CN106928097B - 化合物、其制备方法及其在制备药物中的用途 - Google Patents
化合物、其制备方法及其在制备药物中的用途 Download PDFInfo
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004590 pyridopyridyl group Chemical group N1=C(C=CC2=C1C=CC=N2)* 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
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- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
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- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
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- 125000004434 sulfur atom Chemical group 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/16—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提出了化合物、其制备方法及其在制备药物中的用途。所述化合物为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物或药学上可接受的盐。本发明的化合物不仅可以实现将注射剂型帕拉米苇改造为吸入剂型,改善其用药依从性,使其具有使用方便、适合大范围使用的特点,而且药物吸入后将直接作用于流感病毒侵染的呼吸道和肺部,有望实现一次给药,可以有效地对流感起到预防和治疗双重作用。
Description
技术领域
本发明涉及医药领域。具体地,本发明涉及化合物、其制备方法及其在制备药物中的用途。
背景技术
流感是流感病毒引起的急性呼吸道传染病,具有爆发持续性和高度传染性等特点,能够严重危及人类的健康和生活。从上个世纪初到现在,人类已经经历了六次流感大爆发,如1918年H1N1病毒的大流行中,全世界约有4000万人丧生,1968年香港H3N2流感病毒以及1997年香港H5N1流感病毒均造成大范围的恐慌。而在最近十年内,又爆发了2003-2005年高致死性H5N1流感病毒,影响极广的2009年H1N1流感病毒流行,以及2013年在我国出现的有较高致死率的H7N9疫情。这些疫情都为我国的病毒感染性疾病的防控提出了新的挑战。
然而,目前治疗流感的药物仍有待开发。
发明内容
本发明旨在至少在一定程度上解决现有技术中存在的技术问题至少之一。
需要说明的是,本发明是基于发明人的下列发现而完成的:
目前,针对流感病毒的小分子抗流感病毒药物研发集中在M2+离子通道阻断剂、神经氨酸酶(NA)抑制剂、血凝素(HA)抑制剂和聚合酶(NP)抑制剂这四个靶点上。而正式上市的抗流感药物主要分为两大类:一是以二十世纪六十年代中期发现的以金刚烷胺(Amantadine)为代表的M2+离子通道阻断剂作为抗流感药物,另一类是以达菲(Tamiflu)、乐感清(Relenza)和帕拉米苇(Peramivir)为代表的神经氨酸酶抑制剂。目前,以血凝素和聚合酶为作用靶点的药物还没有上市。
M2+离子通道阻断剂的缺点是只对甲型流感病毒有预防和治疗作用,而且毒性较大,目前已经发现部分甲型流感病毒已经对金刚烷胺产生耐药性。神经氨酸酶抑制剂对甲型和乙型流感病毒均有效,已经成为市场上主流的抗流感药物以及国家战略储备药物。目前,市场上主流的小分子神经氨酸酶抑制剂是以达菲、乐感清和帕拉米苇为代表的抗流感病毒药物,乐感清是首个上市的神经氨酸酶抑制剂药物,为吸入型药物,每个疗程为5天,每天吸入两次,每次10mg;达菲为首个口服神经氨酸酶抑制剂药物,每个疗程为5天,每天服药两次,每次75mg;帕拉米苇新近上市的注射剂型神经氨酸酶抑制剂药物,一个疗程可以实现一次给药,每次静脉注射300mg。达菲、乐感清作为抗流感病毒药物,其使用期已经超过十年,流感病毒已经对达菲、乐感清产生了一定的耐药性。帕拉米苇作为新近上市的抗流感病毒药物,可以实现一次给药,是一种长效型抗流感病毒药物。但由于帕拉米苇为注射剂型药物,注射治疗只能在医院进行,不适合大范围使用。
有鉴于此,发明人经过大量实验,通过在帕拉米苇分子结构中的羟基位进行修饰,形成前药。该前药为吸入剂型,吸入后将在体内转化为活性代谢物帕拉米苇,并且长时间停留在人体内病毒易增殖部位,如气道、肺部,可以选择性阻断A型及B型流感病毒的神经氨酸,切断子代病毒颗粒,使其从受感染细胞表面游离,达到抑制病毒细胞增殖作用。
为此,在本发明的一个方面,本发明提出了一种化合物。根据本发明的实施例,所述化合物为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物或药学上可接受的盐,
所述X为O、S或N;
所述Y为O或S;
所述R1为C1~10烷基、C2~10烯基、C2~10炔基、C1~10杂烷基、C1~10烷氧基、C1~10烷氨基或C1~10烷硫基;
