲氨蝶呤、FK506(他克莫司)和霉酚酸酯;(13)抗TNF抗体或可溶性TNF受体,如依那西普、雷帕霉素和来氟米特;(14)aP2抑制剂;(15)β-肾上腺素能药物,如卡维地洛和美托洛尔;(16)胆汁酸螯合剂,如降胆敏;(17)钙通道阻滞剂,如苯磺酸氨氯地平;(18)化疗剂;(19)环氧合酶-2(COX-2)抑制剂,如塞来昔布和罗非昔布;(20)环胞霉素;(21)细胞毒性药物,如硫唑嘌呤和环磷酰胺;(22)利尿剂,如氯噻嗪、氢氯噻嗪、氟甲噻嗪、氢氟甲噻、苄氟噻嗪、甲基氯噻嗪、三氯甲噻嗪、泊利噻嗪、苄噻嗪、依他尼酸、替尼酸、氯噻酮、腹安酸、莫唑胺、布美他尼、氨苯喋啶、阿米洛利和安体舒通;(23)内皮素转化酶(ECE)抑制剂,如磷氨米酮;(24)酶,如L-天冬酰胺酶;(25)因子VIIa抑制剂和因子Xa抑制剂;(26)法尼基蛋白转移酶抑制剂;(27)贝特类;(28)生长因子抑制剂,如PDGF活性调节剂;(29)生长激素促分泌素受体;(30)HMG CoA还原酶抑制剂,如普伐他汀、洛伐他汀、阿托伐他汀、辛伐他汀、NK-104(又名,伊伐他汀、尼伐他汀或nisbastatin)和ZD-4522(也称为罗苏伐他汀、atavastatin或visastatin);中性肽链内切酶(NEP)抑制剂;(31)激素剂,如糖皮质激素(例如,可的松)、雌激素/抗雌激素、雄激素/抗雄激素、孕激素和促黄体激素释放激素拮抗剂和醋酸奥曲肽;(32)免疫抑制剂;(33)盐皮质激素受体拮抗剂,如螺内酯和醛固酮;(34)微管干扰素剂,如海鞘素;(35)微管稳定剂,如紫杉醇、多西紫杉醇和埃博霉素A-F;(36)MTP抑制剂;(37)尼亚新;(38)磷酸二酯酶抑制剂,如PDE III抑制剂(例如,西洛他唑)和PDE V抑制剂(例如,西地那非、他达拉非和伐地那非);(39)植物衍生产物,如长春花生物碱、鬼臼素和紫杉醇;(40)血小板活化因子(PAF)拮抗剂;(41)铂配合物,如顺铂、赛特铂和卡铂;(42)钾通道开放剂;(43)异戊烯基蛋白转移酶抑制剂;(44)蛋白酪氨酸激酶抑制剂;(45)肾素抑制剂;(46)角鲨烯合成酶抑制剂;(47)类固醇,如醛固酮、倍氯米松、倍他米松、醋酸去氧皮质酮、氟氢可的松、氢化可的松(皮质醇)、泼尼松龙、泼尼松、甲泼尼龙、地塞米松和去炎松;(48)TNF-α抑制剂,如替尼达普;(49)凝血酶抑制剂,如水蛭素;(50)溶栓剂,如阿尼普酶、瑞替普酶、替奈普酶、组织型纤溶酶原激活物(tPA)、重组tPA、链激酶、尿激酶、尿激酶原和苯甲酰纤溶酶原激酶激活物(APSAC);(51)血栓素受体拮抗剂,如伊非曲班;(52)拓扑异构酶抑制剂;(53)血管肽酶抑制剂(双NEP-ACE抑制剂),如奥马曲拉和gemopatrilat;和(54)其他试剂,例如,羟基脲、卡巴肼、米托坦、六甲基三聚氰胺和金化合物。
这类其他药剂或药物可以常用的途径和量与本文提供的化合物同时或相继给予,例如,式I的化合物,包括其单一对映异构体、对映异构体的混合物或非对映异构体的混合物;或其药学上可接受的盐、溶剂化物或前药。当本文提供的化合物与一种或多种其他药物同时使用时,可以使用除了本文提供的化合物之外还含有其他药物的药物组合物,但并不是必需的。因此,本文提供的药物组合物包括除了本文提供的化合物之外还含有一种或多种其他活性成分或治疗剂的那些。
本文提供的化合物与第二种活性成分的重量比可以变化,并且取决于每种成分的有效量。一般来说,使用每种成分的有效剂量。因此,例如,当本文提供的化合物与NSAID联用时,所述化合物与NSAID的重量比可以为约1,000∶1~约1∶1,000,或约200∶1~约1∶200。本文提供的化合物与其他活性成分的组合通常也在上述范围内,但在每一种情况下,应该使用每种活性成分的有效剂量。
本文提供的化合物也可以使用本领域技术人员公知的包装材料作为制造品提供。参见,例如,美国专利No.5,323,907;5,052,558;和5,033,252。药物包装材料的例子包括但不限于泡罩包装、瓶、管、吸入器、泵、袋、小瓶、容器、注射器以及适于给予和治疗的选定制剂和预期模式的任何包装材料。
本发明也提供试剂盒,当由医生使用时,可以简化将适量的活性成分给予至对象。在某些实施方案中,本发明提供的试剂盒包括容器和本文提供的化合物的剂型,包括其单一对映异构体或非对映异构体的混合物;或其药学上可接受的盐、溶剂化物或前药。
在某些实施方案中,试剂盒包括含有本文提供的化合物的剂型的容器,包括其单一对映异构体或非对映异构体的混合物;或其药学上可接受的盐、溶剂化物或前药,在容器中含有一种或多种本发明所述的其他治疗剂。
本发明提供的试剂盒可以进一步包括用来给予活性成分的装置。所述装置的例子包括但不限于注射器、无针头注射器滴包、贴片和吸入器。本发明提供的试剂盒还可以包括给予活性成分的避孕套。
本发明提供的试剂盒可以进一步包括可用于给予一种或多种活性成分的药学上可接受的介质。例如,如果以活性成分必须重构而胃肠外给予的固体形式提供,试剂盒可以包括活性成分可以在其中溶解的适合介质的密封容器,形成适于胃肠外给予的无颗粒消毒溶液。药学上可接受的介质的例子包括但不限于:水性介质,包括但不限于美国药典注射用水、氯化钠注射液、林格氏注射液、葡萄糖注射液、葡萄糖和氯化钠注射液以及乳酸林格氏注射液;水混溶性介质,包括但不限于乙醇、聚乙二醇和聚丙二醇;和非水性介质,包括但不限于玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸异丙酯和苯甲酸苄酯。
通过以下非限制实施例将进一步理解本发明内容。
实施例
本文中所用的,这些方法、方案和实施例中的符号和约定,不论是否是具体定义的缩写,均与当代科学文献中所采用的那些一致,例如,Journalof the American Chemical Society或Journal of Biological Chemistry。具体来说,但不限于此,以下缩写可用于实施例和整个说明书中:g(克);mg(毫克);mL(毫升);μL(微升);mM(毫摩尔);μM(微摩尔);Hz(赫兹);MHz(兆赫);mmol(毫摩尔);hr(小时);min(分钟);MS(质谱);ESI(电喷雾电离);TLC(薄层色谱);HPLC(高压液相色谱);THF(四氢呋喃);CDCl3(氘代氯仿);DMSO(二甲亚砜);DMSO-d6(氘代二甲亚砜);EtOAc(乙酸乙酯);和MeOH(甲醇)。
对于下面的所有实施例,可以利用本领域技术人员已知的标准处理和纯化方法。除非另有说明,所有的温度以℃(摄氏度)表达。除非另有说明,所有反应均在室温下进行。本文中示出的合成方法用于解释具体例子使用中的适用化学并不属于公开范围。
实施例1
制备4-(3,5-二甲基苯氧基)-3-(4-丙酰基哌嗪-1-基磺酰基)苄腈57
化合物57按方案2所示合成。
方案2
4-(3,5-二甲基苯氧基)-3-硝基苄腈21。向4-氯-3-硝基苄腈(12.00g,65.75mmol)在THF中的溶液中加入碳酸钾(45.58g,328.70mmol)和3,5-二甲基苯酚(9.658g,78.88mmol)。反应混合物回流17hr,由此原料消失(TLC,25%EtOAc,己烷中)。然后,反应混合物冷却到室温,过滤碳酸钾,用大量EtOAc洗涤。滤液用饱和碳酸氢钠溶液、水和饱和氯化钠溶液相继洗涤,用无水MgSO4干燥,过滤,真空浓缩,得到粗产物,黄色固体。固体用己烷研磨,过滤,得到化合物21,发白-黄色粉末。(15.022g,85.2%产率,100%HPLC纯度)。1H NMR(500MHz,DMSO-d6):δ8.65(d,J=2Hz,1H),8.06(dd,J1=9Hz,J2=2Hz,1H),7.12(d,J=9Hz,1H),6.97(s,1H),6.84(s,2H),2.29(s,6H)。
3-氨基-4-(3,5-二甲基苯氧基)苄腈22。向化合物21(15.00g,55.91mmol)在THF(250mL)中的溶液加入亚硫酸氢钠(58.41g,335.5mmol)在水(75mL)中的溶液。反应混合物在90℃下搅拌。24hr后,通过TLC监测原料消耗完(10%EtOAc,己烷中),反应混合物从热源移走。反应混合物真空浓缩,直到产物在剩余水中沉淀。通过真空过滤收集沉淀,用水洗涤。产物在40℃下真空干燥过夜,得到化合物22。(12.681g,95.2%产率,99.9%HPLC纯度)。1H NMR(500MHz,DMSO-d6):δ7.08(d,J=2Hz,1H),6.91(dd,J1=8Hz,J2=2Hz,1H),6.80(s,1H),6.73(d,J=8Hz,1H),6.63(s,2H),5.47(s,2H),2.24(s,6H)。
5-氰基-2-(3,5-二甲基苯氧基)苯-1-磺酰氯23。在室温下将化合物22(12.00g,50.36mmol)加到H2O(50.0mL)和浓HCl(100mL)中。然后,反应混合物在冰浴中搅拌。在0℃下将亚硝酸钠(10.434g,151.1mmol)在H2O(50mL)中的溶液滴加到反应混合物中。反应混合物在冰浴中搅拌1小时。在另一个烧瓶中,二氧化硫鼓泡通过乙酸(430mL)45min。然后,将氯化铜二水合物(4.305g,25.2mmol)加到二氧化硫饱和溶液中,再搅拌30min。然后,饱和的二氧化硫溶液在冰浴中再搅拌5min。然后将含有化合物22的反应混合物滴加到氯化铜溶液中。加入完成后,溶液再搅拌1小时,然后缓慢倒在冰水混合物中,搅拌1小时。然后过滤得到的沉淀,黄色固体用水冲洗,得到化合物23(13.944g,86.1%产率)。1H NMR(500MHz,DMSO-d6):δ8.06(d,J=2Hz,1H),7.71(dd,J1=8Hz,J2=2Hz,1H),6.85(s,1H),6.81(d,J=9Hz,1H),6.66(s,2H),2.26(s,6H)。
4-(3,5-二甲基苯氧基)-3-(哌嗪-1-基磺酰基)苄腈24。在2两天,向在冰盐浴中搅拌的哌嗪(16.144g,186.4mmol)在CH2Cl2(80mL)中的溶液中滴加化合物23(3.009g,9.35mmol)在CH2Cl2(270mL)中的溶液。然后,反应搅拌74hr,由此原料消失(TLC,5%MeOH,在CH2Cl2中)。反应混合物在CH2Cl2和水之间分配。然后,有机层用饱和氯化钠溶液洗涤,用无水MgSO4干燥。然后,真空浓缩有机层,再溶解在最少量的CH2Cl2中,通过正相硅胶进行色谱纯化(MeOH/CH2Cl2)。合并含有目标产物的馏分,真空浓缩,得到浅黄色油。然后,油用CH2Cl2/二异丙醚研磨,真空过滤,得到化合物24,白色粉末(2.032g,58.5%产率,95.5%HPLC纯度)。1H NMR(500MHz,DMSO-d6):δ8.21(d,J=2Hz,1H),8.03(dd,J1=9Hz,J2=2Hz,1H),7.01(m,1H),6.96(d,J=11Hz,1H),6.80(d,J=9Hz,2H),3.19(m,2H),3.11(m,2H),2.70(m,2H),2.46(m,2H),2.30(s,1H),2.27(s,6H)。
4-(3,5-二甲基苯氧基)-3-(4-丙酰基哌嗪-1-基磺酰基)苄腈57。向化合物24(0.102g,0.27mmol)在CH2Cl2(2mL)中的溶液中加入丙酰氯(0.035g,0.38mmol)和三乙胺(0.039g,0.38mmol)。反应混合物在室温下搅拌20hr,由此原料消失(TLC,1%MeOH,CH2Cl2中)。真空浓缩反应混合物,再溶解在最少量的CH2Cl2中,通过正相硅胶进行色谱纯化(MeOH/CH2Cl2)。合并含有目标产物的馏分,真空浓缩,得到白色粉末,然后用CH2Cl2/二异丙醚研磨,真空过滤,得到目标产物,粉末。粉末再溶解在CH2Cl2中,通过正相硅胶再次进行色谱纯化(MeOH/CH2Cl2)。合并含有目标产物的馏分,真空浓缩,得到白色粉末。粉末用二异丙醚研磨,真空过滤,得到化合物57(0.061g,52.1%产率,96.6%HPLC纯度)。1H NMR(500MHz,CDCl3):8.27(d,J=2Hz,1H),7.67(dd,J1=9Hz,J2=2Hz,1H),6.94(s,1H),6.90(d,J=9Hz,1H),6.68(s,2H),3.71(m,2H),3.54(m,2H),3.35(m,4H),2.34(s,6H),2.32(m,2H),1.13(t,J=7Hz,3H);MS(ESI,EI+):m/z=428(MH+)。
根据本实施例中所述的过程制备以下化合物。
4-(3,5-二甲基苯氧基)-3-(4-(4-(三氟甲基)苯甲酰基)哌嗪-1-基磺酰基)苄腈54。HPLC纯度:96.6%;1H NMR(500MHz,DMSO-d6):8.23(d,J=2Hz,1H),8.05(dd,J1=9Hz,J2=2Hz,1H),7.80(d,J=8Hz,2H),7.62(d,J=8Hz,2H),7.03(d,J=9Hz,1H),6.97(s,1H),6.86(s,2H),3.71(m,2H),3.35(m,4H),3.26(m,2H),2.30(s,6H);MS(ESI,EI+):m/z=544(MH+)。
3-(4-苯甲酰基哌嗪-1-基磺酰基)-4-(3,5-二甲基苯氧基)苄腈55。HPLC纯度:95.5%;1H NMR(500MHz,DMSO-d6):8.23(d,J=2Hz,1H),8.05(dd,J1=9Hz,J2=2Hz,1H),7.42(m,5H),7.02(d,J=9Hz,1H),6.97(s,1H),6.87(s,2H),3.68(m,2H),3.38(m,2H),3.30(m,4H),2.30(s,6H);MS(ESI,Ef):m/z=478(MH+)。
