CN105523955A - 化合物及其在制备药物中的用途 - Google Patents
化合物及其在制备药物中的用途 Download PDFInfo
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- CN105523955A CN105523955A CN201510925699.7A CN201510925699A CN105523955A CN 105523955 A CN105523955 A CN 105523955A CN 201510925699 A CN201510925699 A CN 201510925699A CN 105523955 A CN105523955 A CN 105523955A
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
- C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
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- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
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- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/20—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having nitrogen atoms of amidino groups acylated
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- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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- C07D213/40—Acylated substituent nitrogen atom
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- C07D213/80—Acids; Esters in position 3
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Abstract
本发明公开了化合物及其在药物中的应用,具体地,本发明提供如式(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,消旋体,氮氧化物,水合物,溶剂化物,代谢产物,药学上可接受的盐或前药,本发明还公开了本发明化合物在制备药品中的用途,该药品用于治疗癌症。
Description
技术领域
本发明属于医药技术领域,具体涉及一类新型化合物以及该新型化合物在制备药物中的用途。
背景技术
在医学上,癌是指起源于上皮组织的恶性肿瘤,是恶性肿瘤中最常见的一类。相对应的,起源于间叶组织的恶性肿瘤统称为肉瘤。有少数恶性肿瘤不按上述原则命名,如肾母细胞瘤、恶性畸胎瘤等。一般人们所说的“癌症”习惯上泛指所有恶性肿瘤。
肿瘤是机体在各种致瘤因素作用下,局部组织的细胞在基因水平上失去对其生长的正常调控导致异常增生与分化而形成的新生物。新生物一旦形成,不因病因消除而停止生长,他的生长不受正常机体生理调节,而是破坏正常组织与器官,这一点在恶性肿瘤尤其明显。与良性肿瘤相比,恶性肿瘤生长速度快,呈浸润性生长,易发生出血、坏死、溃疡等,并常有远处转移,造成人体消瘦、无力、贫血、食欲不振、发热以及严重的脏器功能受损等,最终造成患者死亡。
肺癌是世界上最常见的恶性肿瘤之一,已成为我国城市人口恶性肿瘤死亡原因的第1位。非小细胞型肺癌包括鳞状细胞癌(鳞癌)、腺癌、大细胞癌,与小细胞癌相比其癌细胞生长分裂较慢,扩散转移相对较晚。非小细胞肺癌约占所有肺癌的80%,约75%的患者发现时已处于中晚期,5年生存率很低。
Brg1基因作为一种新的抑癌基因,已在许多肿瘤的研究中发现它是一种重要的抑癌基因,许多肿瘤的发生与其功能失活或出现基因突变、缺失有关。同时发现其与细胞有丝分裂过程中的信号传导有关,与许多重要的抑癌基因如Rb基因、CD44等有密切的关系。
然而,目前治疗癌症尤其是非小细胞肺癌的药物仍有待进一步研究。
发明内容
本发明提出了一种化合物,其为如式(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,消旋体,氮氧化物,水合物,溶剂化物,代谢产物以及药学上可接受的盐或前药:
其中,Q表示C或N,R1表示H,或任选被C1~5烷基、C1~5烷基酯基取代的五元含氮杂环,R6为键,H,C1~5亚烷基,任选被C1~5亚烷基取代的五元含氮杂环,或任选被C1~5亚烷基取代的亚氨基,R7为H,C1~5烷基,或者任选被C1~5烷基、C1~5烷氧基、C1~5亚烷基环烷基、C1~5亚烷基环烯基、芳基、亚烷基芳基、六元杂环、亚烷基六元杂环、氰基、氰基亚氨基C1~5烷基取代的亚氨基或次氨基;以及R2、R3、R4、R5和R6的每一个分别独立地为H、卤素、羟基、C1~5烷氧基、胺基、C1~5羰基亚氨基或者亚氨基、芳基、硝基或者氰基,前提是R2、R3、R4、R5和R6不同时为H;或者R1~R6中相邻的两个连同与其所连接的碳原子构成任选被C1~5烷基、芳基、任选含有氧、硫和氮至少之一的五~七元环或者稠合双环。发明人意外地发现,该化合物能够有效地用于治疗癌症,尤其是非小细胞肺癌。
在本发明的第二方面,本发明提出了前面所述化合物在制备药物中的用途,所述药物用于治疗癌症。可选的,所述癌症为肺癌。可选的,所述肺癌为非小细胞肺癌。可选的,所述非小细胞肺癌为BRG1基因缺失。
另外,本发明还提出了一种用于治疗癌症的方法,包括为受试对象例如患者给药前述化合物或者含有该化合物的组合物。
进而,本发明还提出了一种用于治疗癌症的组合物,其含有前面所述化合物作为活性成分。
需要说明的是,前面所描述的各方面的特征和优点同样适用其他方面。
前面所述内容只概述了本发明的某些方面,但并不限于这些方面及其他的方面的内容将在下面作更加具体完整的描述。
具体实施方式
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,许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。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,应当应用本发明所使用的下列定义。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"OrganicChemistry",ThomasSorrell,UniversityScienceBooks,Sausalito:1999,和"March'sAdvancedOrganicChemistry"byMichaelB.SmithandJerryMarch,JohnWiley&Sons,NewYork:2007中的描述,其全部内容通过引用并入本发明。
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。
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象,例如也指灵长类动物(例如人类,男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中,所述受试对象是灵长类动物。在其他实施方案中,所述受试对象是人。
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中,“患者”是指人。
术语“包含”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。
“手性”是具有与其镜像不能重叠性质的分子;而“非手性”是指与其镜像可以重叠的分子。
“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性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-HillDictionaryofChemicalTerms(1984)McGraw-HillBookCompany,NewYork;andEliel,E.andWilen,S.,"StereochemistryofOrganicCompounds",JohnWiley&Sons,Inc.,NewYork,1994。
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;如果化合物中含有二取代的环烷基,环烷基的取代基可能有顺式或反式构型。
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。
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,例如,可参考Jacques,etal.,Enantiomers,RacematesandResolutions(WileyInterscience,NewYork,1981);PrinciplesofAsymmetricSynthesis(2ndEd.RobertE.Gawley,JeffreyAubé,Elsevier,Oxford,UK,2012);Eliel,E.L.StereochemistryofCarbonCompounds(McGraw-Hill,NY,1962);Wilen,S.H.TablesofResolvingAgentsandOpticalResolutionsp.268(E.L.Eliel,Ed.,Univ.ofNotreDamePress,NotreDame,IN1972);ChiralSeparationTechniques:APracticalApproach(Subramanian,G.Ed.,Wiley-VCHVerlagGmbH&Co.KGaA,Weinheim,Germany,2007)。
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(lowenergybarrier)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(prototropictautomer))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(valencetautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。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。
像本发明所描述的,本发明的化合物可以任选地被一个或多个取代基所取代,如上面的通式化合物,或者像实施例里面特殊的例子,子类,和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言,术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明,一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是,但并不限于,氘,氟,氯,溴,碘,氰基,羟基,硝基,氨基,羧基,烷基,烷氧基,烷氧基烷基,烷氧基烷氧基,烷氧基烷氨基,芳氧基,杂芳基氧基,杂环基氧基,芳基烷氧基,杂芳基烷氧基,杂环基烷氧基,环烷基烷氧基,烷氨基,烷氨基烷基,烷氨基烷氨基,环烷基氨基,环烷基烷氨基,烷硫基,卤代烷基,卤代烷氧基,羟基取代的烷基,羟基取代的烷氨基,氰基取代的烷基,氰基取代的烷氧基,氰基取代的烷氨基,氨基取代的烷基,烷基酰基,杂烷基,环烷基,环烯基,环烷基烷基,杂环基,杂环基烷基,杂环基酰基,芳基,芳基烷基,芳氨基,杂芳基,杂芳基烷基,杂芳基氨基,酰胺基,磺酰基,氨基磺酰基等等。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换,均应做广义理解,其既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C1-C5烷基”或“C1-5烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、和C5烷基。