所述L为C1~10烷基、C2~10烯基、C2~10炔基、C1~10杂烷基、C1~10烷氧基、C1~10烷氨基或C1~10烷硫基,
其中,所述烷基、烯基、炔基、杂烷基、烷氧基、烷氨基和烷硫基均可任选地被一个或多个选自D、F、Cl、Br、I、-OH、-NO2、-NH2、-CN、-COOH、C1~8烷基、C1~8烷氧基、C1~8烷氨基、C1~8烷硫基、C6~10芳基、C6~10芳氧基、C6~10芳氨基、C6~10杂芳基、C6~10杂芳基氧基、C3~8环烷基、C3~8环烷基氧基、C2~8杂环基、C6~10稠合双环基、C6~10稠合双环基烷基、C6~10稠合双环基烯基、C6~10稠合双环基炔基、C6~10稠合杂双环基、C6~10稠合杂双环基烷基、C6~10稠合杂双环基烯基、C6~10稠合杂双环基炔基、C6~10螺双环基、C6~10螺双环基烷基、C6~10螺双环基烯基、C6~10螺双环基炔基、C6~10螺杂双环基、C6~10螺杂双环基烷基、C6~10螺杂双环基烯基或C6~10螺杂双环基炔基的基团所取代。
根据本发明实施例的化合物不仅可以实现将注射剂型帕拉米苇改造为吸入剂型,改善其用药依从性,使其具有使用方便、适合大范围使用的特点,而且药物吸入后将直接作用于流感病毒侵染的呼吸道和肺部,有望实现一次给药,可以有效地对流感起到预防和治疗双重作用。
根据本发明的实施例,上述化合物还可以具有下列附加技术特征:
根据本发明的实施例,所述R1为C1~10烷基、C2~10烯基、C2~10炔基、C2~10杂烷基、C2~10烷氧基、C2~10烷氨基或C2~10烷硫基,所述L为C1~10烷基、C2~10烯基、C2~10炔基、C1~10杂烷基、C1~10烷氧基、C1~10烷氨基或C1~10烷硫基,其中,所述烷基、烯基、炔基、杂烷基、烷氧基、烷氨基和烷硫基均可任选地被一个或多个选自D、F、Cl、Br、I、-OH、-NO2、-NH2、-CN、-COOH、C1~8烷基、C1~8烷氧基、C1~8烷氨基或C1~8烷硫基的基团所取代。
根据本发明的实施例,所述L为C1~4烷基、C2~4烯基、C2~4炔基、C2~4杂烷基、C2~4烷氧基、C2~4烷氨基或C2~4烷硫基,其中,所述烷基、烯基、炔基、杂烷基、烷氧基、烷氨基和烷硫基均可任选地被一个或多个选自D、F、Cl、Br、I、-OH、-NO2、-NH2、-CN、-COOH、C1~4烷基、C1~4烷氧基、C1~4烷氨基或C1~4烷硫基的基团所取代。
根据本发明的实施例,所述R1为C6~10烷基、C6~10烯基、C6~10炔基、C6~10杂烷基、C6~10烷氧基、C6~10烷氨基或C6~10烷硫基,其中,所述烷基、烯基、炔基、杂烷基、烷氧基、烷氨基和烷硫基均可任选地被一个或多个选自D、F、Cl、Br、I、-OH、-NO2、-NH2、-CN、-COOH、C1~4烷基、C1~4烷氧基、C1~4烷氨基或C1~4烷硫基的基团所取代。
根据本发明的实施例,所述L为-CH2-、-(CH2)2-或-(CH2)3-,所述R1为-(CH2)5CH3、-(CH2)6CH3、-(CH2)7CH3或-(CH2)8CH3。
根据本发明的实施例,所述化合物具有下列的结构:
在本发明的另一方面,本发明提出了前面所述化合物在制备药物中的用途。根据本发明的实施例,所述药物用于治疗或预防流感病毒相关疾病。由此,不仅可以实现将注射剂型帕拉米苇改造为吸入剂型,改善其用药依从性,使其具有使用方便、适合大范围使用的特点,而且药物吸入后将直接作用于流感病毒侵染的呼吸道和肺部,有望实现一次给药,可以有效地对流感起到预防和治疗双重作用。
根据本发明的实施例,所述药物的剂型为干粉吸入剂型,所述药物的给药方式为吸入式。由此,不仅可以实现将注射剂型帕拉米苇改造为吸入剂型,改善其用药依从性,使其具有使用方便、适合大范围使用的特点,而且药物吸入后将直接作用于流感病毒侵染的呼吸道和肺部,有望实现一次给药,可以有效地对流感起到预防和治疗双重作用。
本领域技术人员能够理解的是,前面针对化合物所描述的特征和优点,同样适用于该化合物在制备药物中的用途,在此不再赘述。
在本发明的又一方面,本发明提出了一种制备前面所述化合物的方法。根据本发明的实施例,所述方法包括:使式5所示化合物与氢化铝锂进行反应,以便得到式6所示化合物;使所述式6所示化合物依次与乙酸酐及叔丁基二甲基氯硅烷进行反应,以便得到式7所示化合物;使所述式7所示化合物与式7a所示化合物进行反应,以便得到式8所示化合物;使所述式8所示化合物与氢化铝锂进行反应,以便得到式9所示化合物;使所述式9所示化合物与式9a所示化合物进行反应,以便得到式10所示化合物;使所述式10所示化合物与四丁基氟化铵进行反应,以便得到式11所示化合物;使所述式11所示化合物依次与重铬酸吡啶和次氯酸钠进行反应,以便得到式12所示化合物;以及使所述式12所示化合物依次与三氟乙酸和式12a所示化合物进行反应,以便得到式(I)所示化合物,
其中,所述L为n个碳原子的烷基、n个碳原子的烯基、n个碳原子的炔基、n个碳原子的杂烷基、n个碳原子的烷氧基或n个碳原子的烷硫基,所述W为(n-1)个碳原子的烷基、(n-1)个碳原子的烯基、(n-1)个碳原子的炔基、(n-1)个碳原子的杂烷基、(n-1)个碳原子的烷氧基或(n-1)个碳原子的烷硫基,各n分别独立地为1~10的整数。