3-(4-(2,2-二甲基丁酰基)哌嗪-1-基磺酰基)-4-(3,5-二甲基苯氧基)苄腈59。HPLC纯度:92.2%;1H NMR(500MHz,CDCl3):8.27(d,J=2Hz,1H),7.67(dd,J1=9Hz,J2=2Hz,1H),6.93(s,1H),6.90(d,J=9Hz,1H),6.67(s,2H),3.72(m,4H),3.34(m,4H),2.33(s,6H),1.60(m,2H),1.21(s,6H),0.85(t,J=7Hz,3H);MS(ESI,EI+):m/z=470(MH+)。
4-(3,5-二甲基苯氧基)-3-(4-戊酰基哌嗪-1-基磺酰基)苄腈63。HPLC纯度:98.8%;1H NMR(500MHz,CDCl3):8.27(d,J=2Hz,1H),7.67(dd,J1=9Hz,J2=2Hz,1H),6.93(s,1H),6.90(d,J=9Hz,1H),6.68(s,2H),3.72(m,4H),3.34(m,4H),2.33(s,6H),1.25(s,9H);MS(ESI,EI+):m/z=456(MH+)。
3-(4-(环丁烷羰基)哌嗪-1-基磺酰基)-4-(3,5-二甲基苯氧基)苄腈64。HPLC纯度:97.4%;1H NMR(500MHz,CDCl3):8.26(d,J=2Hz,1H),7.67(dd,J1=9Hz,J2=2Hz,1H),6.93(s,1H),6.90(d,J=9Hz,1H),6.67(s,2H),3.69(m,2H),3.42(m,2H),3.30(m,4H),3.21(m,1H),2.33(s,6H),2.29(m,2H),2.12(m,2H),1.96(m,1H),1.85(m,1H);MS(ESI,EI+):m/z=454(MH+)。
3-(4-(环己烷羰基)哌嗪-1-基磺酰基)-4-(3,5-二甲基苯氧基)苄腈65。HPLC纯度:97.9%;1H NMR(500MHz,CDCl3):8.27(d,J=2Hz,1H),7.67(dd,J1=9Hz,J2=2Hz,1H),6.94(s,1H),6.90(d,J=9Hz,1H),6.68(s,2H),3.70(m,2H),3.57(m,2H),3.34(m,4H),2.41(m,1H),2.33(s,6H),1.79(m,2H),1.66(m,3H),1.50(m,2H),1.24(m,3H);MS(ESI,EI+):m/z=482(MH+)。
4-(3,5-二甲基苯氧基)-3-(4-(3-甲基丁酰基)哌嗪-1-基磺酰基)苄腈66。HPLC纯度:100%;1H NMR(500MHz,CDCl3):8.27(d,J=2Hz,1H),7.67(dd,J1=9Hz,J2=2Hz,1H),6.94(s,1H),6.90(d,J=9Hz,1H),6.68(s,2H),3.72(m,2H),3.55(m,2H),3.34(m,4H),2.33(s,6H),2.19(d,J=7Hz,2H),2.09(m,1H),0.95(d,J=7Hz,6H);MS(ESI,EI+):m/z=456(MH+)。
3-(4-(3,3-二甲基丁酰基)哌嗪-1-基磺酰基)-4-(3,5-二甲基苯氧基)苄腈67。HPLC纯度:98.5%;1H NMR(500MHz,CDCl3):8.27(d,J=2Hz,1H),7.67(dd,J1=9Hz,J2=2Hz,1H),6.94(s,1H),6.90(d,J=9Hz,1H),6.689s,2H),3.73(m,2H),3.58(m,2H),3.35(m,4H),2.33(s,6H),2.24(s,2H),1.03(s,9H)。
3-(4-(环戊烷羰基)哌嗪-1-基磺酰基)-4-(3,5-二甲基苯氧基)苄腈68。HPLC纯度:95.3%;1H NMR(500MHz,CDCl3):8.27(d,J=2Hz,1H),7.67(dd,J1=9Hz,J2=2Hz,1H),6.94(s,1H),6.90(d,J=9Hz,1H),6.68(s,2H),3.72(m,2H),3.60(m,2H),3.34(m,4H),2.84(m,1H),2.33(s,6H),1.78(m,4H),1.70(m,2H),1.58(m,2H);MS(ESI,EI+):m/z=468(MH+)。
4-(3,5-二氯苯氧基)-3-(4-(4-(三氟甲基)苯甲酰基)哌嗪-1-基磺酰基)苄腈69。HPLC纯度:99.1%;1H NMR(500MHz,CDCl3):8.29(d,J=2Hz,1H),7.81(dd,J1=9Hz,J2=2Hz,1H),7.70(d,J=8Hz,2H),7.50(d,J=8Hz,2H),7.30(t,J=2Hz,1H),7.04(d,J=9Hz,1H),6.98(s,2H),3.89(m,2H),3.48(m,4H),3.29(m,2H);MS(ESI,EI+):m/z=589(MH+)。
3-(4-苯甲酰基哌嗪-1-基磺酰基)-4-(3,5-二氯苯氧基)苄腈70。HPLC纯度:96.8%;1H NMR(500MHz,CDCl3):8.29(d,J=2Hz,1H),7.80(dd,J1=9Hz,J2=2Hz,1H),7.45(m,3H),7.37(m,2H),7.30(s,1H),7.04(d,J=9Hz,1H),6.99(s,2H),3.85(m,2H),3.64(m,2H),3.36(m,4H);MS(ESI,EI+):m/z=517(MH+)。
4-(3,5-二氯苯氧基)-3-(4-(3,3-二甲基丁酰基)哌嗪-1-基磺酰基)苄腈71。HPLC纯度:99.3%;1H NMR(500MHz,CDCl3):8.30(d,J=2Hz,1H),7.80(dd,J1=9Hz,J2=2Hz,1H),7.29(s,1H),7.02(d,J=9Hz,1H),6.97(s,2H),3.73(m,2H),3.59(m,2H),3.31(m,4H),2.24(s,2H),1.03(s,9H);MS(ESI,EI+):m/z=511(MH+)。
4-(3,5-二氯苯氧基)-3-(4-(3-甲基丁酰基)哌嗪-1-基磺酰基)苄腈72。HPLC纯度:99.1%;1H NMR(500MHz,CDCl3):8.30(d,J=2Hz,1H),7.80(dd,J1=9Hz,J2=2Hz,1H),7.30(t,J=2Hz,1H),7.02(d,J=9Hz,1H),6.98(d,J=2Hz,2H),3.72(m,2H),3.57(m,2H),3.31(m,4H),2.19(d,J=7Hz,2H),2.09(m,1H),0.95(d,J=7Hz,6H);MS(ESI,EI+):m/z=497(MH+)。
3-(4-(环丁烷羰基)哌嗪-1-基磺酰基)-4-(3,5-二氯苯氧基)苄腈73。HPLC纯度:96.6%;1H NMR(500MHz,CDCl3):8.29(d,J=2Hz,1H),7.79(dd,J1=8Hz,J2=2Hz,1H),7.30(t,J=2Hz,1H),7.02(d,J=9Hz,1H),6.97(d,J=2Hz,2H),3.70(m,2H),3.43(m,2H),3.28(m,4H),3.22(m,1H),2.32(m,2H),2.14(m,2H),1.97(m,1H),1.86(m,1H);MS(ESI,EI+):m/z=495(MH+)。
3-(4-(环戊烷羰基)哌嗪-1-基磺酰基)-4-(3,5-二氯苯氧基)苄腈74。HPLC纯度:97.5%;1H NMR(500MHz,CDCl3):8.30(d,J=2Hz,1H),7.80(dd,J1=8Hz,J2=2Hz,1H),7.30(t,J=2Hz,1H),7.03(d,J=9Hz,1H),6.98(d,J=2Hz,2H),3.72(m,2H),3.61(m,2H),3.31(m,4H),2.84(m,1H),1.80(m,4H),1.74(m,2H),1.57(m,2H);MS(ESI,EI+):m/z=509(MH+)。
3-(4-(4-氯苯甲酰基)哌嗪-1-基磺酰基)-4-(3,5-二氯苯氧基)苄腈78。HPLC纯度:94.4%;1H NMR(500MHz,CDCl3):8.29(d,J=2Hz,1H),7.81(dd,J1=8Hz,J2=2Hz,1H),7.40(m,2H),7.33(m,2H),7.30(t,J=2Hz,1H),7.04(d,J=9Hz,1H),6.98(s,2H),3.70(m,4H),3.35(m,4H);MS(ESI,EI+):m/z=551(MH+)。
3-(4-(3-氯苯甲酰基)哌嗪-1-基磺酰基)-4-(3,5-二氯苯氧基)苄腈81。HPLC纯度:92.5%;1H NMR(500MHz,CDCl3):8.30(d,J=2Hz,1H),7.81(dd,J1=9Hz,J2=2Hz,1H),7.42(m,1H),7.35(m,2H),7.30(t,J=2Hz,1H),7.26(m,1H),7.04(d,J=9Hz,1H),6.99(d,J=2Hz,2H),3.85(m,2H),3.55(m,2H),3.38(m,4H);MS(ESI,EI+):m/z=551(MH+)。
4-(3,5-二氯苯氧基)-3-(4-(4-甲基苯甲酰基)哌嗪-1-基磺酰基)苄腈82。HPLC纯度:91.7%;1H NMR(500MHz,CDCl3):8.29(d,J=2Hz,1H),7.80(dd,J1=9Hz,J2=2Hz,1H),7.29(m,3H),7.21(d,J=8Hz,2H),7.03(d,J=9Hz,1H),6.98(d,J=2Hz,2H),3.70(m,4H),3.33(m,4H),2.38(s,3H);MS(ESI,EI+):m/z=531(MH+)。
4-(3,5-二氯苯氧基)-3-(4-(2-甲基苯甲酰基)哌嗪-1-基磺酰基)苄腈83。HPLC纯度:90.1%;1H NMR(500MHz,CDCl3):8.29(d,J=2Hz,1H),7.80(dd,J1=9Hz,J2=2Hz,1H),7.30(m,2H),7.22(m,2H),7.11(d,J=7Hz,1H),7.03(d,J=9Hz,1H),6.98(d,J=2Hz,2H),3.99(m,1H),3.83(m,1H),3.47(m,1H),3.36(m,3H),3.22(m,2H),2.27(s,3H);MS(ESI,EI+):m/z=531(MH+)。
3-(4-(2-氯苯甲酰基)哌嗪-1-基磺酰基)-4-(3,5-二氯苯氧基)苄腈84。HPLC纯度:98.6%;1H NMR(500MHz,CDCl3):8.30(d,J=2Hz,1H),7.80(dd,J1=9Hz,J2=2Hz,1H),7.41(m,1H),7.35(m,3H),7.26(m,1H),7.02(d,J=9Hz,1H),6.99(d,J=2Hz,2H),4.11(m,1H),3.73(m,1H),3.53(m,1H),3.33(m,5H);MS(ESI,EI+):m/z=551(MH+)。
4-(3,5-二氯苯氧基)-3-(4-(2-氟苯甲酰基)哌嗪-1-基磺酰基)苄腈85。HPLC纯度:98.6%;1H NMR(500MHz,CDCl3):8.30(d,J=2Hz,1H),7.80(dd,J1=9Hz,J2=2Hz,1H),7.43(m,1H),7.41(m,1H),7.30(s,1H),7.23(m,1H),7.10(t,J=9Hz,1H),7.03(d,J=9Hz,1H),7.00(d,J=1Hz,2H),3.90(m,2H),3.43(m,4H),3.33(m,2H);MS(ESI,EI+):m/z=535(MH+)。
4-(3,5-二氯苯氧基)-3-(4-(3-氟苯甲酰基)哌嗪-1-基磺酰基)苄腈86。HPLC纯度:98%;1H NMR(500MHz,CDCl3):8.29(d,J=2Hz,1H),7.81(dd,J1=9Hz,J2=2Hz,1H),7.41(m,1H),7.30(s,1H),7.16(m,2H),7.09(d,J=9Hz,1H),7.04(d,J=9Hz,1H),6.99(s,2H),3.85(m,2H),3.55(m,2H),3.36(m,4H);MS(ESI,EI+):m/z=535(MH+)。
4-(3,5-二氯苯氧基)-3-(4-(4-氟苯甲酰基)哌嗪-1-基磺酰基)苄腈87。HPLC纯度:98%;1H NMR(500MHz,CDCl3):8.29(d,J=2Hz,1H),7.81(dd,J1=9Hz,J2=2Hz,1H),7.40(m,2H),7.30(s,1H),7.11(t,J=9Hz,2H),7.04(d,J=9Hz,1H),6.98(s,2H),3.71(m,4H),3.35(m,4H);MS(ESI,EI+):m/z=535(MH+)。
4-(3,5-二甲基苯硫基)-3-(4-(4-(三氟甲基)苯甲酰基)哌嗪-1-基磺酰基)苄腈88。HPLC纯度:98.9%;1H NMR(500MHz,CDCl3):8.18(d,J=2Hz,1H),7.70(d,J=8Hz,2H),7.52(d,J=8Hz,2H),7.48(dd,J1=8Hz,J2=2Hz,1H),7.15(m,3H),6.95(d,J=8Hz,1H),3.92(m,2H),3.54(m,2H),3.48(m,2H),3.36(m,2H),2.36(s,6H);MS(ESI,EI+):m/z=560(MH+)。
3-(4-苯甲酰基哌嗪-1-基磺酰基)-4-(3,5-二甲基苯硫基)苄腈89。HPLC纯度:98.7%;1H NMR(500MHz,CDCl3):8.18(d,J=2Hz,1H),7.47(dd,J1=9Hz,J2=2Hz,1H),7.42(m,5H),7.14(s,3H),6.95(d,J=8Hz,1H),3.90(m,2H),3.60(m,2H),3.40(m,4H),2.36(s,6H);MS(ESI,EI+):m/z=492(MH+)。
4-(3,5-二甲基苯硫基)-3-(4-(4-甲基苯甲酰基)哌嗪-1-基磺酰基)苄腈90。1H NMR(500MHz,CDCl3):8.17(d,J=2Hz,1H),7.47(dd,J1=8Hz,J2=2Hz,1H),7.29(d,J=8Hz,2H),7.22(d,J=8Hz,1H),7.15(m,3H),6.94(d,J=8Hz,1H),3.77(m,4H),3.39(m,4H),2.37(d,J=8Hz,9H);MS(ESI,EI+):m/z=506(MH+)。