本发明使用的术语“烷基”或“烷基基团”,表示含有1至20个碳原子,饱和的直链或支链一价烃基基团,其中,所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明,烷基基团含有1-20个碳原子。在一实施方案中,烷基基团含有1-12个碳原子;在另一实施方案中,烷基基团含有1-6个碳原子;在又一实施方案中,烷基基团含有1-4个碳原子;还在一实施方案中,烷基基团含有1-3个碳原子。
烷基基团的实例包含,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),异丁基(i-Bu、-CH2CH(CH3)2),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“Cx-y烷基”是指C原子数为x-y的烷基。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连,其中烷基基团具有如本发明所述的含义。除非另外详细说明,所述烷氧基基团含有1-12个碳原子。在一实施方案中,烷氧基基团含有1-6个碳原子;在另一实施方案中,烷氧基基团含有1-4个碳原子;在又一实施方案中,烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷氧基基团的实例包括,但并不限于,甲氧基(MeO、-OCH3),乙氧基(EtO、-OCH2CH3),1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3),2-丙氧基(i-PrO、i-丙氧基、-OCH(CH3)2),1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3),2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2),2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3),2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3),1-戊氧基(n-戊氧基、-OCH2CH2CH2CH2CH3),2-戊氧基(-OCH(CH3)CH2CH2CH3),3-戊氧基(-OCH(CH2CH3)2),2-甲基-2-丁氧基(-OC(CH3)2CH2CH3),3-甲基-2-丁氧基(-OCH(CH3)CH(CH3)2),3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2),2-甲基-l-丁氧基(-OCH2CH(CH3)CH2CH3),等等。
术语“杂环基”和“杂环”在此处可交换使用,都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环,其中单环、双环或三环中不包含芳香环,且至少一个环原子选自氮、硫和氧原子。除非另外说明,杂环基可以是碳基或氮基,且-CH2-基团可以任选地被-C(=O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括,但不限于:环氧乙烷基,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,(1-氧代)-硫代吗啉基,(1,1-二氧代)-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,2-氧杂-5-氮杂双环[2.2.1]庚-5-基,四氢吡啶基。杂环基中-CH2-基团被-C(=O)-取代的实例包括,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。杂环基中硫原子被氧化的实例包括,但不限于,环丁砜基,1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。当该结构清楚地需要连接基团时,针对该基团所列举的马库什变量应理解为连接基团。例如,如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“杂环基”,则应该理解,该“杂环基”代表连接的亚杂环基基团。
术语“稠合双环”和“稠合双环基”在此处可交换使用,是指单价或多价的饱和或部分不饱和的桥环体系,所述桥环体系是指双环体系。术语“桥环”是指任意两个环共用两个直接相连或不直接相连的原子。例如,像下面式a和式b所描述的,环A和环A’共用两个直接相连的C原子,环B和环B’共用两个不直接相连的C原子。稠合双环中的每一个环要么是碳环要么是杂环。
术语“杂原子”是指O、S、N、P和Si,包括N、S和P任何氧化态的形式;伯、仲、叔胺和季铵盐的形式;或者杂环中氮原子上的氢被取代的形式,例如,N(像3,4-二氢-2H-吡咯基中的N),NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“芳基”表示含有6-14个环原子,或6-12个环原子,或6-10个环原子的单环、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3-7个原子组成的环,且有一个或多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。芳基基团的实例可以包括苯基,茚基,萘基和蒽。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。当该结构清楚地需要连接基团时,针对该基团所列举的马库什变量应理解为连接基团。例如,如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“芳基”,则应该理解,该“芳基”代表连接的亚芳基基团。
本发明所使用的术语“前药”,代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯,在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(C1-24)酯类,酰氧基甲基酯类,碳酸酯,氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基,即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯,如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献:T.HiguchiandV.Stella,Pro-drugsasNovelDeliverySystems,Vol.14oftheA.C.S.SymposiumSeries,EdwardB.Roche,ed.,BioreversibleCarriersinDrugDesign,AmericanPharmaceuticalAssociationandPergamonPress,1987,J.Rautioetal.,Prodrugs:DesignandClinicalApplications,NatureReviewDrugDiscovery,2008,7,255-270,andS.J.Heckeretal.,ProdrugsofPhosphatesandPhosphonates,JournalofMedicinalChemistry,2008,51,2328-2345。
“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。
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.Bergeetal.,describepharmaceuticallyacceptablesaltsindetailinJ.PharmaceuticalSciences,1977,66:1-19.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,和有机酸盐如乙酸盐,草酸盐,马来酸盐,酒石酸盐,柠檬酸盐,琥珀酸盐,丙二酸盐,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,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,锂,钾,钙,镁,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。
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,乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
如本发明所使用的术语“治疗”任何疾病或病症,在其中一些实施方案中,“治疗”指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中,“治疗”指缓和或改善至少一种身体参数,包括可能不为患者所察觉的身体参数。在另一些实施方案中,“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中,“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
术语“癌症”是指或描述患者中通常以失控的细胞生长为特征的生理学病症。“肿瘤”包含一种或多种癌细胞。癌症的实例包括但不限于癌(carcinoma)、淋巴瘤、胚细胞瘤、肉瘤和白血病,或恶性淋巴增殖性疾病(lymphoidmalignancies)。此类癌症的更具体的实例包括鳞状细胞癌(如上皮鳞状细胞癌)、肺癌(包括小细胞肺癌、非小细胞肺癌(NSCLC)、肺腺癌和肺鳞状癌)、腹膜癌、肝细胞癌(hepatocellularcancer)、胃癌(gastricorstomachcancer)(包括胃肠癌)、胰腺癌、恶性胶质瘤、宫颈癌、卵巢癌、肝癌(livercancer)、膀胱癌、肝细胞瘤(hepatoma)、乳腺癌、结肠癌、直肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌或肾脏癌(kidneyorrenalcancer)、前列腺癌、外阴癌、甲状腺癌、肝脏癌(hepaticcarcinoma)、肛门癌、阴茎癌以及头颈癌。
本发明化合物的描述
本发明提出了一种化合物,其为如式(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,消旋体,氮氧化物,水合物,溶剂化物,代谢产物以及药学上可接受的盐或前药:
其中,Q表示C或N,R1表示H,或任选被C1~5烷基、C1~5烷基酯基取代的五元含氮杂环,R6为键,H,C1~5亚烷基,任选被C1~5亚烷基取代的五元含氮杂环,或任选被C1~5亚烷基取代的亚氨基,R7为H,C1~5烷基,或者任选被C1~5烷基、C1~5烷氧基、C1~5亚烷基环烷基、C1~5亚烷基环烯基、芳基、亚烷基芳基、六元杂环、亚烷基六元杂环、氰基、氰基亚氨基C1~5烷基取代的亚氨基或次氨基;以及R2、R3、R4、R5和R6的每一个分别独立地为H、卤素、羟基、C1~5烷氧基、胺基、C1~5羰基亚氨基或者亚氨基、芳基、硝基或者氰基,前提是R2、R3、R4、R5和R6不同时为H;或者R1~R6中相邻的两个连同与其所连接的碳原子构成任选被C1~5烷基、芳基、任选含有氧、硫和氮至少之一的五~七元环或者稠合双环。发明人意外地发现,该化合物能够有效地用于治疗癌症,尤其是非小细胞肺癌。
可选的,R1为任选取代的亚氨基羰基、次氨基羰基或者五元含氮杂环。可选的,所述卤素为F或者Cl。可选的,R1和R2连同与其所连接的碳原子构成任选被C1~5烷基、芳基、任选含有氧、硫和氮至少之一的五~七元环或者稠合双环,或者R2和R3连同与其所连接的碳原子构成任选被C1~5烷基、芳基、任选含有氧、硫和氮至少之一的五~七元环或者稠合双环。可选的,R1和R2连同与其所连接的碳原子构成任选取代的含有1~3个氮原子的五~七元环或者稠合双环,任选地所述五~七元环或者稠合双环的环上形成有至少一个羰基。可选的,所述化合物为如下式所示的化合物或下式所示化合物的立体异构体,几何异构体,互变异构体,消旋体,氮氧化物,水合物,溶剂化物,代谢产物以及药学上可接受的盐或前药:
在本发明的第二方面,本发明提出了前面所述化合物在制备药物中的用途,所述药物用于治疗癌症。可选的,所述癌症为肺癌。可选的,所述肺癌为非小细胞肺癌。可选的,所述非小细胞肺癌为BRG1基因缺失。
另外,本发明还提出了一种用于治疗癌症的方法,包括为受试对象例如患者给药前述化合物或者含有该化合物的组合物。
进而,本发明还提出了一种用于治疗癌症的组合物,其含有前面所述化合物作为活性成分。
需要说明的是,前面所描述的各方面的特征和优点同样适用其他方面。
除非其他方面表明,本发明的化合物所有的立体异构体,几何异构体,互变异构体,消旋体,氮氧化物,水合物,溶剂化物,代谢产物,代谢前体,盐和药学上可接受的前药都属于本发明的范围。
具体地说,盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学地,与组成制剂的其他组分和用于治疗的哺乳动物有关。
本发明的化合物的盐,还包括用于制备或纯化式(I)所示化合物的中间体或式(I)所示化合物分离的对映异构体的盐,但不一定是药学上可接受的盐。
可药用的酸加成盐可与无机酸和有机酸形成,例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。
可药用碱加成盐可与无机碱和有机碱形成。
可以由其衍生得到盐的无机碱包括,例如铵盐和周期表的I族至XII族的金属。在某些实施方案中,该盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜;特别适合的盐包括铵、钾、钠、钙和镁盐。
可以由其衍生得到盐的有机碱包括伯胺、仲胺和叔胺,取代的胺包括天然存在的取代的胺、环状胺、碱性离子交换树脂等。某些有机胺包括,例如,异丙胺、苄星青霉素(benzathine)、胆碱盐(cholinate)、二乙醇胺、二乙胺、赖氨酸、葡甲胺(meglumine)、哌嗪和氨丁三醇。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言,该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应,或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地,在适当的情况中,需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如"Remington′sPharmaceuticalSciences",第20版,MackPublishingCompany,Easton,Pa.,1985;和“药用盐手册:性质、选择和应用(HandbookofPharmaceuticalSalts:Properties,SelectionandUse)”,StahlandWermuth(Wiley-VCH,Weinheim,Germany,2002)中可找到另外一些适宜盐的列表。
另外,本发明公开的化合物、包括它们的盐,也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO,等等)的形式得到,用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物;因此,本发明旨在包括溶剂化的和未溶剂化的形式。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构,除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,如2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl和125I。
另一方面,本发明所述化合物包括同位素富集的本发明所定义的化合物,例如,其中存在放射性同位素,如3H,14C和18F的那些化合物,或者其中存在非放射性同位素,如2H和13C。该类同位素富集的化合物可用于代谢研究(使用14C)、反应动力学研究(使用例如2H或3H)、检测或成像技术,如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT),或可用于患者的放疗中。18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(I)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外,较重同位素特别是氘(即,2H或D)的取代可提供某些治疗优点,这些优点是由代谢稳定性更高带来的。例如,体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解,本发明中的氘被看作式(I)所示化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘,该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5%的氘掺入)、至少4000(60%的氘掺入)、至少4500(67.5%的氘掺入),至少5000(75%的氘掺入),至少5500(82.5%的氘掺入)、至少6000(90%的氘掺入)、至少6333.3(95%的氘掺入)、至少6466.7(97%的氘掺入)、至少6600(99%的氘掺入)或至少6633.3(99.5%的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D2O、丙酮-d6、DMSO-d6的那些溶剂化物。
本发明化合物的药物组合物,制剂和给药
本发明提供一种药物组合物,其包含本发明公开化合物和药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。本发明公开的药物组合物中化合物的量是指能有效检测到抑制生物样本或患者体内蛋白激酶的量。
也应认识到,本发明的某些化合物可以以游离形式存在用于治疗,或者如果适当可以以其药学上可接受的衍生物的形式存在。药学上可接受衍生物的一些非限制性的实施方案包括药学上可接受的前药,盐,酯,这些酯的盐,或者对有需要的患者给药时能直接或间接提供本发明所述化合物或其代谢产物或残留物的任何另外的加合物或衍生物。
本发明公开的药物药物组合物可制备并包装为散装(bulk)形式,其中可提取安全有效量的式(I)所示的化合物,然后以粉末或糖浆形式给予患者。或者,本发明公开的药物组合物可制备并包装为单位剂型,其中每个物理上离散的单位含有安全有效量的式(I)所示的化合物。当以单位剂型制备时,本发明公开的药物组合物通常可含,例如,0.5mg至1g、或1mg至700mg、或5mg至100mg的本发明公开的化合物。
本发明所用“药学上可接受的赋形剂”意指与给药剂型或药物组合物一致性相关的药学上可接受的材料,混合物或溶媒。每种赋形剂在混合时必须与药物组合物的其它成分相容,以避免对患者给药时会大大降低本发明公开化合物的功效的相互作用和会导致不是药学上可接受的药物组合物的相互作用。此外,每种赋形剂必须是药学上可接受的,例如,具有足够高的纯度。
合适的药学上可接受的赋形剂会依所选具体剂型而不同。此外,可根据它们在组合物中的特定功能来选择药学上可接受的赋形剂。例如,可选择能有助于生产均一剂型的某些药学上可接受的赋形剂。可选择能有助于生产稳定剂型的某些药学上可接受的赋形剂。可选择对患者给药时有助于携带或运输本发明公开化合物从身体的一个器官或部分到身体的另一个器官或部分的某些药学上可接受的赋形剂。可选择增强患者依从性的某些药学上可接受的赋形剂。
合适的药学上可接受的赋形剂包括以下类型的赋形剂:稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、甜味剂、矫味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、塑化剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。技术人员可认识到,某些药学上可接受的赋形剂可提供不止一种功能,并提供可供选择的功能,这取决于制剂中存在多少该赋形剂和制剂中存在那些其他赋形剂。
技术人员掌握本领域的知识和技能,以使他们能选择用于本发明的适当量的合适的药学上可接受的赋形剂。此外,存在大量技术人员可获得的资源,他们描述药学上可接受的赋形剂,并用于选择合适的药学上可接受的赋形剂。实例包括Remington'sPharmaceuticalSciences(MackPublishingCompany),TheHandbookofPharmaceuticalAdditives(GowerPublishingLimited),andTheHandbookofPharmaceuticalExcipients(theAmericanPharmaceuticalAssociationandthePharmaceuticalPress)。
在Remington:TheScienceandPracticeofPharmacy,21stedition,2005,ed.D.B.Troy,LippincottWilliams&Wilkins,Philadelphia,andEncyclopediaofPharmaceuticalTechnology,eds.J.SwarbrickandJ.C.Boylan,1988-1999,MarcelDekker,NewYork中披露了用于配置药学上可接受的组合物的各种载体,和用于其制备的公知技术,这些文献各自的内容通过引用并入本发明。除任何诸如因产生任何不期望的生物作用,或以有害方式与药学上可接受组合物中的任何其它成分发生相互作用而与本发明公开化合物不相容的任何常用载体外,关注其应用属于本发明的范围。
本发明公开的药物组合物使用本领域技术人员已知的技术和方法来制备。本领域一些常用方法的描述可参见Remington'sPharmaceuticalSciences(MackPublishingCompany)。
因此,另一方面,本发明涉及制备药物组合物的工艺,所述药物组合物包含本发明公开化合物和药学上可接受的赋形剂,载体,辅剂,溶媒或它们的组合,该工艺包括混合各种成分。包含本发明公开化合物的药物组合物,可以在例如环境温度和大气压下混合来制备。
本发明公开的化合物通常被配制成适合于通过所需途径对患者给药的剂型。例如,剂型包括那些适合于以下给药途径的剂型:(1)口服给药,例如片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、香包剂和扁囊剂;(2)胃肠外给药,例如无菌溶液剂、混悬剂和复溶粉末;(3)透皮给药,例如透皮贴片剂;(4)直肠给药,例如栓剂;(5)吸入,例如气雾剂、溶液剂和干粉剂;和(6)局部给药,例如乳膏剂、油膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂和凝胶剂。