化合物5经过氢化铝锂的还原得到氨基醇化合物6,再经过氨基保护和羟基保护得到化合物7。化合物7经过烷基化得到化合物8,再经过还原得到化合物9,经过酯化反应得到辛酸酯化合物10,进而经过脱保护、氧化反应和胍基的引入得到目标的前药。由此,根据本发明实施例的方法能够有效地制备得到化合物,且操作简便,产物得率较高。
根据本发明的实施例,所述式5所示化合物是通过下列方式获得的:使式1所示化合物与甲醇及盐酸进行反应,以便得到式2所示化合物;使所述式2所示化合物与L-酒石酸进行反应,以便得到式3所示化合物;使所述式3所示化合物与二碳酸二叔丁酯进行反应,以便得到式4所示化合物;以及使所述式4所示化合物与式4a所示化合物进行反应,以便得到式5所示化合物,
用消旋的文斯内酯(化合物1)为原料,经过拆分得到需要的光学纯的化合物3,进而合成得到化合物5。由此,根据本发明实施例的方法能够有效地制备得到化合物,且操作简便,产物得率较高。
本领域技术人员能够理解的是,前面针对化合物所描述的特征和优点,同样适用于该制备化合物的方法,在此不再赘述。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解,其中:
图1显示了根据本发明一个实施例的单晶结构示意图;
图2显示了根据本发明一个实施例的1H NMR谱图;
图3显示了根据本发明一个实施例的1C NMR谱图;
图4显示了根据本发明一个实施例的HRMS谱图;以及
图5显示了根据本发明一个实施例的空斑实验结果示意图。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的,仅用于解释本发明,而不能理解为对本发明的限制。
定义和一般术语
现在详细描述本发明的某些实施方案,其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案,它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到,许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术,等等),以本申请为准。
应进一步认识到,本发明的某些特征,为清楚可见,在多个独立的实施方案中进行了描述,但也可以在单个实施例中以组合形式提供。反之,本发明的各种特征,为简洁起见,在单个实施方案中进行了描述,但也可以单独或以任意适合的子组合提供。
除非另外说明,本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明,应当应用本文所使用的下列定义。出于本发明的目的,化学元素与元素周期表CAS版,和《化学和物理手册》,第75版,1994一致。此外,有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,JohnWiley&Sons,New York:2007中的描述,其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突,本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此,本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如,“一组分”指一个或多个组分,即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“包括”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体,等等。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质,如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱,例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker,Ed.,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;andEliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc.,New York,1994。
许多有机化合物以光学活性形式存在,即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时,使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号,其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体,这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体,当在化学反应或过程中没有立体选择性或立体特异性时,可出现这种情况。
本发明公开化合物的任何不对称原子(例如,碳等)都可以以外消旋或对映体富集的形式存在,例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中,各不对称原子在(R)-或(S)-构型方面具有至少50%对映体过量,至少60%对映体过量,至少70%对映体过量,至少80%对映体过量,至少90%对映体过量,至少95%对映体过量,或至少99%对映体过量。