4-(3,5-二甲基苯硫基)-3-(4-(3-甲基苯甲酰基)哌嗪-1-基磺酰基)苄腈91。1H NMR(500MHz,CDCl3):8.18(d,J=2Hz,1H),7.47(dd,J1=9Hz,J2=2Hz,1H),7.26(m,3H),7.15(m,4H),6.95(d,J=8Hz,1H),3.88(m,2H),3.60(m,2H),3.40(m,4H),2.36(s,9H);MS(ESI,EI+):m/z=506(MH+)。
4-(3,5-二甲基苯硫基)-3-(4-(2-甲基苯甲酰基)哌嗪-1-基磺酰基)苄腈92。1H NMR(500MHz,CDCl3):8.18(d,J=2Hz,1H),7.48(dd,J1=8Hz,J2=2Hz,1H),7.29(m,1H),7.23(m,2H),7.14(m,4H),6.96(d,J=8Hz,1H),4.02(m,1H),3.87(m,1H),3.52(m,1H),3.37(m,4H),3.26(m,1H),2.36(s,6H),2.29(s,3H);MS(ESI,EI+):m/z=506(MH+)。
实施例2
制备4-(5-氰基-2-(3,5-二甲基苯氧基)苯基磺酰基)-N-异丙基哌嗪-1-甲酰胺58
化合物58按方案3所示合成。
4-(5-氰基-2-(3,5-二甲基苯氧基)苯基磺酰基)-N-异丙基哌嗪-1-甲酰胺58。向化合物24(0.100g,0.27mmol)在CH2Cl2(3mL)中的溶液中加入异丙基异氰酸酯(0.032g,0.38mmol)和三乙胺(0.039g,0.38mmol)。反应在室温下搅拌20hr,由此原料消失(TLC,1%MeOH,CH2Cl2中)。然后,反应混合物真空浓缩,再溶解在中最少量的CH2Cl2,通过正相硅胶进行色谱纯化(MeOH/CH2Cl2)。合并含有目标产物的馏分,真空浓缩,得到白色粉末,然后用CH2Cl2/己烷研磨,真空过滤,得到粉末。粉末再溶解在CH2Cl2中通过正相硅胶再次进行色谱纯化(MeOH/CH2Cl2)。合并含有目标产物的馏分,真空浓缩,得到白色粉末,然后用己烷研磨,真空过滤,得到化合物58,白色粉末(0.014g,11.3%产率,99.1%HPLC纯度)。1H NMR(500MHz,CDCl3):8.27(d,J=2Hz,1H),7.67(dd,J1=9Hz,J2=2Hz,1H)6.93(s,1H),6.89(s,J=9Hz,1H),6.69(s,2H),4.17(m,1H),3.95(m,1H),3.44(m,4H),3.35(m,4H),2.34(s,6H),1.14(d,J=7Hz,6H);MS(ESI,EI+):m/z=457(MH+)。
方案3
根据本实施例中所述的过程制备以下化合物。
4-(5-氰基-2-(3,5-二甲基苯氧基)苯基磺酰基)-N-(3-氟苯基)哌嗪-1-甲酰胺61。HPLC纯度:99.2%;1H NMR(500MHz,CDCl3):8.28(d,J=2Hz,1H),7.68(dd,J1=9Hz,J2=2Hz,1H),7.25(m,1H),7.20(m,1H),6.97(dd,J1=8Hz,J2=2Hz,1H),6.94(s,1H),6.91(d,J=9Hz,1H),6.74(m,1H),6.70(s,2H),6.43(s,1H),3.59(m,4H),3.42(m,4H),2.33(s,6H);MS(ESI,EI+):m/z=509(MH+)。
4-(5-氰基-2-(3,5-二甲基苯氧基)苯基磺酰基)-N-(4-乙基苯基)哌嗪-1-甲酰胺62。HPLC纯度:98.7%;1H NMR(500MHz,CDCl3):8.28(d,J=2Hz,1H),7.68(dd,J1=9Hz,J2=2Hz,1H),7.20(m,2H),7.11(d,J=8Hz,2H),6.93(s,1H),6.90(d,J=9Hz,1H),6.70(s,2H),6.28(s,1H),3.57(m,4H),3.41(m,4H),2.59(q,J1=15Hz,J2=8Hz,2H),2.33(s,6H),1.20(t,J=8Hz,3H);MS(ESI,EI+):m/z=519(MH+)。
4-(5-氰基-2-(3,5-二氯苯氧基)苯基磺酰基)-N-(3-氟苯基)哌嗪-1-甲酰胺75。HPLC纯度:97%;1H NMR(500MHz,CDCl3):8.31(d,J=2Hz,1H),7.80(dd,J1=9Hz,J2=2Hz,1H)7.30(t,J=2Hz,1H),7.27(m,1H),7.23(m,1H),7.03(d,J=9Hz,1H),7.00(d,J=1Hz,2H),6.97(m,1H),6.75(m,1H),6.37(s,1H),3.61(m,4H),3.40(m,4H);MS(ESI,EI+):m/z=550(MH+)。
4-(5-氰基-2-(3,5-二氯苯氧基)苯基磺酰基)-N-异丙基哌嗪-1-甲酰胺80。HPLC纯度:99.4%;1H NMR(500MHz,CDCl3):8.30(d,J=2Hz,1H),7.79(dd,J1=9Hz,J2=2Hz,1H),7.29(t,J=2Hz,1H),7.02(d,J=9Hz,1H),6.98(d,J=2Hz,2H),4.18(d,J=7Hz,1H),3.95(m,1H),3.45(m,4H),3.32(m,4H),1.15(d,J=7Hz,6H);MS(ESI,EI+):m/z=498(MH+)。
4-(5-氰基-2-(3,5-二氯苯硫基)苯基磺酰基)哌嗪-1-甲酸乙酯94。1HNMR(500MHz,CDCl3):8.29(d,J=2Hz,1H),7.79(dd,J1=9Hz,J2=2Hz,1H),7.29(t,2Hz,1H),7.02(d,J=9Hz,1H),6.98(s,2H),4.14(m,2H),3.57(m,4H),3.30(m,4H),1.25(t,J=7Hz,3H);MS(ESI,EI+):m/z=525(MH+)。
实施例3
制备4-(3,5-二甲基苯氧基)-3-(4-(4-(三氟甲基)苯基磺酰基)哌嗪-1-基磺酰基)苄腈60
化合物60按方案4所示合成。
4-(3,5-二甲基苯氧基)-3-(4-(4-(三氟甲基)苯基磺酰基)哌嗪-1-基磺酰基)苄腈60。向化合物24(0.099g,0.27mmol)在CH2Cl2(3mL)中的溶液中加入4-(三氟甲基)苯磺酰氯(0.093g,0.38mmol)和三乙胺(0.039g,0.38mmol)。反应混合物搅拌18hr,由此原料消失(TLC,1%MeOH,CH2Cl2中)。然后,真空浓缩反应混合物,再溶解在最少量的CH2Cl2中,通过正相硅胶进行色谱纯化(MeOH/CH2Cl2)。合并含有目标产物的馏分,真空浓缩,得到白色固体。固体用二异丙醚/己烷研磨,真空过滤,得到化合物60,白色粉末。(0.065g,42.2%产率,95.7%HPLC纯度)。1H NMR(500MHz,CDCl3):8.23(d,J=2Hz,1H),7.86(m,4H),7.67(dd,J1=9Hz,J2=2Hz,1H),6.95(s,1H),6.89(d,J=9Hz,1H),6.68(s,2H),3.48(m,4H),3.15(m,4H),2.35(s,6H);MS(ESI,EI+):m/z=580(MH+)。
方案4
根据本实施例中所述的过程制备以下化合物。
3-(4-((7,7-二甲基双环[2.2.1]庚-1-基)甲基磺酰基)哌嗪-1-基磺酰基)-4-(3,5-二甲基苯氧基)苄腈51。HPLC纯度:99.3%;1H NMR(500MHz,CDCl3):δ8.27(d,J=2Hz,1H),7.68(dd,J1=9Hz,J2=2Hz,1H),6.94(s,1H),6.90(d,J=9Hz,1H),6.71(s,2H),3.43(m,5H),3.32(d,J=15Hz,1H),2.75(d,J=15Hz,1H),2.41(m,4H),2.34(s,6H),2.12(t,J=4Hz,1H),2.05(m,1H),1.94(d,J=19Hz,1H),1.63(m,1H),1.56(s,1H),1.43(m,1H),1.10(s,3H),0.87(s,3H);MS(ESI,EI+):m/z=586(MH+)。
4-(3,5-二甲基苯氧基)-3-(4-(甲基磺酰基)哌嗪-1-基磺酰基)苄腈52。HPLC纯度:97.2%;1H NMR(500MHz,DMSO-d6):δ8.25(d,J=2Hz,1H),8.04(dd,J1=9Hz,J2=2Hz,1H),7.00(d,J=9Hz,1H),6.98(s,1H),6.87(s,2H),3.36(t,J=4Hz,4H),3.19(t,J=5Hz,4H),2.90(s,3H),2.30(s,6H);MS(ESI,EI+):m/z=450(MH+)。
4-(3,5-二甲基苯氧基)-3-(4-甲苯磺酰基哌嗪-1-基磺酰基)苄腈53.
HPLC纯度:98.2%;1H NMR(500MHz,DMSO-d6):δ8.19(d,J=2Hz,1H),8.01(dd,J1=9Hz,J2=2Hz,1H),7.60(d,J=8Hz,2H),7.45(d,J=8Hz,2H),6.94(d,J=9Hz,2H),6.77(s,2H),3.35(m,4H),2.92(m,4H),2.41(s,3H),2.29(s,6H);MS(ESI,EI+):m/z=526(MH+)。
4-(3,5-二甲基苯氧基)-3-(4-(异丁基磺酰基)哌嗪-1-基磺酰基)苄腈56。HPLC纯度:97.9%;1H NMR(500MHz,CDCl3):8.26(d,J=2Hz,1H),7.68(dd,J1=9Hz,J2=2Hz,1H),6.94(s,1H),6.90(d,J=9Hz,1H),6.70(s,2H),3.46(m,4H),3.35(m,4H),2.75(d,J=7Hz,2H),2.34(s,6H),2.28(m,1H),1.11(s,J=7Hz,6H);MS(ESI,EI+):m/z=492(MH+)。
4-(3,5-二氯苯氧基)-3-(4-(甲基磺酰基)哌嗪-1-基磺酰基)苄腈76。HPLC纯度:88.5%;1H NMR(500MHz,CDCl3):8.30(d,J=2Hz,1H),7.81(dd,J1=9Hz,J2=2Hz,1H),7.31(s,1H),7.03(d,J=9Hz,1H),7.00(d,J=2Hz,2H),3.46(m,4H),3.35(m,4H),2.82(s,3H);MS(ESI,EI+):m/z=491(MH+)。
4-(3,5-二氯苯氧基)-3-(4-甲苯磺酰基哌嗪-1-基磺酰基)苄腈77。HPLC纯度:91.7%;1H NMR(500MHz,CDCl3):8.25(d,J=2Hz,1H),7.78(dd,J1=9Hz,J2=2Hz,1H),7.61(d,J=8Hz,2H),7.36(d,J=8Hz,2H),7.30(t,J=2Hz,1H),7.00(d,J=9Hz,1H),6.97(d J=2Hz,2H),3.43(m,4H),3.09(m,4H),2.46(s,3H);MS(ESI,EI+):m/z=567(MH+)。
4-(3,5-二氯苯氧基)-3-(4-(3-甲基苯甲酰基)哌嗪-1-基磺酰基)苄腈79。HPLC纯度:90.2%;1H NMR(500MHz,CDCl3):8.29(d,J=2Hz,1H),7.80(dd,J1=9Hz,J2=2Hz,1H),7.30(m,1H),7.25(m,2H),7.19(s,1H)7.14(d,J=I Uz,1H),7.04(d,J=9Hz,1H),6.99(d,J=2Hz,2H),3.85(m,2H),3.57(m,2H),3.36(m,4H),2.37(s,3H);MS(ESI,EI+):m/z=531(MH+)。
4-(3,5-二甲基苯硫基)-3-(4-(3-氟苯甲酰基)哌嗪-1-基磺酰基)苄腈93。1HNMR(500MHz,CDCl3):8.18(d,J=2Hz,1H),7.48(dd,J1=8Hz,J2=2Hz,1H),7.28(s,1H),7.23(m,1H),7.14(s,3H),6.98(m,1H),6.94(d,J=8Hz,1H),6.75(m,1H),6.42(s,1H),3.64(m,4H),3.44(m,4H),2.36(s,6H);MS(ESI,EI+):m/z=525(MH+)。
实施例4
制备1-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪
化合物40按方案5所示合成。
方案5
2-氯-5-硝基苯-1-磺酰氯37。向浓HCl(100mL)的冰浴冷却的溶液中分批加入2-氯-5-硝基苯胺(10g)。当完全溶解时,滴加亚硝酸钠的水溶液(6.0g,50mL水中),得到的反应混合物在0℃下搅拌1hr。然后,将上面得到的重氮离子溶液小心地加到氯化铜二水合物(5g)在用二氧化硫气体预先饱和的乙酸(500mL)中的冰浴冷却的混合物中。将得到的反应混合物在0℃下搅拌1hr后,剧烈搅拌下小心地分批加到冰水混合物中。抽滤收集析出的固体,用水冲洗,真空干燥,得到目标产物37,奶油色粉末(8.2g,55%)。1HNMR(500MHz,DMSO-d6):δ8.61(d,J=3Hz,1H),8.16(dd,J1=9Hz,J2=3Hz,1H),7.70(d,J=9Hz,1H)。