在一实施方案中,本发明公开的化合物可以配制成口服剂型。在另一实施方案中,本发明公开的化合物可以配制成吸入剂型。在另一实施方案中,本发明公开的化合物可以配制成经鼻给药剂型。在又一实施方案中,本发明公开的化合物可以配制成透皮给药剂型。还在一实施方案中,本发明公开的化合物可以配制成局部给药剂型。
本发明提供的药物组合物可以以压制片、研制片、可咀嚼锭剂、速溶片、复压片、或肠溶片、糖衣或薄膜衣片来提供。肠溶片是用能抗胃酸作用但在肠中溶解或崩解的物质包衣的压制片,从而防止了活性成分接触胃的酸性环境。肠包衣包括,但不限于,脂肪酸、脂肪、水杨酸苯酯、蜡、紫胶、氨化紫胶和邻苯二甲酸乙酸纤维素酯。
糖衣片为糖衣包围的压制片,其可利于掩盖令人不愉快的味道或气味并且能防止片剂氧化。薄膜包衣片为用水溶性物质的薄层或薄膜覆盖的压制片。薄膜包衣包括,但不限于,羟乙基纤维素、羧甲基纤维素钠、聚乙二醇4000和邻苯二甲酸乙酸纤维素酯。薄膜包衣赋有和糖包衣相同的一般特性。复压片为经过超过一个压缩周期制备的压制片,包括多层片、和压制包衣或干包衣片。
片剂剂型可以由呈粉末、结晶或颗粒状的活性成分单独的或与本发明描述的一种或多种载体或赋形剂组合来制备,所述载体和赋形剂包括粘合剂、崩解剂、控释聚合物、润滑剂、稀释剂和/或着色剂。增香剂和甜味剂在形成咀嚼片和锭剂时特别有用。
示例性的药学可接受的载体或其组分是糖类,例如乳糖,葡萄糖和蔗糖;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素和甲基纤维素;西黄蓍胶粉;麦芽;明胶;滑石;固体润滑剂,例如硬脂酸和硬脂酸镁;硫酸钙;合成油;植物油,例如花生油,棉籽油,芝麻油,橄榄油和玉米油;多元醇,如丙二醇、甘油、山梨醇、甘露醇和聚乙二醇;藻酸;磷酸盐缓冲溶液;乳化剂,例如吐温类;润湿剂,例如十二烷基硫酸钠;着色剂;调味剂;压片剂;稳定剂;抗氧化剂;防腐剂;无热原水;等渗盐水;和磷酸盐缓冲溶液。
本发明提供的药物组合物可以以软胶囊或硬胶囊来提供,其可以由明胶、甲基纤维素、淀粉或海藻酸钙来制备。所述硬明胶胶囊也称为干填充胶囊(DFC),由两段组成,一段塞入另一段中,因此完全包封了活性成分。软弹性胶囊(SEC)是软的、球形壳,比如明胶壳,其通过加入甘油、山梨醇或类似的多元醇塑化。软明胶壳可以包含防腐剂来预防微生物生长。合适的防腐剂为如本发明所述的那些,包括尼泊金甲酯和尼泊金并指,以及山梨酸。本发明提供的液体、半固体和固体剂型可以包囊在胶囊中。合适的液体和半固体剂型包括在碳酸丙烯酯、植物油或甘油三酯中的溶液和混悬剂。包含这样的溶液的胶囊可以如在美国专利U.S.Pat.Nos.4,328,245;4,409,239和4,410,545中描述的来制备。所述胶囊也可以采用如本领域技术人员已知的涂层,从而改善或维持活性成分的溶出。
本发明提供的药物组合物可以以液体和半固体剂型来提供,包括乳剂、溶液、混悬剂、酏剂和糖浆剂。乳剂为二相系统,其中一种液体以小球形式完全分散在另一种液体中,其可以是水包油型或油包水型。乳剂可以包括药学上可接受的非水液体和溶剂、乳化剂和防腐剂。混悬剂可以包括药学上可接受的助悬剂和防腐剂。含水醇溶液可以包括药学上可接受的缩醛,比如低级烷基醛的二(低级烷基)缩醛,例如乙醛二乙基缩醛;和具有一个或多个羟基的水溶性溶剂,比如丙二醇和乙醇。酏剂是透明的、甜味的水醇溶液。糖浆剂是浓的糖例如蔗糖的水溶液,并且还可以包含防腐剂。对于液体剂型,例如,在聚乙二醇中的溶液可以用足量的药学上可接受的液体载体例如水稀释,以精确方便地给药。
其它有用的液体和半固体剂型包括,但不限于包含本发明提供的活性成分和二级化单-或聚-烷撑二醇的那些剂型,所述单-或聚-烷撑二醇包括: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、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剂,比如丁羟甲苯(BHT)、丁羟茴醚(BHA),没食子酸丙酯、维生素E、氢醌、羟基香豆素、乙醇胺、卵磷脂、脑磷脂、抗坏血酸、苹果酸、山梨醇、磷酸、亚硫酸氢盐、焦亚硫酸钠、硫代二丙酸及其酯和二硫代氨基甲酸酯。
适当时,可以将口服给药的剂量单位制剂微囊包封。也可以将其制备成延长或维持释放的组合物,例如通过将微粒材料包衣或包埋在聚合物、蜡或类似物中。
本发明提供的口服药物组合物还可以以脂质体、胶束、微球或纳米体系的形式提供。胶束剂型可以用U.S.Pat.No.6,350,458描述的方法来制备。
本发明提供的药物组合物可以以非泡腾或泡腾的颗粒剂和粉剂来提供,以重构成液体剂型。在非泡腾颗粒剂或粉剂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。在泡腾颗粒剂或粉剂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源。
在所有上述剂型中可以使用着色剂和调味剂。
本发明所公开的化合物也可以与作为靶向药物载体的可溶性聚合物结合。这样的聚合物包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-苯酚、聚羟乙基天冬酰胺苯酚或棕榈酰残基取代的聚氧乙烯聚赖氨酸。此外,本发明所公开的化合物可以与在实现药物的控制释放中使用的一类生物可降解的聚合物结合,例如,聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。
本发明提供的药物组合物可以配制成立即或改性释放剂型,包括延迟-、缓释-、脉冲-、控制-、靶向-和程序化释放形式。
本发明提供的药物组合物可以与不会损害预期的治疗作用的其它活性成分共同配制,或者与补充预期的作用的物质共同配制。
本发明提供的药物组合物可以通过注射、输注或植入肠胃外给药,用于局部或全身给药。如本发明使用的肠胃外给药包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内、滑膜内和皮下给药。
本发明提供的药物组合物可以配制成适于肠胃外给药的任何剂型,包括溶液、混悬剂、乳剂、胶束、脂质体、微球、纳米体系和适于在注射前在液体中制成溶液或混悬液的固体形式。这样的剂型可以根据药物科学领域的技术人员已知的常规方法来制备(参见Remington:TheScience和PracticeofPharmacy,同上)。
预期用于肠胃外给药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,含水运载体、水混溶性运载体、非水运载体、抗微生物剂或抗微生物生长的防腐剂、稳定剂、溶解增强剂、等渗剂、缓冲剂、抗氧剂、局部麻醉剂、助悬剂和分散剂、湿润剂或乳化剂、络合剂、多价螯合剂或螯合剂、防冻剂、冷冻保护剂、增稠剂、pH调节剂和惰性气体。
合适的含水运载体包括,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、Ringers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Ringers注射液。非水运载体包括,但不限于,植物来源的非挥发油、蓖麻油、玉米油、棉籽油、橄榄油、花生油、薄荷油、红花油、芝麻油、豆油、氢化植物油、氢化豆油和椰子油的中链甘油三酯、及棕榈种子油。水混溶性运载体包括,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。
合适的抗微生物剂或防腐剂包括,但不限于,苯酚、甲酚、汞剂、苯甲醇、氯代丁醇、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、硫柳汞、苯扎氯铵(例如苄索氯铵)、尼泊金甲酯和尼泊金丙酯及山梨酸。合适的等渗剂包括,但不限于,氯化钠、甘油和葡萄糖。合适的缓冲剂包括,但不限于,磷酸盐和柠檬酸盐。合适的抗氧化剂为如本发明描述的那些,包括亚硫酸氢盐和偏亚硫酸氢钠。合适的局部麻醉剂包括,但不限于盐酸普鲁卡因。合适的助悬剂和分散剂为如本发明描述的那些,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。合适的乳化剂包括本发明描述的那些,包括聚氧乙烯脱水山梨醇单月桂酸酯。聚氧乙烯脱水山梨醇单油酸酯80和油酸三乙醇胺酯。合适的多价螯合剂或螯合剂包括,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。合适的络合剂包括,但不限于环糊精,包括α-环糊精、β-环糊精、羟丙基-β-环糊精、磺基丁基醚-β-环糊精和磺基丁基醚7-β-环糊精(CyDex,Lenexa,KS)。
本发明提供的药物组合物可以配制成单剂量或多剂量给药。所述单剂量制剂被包装在安瓿剂、小瓶或注射器中。所述多剂量肠胃外制剂必须包含抑菌或抑真菌浓度的抗微生物剂。所有的肠胃外制剂都必须是无菌的,如本领域已知和实践的。
在一实施方案中,药物组合物以即用型无菌溶液来提供。在另一实施方案中,药物组合物以无菌干燥可溶性产品提供,包括冻干粉末和皮下注射片剂,其在使用前用运载体重构。在又一实施方案中,药物组合物被配制成即用型无菌悬浮液。在又一实施方案中,药物组合物被配制成使用之前用运载体重构的无菌干燥不可溶性产品。还在一实施方案中,药物组合物被配制成即用型无菌乳剂。
本发明所公开的药物组合物可以配置成立即或改性释放剂型,包括延迟-、缓释-、脉冲-、控制-、靶向-和程序化释放形式。
药物组合物可以配置成混悬剂、固体、半固体或触变液体,用作植入的贮库给药。在一实施方案中,本发明所公开的药物组合物分散在固体内部基质中,其被不溶于体液但允许药物组合物中的活性成分扩散通过的外部聚合膜所包围。
适合的内部基质包括聚甲基丙烯酸甲酯、聚丁基丙烯酸甲酯、增塑的或未增塑的聚氯乙烯、增塑的尼龙、增塑的聚对苯二甲酸乙二酯、增塑的聚对苯二甲酸乙酯、天然橡胶、聚异戊二烯、聚异丁烯、聚丁二烯、聚乙烯、乙烯-醋酸乙烯酯共聚物、硅酮橡胶、聚二甲硅氧烷、硅酮碳酸酯共聚物、亲水性聚合物比如丙烯酸和甲基丙烯酸的酯的水凝胶、胶原、交联聚乙烯醇及教练的部分水解的聚乙酸乙烯酯。
适合的外部聚合膜包括聚乙烯、聚丙烯、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、乙烯/乙烯基乙酸酯共聚物、硅酮橡胶、聚二甲基硅氧烷、氯丁橡胶、氯化聚乙烯、聚氯乙烯、氯化乙烯与乙酸乙烯酯的共聚物、偏二氯乙烯、乙烯和丙烯、离子交联聚合物聚对苯二甲酸乙二酯、丁基橡胶氯醇橡胶、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三聚物和乙烯/乙烯氧基乙醇共聚物。
另一方面,本发明所公开的药物组合物可以配制成适于对患者吸入给药的任何剂型,例如干粉剂、气雾剂、混悬剂或溶液组合物。在一实施方案中,本发明所公开的药物组合物可以配制成适于用干粉剂对患者吸入给药的剂型。在又一实施方案中,本发明所公开的药物组合物可以配制成适于通过喷雾器对患者吸入给药的剂型。通过吸入递送至肺的干粉组合物通常包含精细粉末状的本发明所公开的化合物和一种或多种精细粉末状的药学上可接受的赋形剂。特别适合用作干粉剂的药学上可接受的赋形剂为本领域技术人员所知晓,其包括乳糖、淀粉、甘露醇、和单-、二-和多糖。精细粉末可通过例如微粉化和研磨制备得到。一般来说,尺寸减小的(如微粉化的)化合物可以通过约1至10微米的D50值(例如,用激光衍射法测量的)来定义。
气雾剂可以通过将本发明所公开的化合物悬浮或溶解在液化推进剂中配制。适合的推进剂包括氯代烃、烃类和其它液化气体。代表性的推进剂包括:三氯氟甲烷(推进剂11)、二氯氟甲烷(推进剂12)、二氯四氟乙烷(推进剂114)、四氟乙烷(HFA-134a)、1,1-二氟乙烷(HFA-152a)、二氟甲烷(HFA-32)、五氟乙烷(HFA-12)、七氟丙烷(HFA-227a)、全氟丙烷、全氟丁烷、全氟戊烷、丁烷、异丁烷和戊烷。包含本发明所公开的化合物的气雾剂通常通过计量剂量吸入器(MDI)对患者给药。这样的装置为本领域技术人员所知晓。