依据起始物料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物,例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备,或使用常规技术拆分。如果化合物含有一个双键,取代基可能为E或Z构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体,对映异构体,非对映异构体,例如,通过色谱法和/或分步结晶法。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(lowenergy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。除非另外指出,本发明化合物的所有互变异构体形式都在本发明的范围之内。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体,如,通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离,如,使用手性吸附剂的高效液相色谱(HPLC)。特别地,对映异构体可以通过不对称合成制备。
本发明使用的术语“烷基”包括饱和直链或支链的单价烃基,其中烷基可以独立独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是,烷基基团含有1-10个碳原子;另外一些实施例是,烷基基团含有1-8个碳原子;另外一些实施例是,烷基基团含有1-6个碳原子,另外一些实施例是,烷基基团含有1-4个碳原子;另外一些实施例是,烷基基团含有1-3个碳原子。烷基基团更进一步的实例包括,但并不限于,甲基(Me,-CH3),乙基(Et,-CH2CH3),正丙基(n-Pr,-CH2CH2CH3),异丙基(i-Pr,-CH(CH3)2),正丁基(n-Bu,-CH2CH2CH2CH3),2-甲基丙基或异丁基(i-Bu,-CH2CH(CH3)2),1-甲基丙基或仲丁基(s-Bu,-CH(CH3)CH2CH3),叔丁基(t-Bu,-C(CH3)3),正戊基(-CH2CH2CH2CH2CH3),2-戊基(-CH(CH3)CH2CH2CH3),3-戊基(-CH(CH2CH3)2),2-甲基-2-丁基(-C(CH3)2CH2CH3),3-甲基-2-丁基(-CH(CH3)CH(CH3)2),3-甲基-1-丁基(-CH2CH2CH(CH3)2),2-甲基-1-丁基(-CH2CH(CH3)CH2CH3),正己基(-CH2CH2CH2CH2CH2CH3),2-己基(-CH(CH3)CH2CH2CH2CH3),3-己基(-CH(CH2CH3)(CH2CH2CH3)),2-甲基-2-戊基(-C(CH3)2CH2CH2CH3),3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3),4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2),3-甲基-3-戊基(-C(CH3)(CH2CH3)2),2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2),2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2),3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3),正庚基,正辛基,等等。术语“烷基”和其前缀“烷”在此处使用,都包含直链和支链的饱和碳链。烷基可以被本发明所述的取代基所取代。
术语“烷氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”,其中氨基基团分别独立地被一个或两个烷基基团所取代,其中烷基基团具有如本发明所述的含义。其中一些实施例是,烷基氨基是一个或两个C1-6烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是,烷基氨基是C1-3的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基,这样的实例包括,但并不限于,N-甲氨基,N-乙氨基,N,N-二甲氨基,N,N-二乙氨基等等。烷氨基或者烷基氨基可以被本发明所述的取代基所取代。
本发明中所使用的术语“烷氧基”,涉及到烷基,像本发明所定义的,通过氧原子连接到主要的碳链上。这样的实施例包括,但并不限于,甲氧基,乙氧基,丙氧基等等。烷氧基可以被本发明所述的取代基所取代。
术语“环烷基”或“碳环”是指一价或多价,非芳香族,饱和或部分不饱和环,且不包含杂原子,其中包括3~8个碳原子的单环或3~8个碳原子的二环或三环。合适的环烷基基团包括,但并不限于,环烷基,环烯基和环炔基。环烷基基团的实例进一步包括,但绝不限于,环丙基,环丁基,环戊基,1-环戊基-1-烯基,1-环戊基-2-烯基,1-环戊基-3-烯基,环己基,1-环己基-1-烯基,1-环己基-2-烯基,1-环己基-3-烯基,环己二烯基等等。视结构而定,环烷基可为单价基团或二价基团,即亚环烷基。C4环烷基是指环丁基,C5环烷基是指环戊基,C7环烷基是指环庚基。环烷基可以被本发明所述的取代基所取代。