4-(2-氯-5-硝基苯基磺酰基)哌嗪-1-甲酸叔丁酯38。向化合物37(0.600g,2.34mmol)在DCM(20.00mL)中的溶液中加入1-哌嗪甲酸叔丁酯(0.566g,3.04mmol)和TEA(0.422mL,3.04mmol)。通过TLC监测反应(25%EtOAc,己烷中,Rf=0.53)。在室温下搅拌1hr后反应完成,通过原料消失表明(TLC)。加入水,水层用DCM萃取两次。合并萃取物,相继用水和盐水洗涤,用MgSO4干燥,过滤,真空蒸发,得到黄色固体。固体用DCM和己烷研磨,然后过滤,得到化合物38,黄色固体(0.789g,100%HPLC纯度,83%产率)。1H NMR(500MHz,DMSO-d6):δ8.60(d,J=3Hz,1H),8.47(dd,J1=3Hz,J2=%Hz,1H),8.01(d,J=8Hz,1H),3.37(m,4H),3.23(m,4H),1.37(s,9H)。
4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪-1-甲酸叔丁酯39。向2,5-二氯苯酚(0.414g,2.54mmol)在THF(20.00mL)中的冰浴中搅拌的溶液中缓慢加入NaH(0.101g,2.54mmol)。加入后,混合物搅拌5min。然后加入化合物38(0.790g,1.95mmol),得到的反应混合物加热至75℃过夜。通过HPLC监测反应。然后,16hr后,反应未完成(HPLC),因而蒸发THF,加入18-冠-6(1.057g,4.00mmol)、DMF(15mL)和K2CO3(0.553g,4.00mmol)。反应混合物加热至100℃再保持16hr,此时HPLC表明反应完成,原料消失。反应混合物冷却到室温,加入水(0.250mL)。反应混合物用EtOAc萃取三次。合并萃取物,用1N NaOH、水和盐水相继洗涤,用MgSO4干燥,过滤,真空蒸发。残余物溶解在最少量的DCM中,用色谱法纯化,使用己烷中的梯度5~30%EtOAc。合并纯馏分,真空蒸发。得到的固体用DCM和己烷研磨,然后过滤,得到化合物39,白色/黄色粉末(0.120g,100%HPLC纯度,10.0%产率)。1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.42(dd,J1=2Hz,J2=8Hz,1H),7.76(d,J=8Hz,1H),7.66(d,J=3Hz,1H),7.50(dd,J1=2Hz,J2=8Hz,1H),7.10(d,J=8Hz,1H),3.40(m,4H),3.25(m,4H),1.37(s,9H)。
1-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪40。向化合物39(0.100g,0.19mmol)在DCM(6.00mL)中的溶液中加入1N HCl在1,4-二噁烷(0.570mL)中的溶液。通过TLC监测反应(25%EtOAc,己烷中,Rf=0.0)。在室温下搅拌16hr后反应完成,通过原料消失表明。浓缩反应混合物,残余物再溶解在MeOH(2.00mL)中。然后加入Et2O(4.00mL),搅拌混合物,直到形成沉淀(10min)。过滤收集固体,得到化合物40,白色固体(0.080g,100%HPLC纯度,83%产率)。1H NMR(500MHz,DMSO-d6):δ9.39(s,2H),8.61(d,J=2Hz,1H),8.45(dd,J1=3Hz,J2=9Hz,1H),7.78(d,J=9Hz,1H),7.73(d,J=2Hz,1H),7.53(dd,J1=2Hz,J2=8Hz,1H),7.12(d,J=8Hz,1H),3.57(m,4H),3.16(m,4H)。
根据本实施例中所述的过程制备以下化合物,然后按本文所述的改进,例如,在实施例1~3中。
1-(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)乙酮151。HPLC纯度:99.5%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.00(d,J=2Hz,1H),7.81(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.01(d,J=8Hz,1H),3.54(m,4H),3.35(m,2H),3.25(m,2H),1.99(s,3H);熔点:190-193℃。
1-(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)-3-甲基丁-1-酮152。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.00(d,J=2Hz,1H),7.81(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.01(d,J=8Hz,1H),3.57(m,4H),3.34(m,2H),3.25(m,2H),2.17(d,J=8Hz,2H),1.93(m,1H),0.86(d,J=8Hz,6H);熔点:180-183℃。
(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)(4-(三氟甲基)苯基)甲酮153。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.30(dd,J1=2Hz,J2=8Hz,1H),8.01(d,J=2Hz,1H),7.83(s,1H),7.80(d,J=8Hz,2H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.62(d,J=8Hz,2H),7.03(d,J=8Hz,1H),3.75(m,2H),3.35-3.40(m,6H);熔点:190-193℃。
4-氯-1-(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)丁-1-酮160。HPLC纯度:98.5%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.00(d,J=2Hz,1H),7.81(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.01(d,J=8Hz,1H),3.63(t,J=8Hz,2H),3.56(m,4H),3.33(m,2H),3.27(m,2H),2.45(m,2H),1.91(m,2H);熔点:179-182℃。
环丁基(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)甲酮161。HPLC纯度:99.6%;1H NMR(500MHz,DMSO-d6):δ8.50(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),7.99(d,J=2Hz,1H),7.81(d,J=8Hz,1H),7.73(dd,J1=2Hz,J2=8Hz,1H),7.01(d,J=8Hz,1H),3.54(m,2H),3.42(m,2H),3.24-3.31(m,5H),2.12(m,2H),2.06(m,2H),1.85(m,1H),1.69(m,1H);熔点:189-192℃。
环己基(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)甲酮162。HPLC纯度:99.3%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.00(d,J=2Hz,1H),7.80(d,J=8Hz,1H),7.73(dd,J1=2Hz,J2=8Hz,1H),7.01(d,J=8Hz,1H),3.59(m,4H),3.25(m,2H),2.53(m,1H),1.65(m,2H),1.59(m,3H),1.25(m,4H),1.13(m,1H);熔点:207-210℃。
(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)(苯基)甲酮163。HPLC纯度:99%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.29(dd,J1=2Hz,J2=8Hz,1H),8.02(d,J=2Hz,1H),7.82(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.44(m,3H),7.39(m,2H),7.02(d,J=8Hz,1H),3.72(m,2H),3.38(m,6H)。
(4-氯苯基)(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-哌嗪-1-基)甲酮164。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.29(dd,J1=2Hz,J2=8Hz,1H),8.01(d,J=2Hz,1H),7.82(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.48(d,J=8Hz,2H),7.42(d,J=8Hz,2H),7.02(d,J=8Hz,1H),3.71(m,2H),3.37(m,6H);熔点:172-175℃。
(4-甲氧基苯基)(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-哌嗪-1-基)甲酮165。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.29(dd,J1=2Hz,J2=8Hz,1H),8.02(d,J=2Hz,1H),7.82(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.35(d,J=8Hz,1H),7.02(d,J=8Hz,1H),6.95(d,J=8Hz,2H),3.78(s,3H),3.60(m,4H),3.37(m,4H);熔点:185-188℃。
(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)(呋喃-2-基)甲酮166。HPLC纯度:99%;1H NMR(500MHz,DMSO-d6):δ8.52(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.02(d,J=2Hz,1H),7.82(d,J=2Hz,1H),7.80(s,1H),7.73(dd,J1=2Hz,J2=8Hz,1H),7.00(m,2H),6.62(m,1H),3.78(m,4H),3.40(m,4H);熔点:199-202℃。
1-(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)乙酮167。HPLC纯度:99%;1H NMR(500MHz,DMSO-d6):δ8.50(d,J=2Hz,1H),8.26(dd,J1=2Hz,J2=8Hz,1H),7.47(s,1H),7.41(d,J=8Hz,1H),7.35(d,J=8Hz,1H),6.81(d,J=8Hz,1H),3.55(m,4H),3.35(m,2H),3.24(m,2H),2.32(s,3H),2.24(s,3H),2.00(s,3H);熔点:151-153℃。
(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)(4-(三氟甲基)苯基)甲酮168。HPLC纯度:99%;1H NMR(500MHz,DMSO-d6):δ8.50(d,J=2Hz,1H),8.27(dd,J1=2Hz,J2=8Hz,1H),7.81(d,J=8Hz,2H),7.63(d,J=8Hz,2H),7.48(s,1H),7.42(d,J=8Hz,1H),7.36(d,J=8Hz,1H),6.82(d,J=8Hz,1H),3.76(m,2H),3.35-3.41(m,6H),2.33(s,3H),2.26(s,3H);熔点:200-203℃。
1-(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)-3-甲基丁-1-酮169。HPLC纯度:99%;1H NMR(500MHz,DMSO-d6):δ8.50(d,J=2Hz,1H),8.25(dd,J1=2Hz,J2=8Hz,1H),7.47(s,1H),7.42(d,J=8Hz,1H),7.35(d,J=8Hz,1H),6.81(d,J=8Hz,1H),3.57(m,4H),3.32(m,2H),3.25(m,2H),2.32(s,3H),2.23(s,3H),2.19(d,J=8Hz,2H),1.94(m,1H),0.87(d,J=8Hz,6H);熔点:157-160℃。
4-氯-1-(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)丁-1-酮170。HPLC纯度:99%;1H NMR(500MHz,DMSO-d6):δ8.50(d,J=2Hz,1H),8.26(dd,J1=2Hz,J2=8Hz,1H),7.47(s,1H),7.41(d,J=8Hz,1H),7.35(d,J=8Hz,1H),6.81(d,J=8Hz,1H),3.64(t,J1=J2=7Hz,2H),3.57(m,4H),3.33(m,2H),3.27(m,2H),2.46(t,J1=J2=7Hz,2H),2.32(s,3H),2.24(s,3H),1.93(m,2H);熔点:156-159℃。
环己基(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)甲酮171。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.50(d,J=2Hz,1H),8.26(dd,J1=2Hz,J2=8Hz,1H),7.47(s,1H),7.42(d,J=8Hz,1H),7.35(d,J=8Hz,1H),6.81(d,J=8Hz,1H),3.62(s,2H),3.55(s,2H),3.24(s,2H),2.56(m,1H),2.32(s,3H),2.23(s,3H),1.67(m,2H),1.59(m,3H),1.27(m,4H),1.12(m,1H);熔点:170-173℃。