气雾剂可包含额外的、可通过MDIs使用的药学上可接受的赋形剂,例如表面活性剂、润滑剂、共溶剂和其它赋形剂,以改善制剂的物理稳定性、改善阀门特性、改善溶解性、或者改善口味。
适合于透皮给药的药物组合物可制备成不连续的贴片剂,意在与患者的表皮保持紧密接触一段延长的时间。例如,可通过离子渗透从贴片剂中递送活性成分,如PharmaceuticalResearch,1986,3(6),318中的一般描述。
适合于局部给药的药物组合物可以被配制成油膏剂、乳膏剂、混悬剂、洗剂、粉剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。例如,油膏剂、乳膏剂和凝胶剂可以用水或油基质,和适合的增稠剂和/或凝胶剂和/或溶剂来配置。这样的基质可以包括,水,和/或油例如液体液体石蜡和植物油(例如花生油或蓖麻油),或溶剂例如聚乙二醇。根据基质性质使用的增稠剂和凝胶剂包括软石蜡、硬脂酸铝、鲸蜡硬脂醇、聚乙二醇、羊毛脂、蜂蜡、聚羧乙烯和纤维素衍生物,和/或单硬脂酸甘油脂和/或非离子型乳化剂。
洗剂可以用水或油基质配制,并且通常也含有一种或多种乳化剂、稳定剂、分散剂、助悬剂或增稠剂。
外用粉剂可以在任意适合的粉基质例如滑石粉、乳糖或淀粉的存在下成型。滴剂可以用包含一种或多种分散剂、增溶剂、助悬剂或防腐剂的水或非水基质配制而成。
局部制剂可以通过在患处每天应用一次或多次来给药;覆盖皮肤的封闭敷料优先被使用。粘附性储库系统可实现连续或延长的给药。
治疗眼睛,或其它器官如嘴巴和皮肤时,可施用作为局部油膏剂或乳膏剂的组合物。当配制为油膏剂时,本发明所公开的化合物可与石蜡或水溶的油膏剂基质一起使用。或者,本发明所公开的化合物可以与水包油乳膏剂基质或水包油基质一起配制成乳膏剂。
联合治疗
本发明化合物可以作为单独的活性试剂给药,或者可以与其它治疗剂联合给药,包括具有相同或相似治疗活性并且对于此类联合给药确定为安全且有效的其它化合物。
一方面,本发明提供治疗、预防或改善疾病或病症的方法,包括给予安全有效量的包含本发明公开化合物与一种或多种治疗活性剂的联合药物。在一实施方案中,联合药物包含一种或两种其他治疗剂。
其它治疗剂的实例包括但不限于:抗癌剂,包括化疗剂和抗增殖剂;抗炎剂;和免疫调节剂或免疫抑制剂。
治疗方法
在一实施方案中,本发明公开的治疗方法包括对有需要的患者给予安全有效量的本发明化合物或包含本发明化合物的药物组合物。本发明公开的各实施方案包括通过对有需要的患者给予安全有效量的本发明公开化合物或包含本发明公开化合物的药物组合物,来治疗上面所提到疾病的方法。
在一实施方案中,本发明公开化合物或包含本发明公开化合物的药物组合物可以通过任何适合的给药途径来给药,包括全身给药和局部给药。全身给药包括口服给药、胃肠外给药、透皮给药和直肠给药。典型的胃肠外给药是指通过注射或输注给药,包括静脉内、肌内和皮下注射或输注给药。局部给药包括施用于皮肤以及眼内、耳、阴道内、吸入和鼻内给药。在一个实施方案中,本发明公开化合物或包含本发明公开化合物的药物组合物可以是口服给药。在另一实施方案中,本发明公开化合物或包含本发明公开化合物的药物组合物可以是吸入给药。还有一实施例中,本发明公开化合物或包含本发明公开化合物可以是经鼻内给药。
在一实施方案中,本发明公开化合物或包含本发明公开化合物的药物组合物可以一次性给药,或者根据给药方案,在指定时间段内,在不同的时间间隔给药若干次。例如,每天给药一次、两次、三次或四次。在一实施方案中,每天给药一次。在又一实施方案中,每天给药两次。可以给药直至达到想要的治疗效果或无限期地维持想要的治疗效果。本发明公开化合物或包含本发明公开化合物的药物组合物的合适给药方案取决于该化合物的药代动力学性质,例如稀释、分布和半衰期,这些可以由技术人员测定。此外,本发明公开化合物或包含本发明公开化合物的药物组合物的合适给药方案,包括实施该方案的持续时间,取决于被治疗的疾病,被治疗疾病的严重程度、被治疗患者的年龄和身体状况、被治疗患者的医疗史、同时疗法的性质、想要的治疗效果等在技术人员知识和经验范围内的因素。这样的技术人员还应该理解,对于个体患者对给药方案的反应,或随着时间推移个体患者需要变化时,可要求调整事宜的给药方案。
本发明公开化合物可以与一种或多种其它治疗剂同时,或在其之前或之后给药。本发明化合物可以与其他治疗剂通过相同或不同给药途径分别给药,或与之以同以药物组合物形式给药。
对于约50-70kg的个体,本发明公开药物组合物和联合物可以是含有约1-1000mg、或约1-500mg、或约1-250mg、或约1-150mg、或约0.5-100mg、或约1-50mg活性成分的单位剂量形式。化合物、药物组合物或其联合物的治疗有效量是取决于个体的物种、体重、年龄及个体情况、被治疗的疾病(disorder)或疾病(disease)或其严重程度。具备常用技能的医师、临床医师或兽医可以容易决定预防、治疗或抑制疾病(disorder)或疾病(disease)发展过程中所需各活性成分的有效量。
以上所引用的剂量特性已在采用有利的哺乳动物(例如小鼠、大鼠、狗、猴)或其离体器官、组织及标本的体外及体内试验中证实。本发明公开化合物以溶液,例如水溶液形式在体外使用,也可以例如悬浮液或水溶液形式在体内的肠内,胃肠外,尤其是静脉内使用。
在一实施方案中,本发明公开化合物的治疗有效剂量为每天约0.1mg至约2,000mg。其药物组合物应当提供约0.1mg至约2,000mg剂量的该化合物。在一特定实施方案中,制备的药物剂量单位形式能提供约1mg至约2,000mg,约10mg至约1,000mg,约20mg至约500mg,或约25mg至约250mg的主要活性成分或每剂量单位形式中各主要成分的组合。在一特定实施方案中,制备的药物剂量单位形式能提供约10mg,20mg,25mg,50mg,100mg,250mg,500mg,1000mg或2000mg主要活性成分。
此外,本发明公开的化合物可以以前药形式给药。在本发明中,本发明公开化合物的“前药”是对患者给药时,最终能在体内释放出本发明公开化合物的功能性衍生物。以前药形式给予本发明公开的化合物时,本领域技术人员可实施下列方式中的一种及以上:(a)变更化合物的体内起效时间;(b)变更化合物的体内作用持续时间;(c)变更化合物的体内输送或分布;(d)变更化合物的体内溶解度;及(e)克服化合物所面临的副作用或其他难点。用于制备前药的典型的功能性衍生物,包含在体内以化学方式或酶的方式裂解的化合物的变体。包含制备磷酸盐、酰胺、酯、硫代酯、碳酸盐及氨基甲酸盐的这些变体对本领域技术人员来讲是众所周知的。
一般合成过程
一般地,本发明的化合物可以通过本发明所描述的方法制备得到,除非有进一步的说明,其中取代基的定义如式(I)所示。
所属领域的技术人员将认识到:本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物,且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如,根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成,如适当的保护干扰基团,通过利用其他已知的试剂除了本发明所描述的,或将反应条件做一些常规的修改。另外,本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例,除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如AldrichChemicalCompany,ArcoChemicalCompanyandAlfaChemicalCompany,使用时都没有经过进一步纯化,除非其他方面表明(以下中将路线N统一描述为数字编号,不再赘述)。
1.(1表示路线1,以下将路线N统一描述为数字编号,不再赘述)合成酰胺类化合物(3):
取代的芳香羧酸(1,1eq.)、卡特缩合剂(BOP,1.2eq.)和N,N-二异丙基乙胺(DIEA,2.5eq)加入适量体积的N,N-二甲基甲酰胺溶剂中。所得的混合液在室温下搅拌10min。氨基类化合物(2,2.5eq.)分批或逐滴滴入反应液中。所得反应液在室温下搅拌5h。反应结束后,反应液使用等体积水淬灭,并用双倍体积的乙酸乙酯进行萃取三次。合并乙酸乙酯相,有机相使用水和盐水洗,并使用无水硫酸钠干燥。过滤后,使用旋转蒸发仪去除乙酸乙酯,所得粗品拌硅胶粉后,干法上样,使用硅胶柱层析的方法分离纯化。
2.吡唑类化合物(7)的合成:
溶解在乙醇中取代的苯甲醛(4,1eq.)和烷基乙酮(5,1.5eq.)分批加入NaOH(3eq.)的水溶液中。所得的混合液回流4h。反应液降至室温,并使用2N的盐酸调pH至4~5。所得混合液使用等体积乙酸乙酯萃取三次。有机相使用水和盐水洗之后,使用无水硫酸钠进行干燥。过滤出去硫酸钠后,有机相使用旋转蒸发仪去除后,所得粗品中间体(6)直接用于下一步。
中间体(6,1eq.),对甲苯磺酰肼(2eq.)和四丁基溴化铵(TBAB,1eq.)分批缓慢加入NaOH(3eq.)的水溶液中,边加边搅拌。所得的混合液在95℃下搅拌12h。反应液降至室温,并使用2N的盐酸调pH至4~5。所得混合液使用等体积乙酸乙酯萃取三次。有机相使用水和盐水洗之后,使用无水硫酸钠进行干燥。过滤出去硫酸钠后,有机相使用旋转蒸发仪去除。所得粗品使用重结晶或硅胶柱层析的方法进行分离纯化。
3.羟基茚酮类(11)结构的合成路线2:
酚类化合物(8,1eq.)溶于溶剂二氯甲烷(DCM)中,并将反应瓶充满氩气,使用氩气球保护。室温下,使用注射器加入吡啶(1.2eq.)。3-氯气丙酰氯(9,1.1eq.)通过注射器缓慢滴加至反应瓶中。所得的混合液在室温下搅拌1h。反应结束后,反应液使用水淬灭。分液后,二氯甲烷相使用水和盐水洗。二氯甲烷相使用无水硫酸镁干燥后,过滤,并用旋转蒸发仪去除有机溶剂,粗品使用硅胶柱层析分离纯化,得到中间体10。中间体(10,1eq.)和AlCl3(3eq.)加入反应瓶中,在没有溶剂的情况的下,加热到180℃反应6h。反应冷至室温后,使用冰冷的2M盐酸淬灭并搅拌,使黑色固体溶解。使用乙酸乙酯萃取三次。有机相合并,盐水洗,无水硫酸钠干燥后,在旋转蒸发以上旋干,粗品使用硅胶柱层析分离,得到羟基茚酮类化合物(11)。
4.羟基异喹啉类化合物的合成路线:
羟基茚酮类化合物(11,1eq.)加入冰冷的浓盐酸中,NaN3(2eq.)分批缓慢加入。反应液在0℃~r.t.搅拌20h。反应结束后,反应液用水淬灭。水相用二氯甲烷萃取三次,有机相使用无水硫酸镁干燥。干燥剂过滤后,有机相拌硅胶,使用硅胶柱层析分离纯化,得到羟基异喹啉类化合物12。化合物12(1eq.),NaH(2eq.)在溶剂四氢呋喃中反应0.5h,加入碘代物R’I(3eq.),反应过夜可得化合物13。化合物13与48%HBr水溶液在180℃搅拌过夜可得化合物14。
苯甲酰胍基(18)和苯甲酰脒基(20)化合物的合成:
邻羟基苯甲酸类化合物(15,1eq.)加入反应溶剂二氯甲烷中,SOCl2(3eq.)滴加至溶液中。所得反应液在50℃反应1h后,在旋转蒸发仪上旋蒸去除SOCl2。所得粗品使用二氯甲烷溶解,然后滴入苯酚(phenol,1eq.)和三乙胺(TEA,3eq.)在二氯甲烷中的混合液。所得反应液在r.t.下搅拌1h后,加水淬灭。使用二氯甲烷萃取,有机相使用无水硫酸镁干燥。干燥剂被过滤后,有机相拌硅胶,使用硅胶层析柱分离纯化,得到中间体16。中间体16(1eq.)和1,1,3,3-四甲基胍(TMG,1.5eq.)加入反应溶剂N,N-二甲基甲酰胺中,搅拌5min后,加入胍基化合物(17,1.6eq.),室温搅拌过夜。反应结束使用水淬灭,乙酸乙酯萃取后使用硅胶柱层析分离可得苯甲酰胍基类化合物(18)。中间体16(1eq.),O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU,1.6eq.),N,N-二异丙基乙胺(DIEA,3eq.)加入溶剂N,N-二甲基甲酰胺中。反应液室温搅拌30min,脒基化合物(19,1.2eq.)加入反应液中。反应液室温搅拌过夜后,加水淬灭。使用乙酸乙酯萃取后,硅胶柱层析分离可得苯甲酰脒类化合物(20)。