术语“芳基”可以是单环、双环和三环的碳环体系,其中,至少一个环体系是芳香族的,其中每一个环体系包含6~10个原子,且只有一个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用,如芳香环可以包括苯基,萘基和蒽。视结构而定,芳基可为单价基团或二价基团,即亚芳基。芳基可以被本发明所述的取代基所取代。
术语“杂芳基”,“杂芳环”在此处可交换使用,都是指单环,双环,三环或者四环体系,其中,双环杂芳环,三环杂芳环或者四环杂芳环体系以稠合的形式成环。其中,杂芳环体系至少一个环体系是芳香族的,环上一个或多个原子独立任选地被杂原子所取代(杂原子选自N,O,P,S,在此S或P独立任选地被一个或多个氧原子所取代得到像SO,SO2,PO,PO2的基团)。杂芳体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。杂芳体系基团可以是3-7个原子组成的单环。
另外一些实施例是,杂芳体系(包含杂芳基,杂芳环)包括以下例子,但并不限于这些例子:呋喃-2-基,呋喃-3-基,N-咪唑基,咪唑-2-基,咪唑-4-基,咪唑-5-基,异噁唑-3-基,异噁唑-4-基,异噁唑-5-基,噁唑-2-基,噁唑-4-基,噁唑-5-基,4-甲基异噁唑-5-基,N-吡咯基,吡咯-2-基,吡咯-3-基,吡啶-2-基,吡啶-3-基,吡啶-4-基,嘧啶-2-基,嘧啶-4-基,嘧啶-5-基,哒嗪基(如哒嗪-3-基),噻唑-2-基,噻唑-4-基,噻唑-5-基,四唑基(如四唑-5-基),三唑基(如三唑-2-基和三唑-5-基),噻吩-2-基,噻吩-3-基,吡唑基(如吡唑-2-基),异噻唑基,噁唑并吡啶基,环氧乙烷基,茶嵌二氮苯基,菲啶基,菲绕啉基,吩砒嗪基,吩嗪基,吩噻嗪基,吩噁嗪基,酞嗪基,蝶啶基,吡啶并吡啶基,喹唑啉基,喹噁啉基,硫代苯基,三嗪基,咪唑并[2',1':2,3]噻唑并[5,4-b]吡啶基,咪唑并[2',1':2,3]噻唑并[4,5-c]吡啶基,1H-苯并[f]咪唑并[4,5-b][1,4]硫氮杂卓基等。杂芳基可以被本发明所述的取代基所取代。
“杂环基”可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和碳环或杂环并合所形成的基团。杂环的实例包括,但并不限于,吡咯烷基,四氢呋喃基,二氢呋喃基,四氢噻吩基,四氢吡喃基,二氢吡喃基,四氢噻喃基,哌啶基,噻噁烷基,氮杂环丁基,氧杂环丁基,硫杂环丁基,哌啶基,高哌啶基,环氧丙基,氮杂环庚基,氧杂环庚基,硫杂环庚基,N-吗啉基,2-吗啉基,3-吗啉基,硫代吗啉基,N-哌嗪基,2-哌嗪基,3-哌嗪基,高哌嗪基,1,2,3,6-四氢吡啶-1-基,氧氮杂卓基,二氮杂卓基,硫氮杂卓基,吡咯啉-1-基,2-吡咯啉基,3-吡咯啉基,二氢吲哚基,2-吲哚啉基,2H-吡喃基,4H-吡喃基,二氧杂环己基,1,3-二氧戊基,二噻烷基,二噻茂烷基,二氢噻吩基,咪唑烷基,1,2,3,4-四氢异喹啉基,1,2,6-噻二嗪烷1,1-二氧-2-基,六氢-2H-[1,4]二氧芑[2,3-c]吡咯基,喹嗪基,1,1-二氧化硫代吗啉基,2,3,3a,7a-四氢-1H-异吲哚基,异吲哚啉基,1,2,3,4-四氢喹啉基,二氢苯并异噻嗪基,二氢苯并异噁嗪基,二氧戊环基,二氢吡嗪基,二氢吡啶基,二氢吡唑基,二氢嘧啶基,二氢吡咯基,1,4-二噻烷基,呋喃酮基,呋喃基,咪唑烷基,咪唑啉基,咪唑基,咪唑并吡啶基,咪唑并噻唑基,吲唑基,二氢吲哚基,吲哚嗪基,吲哚基,异苯并四氢呋喃基,异苯并四氢噻嗯基,异苯并二氢吡喃基,异香豆素基,异二氢吲哚基,异噻唑烷基,异噁唑烷基,吗啉基,十氢吲哚基,十氢异吲哚基,噁唑烷二酮基,噁唑烷基,环氧乙烷基,哌嗪基,哌啶基,4-哌啶酮基,吡唑烷基,喹宁环基,四氢异喹啉基,四氢噻嗯基,硫吗啉基,噻唑烷基,1,3,5-三噻烷基,2-氧代吡咯烷基,氧代-1,3-噻唑烷基,2-哌啶酮基,3,5-二氧代哌啶基,吲哚啉基,1,2,3,4-四氢异喹啉基,1,3-苯并二噁茂基,2-氧杂-5-氮杂双环[2.2.1]庚-5-基,4-氧代吗啉基和嘧啶二酮基。
在一些实施例中,杂环基为4-7个原子组成的杂环基,是指包含4-7个环原子的饱和或部分不饱和的单环,其中至少一个环原子选自氮、硫和氧原子。4-7个原子组成的杂环基的实例包括,但不限于,氮杂环丁基,氧杂环丁基,硫杂环丁基,吡咯烷基,2-吡咯啉基,3-吡咯啉基,吡唑啉基,吡唑烷基,咪唑啉基,咪唑烷基,四氢呋喃基,二氢呋喃基,四氢噻吩基,二氢噻吩基,1,3-二氧环戊基,二硫环戊基,四氢吡喃基,二氢吡喃基,2H-吡喃基,4H-吡喃基,四氢噻喃基,哌啶基,吗啉基,硫代吗啉基,哌嗪基,二噁烷基,二噻烷基,噻噁烷基,高哌嗪基,高哌啶基,氧杂环庚烷基,硫杂环庚烷基,氧氮杂基,二氮杂基,硫氮杂基,等等。杂环基中-CH2-基团被-C(=O)-替代的实例包括,但不限于,2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基、嘧啶二酮基,等等。杂环基中硫原子被氧化的实例包括,但不限于,环丁砜基、硫代吗啉基1,1-二氧化物,等等。所述的4-7个原子组成的杂环基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“螺环基”,“螺环”,“螺双环基”,“螺双环”表示一个环起源于另一个环上特殊的环状碳。例如,像下面所描述的,一个饱和的桥环体系(环D和B')被称为“稠合双环”,反之环A’和环D在两个饱和的环体系中共享一个碳原子,则被称为“螺环”。螺环里面的每一个环要么是碳环要么是杂脂环族。这样的实例包括,但并不限于,螺[2.4]庚烷-5-基,螺[4.4]壬烷基,等。