(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)(苯基)甲酮172。HPLC纯度:99.9%;1H NMR(500MHz,DMSO-d6):δ8.50(d,J=2Hz,1H),8.27(dd,J1=2Hz,J2=8Hz,1H),7.35-7.48(m,8H),6.82(d,J=8Hz,1H),3.70(m,2H),3.38(m,6H),2.33(s,3H),2.25(s,3H);熔点:190-193℃。
(4-氯苯基)(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺酰基)-哌嗪-1-基)甲酮173。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.50(d,J=2Hz,1H),8.27(dd,J1=2Hz,J2=8Hz,1H),7.49(t,J1=J2=8Hz,3H),7.44(t,J1=J2=8Hz,3H),7.35(d,J=8Hz,1H),6.82(d,J=8Hz,1H),3.71(m,2H),3.37(m,6H),2.33(s,3H),2.25(s,3H);熔点:205-207℃。
(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)(4-甲氧基苯基)甲酮174。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.50(d,J=2Hz,1H),8.27(dd,J1=2Hz,J2=8Hz,1H),7.48(s,1H),7.42(d,J=8Hz,1H),7.37(m,3H),6.97(d,J=8Hz,2H),5.82(d,J=8Hz,1H),3.78(s,3H),3.60(m,4H),3.36(m,4H),2.33(s,3H),2.25(s,3H);熔点:163-167℃。
(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺酰基)哌嗪-1-基)(呋喃-2-基)甲酮175。HPLC纯度:96%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.26(dd,J1=2Hz,J2=8Hz,1H),7.83(s,1H),7.48(s,1H),7.41(d,J=8Hz,1H),7.36(d,J=8Hz,1H),7.02(d,J=2Hz,1H),6.81(d,J=8Hz,1H),6.62(dd,J1=2Hz,J2=8Hz,1H),3.79(m,4H),3.40(m,4H),2.32(s,3H),2.24(s,3H);熔点:160-163℃。
1-(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)乙酮176。HPLC纯度:98.7%;1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.43(dd,J1=2Hz,J2=8Hz,1H),7.76(d,J=8Hz,1H),7.66(d,J=2Hz,1H),7.50(dd,J1=2Hz,J2=8Hz,1H),7.11(d,J=8Hz,1H),3.51(m,4H),3.31(m,2H),3.23(m,2H),1.98(s,3H);熔点:270-273℃。
1-(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)-3-甲基丁-1-酮177。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.43(dd,J1=2Hz,J2=8Hz,1H),7.76(d,J=8Hz,1H),7.65(d,J=2Hz,1H),7.50(dd,J1=2Hz,J2=8Hz,1H),7.11(d,J=8Hz,1H),3.54(m,4H),3.29(m,2H),3.22(m,2H),2.16(d,J=8Hz,2H),1.92(m,1H),0.86(d,J=8Hz,6H);熔点:157-160℃。
(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)(4-(三氟甲基)苯基)甲酮178。HPLC纯度:99%;1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.45(dd,J1=2Hz,J2=8Hz,1H),7.79(d,J=8Hz,2H),7.76(d,J=8Hz,1H),7.70(d,J=2Hz,1H),7.61(d,J=8Hz,2H),7.51(dd,J1=2Hz,J2=8Hz,1H),7.13(d,J=8Hz,1H),3.73(m,2H),3.30-3.60(m,6H);熔点:230-233℃。
4-氯-1-(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)丁-1-酮179。HPLC纯度:97.5%;1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.43(dd,J1=2Hz,J2=8Hz,1H),7.76(d,J=8Hz,1H),7.65(d,J=2Hz,1H),7.51(dd,J1=2Hz,J2=8Hz,1H),7.11(d,J=8Hz,1H),3.63(t,J1=J2=8Hz,2H),3.53(m,4H),3.31(m,2H),3.24(m,2H),2.43(t,J1=J2=8Hz,2H),1.91(m,2H);熔点:145-149℃。
环丁基(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)甲酮180。HPLC纯度:98%;1H NMR(500MHz,DMSO-d6):δ8.58(d,J=2Hz,1H),8.43(dd,J1=2Hz,J2=8Hz,1H),7.76(d,J=8Hz,1H),7.65(d,J=2Hz,1H),7.50(dd,J1=2Hz,J2=8Hz,1H),7.11(d,J=8Hz,1H),3.52(m,2H),3.39(m,2H),3.25(m,5H),2.10(m,2H),2.03(m,2H),1.84(m,1H),1.70(m,1H);熔点:237-241℃。
环己基(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)甲酮181。HPLC纯度:99%;1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.43(dd,J1=2Hz,J2=8Hz,1H),7.76(d,J=8Hz,1H),7.65(d,J=2Hz,1H),7.51(dd,J1=2Hz,J2=8Hz,1H),7.11(d,J=8Hz,1H),3.55(d,J=32Hz,4H),3.24(d,J=32Hz,4H),2.52(m,1H),1.56-1.66(m,5H),1.27(m,4H),1.13(m,1H);熔点:200-203℃。
(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)(苯基)甲酮182。HPLC纯度:98%;1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.44(dd,J1=2Hz,J2=8Hz,1H),7.76(d,J=8Hz,1H),7.71(d,J=2Hz,1H),7.50(dd,J1=2Hz,J2=8Hz,1H),7.36-7.45(m,5H),7.13(d,J=8Hz,1H),3.70(m,2H),3.35(m,6H);熔点:206-209℃。
(4-氯苯基)(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)-哌嗪-1-基)甲酮183。HPLC纯度:97%;1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.45(dd,J1=2Hz,J2=8Hz,1H),7.76(d,J=8Hz,1H),7.70(d,J=2Hz,1H),7.50(dd,J1=2Hz,J2=8Hz,1H),7.48(d,J=8Hz,2H),7.42(d,J=8Hz,2H),7.13(d,J=8Hz,1H),3.69(m,2H),3.34(m,6H);熔点:226-229℃。
(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)(4-甲氧基苯基)甲酮184。HPLC纯度:97%;1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.44(dd,J1=2Hz,J2=8Hz,1H),7.76(d,J=8Hz,1H),7.69(d,J=2Hz,1H),7.50(dd,J1=2Hz,J2=8Hz,1H),7.36(d,J=8Hz,2H),7.12(d,J=8Hz,1H),6.95(d,J=8Hz,2H),3.78(s,3H),3.56(m,4H),3.29(m,4H);熔点:197-200℃。
(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)(呋喃-2-基)甲酮185。HPLC纯度:98%;1H NMR(500MHz,DMSO-d6):δ8.60(d,J=2Hz,1H),8.43(dd,J1=2Hz,J2=8Hz,1H),7.82(s,1H),7.75(d,J=8Hz,1H),7.67(d,J=2Hz,1H),7.50(dd,J1=2Hz,J2=8Hz,1H),7.10(d,J=8Hz,1H),6.99(d,J=2Hz,1H),6.61(d,J=2Hz,1H),3.75(m,4H),3.37(m,4H);熔点:236-240℃。
1-(4-(2-(2,5-二甲基苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)-3-甲基丁-1-酮187。HPLC纯度:97.3%;1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.41(dd,J1=2Hz,J2=8Hz,1H),7.31(d,J=8Hz,1H),7.11(d,J=8Hz,1H),7.01(s,1H),6.84(d,J=8Hz,1H),3.54(m,4H),3.29(m,2H),3.22(m,2H),2.30(s,3H),2.17(d,J=8Hz,2H),2.08(s,3H),1.93(m,1H),0.86(d,J=8Hz,6H);熔点:155-158℃。
(4-(2-(2,5-二甲基苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)(4-(三氟metriyl)苯基)metrianone 188。HPLC纯度:99%;1H NMR(500MHz,DMSO-d6):δ8.58(d,J=2Hz,1H),8.42(dd,J1=2Hz,J2=8Hz,1H),7.79(d,J=8Hz,2H),7.62(d,J=8Hz,2H),7.31(d,J=8Hz,1H),7.12(d,J=8Hz,1H),7.08(s,1H),6.86(d,J=8Hz,1H),3.73(m,2H),3.40(m,6H),2.32(s,3H),2.09(s,3H);熔点:177-180℃。
(4-(2-(2,5-二甲基苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)(4-甲氧基苯基)甲酮189。HPLC纯度:99.7%;1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.42(dd,J1=2Hz,J2=8Hz,1H),7.35(d,J=8Hz,2H),7.31(d,J=8Hz,1H),7.12(d,J=8Hz,1H),7.07(s,1H),6.95(d,J=8Hz,H),6.86(d,J=8Hz,1H),3.78(s,3H),3.57(m,4H),3.33(m,4H),2.32(s,3H),2.09(s,3H);熔点:161-164℃。
(4-(2-(2,5-二甲基苯氧基)-5-硝基苯基磺酰基)哌嗪-1-基)(呋喃-2-基)甲酮190。HPLC纯度:99.5%;1H NMR(500MHz,DMSO-d6):δ8.59(d,J=2Hz,1H),8.41(dd,J1=2Hz,J2=8Hz,1H),7.82(d,J=2Hz,1H),7.31(d,J=8Hz,1H),7.11(d,J=8Hz,1H),7.05(s,1H),6.99(d,J=4Hz,1H),6.84(d,J=8Hz,1H),6.62(d,J=2Hz,1H),3.75(m,4H),3.37(m,4H),2.29(s,3H),2.08(s,3H);熔点:170-174℃。