吲唑类化合物(23)的合成:
将取代的氟苯甲腈(21,1eq.),水合肼(4eq.)和适量溶剂正丁醇加入圆底烧瓶。反应加热至100℃过夜。反应结束后浓缩过滤,得到中间体22,直接用于下一步。中间体22(1eq.)溶解于适量四氢呋喃溶剂中,醛类化合物(5eq.),钯碳(0.04eq.),分别加入反应中,以氢气球提供氢气,室温反应过夜,TLC检测反应。反应结束后过滤除去钯碳,溶液拌硅胶后使用硅胶柱层析的方法分离,得到目标吲唑类化合物。
三唑类(26)化合物的合成:
取代的水杨酰胺(24,1eq.)溶于丙酮中,再加入三乙胺(Et3N,1.2eq.),乙酸酐(1.1eq),加热回流四个小时。TLC检测反应结束后,使用旋转蒸发仪去除容剂,粗品用硅胶柱层析纯化,得到中间体26。将HClO4(70%,1eq.)滴入乙酸酐(3eq.)中,并将混合液滴入中间体25(1eq.)的乙酸溶液中,95℃加热反应液1.5h,溶液变为茶红色,再加入水合肼(2eq.),把温度降至80℃,搅拌半小时。反应冷却至室温后,用乙酸乙酯稀释,用饱和碳酸氢钠溶液洗去酸液,有机相用无水硫酸镁干燥,使用旋转蒸发仪去除溶剂后硅胶柱层析纯化得到目标三唑类化合物26。
4-位甲酰酯咪唑类化合物(29)的合成:
将盐酸羟胺(4eq.)和碳酸钠(2eq.)的水溶液加入到取代的羟基苯甲腈(27,1eq.)的乙醇溶液中,回流10小时。反应结束后用旋转蒸发仪去除乙醇,用乙酸乙酯萃取,无水硫酸镁干燥后,硅胶柱层析纯化得到中间体28。将丙炔酸乙酯(2eq.)滴入中间体28(1eq.)的乙醇溶液中,加热回流10小时,用旋转蒸发仪去除乙醇后再加入二苯醚190℃加热三小时。反应停止后,降至室温,将整个反应液倾入较大硅胶柱,使用石油醚冲洗,去除二苯醚后,使用乙酸乙酯冲出其余组分。合并组分,拌硅胶粉后,使用较小的硅胶柱层析分离纯化,得到目标产物咪唑类化合物29。
4-位甲酰酯咪唑类化合物(30)的合成:
将4-位甲酰酯咪唑类化合物29(1eq.)溶于四氢呋喃和水的混合溶剂中,再滴入40%甲胺水溶液(20eq.),60℃加热反应4h。反应结束后,使用旋转蒸发仪减压去除四氢呋喃,剩余水相用乙酸乙酯萃取。合并后的有机相,使用无水硫酸钠干燥。干燥剂被滤除后,有机相拌硅胶,通过硅胶柱层析纯化得到4-位甲酰酯咪唑类化合物30。
喹唑啉二酮类(35)的合成:
将化合物32(1eq.)加入化合物31(1eq.)的二氯甲烷溶液,并加入N,N'-羰基二咪唑(CDI,1.3eq.)和N,N-二异丙基乙胺(DIPEA,2eq.),室温下反应6h,旋转蒸发仪除去二氯甲烷,通过硅胶柱色谱分离得到中间体33。中间体33(1eq.)的二氯甲烷溶液中加入三光气(0.4eq.),回流12h,得到中间体34。在反应体系中,直接加入三溴化硼(3eq.)反应,得到喹唑啉二酮类化合物35。
吡唑并喹啉类化合物(KQ76,KQ77)的合成:
化合物36(1eq.)溶于丙酮中,加入KOH(4eq.),在搅拌下加入硫酸二甲酯(1.5eq.),反应液搅拌1小时,再加入1ml水,搅拌1.5h。反应结束后用乙酸乙酯萃取,无水硫酸镁干燥后,用硅胶柱层析纯化得到中间体37。中间体37(1eq.)溶于冰醋酸中,再将丙烯酸(2eq.)滴入,搅拌下加入98%硫酸(0.1eq.),80℃加热5h。反应结束后,饱和碳酸氢钠溶液中和,乙酸乙酯萃取,有机相无水硫酸镁干燥后,硅胶柱层析纯化得到中间体38。中间体38(1mmol)溶解于6mlEaton’s试剂,将反应液加热到65℃过夜。反应结束后用氢氧化钠溶液中和,乙酸乙酯萃取,有机相无水硫酸镁干燥后,硅胶柱层析纯化得到中间体39。化合物39(1eq.)溶于无水二氯甲烷中,将反应瓶用氩气置换,-78℃加入BBr3(5eq.),逐渐升温到室温,反应5h后,用饱和碳酸氢钠溶液淬灭并中和,乙酸乙酯萃取,有机相干燥后,硅胶柱层析纯化得到中间体40。化合物40(1eq.)溶解于丙酮中,加入Cs2CO3(6eq.),严格将反应瓶用氮气保护,冰浴下加入氯甲基甲醚(3eq.),将温度升到10℃,反应2h。反应结束后用2N盐酸中和反应,乙酸乙酯萃取,有机相干燥后硅胶柱层析纯化,得到中间体41。化合物41溶解于无水四氢呋喃中,-40℃加入LDA(2eq.),半小时后再加入丁酰氯(1.1eq.),将反应升到室温,反应0.5h,加入水淬灭反应,减压旋走四氢呋喃,用乙酸乙酯萃取,有机相干燥后加压旋走溶剂,粗品用乙醇溶解,再加入水合肼(3eq.),60℃反应2h。反应结束后通过硅胶柱层析纯化得到中间体42。化合物42(1eq.)加入到三氟乙酸中,室温搅拌1h,反应结束后,减压旋干溶剂,将粗品用硅胶柱层析纯化得到目标产物43。将化合物43溶解于干燥四氢呋喃中,加入硼氢化钠(5eq.),室温搅拌3h,反应结束后,加入水淬灭反应,减压旋走四氢呋喃,用乙酸乙酯萃取,无水硫酸镁干燥后硅胶柱层析纯化得到化合物KQ77。
吡唑并喹啉酮类化合物(KQ78)的合成:
化合物45(1eq.)放置于密封管中,加入三氟乙酸,再加入乌洛托品(1.1eq.),将密封管用氩气置换后,加热至100℃,反应24h后,冷却反应液至室温。将等体积4N盐酸加入反应液中,搅拌1h。反应结束后旋干溶剂,加入适量蒸馏水,用二氯甲烷萃取。粗品用硅胶柱层析纯化得到化合物46。将DBU(2eq.),碘甲烷(3eq.)加入到化合物46(1eq.)的丙酮溶液中,室温搅拌过夜。反应结束后,减压旋干溶剂,将粗品用硅胶柱层析纯化得到化合物47。将化合物47溶解于丙酮中,加入亚氯酸钠(5eq.)的饱和溶液,再加入2N盐酸(8eq.),反应过夜。反应结束后,减压旋干溶剂,再用乙酸乙酯萃取,粗品干燥后,硅胶柱层析纯化得到化合物48。将化合物48溶解于干燥二氯甲烷中,滴入两滴DMF,再加入草酰氯(2eq.),室温搅拌2h,反应结束后旋干溶剂待用。将化合物49(1.2eq.)溶解干燥THF中,加入NaH(1.5eq.),室温搅拌0.5h。再将化合物48的反应产物用干燥THF溶解,滴入化合物49的反应液中,室温搅拌1h。反应结束后加入少量水淬灭反应,旋干溶剂后,粗品用硅胶柱层析纯化得到化合物50。将化合物50溶解于乙醇中,加入水合肼(2eq.),60℃搅拌2h,反应结束后,旋干溶剂,粗品用硅胶柱层析纯化得到化合物51。将化合物51(1eq.)溶解于乙二醇二甲醚中,加入还原铁粉(10eq.),加入0.1N盐酸(10eq.),加热至82℃,反应5h,反应结束后旋干溶剂,粗品用硅胶柱层析纯化得到化合物52。将化合物52溶解于乙醇中,再加入等体积2N盐酸,40℃加热搅拌5h,得到白色浑浊液体,过滤得到白色固体,用少量乙酸乙酯冲洗,得到化合物53。将化合物53溶解于无水二氯甲烷中,-30℃加入BBr3(10eq.),再将温度甚至40℃,反应3天,反应结束后,直接减压旋走溶剂以及BBr3。将粗品用乙酸乙酯溶解,水洗一次,无水硫酸镁干燥,减压旋干溶剂后硅胶柱层析纯化得到化合物54。
环丙烷取代的吡唑并喹啉类化合物(KQ79)的合成:
化合物53(1eq.)溶解于干燥N,N-二甲基甲酰胺中,加入NaH(60%油分散,3eq.),室温搅拌0.5h,再加入溴化苄(4eq.),加热反应4h。反应结束后,加入乙酸乙酯,用水洗反应液三次,有机相用无水硫酸镁干燥后,硅胶柱层析纯化得到化合物55。将Ti(OiPr)4(1eq.)溶解于无水四氢呋喃中,将反应瓶用氩气置换空气,-78℃加入EtMgBr(3MinTHF,3eq.),搅拌2min后,再慢慢滴入化合物55(1eq.)的四氢呋喃溶液,加完后将反应提到室温,搅拌5h。反应结束后加入饱和氯化铵溶液,搅拌10min,再用乙酸乙酯萃取,有机相无水硫酸镁干燥后,硅胶柱层析纯化,得到化合物56。将化合物56(1eq.)溶解于甲醇中,加入Pd/C(0.1eq.),反应瓶用氢气置换,并在反应瓶上插一氢气气球,室温反应3h,反应结束后过滤反应液除去Pd/C,得到化合物57。将化合物57(1eq.)溶解于干燥二氯甲烷中,-78℃加入BBr3(6eq.),将反应升至室温,搅拌24h,反应结束后,减压旋走溶剂,将粗品用乙酸乙酯溶解,碳酸氢钠溶液洗一次,饱和氯化钠溶液洗一次,无水硫酸镁干燥后,硅胶柱层析纯化得到化合物KQ79。
二甲基取代的吡唑并喹啉类化合物(KQ80)的合成:
将化合物51(1eq.)溶解于N,N-二甲基甲酰胺中,加入碳酸铯(1eq.),对甲苯磺酰氯(2eq.),室温下搅拌5h,反应结束后用乙酸乙酯稀释,水洗三次,有机相无水硫酸镁干燥后,硅胶柱层析纯化得到化合物59。将化合物59溶解于乙二醇二甲醚中,加入还原铁粉(10eq.),0.1N盐酸(6eq.),室温搅拌15h。反应结束后减压旋走溶剂,用乙酸乙酯萃取产物,粗品用硅胶柱层析纯化后得到化合物60。化合物60溶解于无水N,N-二甲基甲酰胺中,加入NaH(1.5eq.),室温搅拌15min,再加入溴化苄(2eq.),室温反应5h,反应结束后加入乙酸乙酯稀释,水洗三次,有机相无水硫酸干燥后硅胶柱层析纯化得到化合物61。将化合物溶解于无水二氯甲烷中,再加入DTBMP(1eq.),-78℃加入三氟甲磺酸酐(1eq),将反应升至室温,搅拌1h,再次将反应降温至-78℃,加入甲基格氏试剂(3eq.),搅拌10min后将反应升温至室温搅拌5h,反应结束后加入乙酸乙酯,水洗一次,盐水洗一次,有机相无水硫酸镁干燥后,硅胶柱层析纯化得到化合物62。将化合物62(1eq.)溶解于甲醇中,加入Pd/C(0.1eq.),在氢气环境下还原脱掉苄基保护基。反应结束后直接过滤除掉Pd/C。将在滤液中加入6N盐酸(10eq.),加热至50℃,搅拌5h后,将反应降至室温,减压旋走有机溶剂,用乙酸乙酯萃取产物,有机相干燥后硅胶柱层析纯化得到化合物63。将化合物63(1eq.)溶解于无水二氯甲烷中,-78℃加入BBr3(10eq.),然后将反应升温至室温,反应24h,反应结束后,减压旋走溶剂,粗品用乙酸乙酯溶解后,水洗一次,盐水洗一次,有机相干燥后硅胶柱层析纯化得到化合物KQ80。
苯并氮杂卓并吡唑类化合物(KQ81)的合成:
将化合物65经过Pd/C还原得到中间体66。中间体66(1eq.)溶解于四氢呋喃溶液,在冰浴下向上述溶液慢慢滴加三氟乙酸酐(1eq.),反应1h,之后二氯甲烷萃取,得到的有机相经过旋转蒸发仪除去溶解,最后得到中间体67,直接用于下步反应。将化合物68(3eq.)慢慢滴加于中间体67(1eq.)和碳酸钾(5eq.)的N,N-二甲基甲酰胺溶液,反应回流12h。反应停止后降温,经过乙酸乙酯萃取,将得到的有机相浓缩,通过硅胶柱色谱分离得到中间体69。中间体69(1eq.)加到三氯化铁(5%)的乙腈溶液,回流8h,除去溶剂,得到中间体70,直接用于下一步反应。中间体70(1eq.)加入对甲苯磺酰肼(1.1eq.)的甲醇溶液,室温反应过夜,除去溶剂,接着加入NaOH(2eq.)的水溶液,在95℃下,反应12h。冷至室温后,使用2N的盐酸调pH至4~5,用乙醚萃取,有机相合并,硅胶柱色谱分离得到中间体71,中间体71溶解于二氯甲烷,-78℃加入BBr3(10eq.),然后将反应升温至室温,反应24h,反应结束后,减压旋走溶剂,粗品用乙酸乙酯溶解后,水洗一次,盐水洗一次,有机相干燥后硅胶柱层析纯化得到化合物KQ81。
本领域技术人员可以根据所期望合成的化合物的结构,按照前面所述的合成路线有效地进行制备相应的化合物。
合成实施例
在本实施例中,发明人按照前面所描述的一般合成方法,制备了表1中所列出的化合物,相应的合成方法总结在表1中,各化合物的合成鉴定结果如下:
KQ1:1HNMR(400MHz,d6-DMSO,ppm)δ8.03(brs,1H),7.86(m,1H),7.53(m,1H),7.19(m,1H),6.95(m,1H),5.35(s,1H),3.28(q,2H,J=7.2Hz),1.04(t,3H,J=7.2Hz).