术语“螺杂双环基”表示一个环起源于另一个环上特殊的环状碳。例如,像上面所描述的,一个饱和的桥环体系(环D和B')被称为“稠合双环”,反之环A’和环D在两个饱和的环体系中共享一个碳原子,则被称为“螺环”。且至少一个环体系包含一个或多个杂原子,其中每一个环体系包含3-7个原子,即包含1-6个碳原子和选自N,O,P,S的1-3个杂原子,在此N,S或P独立任选地被一个或多个氧原子所取代得到像NO,NO2,SO,SO2,PO,PO2的基团,-CH2-基团可以独立任选地被-C(=O)-替代;这样的实例包括,但并不限于4-氮杂螺[2.4]庚烷基,4-氧杂螺[2.4]庚烷基,5-氮杂螺[2.4]庚烷基,2-氮杂螺[4.5]癸烷基,2-氮杂螺[3.3]庚烷基,2-氮杂螺[4.4]壬烷基,3-氮杂螺[5.4]癸烷基,2-氧-6-氮杂螺[3.3]庚烷基,2,6-二氮杂螺[3.3]庚烷基,2-硫-6-氮杂螺[3.3]庚烷基2-一氧化物,2-硫-6-氮杂螺[3.3]庚烷基2,2-二氧化物,2,8-二氮杂螺[4.5]癸烷基,2,7-二氮杂螺[4.4]辛烷基,2,7-二氮杂螺[4.5]癸烷基,2,6-二氮杂螺[4.5]癸烷基,2,8-二氮杂螺[4.5]癸烷-3-酮-基,1,8-二氮杂螺[4.5]癸烷基,1,7-二氮杂螺[4.4]壬烷基,1,7-二氮杂螺[4.4]壬烷-6-酮-基,2,9-二氮杂螺[5.5]十一烷-1-酮-基,1-氧-3,8-二氮杂螺[4.5]癸烷-2-酮-基,1-氧-3,7-二氮杂螺[4.5]癸烷-2-酮-基,2,6-二氮杂螺[3.4]辛烷基,2,5-二氮杂螺[3.5]壬烷基,2,6-二氮杂螺[3.3]庚烷基,2-氧-7-氮杂螺[3.5]壬烷基,2-氧-6-氮杂螺[3.4]辛烷基等。视结构而定,螺杂双环基可为单价基团或二价基团,即亚螺杂双环基。螺杂环基可以被本发明所述的取代基所取代。
术语“稠合双环”,“稠环”,“稠合双环基”或“稠环基”表示饱和或不饱和的稠环体系,涉及到非芳香族的双环体系,至少有一个环是非芳香性的。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。稠合双环中的每一个环要么是碳环要么是杂脂环族,这样的实例包括,但并不限于,六氢-呋喃[3,2-b]呋喃基,2,3,3a,4,7,7a-六氢-1H-茚基,7-氮杂双环[2.2.1]庚烷基,稠合双环[3.3.0]辛烷基,稠合双环[3.1.0]己烷基,1,2,3,4,4a,5,8,8a-八氢萘基,这些都包含在稠合双环的体系之内。
术语“稠合杂双环基”表示饱和或不饱和的稠环体系,涉及到非芳香族的双环体系,至少有一个环是非芳香性的。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。且至少一个环体系包含一个或多个杂原子,其中每一个环体系包含3-7个原子组成的环,即包含1-6个碳原子和选自N,O,P,S的1-3个杂原子,在此N,S或P独立任选地被一个或多个氧原子所取代得到像NO,NO2,SO,SO2,PO,PO2的基团,-CH2-基团可以独立任选地被-C(=O)-替代。
本发明的药物还可以进一步包括药学上可接受的赋形剂,载体,辅剂,溶媒或它们的组合。
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应,例如肠胃不适、眩晕等的分子实体和组合物。优选地,本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、更特别在人体中使用的。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的,如文献:S.M.Berge et al.,describepharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括,但并不限于,与氨基基团反应形成的无机酸盐有盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,高氯酸盐,硝酸盐等,和有机酸盐如乙酸盐,丙酸盐,乙醇酸盐,草酸盐,马来酸盐,丙二酸盐,琥珀酸盐,富马酸盐,酒石酸盐,枸橼酸盐,苯甲酸盐,扁桃酸盐,甲磺酸盐,乙磺酸盐,甲苯磺酸盐,磺基水杨酸盐等,或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。
其他药学上可接受的盐包括己二酸盐、苹果酸盐、2-羟基丙酸、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐、等等。通过适当的碱得到的盐包括碱金属,碱土金属,铵和N+(C1-4烷基)4的盐。
本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,氢氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C1-8磺酸化物和芳香磺酸化物。胺盐,例如但不限于N,N’-二苄基乙二胺,氯普鲁卡因,胆碱,氨,二乙醇胺和其它羟烷基胺,乙二胺,N-甲基还原葡糖胺,普鲁卡因,N-苄基苯乙胺,1-对-氯苄基-2-吡咯烷-1’-基甲基-苯并咪唑,二乙胺和其它烷基胺,哌嗪和三(羟甲基)氨基甲烷;碱土金属盐,例如但不限于钡,钙和镁;过渡金属盐,例如但不限于锌。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括,但并不限于,水,异丙醇,乙醇,甲醇,二甲亚砜,乙酸乙酯,乙酸,氨基乙醇。