N-烯丙基-4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)哌嗪-1-甲酰胺191。HPLC纯度:98.2%;1H NMR(500MHz,DMSO-d6):δ8.52(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),7.98(d,J=2Hz,1H),7.80(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.00(d,J=8Hz,1H),6.70(t,J=4Hz,1H),5.76(m,1H),5.06(d,J=9Hz,1H),4.97(d,J=4Hz,1H),3.62(m,2H),3.42(m,4H),3.26(m,4H);熔点:198-202℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-N,N-二乙基哌嗪-1-甲酰胺192。HPLC纯度:99%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),7.99(d,J=2Hz,1H),7.81(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.01(d,J=8Hz,1H),3.32(m,4H),3.17(m,4H),3.09(m,4H),1.00(m,6H);熔点:160-163℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-N-/?-tolyl哌嗪-1-甲酰胺193。HPLC纯度:97%;1H NMR(500MHz,DMSO-d6):δ8.53(m,2H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.01(d,J=2Hz,1H),7.81(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.28(d,J=8Hz,2H),7.01(d,J=8Hz,3H),3.56(m,4H),3.35(m,4H),2.21(s,3H);熔点:231-234℃。
N-(4-氰基苯基)-4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-哌嗪-1-甲酰胺194。HPLC纯度:97.7%;1H NMR(500MHz,DMSO-d6):δ9.09(s,1H),8.53(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.00(d,J=2Hz,1H),7.81(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.68(d,J=8Hz,2H),7.62(d,J=2Hz,2H),7.01(d,J=8Hz,1H),3.60(m,4H),3.36(m,4H);熔点:232-235℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-N-(4-硝基苯基)-哌嗪-1-甲酰胺195。HPLC纯度:98.3%;1H NMR(500MHz,DMSO-d6):δ9.31(s,1H),8.53(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.14(d,J=8Hz,2H),8.00(d,J=2Hz,1H),7.81(d,J=8Hz,1H),7.75(dd,J1=2Hz,J2=8Hz,1H),7.67(d,J=8Hz,1H),7.02(d,J=8Hz,1H),3.62(m,4H),3.37(m,4H);熔点:242-246℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-N-异丙基哌嗪-1-硫代甲酰胺196。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.00(d,J=2Hz,1H),7.81(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.46(d,J=6Hz,1H),7.00(d,J=8Hz,1H),4.46(m,1H),3.90(s,4H),3.32(s,4H),1.10(d,6H);熔点:190-193℃。
N-(3-氯苄基)-4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-哌嗪-1-硫代甲酰胺197。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.52(d,J=2Hz,1H),8.41(t,J1=J2=4Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.00(d,J=2Hz,1H),7.81(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.27(m,3H),7.21(d,J=8Hz,1H),7.01(d,J=8Hz,1H),4.75(d,J=8Hz,2H),3.97(m,4H),3.37(m,4H);熔点:170-174℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-N-(3-oxo戊基)-哌嗪-1-硫代甲酰胺198。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.00(d,J=2Hz,1H),7.89(t,J1=J2=4Hz,1H),7.81(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.00(d,J=8Hz,1H),4.02(q,J1=J2=8Hz,2H),3.89(m,4H),3.67(m,2H),2.57(t,J1=J2=6Hz,2H),1.15(t,/;=J2=6Hz,3H);熔点:200-204℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-N-苯基哌嗪-1-硫代甲酰胺199。HPLC纯度:99.8%;1H NMR(500MHz,DMSO-d6):δ9.46(s,1H),8.54(d,J=2Hz,1H),8.29(dd,J1=2Hz,J2=8Hz,1H),8.02(d,J=2Hz,1H),7.82(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.26(m,4H),7.10(m,1H),7.02(d,J=8Hz,1H),4.03(m,4H),3.42(m,4H);熔点:198-201℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-N-(2-吗啉基乙基)-哌嗪-1-硫代甲酰胺200。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.28(dd,J1=2Hz,J2=8Hz,1H),8.00(d,J=2Hz,1H),7.81(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,2H),7.00(d,J=8Hz,1H),3.89(m,4H),3.58(m,2H),3.50(m,4H),2.43(t,J1=J2=6Hz,2H),2.35(m,4H);熔点:130-136℃。
1-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-4-(甲基磺酰基)-哌嗪202。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.54(d,J=8Hz,2H),8.30(dd,J1=2Hz,J2=8Hz,1H),8.02(d,J=2Hz,1H),7.82(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.02(d,J=8Hz,1H),3.44(m,4H),3.24(m,4H),2.92(s,3H);熔点:277-281℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-N,N-二甲基-哌嗪-1-磺酰胺203。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.53(d,J=2Hz,1H),8.29(dd,J1=2Hz,J2=8Hz,1H),8.00(d,J=2Hz,1H),7.82(d,J=8Hz,1H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.03(d,J=8Hz,1H),3.39(m,4H),3.26(m,4H),2.74(s,6H);熔点:231-234℃。
1-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-4-(苯基磺酰基)-哌嗪204。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.48(d,J=2Hz,1H),8.23(dd,J1=2Hz,J2=8Hz,1H),7.90(d,J=2Hz,1H),7.69-7.76(m,5H),7.60(m,2H),6.93(d,J=8Hz,1H),3.43(m,4H),2.99(m,4H);熔点:236-239℃。
1-(2-(2,5-二氯苯硫基)-5-硝基苯基磺酰基)-4-(4-(三氟甲基)苯基磺酰基)哌嗪205。HPLC纯度:100%;1H NMR(500MHz,DMSO-d6):δ8.51(d,J=2Hz,1H),8.23(dd,J1=2Hz,J2=8Hz,1H),8.01(d,J=8Hz,2H),7.94(d,J=8Hz,3H),7.74(dd,J1=2Hz,J2=8Hz,1H),7.64(d,J=8Hz,1H),6.92(d,J=8Hz,1H),3.44(m,4H),3.05(m,4H);熔点:264-267℃。
实施例4
CCR3受体结合分析
用PBS洗涤细胞一次,重新悬浮在结合缓冲液中(25mM HEPES pH7.6,5mM MgCl2,1mM CaCl2,0.5%BSA,0.1%NaN3)。将100mL细胞悬浮液(2×105个细胞/孔)和0.1nM[125I]-标记的人嗜酸性粒细胞趋化因子/CCL11(2000Ci/mmol比活性)在96孔U型底聚丙烯板中混合,在室温下孵育60分钟,进行结合反应。然后,将细胞悬浮液转移到过滤板(#MAFB,Millipore),用含有0.5M NaCl的结合缓冲液洗涤3次,加入闪烁剂,在TopCount(Packard)上计数放射性。为测定非特异性结合,将细胞悬浮液和[125I]-标记的人嗜酸性粒细胞趋化因子/CCL11在500nM未标记的人嗜酸性粒细胞趋化因子/CCL11存在下孵育。参见,Iino等人,″Molecular cloning andfunctional characterization of cynomolgus monkey(Macaca fascicularis)CCchemokine receptor,CCR3″,Cytokine 2002,19,276-286。
生物学结果列于表1,其中A代表值不大于50nM;B代表值大于50nM但不大于500nM;C代表值大于500nM但不大于5μM;和D代表值大于5μM。
表1
化合物# | Ki | 化合物# | Ki |
51 | D | 52 | D |
53 | D | 54 | D |
55 | D | 56 | D |
57 | C | 58 | B |
59 | D | 60 | D |
61 | D | 62 | D |
63 | D | 64 | D |
65 | D | 66 | D |
67 | D | 68 | D |
69 | D | 70 | A |
71 | D | 72 | C |
73 | D | 74 | D |
75 | A | 76 | A |
77 | A | 78 | B |
化合物# | Ki | 化合物# | Ki |
79 | A | 80 | C |
81 | C | 82 | C |
83 | C | 84 | C |
85 | C | 86 | D |
87 | D | 88 | D |
89 | B | 90 | B |
91 | B | 92 | D |
93 | B | 94 | D |
95 | B | 96 | C |
97 | B | 98 | D |
99 | D | 100 | D |
101 | D | 102 | D |
103 | D | 104 | D |
105 | D | 106 | D |
107 | D | 108 | D |
109 | A | 110 | A |
111 | A | 112 | D |
113 | D | 114 | C |
115 | D | 116 | D |
117 | D | 118 | D |
119 | D | 120 | D |
121 | D | 122 | D |
123 | D | 124 | B |
125 | A | 126 | D |
127 | A | 128 | C |
化合物# | Ki | 化合物# | Ki |
129 | D | 130 | D |
131 | D | 132 | D |
133 | B | 134 | B |
135 | A | 136 | A |
1371 | B | 138 | B |
139 | A | 140 | A |
141 | A | 142 | B |
143 | B | 144 | A |
145 | A | 146 | A |
147 | D | 148 | B |
149 | D | 150 | D |
152 | D | 153 | D |
154 | D | 155 | D |
156 | D | 157 | D |
158 | D | 159 | D |
160 | D | 161 | D |
162 | D | 163 | D |