KQ2:1HNMR(400MHz,d6-DMSO,ppm)δ8.05(brs,1H),7.92(m,1H),7.59(m,1H),7.19(m,1H),7.17(m,1H),3.83(s,3H),3.26(q,2H,J=7.2Hz),1.02(t,3H,J=7.2Hz).
KQ3:1HNMR(400MHz,d6-DMSO,ppm)δ8.02(brs,1H),7.64(m,1H),7.10(m,1H),6.99(m,1H),6.81(m,1H),6.27(brs,2H),3.23(q,2H,J=7.2Hz),1.07(t,3H,J=7.2Hz).
KQ4:1HNMR(300MHz,CDCl3,ppm)δ12.11(s,1H),8.16(d,J=2.44Hz,1H),7.33(dd,J=8.79Hz,1H),7.30(brs,1H),6.92(d,J=8.79Hz,1H),2.63(s,3H),2.18(s,3H).
KQ5:1HNMR(400MHz,d6-DMSO,ppm)δ11.65(s,1H),10.29(brs,1H),7.81(d,1H,J=2.6Hz),7.49(dd,1H,J1=8.8Hz,J2=2.6Hz),2.61(s,3H).
KQ6:1HNMR(400MHz,d6-DMSO,ppm)δ8.10(brs,1H),7.09(m,1H),7.06(m,1H),6.89(m,1H),6.83(m,1H),5.35(s,1H),4.47(s,2H),3.29(s,2H),2.51(m,4H),1.68(m,4H).
KQ7:1HNMR(400MHz,d6-DMSO,ppm)δ8.78(brs,1H),7.19-7.14(m,1H),6.74-6.71(m,1H),3.31-3.11(m,2H),2.76-2.73(m,2H).
KQ8:1HNMR(400MHz,CDCl3,ppm)δ7.55(d,1H,J=8.0Hz),7.36-7.28(m,2H),7.03(d,1H,J=7.5Hz),3.50(q,2H,J=7.1Hz),1.34(t,3H,J=7.1Hz).
KQ9:1HNMR(400MHz,CDCl3,ppm)δ9.37(brs,1H),7.07-7.02(m,1H),6.98-6.93(m,2H),3.52(q,4H,J=7.1Hz),1.28(t,6H,J=7.1Hz).
KQ10:1HNMR(400MHz,CD3Cl,ppm)δ9.40(brs,1H),7.00-6.94(m,2H),6.90-6.86(m,1H),3.50(q,2H,J=7.0Hz),3.08(s,3H),1.23(t,3H,J=7.0Hz).
KQ11:1HNMR(400MHz,CD3Cl,ppm)δ12.64(brs,1H),7.30-7.27(m,1H),6.82-6.80(m,1H),6.62-6.60(m,1H),3.58-3.55(m,2H),3.13(s,3H),3.00-2.97(m,1H).
KQ12:1HNMR(400MHz,CD3Cl,ppm)δ12.74(brs,1H),7.30(d,J=8.92Hz,1H),6.77(d,J=8.92Hz,1H),3.57(t,J=6.88Hz,2H),3.12(s,3H),3.05(t,J=6.92Hz,2H).
KQ13:1HNMR(400MHz,CD3Cl,ppm)δ12.76(brs,1H),7.35-7.31(m,1H),6.67-6.64(m,1H),6.57-6.53(m,1H),6.21(brs,1H),3.48(m,2H),1.26(t,1H,J=7.2Hz).
KQ14:1HNMR(400MHz,CD3Cl,ppm)δ10.79(brs,1H),7.96-7.95(m,1H),7.53-7.51(m,1H),6.89-6.87(m,1H),4.41(m,2H),1.42(t,3H,J=7.1Hz).
KQ15:1HNMR(400MHz,CD3Cl,ppm)δ12.68(brs,1H),7.12(d,1H,J=8.5Hz),6.18(s,1H),6.12(d,1H,J=8.5Hz),5.98(brs,1H),3.97(brs,2H),3.45(m,2H),1.24(t,3H,J=7.2Hz).
KQ16:1HNMR(400MHz,CD3OD,ppm)δ7.61(brs,1H),7.20(d,1H,J=8.28Hz),6.93(d,1H,J=8.28Hz),3.42(q,2H,J=7.2Hz),1.23(t,3H,J=7.2Hz).
KQ17:1HNMR(400MHz,d6-DMSO,ppm)δ12.43(brs,1H),8.81(brs,1H),7.73-7.70(m,1H),7.30-7.25(m,1H),6.93-6.90(m,1H),3.24(t,2H,J=6.4Hz),1.60-1.50(m,2H),0.90(t,3H,J=7.2Hz).
KQ18:1HNMR(400MHz,CD3Cl,ppm)δ12.06(brs,1H),7.13-7.08(m,1H),7.06-7.03(m,1H),6.95-6.91(m,1H),6.30(brs,1H),3.47-3.42(m,2H),1.65-1.57(m,2H),1.46-1.1.36(m,2H),0.96(t,3H,J=7.3Hz).
KQ19:1HNMR(400MHz,CD3Cl,ppm)δ12.40(brs,1H),7.39-7.35(m,2H),6.98-6.96(m,1H),6.84-6.80(m,1H),6.45(brs,1H),3.43-3.38(m,2H),1.69-1.60(m,2H),0.98(t,3H,J=7.4Hz).
KQ20:1HNMR(400MHz,CD3Cl,ppm)δ12.41(brs,1H),7.39-7.34(m,2H),6.98-6.96(m,1H),6.84-6.81(m,1H),6.40(brs,1H),3.47-3.3.42(m,2H),1.64-1.57(m,2H),1.45-1.36(m,2H),0.95(t,3H,J=7.3Hz).
KQ21:1HNMR(400MHz,CD3Cl,ppm)δ12.37(brs,1H),7.38-7.34(m,2H),6.97-6.95(m,1H),6.83-6.80(m,1H),6.52(brs,1H),3.44-3.3.39(m,2H),1.64-1.57(m,2H),1.35-1.34(m,4H),0.90(t,3H,J=7.4Hz).
KQ22:1HNMR(400MHz,CD3Cl,ppm)δ8.07(s,1H),7.86(brs,1H),7.57-7.55(d,1H,J=8.4Hz),6.96-6.94(d,1H,J=8.5Hz),3.48(m,2H),1.28(t,3H,J=7.2Hz).
KQ23:1HNMR(400MHz,CD3Cl,ppm)δ12.70(brs,1H),7.23-7.21(d,1H,J=8.7Hz),6.40(s,1H),6.35-6.33(d,1H,J=8.8Hz),6.06(brs,1H),3.50-3.44(m,2H),1.25(t,3H,J=7.8Hz).
KQ24:1HNMR(400MHz,CD3Cl,ppm)δ7.87(brs,1H),7.37(d,1H,J=8.24Hz),7.03(d,1H,J=8.24Hz),3.37-3.31(m,2H),1.65-1.60(m,2H),0.95(t,3H,J=7.32Hz).
KQ25:1HNMR(400MHz,CD3Cl,ppm)δ9.06(brs,1H),7.46(t,1H,J=7.6Hz),6.93(dd,1H,J1=8.0Hz,J2=0.4Hz),6.74(t,1H,J=7.6Hz),3.12-3.09(m,2H),2.72-2.70(m,2H).
KQ26:1HNMR(400MHz,CD3Cl,ppm)δ7.16(m,1H),6.78(m,1H),6.70(m,1H),5.64(m,1H),5.35(brs,1H),3.65(s,1H),2.74(m,2H),2.64(m,2H),2.26(s,3H).
KQ27:1HNMR(400MHz,d6-DMSO,ppm)δ9.97(s,1H),8.34(t,1H,J=5.6Hz),7.21(dd,1H,J1=J2=9.2Hz),6.80(dd,1H,J1=4.0Hz,J2=9.2Hz),3.21(dq,2H,J1=5.6Hz,J2=7.2Hz),1.08(t,3H,J=7.2Hz).
KQ28:1HNMR(400MHz,CD3Cl,ppm)δ12.47(brs,1H),7.19-7.14(m,1H),6.79-6.75(m,1H),6.13(brs,1H),3.52-3.45(m,2H),1.27(t,3H,J=7.2Hz).
KQ29:1HNMR(400MHz,d6-DMSO,ppm)δ9.40(s,1H),8.15(t,1H,J=5.2Hz),6.94(dd,1H,J1=J2=9.2Hz),6.65(dd,1H,J1=4.4Hz,J2=8.8Hz),3.24-3.17(m,2H),2.05(d,3H,J=2.0Hz),1.08(t,3H,J=7.2Hz).
KQ30:1HNMR(400MHz,CDCl3,ppm)δ12.44(s,1H),7.14(d,1H,J=8.1Hz),6.63(d,1H,J=11.0Hz),6.12(s,1H),3.52-3.45(m,2H),2.20(s,3H),1.27(t,3H,J=7.2Hz).
KQ31:1HNMR(400MHz,CDCl3,ppm)δ12.46(s,1H),6.98(d,1H,J=11.6Hz),6.27(d,1H,J=7.9Hz),6.04(s,1H),3.48-3.41(m,2H),1.24(t,3H,J=7.2Hz).
KQ32:1HNMR(400MHz,CDCl3,ppm)δ8.24(brs),8.08(m,1H),7.59(m,1H),7.52-7.41(m,5H),5.35(brs,1H),3.42(t,J=7.2Hz,2H),1.64(m,2H),0.90(t,J=7.2Hz,3H).
KQ33:1HNMR(400MHz,CDCl3,ppm)δ7.41(d,2H,J=8.32Hz),7.33-7.29(m,3H),6.96(d,1H,J=8.32Hz),6.98(d,1H,J=7.48Hz),5.28(brs,1H),3.07(q,2H,J=6.84Hz),1.17(m,3H),0.65(t,3H,J=7.4Hz).