本发明的“氮氧化物”是指当化合物含几个胺官能团时,可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是,N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514),其中例如在惰性溶剂例如二氯甲烷中,使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定,其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化,还原,水解,酰氨化,脱酰氨作用,酯化,脱脂作用,酶裂解等等方法得到。相应地,本发明包括化合物的代谢产物,包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
在本说明书中,如果在化学名称和化学结构间存在任何差异,结构是占优的。
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写,除非另有说明,都以它们通常使用的、公认的缩写为准,或参照IUPAC-IUB Commission on BiochemicalNomenclature(参见Biochem.1972,11:942-944)。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解,下面的实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体技术或条件的,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
下面简写词的使用贯穿本发明:
MeOH 甲醇
HCl 盐酸
L-tartic acid 酒石酸
Boc2O 二碳酸二叔丁酯
Et3N 三乙胺
THF 四氢呋喃
LiAH4 氢化铝锂
Ac2O 乙酸酐
TBSCl 叔丁基二甲基氯硅烷
TBAF 四丁基氟化铵
PDC 重铬酸吡啶
NaClO2 次氯酸钠
K2HPO4 磷酸氢二钾
TFA 三氟乙酸
mL,ml 毫升
N2 氮气
resolution 拆分
一般合成路线:
实施例1
按照下列路线合成式(I-1)所示化合物。
实施例2
实施例1所得到的化合物9的单晶衍射结果确证化合物(I-1)的结构正确性:乙二醇组分顺利地连接在五元环骨架的-OH位(图1)。化合物9的核磁数据为:1H NMR(CDCl3,500MHz):δ=7.72-7.70(d,J=10.3Hz,1H),4.67-4.66(d,J=9.2Hz,1H),4.33-4.30(t,J=9.3Hz,1H),4.17-4.10(m,1H),3.56-3.51(m,5H),3.40-3.36(m,1H),3.19-3.14(m,1H),2.19-2.14(m,1H),2.10-2.07(m,1H),1.99(s,3H),1.82-1.78(m,1H),1.41(s,9H),1.35-1.28(m,3H),1.18-1.10(m,3H),0.85(s,9H),0.83-0.77(m,6H),0.01(s,6H);13C NMR(CDCl3,125MHz):δ=170.3,156.2,85.9,80.1,77.6,77.2,76.7,73.6,71.3,65.1,51.6,50.6,47.7,45.2,42.9,33.5,28.4,25.9,23.6,22.2,21.6,18.3,11.4,10.8,-5.4,-5.5;HRMS(ESI)Calcd.forC27H55N2O6Si+[M+H+]531.3824,found 531.3822。
最终的目标分子前药(化合物(I-1))经过NMR和HRMS得到确证(图2~4)。其核磁数据为:1H NMR(DMSO-d6,400MHz):δ=12.65(br,1H),7.71-7.69(d,1H),7.34(s,2H),6.84(s,1H),6.82(s,2H),4.44-4.39(t,J=10.1Hz,1H),4.14-4.02(m,2H),3.93-3.91(d,J=4.6Hz,1H),3.90-3.82(m,1H),3.76-3.71(m,1H),3.52-3.47(m,1H),2.92-2.90(m,1H),2.28-2.25(t,J=7.5Hz,2H),2.17-2.10(m,1H),1.74(s,3H),1.62-1.30(m,5H),1.23(s,9H),1.02-0.83(m,11H);13C NMR(DMSO-d6,100MHz):δ=174.9,172.9,169.2,155.9,82.3,66.6,63.4,54.7,48.9,47.8,46.1,43.1,40.1,39.9,39.7,39.5,39.3,39.1,38.9,34.1,33.4,33.4,31.1,28.5,28.4,24.4,22.7,22.6,22.1,20.9,13.9,12.6,11.8;HRMS(ESI)Calcd.for C25H47N4O6 +[M+H+]499.3490,found 499.3487.