164 | D | 165 | D |
172 | D | 173 | D |
174 | D | 177 | D |
182 | D | 184 | D |
185 | D | 189 | D |
190 | D | 191 | A |
193 | D | 194 | D |
195 | D | 198 | A |
化合物# | Ki | 化合物# | Ki |
202 | D | 203 | D |
204 | D | 205 | D |
1.化合物以盐酸盐测试。
提供上面例子用于向本领域技术人员充分公开如何制造和使用要求保护的实施方案,而不是限制本文所披露的范围。本领域技术人员显然可以
在所附权利要求书的范围内作出变化。本说明书中引用的所有出版物、专利和专利申请全部引入作为参考,就好象每个出版物、专利或专利申请均被具体和单独地被引入作为参考。
Claims (30)
1.一种式I的化合物:
或其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐;
其中:
R1、R2、R3、R4、R5每一个独立地是氢、卤素、或C1-6烷基;
R6是氰基;
X是O或S;
RYa是-C(O)R1a、-C(O)NR1bR1c或-S(O)2R1a;
m是1;
n是1;
p是0;和
每个R1a、R1b和R1c独立地是氢、C1-6烷基、C6-14芳基或杂芳基;或每对R1b和R1c与它们连接的氮原子一起独立地形成杂环基;
其中每个烷基、芳基、杂环基和杂芳基任选地被一个或多个基团所取代,每一个基团独立地选自氰基、卤素、C1-6烷基、C6-14芳基和-C(O)Ra,其中每个Ra是C1-6烷基。
2.如权利要求1所述的化合物,其中R1a是(a)甲基、乙基、丙基,丁基或戊基,每一个任选地被取代基所取代,所述取代基选自氯、氰基或呋喃基;(b)苯基,任选地被1或2个取代基所取代,每个取代基独立地选自氟、氯或甲基;或(c)噻吩基、异噁唑基、1,2,3-噻二唑基或吡嗪基,每一个任选地被1或2个甲基所取代。
3.如权利要求1所述的化合物,其中R1b是氢或C1-6烷基。
4.如权利要求3所述的化合物,其中R1b是氢、甲基或乙基。
5.如权利要求1所述的化合物,其中R1c是(a)氢;(b)甲基、乙基、丙基,丁基或戊基,每一个任选地被取代基所取代,所述取代基选自苯基或呋喃基;或(c)苯基,任选地被氟取代。
6.如权利要求1所述的化合物,其中R1、R2、R3、R4和R5每一个独立地是氢、卤素或C1-6烷基。
7.如权利要求6所述的化合物,其中R1、R2、R3、R4和R5中的两个是卤素或C1-6烷基,其余三个是氢。
8.如权利要求6所述的化合物,其中R1、R2、R3、R4和R5中的两个是氯或甲基,其余三个是氢。
9.如权利要求8所述的化合物,其中R1、R3和R5是氢,R2和R4是氯或甲基。
10.如权利要求9所述的化合物,其中R2和R4是氯。
11.如权利要求9所述的化合物,其中R2和R4是甲基。
12.如权利要求1所述的化合物,其中X是O。
13.如权利要求1所述的化合物,其中X是S。
14.如权利要求1所述的化合物,选自:
和其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体和两种或两种以上的互变异构体的混合物;和其药学上可接受的盐。
15.如权利要求1所述的化合物,其中所述化合物是盐酸盐。
16.一种药物组合物,含有如权利要求1~15中任一项所述的化合物,或其对映异构体、对映异构体的混合物、两种或两种以上的非对映异构体的混合物、互变异构体或两种或两种以上的互变异构体的混合物;或其药学上可接受的盐;和一种或多种药学上可接受的载体或赋形剂。
17.如权利要求16所述的药物组合物,还含有第二种治疗剂。
18.如权利要求16所述的药物组合物,其中所述组合物配制成单次剂量给予。
19.如权利要求18所述的药物组合物,其中所述组合物配制成口服、胃肠外或静脉剂型。
20.如权利要求19所述的药物组合物,其中口服剂型是片剂或胶囊剂。
21.如权利要求1~15中任一项所述的化合物在制备用于治疗、预防或缓解CCR3-介导的紊乱、疾病或病症的一种或多种症状的药物中的用途。
22.如权利要求1~15中任一项所述的化合物在制备用于治疗、预防或缓解嗜红细胞相关的紊乱、疾病或病症的一种或多种症状的药物中的用途。
23.如权利要求1~15中任一项所述的化合物在制备用于种治疗、预防或缓解嗜碱细胞相关的紊乱、疾病或病症的一种或多种症状的药物中的用途。
24.如权利要求1~15中任一项所述的化合物在制备用于治疗、预防或缓解肥大细胞相关的紊乱、疾病或病症的一种或多种症状的药物中的用途。
25.如权利要求1~15中任一项所述的化合物在制备用于治疗、预防或缓解炎性疾病的一种或多种症状的药物中的用途。
26.如权利要求21所述的用途,其中所述紊乱、疾病或病症选自哮喘、过敏性鼻炎、过敏性皮炎、接触过敏、接触性皮炎、结膜炎、嗜酸细胞性支气管炎、食物过敏、嗜酸细胞性胃肠炎、炎症性肠道疾病、克罗恩病、肥大细胞增多症、超IgE综合征、系统性红斑狼疮、牛皮癣、痤疮、多发性硬化症、移植排斥、再灌注损伤、Churg-Strauss综合征、鼻窦炎、嗜碱性白血病、慢性荨麻疹、嗜碱性白细胞增多、湿疹、COPD(慢性阻塞性肺紊乱)、关节炎和心血管紊乱。
27.如权利要求26所述的用途,其中所述紊乱、疾病或病症是哮喘、过敏性鼻炎、过敏性皮炎、慢性阻塞性肺疾病或结膜炎。
28.如权利要求21所述的用途,其中所述化合物经口服、胃肠外或局部给予。
29.如权利要求21所述的用途,其中所述化合物与第二种治疗剂联合给予。
30.如权利要求1~15中任一项所述的化合物在制备用于调控CCR3活性的药物中的用途。
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NZ595797A (en) * | 2009-04-22 | 2014-03-28 | Axikin Pharmaceuticals Inc | 2,5-disubstituted arylsulfonamide ccr3 antagonists |
US8999995B2 (en) * | 2010-03-02 | 2015-04-07 | Axikin Pharmaceuticals, Inc. | Isotopically enriched arylsulfonamide CCR3 antagonists |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1376063A (zh) * | 1999-08-04 | 2002-10-23 | 帝人株式会社 | 环胺ccr3拮抗剂 |
WO2003022277A1 (en) * | 2001-09-07 | 2003-03-20 | Bayer Healthcare Ag | Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders |
CN1599611A (zh) * | 2001-11-30 | 2005-03-23 | 霍夫曼-拉罗奇有限公司 | 作为哮喘治疗中的ccr-3受体拮抗剂的哌嗪衍生物 |
CN1802159A (zh) * | 2003-03-24 | 2006-07-12 | 阿克蒂米斯药品公司 | 治疗哮喘及其它炎症或免疫性疾病的具有ccr3拮抗活性的2-苯氧基-和2-苯基磺酰胺衍生物 |
Family Cites Families (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3536809A (en) | 1969-02-17 | 1970-10-27 | Alza Corp | Medication method |
US3598123A (en) | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
US3845770A (en) | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US3916899A (en) | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
US4008719A (en) | 1976-02-02 | 1977-02-22 | Alza Corporation | Osmotic system having laminar arrangement for programming delivery of active agent |
US4410545A (en) | 1981-02-13 | 1983-10-18 | Syntex (U.S.A.) Inc. | Carbonate diester solutions of PGE-type compounds |
US4328245A (en) | 1981-02-13 | 1982-05-04 | Syntex (U.S.A.) Inc. | Carbonate diester solutions of PGE-type compounds |
US4409239A (en) | 1982-01-21 | 1983-10-11 | Syntex (U.S.A.) Inc. | Propylene glycol diester solutions of PGE-type compounds |
ES8702440A1 (es) | 1984-10-04 | 1986-12-16 | Monsanto Co | Un procedimiento para la preparacion de una composicion de polipeptido inyectable sustancialmente no acuosa. |
IE58110B1 (en) | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
US5033252A (en) | 1987-12-23 | 1991-07-23 | Entravision, Inc. | Method of packaging and sterilizing a pharmaceutical product |
US5052558A (en) | 1987-12-23 | 1991-10-01 | Entravision, Inc. | Packaged pharmaceutical product |
US5073543A (en) | 1988-07-21 | 1991-12-17 | G. D. Searle & Co. | Controlled release formulations of trophic factors in ganglioside-lipsome vehicle |
US5612059A (en) | 1988-08-30 | 1997-03-18 | Pfizer Inc. | Use of asymmetric membranes in delivery devices |
IT1229203B (it) | 1989-03-22 | 1991-07-25 | Bioresearch Spa | Impiego di acido 5 metiltetraidrofolico, di acido 5 formiltetraidrofolico e dei loro sali farmaceuticamente accettabili per la preparazione di composizioni farmaceutiche in forma a rilascio controllato attive nella terapia dei disturbi mentali organici e composizioni farmaceutiche relative. |
PH30995A (en) | 1989-07-07 | 1997-12-23 | Novartis Inc | Sustained release formulations of water soluble peptides. |
US5120548A (en) | 1989-11-07 | 1992-06-09 | Merck & Co., Inc. | Swelling modulated polymeric drug delivery device |
US5585112A (en) | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
IT1246382B (it) | 1990-04-17 | 1994-11-18 | Eurand Int | Metodo per la cessione mirata e controllata di farmaci nell'intestino e particolarmente nel colon |
US5733566A (en) | 1990-05-15 | 1998-03-31 | Alkermes Controlled Therapeutics Inc. Ii | Controlled release of antiparasitic agents in animals |
US5543390A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | Covalent microparticle-drug conjugates for biological targeting |