其中,1H NMR和13C NMR采用Brüker Avance 300(1H:400MHz,13C:100MHz),BrükerAvance 500(1H:500MHz,13C:125MHz)型核磁共振仪测定;使用氘代二甲基亚砜作为溶剂。高分辨数据通过Bruker Apex IV RTMS来测定。低分辨率质谱采用液相质谱联用仪(LC-MS),仪器型号:HPLC1260MSD6120,色谱柱为Agilent Zorbax SB-C18(2.1×30mm,3.5μm)。
实施例3
将MDCK细胞接种于12孔组织培养板上(1.2×105个细胞/孔,含10%FBS的DMEM),37℃下,于湿润5%二氧化碳培养箱中孵育48小时。细胞在培养箱中用病毒(100PFU,Udorn-4)感染1小时。吸附病毒以后,将病毒悬浮物移除,用DMEM清洗细胞。将感染后的细胞单层平铺在DMED固体培养基(含1%琼脂、1‰TCPK-胰蛋白酶及1%抗生素)中,培养基中含2倍梯度稀释的化合物(I-1),共6个梯度,每个浓度有2个孔。感染48小时以后,固定单层细胞并用0.5%结晶紫溶液染色,统计病毒诱导的斑块数量。
结果如图5所示,说明化合物(I-1)具有较强的抗流感病毒活性,其体外抗流感病毒的活性EC50约为1nM。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (6)
1.一种化合物,其为式(I)所示的化合物或式(I)所示化合物药学上可接受的盐,
所述X为O、S或N;
所述Y为O或S;
所述L为-CH2-、-(CH2)2-或-(CH2)3-;
所述R1为-(CH2)5CH3、-(CH2)6CH3、-(CH2)7CH3或-(CH2)8CH3。
2.根据权利要求1所述的化合物,其特征在于,具有下列的结构:
3.权利要求1或2所述化合物在制备药物中的用途,其特征在于,所述药物用于治疗或预防流感病毒相关疾病。
4.根据权利要求3所述的用途,其特征在于,所述药物的剂型为干粉吸入剂型,所述药物的给药方式为吸入式。
5.一种制备权利要求1或2所述化合物的方法,其特征在于,包括:
使式5所示化合物与氢化铝锂进行反应,以便得到式6所示化合物;
使所述式6所示化合物依次与乙酸酐及叔丁基二甲基氯硅烷进行反应,以便得到式7所示化合物;
使所述式7所示化合物与式7a所示化合物进行反应,以便得到式8所示化合物;
使所述式8所示化合物与氢化铝锂进行反应,以便得到式9所示化合物;
使所述式9所示化合物与式9a所示化合物进行反应,以便得到式10所示化合物;
使所述式10所示化合物与四丁基氟化铵进行反应,以便得到式11所示化合物;
使所述式11所示化合物依次与重铬酸吡啶和次氯酸钠进行反应,以便得到式12所示化合物;以及
使所述式12所示化合物依次与三氟乙酸和式12a所示化合物进行反应,以便得到式(I)所示化合物,
其中,
所述W为键、-CH2-或-(CH2)2-。
6.根据权利要求5所述的方法,其特征在于,所述式5所示化合物是通过下列方式获得的:
使式1所示化合物与甲醇及盐酸进行反应,以便得到式2所示化合物;
使所述式2所示化合物与L-酒石酸进行反应,以便得到式3所示化合物;
使所述式3所示化合物与二碳酸二叔丁酯进行反应,以便得到式4所示化合物;以及
使所述式4所示化合物与式4a所示化合物进行反应,以便得到所述式5所示化合物,
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