US5580578A (en) | 1992-01-27 | 1996-12-03 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5323907A (en) | 1992-06-23 | 1994-06-28 | Multi-Comp, Inc. | Child resistant package assembly for dispensing pharmaceutical medications |
TW333456B (en) | 1992-12-07 | 1998-06-11 | Takeda Pharm Ind Co Ltd | A pharmaceutical composition of sustained-release preparation the invention relates to a pharmaceutical composition of sustained-release preparation which comprises a physiologically active peptide. |
US5591767A (en) | 1993-01-25 | 1997-01-07 | Pharmetrix Corporation | Liquid reservoir transdermal patch for the administration of ketorolac |
GB9305282D0 (en) * | 1993-03-15 | 1993-05-05 | Ucb Sa | Enantiomers of 1-(4-chlorophenyl)phenylmethyl)-4-(4-methylphenyl)sulphonyl)piperazine |
US6274552B1 (en) | 1993-03-18 | 2001-08-14 | Cytimmune Sciences, Inc. | Composition and method for delivery of biologically-active factors |
US5985307A (en) | 1993-04-14 | 1999-11-16 | Emory University | Device and method for non-occlusive localized drug delivery |
US5523092A (en) | 1993-04-14 | 1996-06-04 | Emory University | Device for local drug delivery and methods for using the same |
US6087324A (en) | 1993-06-24 | 2000-07-11 | Takeda Chemical Industries, Ltd. | Sustained-release preparation |
US6004534A (en) | 1993-07-23 | 1999-12-21 | Massachusetts Institute Of Technology | Targeted polymerized liposomes for improved drug delivery |
IT1270594B (it) | 1994-07-07 | 1997-05-07 | Recordati Chem Pharm | Composizione farmaceutica a rilascio controllato di moguisteina in sospensione liquida |
US5759542A (en) | 1994-08-05 | 1998-06-02 | New England Deaconess Hospital Corporation | Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases |
US5660854A (en) | 1994-11-28 | 1997-08-26 | Haynes; Duncan H | Drug releasing surgical implant or dressing material |
US6316652B1 (en) | 1995-06-06 | 2001-11-13 | Kosta Steliou | Drug mitochondrial targeting agents |
US5798119A (en) | 1995-06-13 | 1998-08-25 | S. C. Johnson & Son, Inc. | Osmotic-delivery devices having vapor-permeable coatings |
AU6242096A (en) | 1995-06-27 | 1997-01-30 | Takeda Chemical Industries Ltd. | Method of producing sustained-release preparation |
TW448055B (en) | 1995-09-04 | 2001-08-01 | Takeda Chemical Industries Ltd | Method of production of sustained-release preparation |
JP2909418B2 (ja) | 1995-09-18 | 1999-06-23 | 株式会社資生堂 | 薬物の遅延放出型マイクロスフイア |
US6039975A (en) | 1995-10-17 | 2000-03-21 | Hoffman-La Roche Inc. | Colon targeted delivery system |
US5980945A (en) | 1996-01-16 | 1999-11-09 | Societe De Conseils De Recherches Et D'applications Scientifique S.A. | Sustained release drug formulations |
TW345603B (en) | 1996-05-29 | 1998-11-21 | Gmundner Fertigteile Gmbh | A noise control device for tracks |
US6264970B1 (en) | 1996-06-26 | 2001-07-24 | Takeda Chemical Industries, Ltd. | Sustained-release preparation |
US6419961B1 (en) | 1996-08-29 | 2002-07-16 | Takeda Chemical Industries, Ltd. | Sustained release microcapsules of a bioactive substance and a biodegradable polymer |
CN1233954A (zh) | 1996-10-01 | 1999-11-03 | 西马实验室股份有限公司 | 掩盖味道的微胶囊组合物及其制备方法 |
CA2217134A1 (en) | 1996-10-09 | 1998-04-09 | Sumitomo Pharmaceuticals Co., Ltd. | Sustained release formulation |
ES2221019T3 (es) | 1996-10-31 | 2004-12-16 | Takeda Chemical Industries, Ltd. | Preparacion de liberacion mantenida. |
US6131570A (en) | 1998-06-30 | 2000-10-17 | Aradigm Corporation | Temperature controlling device for aerosol drug delivery |
EP0946169B1 (en) | 1996-12-20 | 2003-02-26 | Takeda Chemical Industries, Ltd. | Method of producing a sustained-release preparation |
US5891474A (en) | 1997-01-29 | 1999-04-06 | Poli Industria Chimica, S.P.A. | Time-specific controlled release dosage formulations and method of preparing same |
US6120751A (en) | 1997-03-21 | 2000-09-19 | Imarx Pharmaceutical Corp. | Charged lipids and uses for the same |
US6060082A (en) | 1997-04-18 | 2000-05-09 | Massachusetts Institute Of Technology | Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery |
US6350458B1 (en) | 1998-02-10 | 2002-02-26 | Generex Pharmaceuticals Incorporated | Mixed micellar drug deliver system and method of preparation |
US6613358B2 (en) | 1998-03-18 | 2003-09-02 | Theodore W. Randolph | Sustained-release composition including amorphous polymer |
US6048736A (en) | 1998-04-29 | 2000-04-11 | Kosak; Kenneth M. | Cyclodextrin polymers for carrying and releasing drugs |
KR19990085365A (ko) | 1998-05-16 | 1999-12-06 | 허영섭 | 지속적으로 약물 조절방출이 가능한 생분해성 고분자 미립구 및그 제조방법 |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US6271359B1 (en) | 1999-04-14 | 2001-08-07 | Musc Foundation For Research Development | Tissue-specific and pathogen-specific toxic agents and ribozymes |
US6465467B1 (en) | 1999-05-21 | 2002-10-15 | Biovitrum Ab | Certain aryl-aliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases |
JP2004507502A (ja) | 2000-08-30 | 2004-03-11 | ファイザー・プロダクツ・インク | 成長ホルモン分泌促進物質のための徐放性製剤 |
WO2003055851A1 (fr) * | 2001-12-27 | 2003-07-10 | Sumitomo Pharmaceuticals Company, Limited | Derives d'acide hydroxamique et inhibiteur des mmp contenant ces derniers en tant que substance active |
CA2567166A1 (en) * | 2004-05-19 | 2005-11-24 | Solvay Pharmaceuticals Gmbh | Medicaments containing n-sulfamoyl-n'-arylpiperazines for the prophylaxis or treatment of obesity and related conditions |
US7759339B2 (en) | 2005-03-31 | 2010-07-20 | Takeda San Diego, Inc. | Hydroxysteroid dehydrogenase inhibitors |
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2010
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1376063A (zh) * | 1999-08-04 | 2002-10-23 | 帝人株式会社 | 环胺ccr3拮抗剂 |
WO2003022277A1 (en) * | 2001-09-07 | 2003-03-20 | Bayer Healthcare Ag | Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders |
CN1599611A (zh) * | 2001-11-30 | 2005-03-23 | 霍夫曼-拉罗奇有限公司 | 作为哮喘治疗中的ccr-3受体拮抗剂的哌嗪衍生物 |
CN1802159A (zh) * | 2003-03-24 | 2006-07-12 | 阿克蒂米斯药品公司 | 治疗哮喘及其它炎症或免疫性疾病的具有ccr3拮抗活性的2-苯氧基-和2-苯基磺酰胺衍生物 |
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