KQ34:1HNMR(400MHz,CDCl3,ppm)δ7.90(s,1H),7.82(s,1H),7.57-7.50(m,2H),7.28(m,1H),6.54(brs,1H),3.48(q,2H,J=6.68Hz),1.71(m,2H),1.04(t,3H,J=7.4Hz).
KQ35:1HNMR(400MHz,d6-DMSO,ppm)δ11.5(s,1H),8.62(s,1H),8.17(s,1H),7.77-7.53(m,2H),7.44(m,1H),5.35(brs,1H).
KQ36:1HNMR(400MHz,CDCl3,ppm)δ7.98-7.91(m,2H),7.77(m,1H),7.75-7.58(m,2H),7.48-7.34(m,3H),6.57(brs,1H),3.50(q,2H,J=6.64Hz),1.75-1.71(m,2H),1.05(t,3H,J=6.64Hz).
KQ37:1HNMR(400MHz,CD3OD,ppm)δ8.48(d,0.2H,J=2.2Hz),8.46(d,1H,J=2.2Hz),8.29-8.21(m,1H),7.67-7.65(m,0.2H),7.38-7.35(m,1H),6.58-6.55(m,0.2H),3.39-3.35(m,0.4H),3.32-3.26(m,2H),1.68-1.62(m,2H),1.59-1.46(m,2H),0.99(t,0.6H,J=7.4Hz),0.87(t,3H,J=7.4Hz).
KQ38:1HNMR(400MHz,CD3OD,ppm)δ8.84(s,1H),8.26(m,1H),8.03(brs,1H),6.66(m,1H),5.35(brs,1H),3.04(q,2H,J=7.4Hz),1.04(t,3H,J=7.4Hz).
KQ39:1HNMR(400MHz,CD3OD,ppm)δ8.76(s,1H),8.04(m,1H),8.03(brs,1H),8.02(s,1H),5.35(m,1H),3.04(q,2H,J=7.4Hz),1.04(t,3H,J=7.4Hz).
KQ40:1HNMR(400MHz,CDCl3,ppm)δ10.54(brs,1H),8.55(s,1H),7.54(d,1H,J=6.1Hz),7.12(s,1H),6.60(d,1H,J=7.3Hz),3.40(dd,2H,J=12.9,6.8Hz),1.65(dq,2H,J=14.5,7.3Hz),1.00(t,3H,J=7.4Hz).
KQ41:1HNMR(400MHz,CDCl3,ppm)δ8.46(s,1H),8.15(d,1H,J=5.2Hz),7.18(d,1H,J=5.2Hz),6.58(brs,1H),3.52(dt,2H,J=14.2,7.2Hz),1.29(t,3H,J=7.3Hz).
KQ42:1HNMR(400MHz,CD3OD,ppm)δ11.77(brs,1H),10.76(brs,1H),8.01(s,1H),5.60(s,1H),4.25(q,2H,J=7.08Hz),1.28(t,3H,J=7.12Hz).
KQ43:1HNMR(400MHz,CDCl3,ppm)δ12.02(brs,1H),7.13-7.07(m,2H),6.94-6.90(m,1H),6.74(brs,1H),3.65-3.61(m,2H),3.58-3.55(m,1H),3.40(s,3H).
KQ44:1HNMR(400MHz,CDCl3,ppm)δ12.05(brs,1H),7.16-7.14(m,1H),7.10-7.05(m,1H),6.92-6.88(m.1H),6.73(brs,1H),3.24(t,2H,J=6.5Hz),1.94-1.84(m,1H),3.40(d,6H,J=6.6Hz).
KQ45:1HNMR(400MHz,CDCl3,ppm)δ12.11(brs,1H),7.17-7.11(m,2H),7.00-6.98(m,1H),6.34(brs,1H),3.36-3.33(m,2H),1.10(m,1H),0.65-0.63(m,2H),0.35-0.34(m,2H).
KQ46:1HNMR(400MHz,CDCl3,ppm)δ12.07(brs,1H),7.14-7.09(m,1H),7.05-7.02(m,1H),6.95-6.92(m.1H),6.30(brs,1H),3.38(t,2H,J=7.1Hz),2.20-2.12(m,1H),1.85-1.56(m,8H).
KQ47:1HNMR(400MHz,CDCl3,ppm)δ12.08(brs,1H),7.12-7.07(m,2H),6.94-6.90(m,1H),6.48(brs,1H),3.27(t,2H,J=6.4Hz),1.80-1.55(m,6H),1.28-1.14(m,2H),1.01-0.96(m,2H).
KQ48:1HNMR(400MHz,CDCl3,ppm)δ12.09(brs,1H),7.14-7.09(m,1H),6.96-6.92(m,2H),6.20(brs,1H),3.53-3.48(m,2H),2.28-2.24(m,2H),1.68-1.62(m,4H),1.61-1.55(m,4H).
KQ49:1HNMR(400MHz,CDCl3,ppm)δ12.09(brs,1H),7.14-7.09(m,1H),7.03-7.00(m,1H),6.95-6.92(m.1H),6.17(brs,1H),3.49-3.44(m,2H),1.76-1.65(m,4H),1.60-1.49(m,2H),1.39-1.30(m,1H),1.29-1.14(m,4H),1.00-0.91(m,2H).
KQ50:1HNMR(400MHz,CDCl3,ppm)δ11.65(brs,1H),7.14-7.09(m,1H),7.07-7.05(m,1H),6.95-6.91(m,1H),3.75(t,4H,J=4.1Hz),3.55-3.51(m,2H),2.62(t,4H,J=5.8Hz),2.52(t,4H,J=4.2Hz).
KQ51:1HNMR(400MHz,CDCl3,ppm)δ12.01(brs,1H),7.37-7.29(m,2H),7.27-7.22(m,3H),7.14-7.09(m,1H),6.95-6.92(m,1H),6.88-6.85(m,1H),6.20(brs,1H),3.72-3.69(m,2H),2.96-2.92(m,2H).
KQ52:1HNMR(400MHz,CDCl3ppm)δ12.05(brs,1H),8.02(d,1H,J=8.1Hz),7.92-7.86(m,2H),7.60-7.45(m,4H),7.13-7.08(m,1H),6.96-6.40(m,2H),6.40(brs,1H),5.7(d,2H,J=5.1Hz).
KQ53:1HNMR(400MHz,CDCl3,ppm)δ8.03(brs,1H),7.44(m,1H),7.33-7.23(m,6H),7.11(m,1H),5.35(brs,1H),4.35(m,2H).
KQ54:1HNMR(400M,CDCl3,ppm)δ11.96(s,1H),7.49-7.32(m,5H),7.12(dd,1H,J1=J2=8.0Hz),7.03(d,1H,J=8.6Hz),6.94(dd,1H,J1=9.0Hz,J2=4.7Hz),6.33(s,1H),5.33-5.26(m,1H),1.63(d,1H,J=6.8Hz).
KQ55:1HNMR(400M,CDCl3,ppm)δ12.01(s,1H),7.27(d,2H,J=8.8Hz),7.12(dd,1H,J1=J2=8.7Hz),7.00(d,1H,J=8.7Hz),6.97-6.93(m,1H),6.90(d,2H,J=7.8Hz),6.38(s,1H),4.56(d,2H,J=5.3Hz),3.81(s,3H).
KQ56:1HNMR(400MHz,CDCl3,ppm)δ8.46(m,1H),8.03(brs,1H),7.73(m,1H),7.44(m,1H),7.33-7.23(m,3H),7.11(m,1H),5.35(brs,1H),4.35(m,2H).
KQ57:1HNMR(400MHz,CDCl3,ppm)δ8.56(m,1H),8.55(m,1H),8.03(brs,1H),7.44(m,1H),7.35-7.32(m,2H),7.11(m,1H),5.35(brs,1H),4.35(m,2H).
KQ58:1HNMR(400MHz,CDCl3,ppm)δ11.96(brs,1H),7.22-7.21(m,1H),7.15-7.10(m,1H),7.00-6.89(m,4H),6.33(brs,1H),3.75-3.70(m,2H),3.16(t,2H,J=7.0Hz).
KQ59:1HNMR(400MHz,CD3OD,ppm)δ7.95(d,1H,J=8.0Hz),7.48-7.44(m,1H),6.98(t,2H,J=8.28Hz),2.46(s,3H).
KQ60:1HNMR(400MHz,d6-DMSO,ppm)δ15.04(brs,0.2H),14.67(brs,0.8H),9.03(brs,0.9H),8.67(brs,0.7H),7.83(m,1H),7.28(m,1.8H),7.07(m,0.2H),6.77(m,2H),2.72(m,3H).[互变异构]
KQ61:1HNMR(400MHz,d6-DMSO,ppm)δ12.47(s,1H),10.04(s,1H),7.79(d,1H,J=7.9Hz),7.37(t,1H,J=7.7Hz),6.93–6.80(m,2H),2.50(s,3H).
KQ62:1HNMR(400MHz,CDCl3,ppm)δ7.53(dd,1H,J=7.7,1.4Hz),7.25–7.15(m,1H),7.03(d,1H,J=7.7Hz),6.91(dd,1H,J=10.9,4.0Hz),6.44(s,1H),2.40(s,3H).13CNMR(101MHz,CDCl3,ppm)δ156.02,152.63,139.97,129.24,126.59,119.42,116.91,117.06,101.34,10.96.
KQ63:1HNMR(400MHz,CDCl3,ppm)δ7.78(s,1H),7.44–7.30(m,1H),7.09(d,1H,J=8.3Hz),6.90(t,1H,J=7.5Hz),4.46(q,2H,J=7.1Hz),1.45(t,3H,J=7.1Hz).13CNMR(101MHz,CDCl3,ppm)δ161.07,158.07,149.31,131.89,131.54,124.62,119.20,118.18,111.96,100.12,61.64,14.51.
KQ64:1HNMR(400MHz,d6-DMSO,ppm)δ13.09(s,1H),11.81(s,1H),8.36(s,1H),7.90(d,1H,J=6.1Hz),7.79(s,1H),7.34–7.22(m,1H),6.98(d,1H,J=8.2Hz),6.93(t,1H,J=7.5Hz),2.77(t,3H,J=11.5Hz).
KQ65:1HNMR(400MHz,CDCl3,ppm)δ11.47(s,1H),7.85(dd,1H,J=7.8,1.4Hz),7.04(dd,1H,J=8.3,0.6Hz),6.90–6.82(m,1H),2.82(q,2H,J=7.6Hz),1.35(t,3H,J=7.6Hz).13CNMR(101MHz,CDCl3,ppm)δ159.74,158.80,156.95,131.62,125.97,119.55,117.48,112.65,20.30,11.84.
KQ66:1HNMR(400MHz,CDCl3,ppm)δ11.49(s,1H),7.85(d,1H,J=7.8Hz),7.28(dd,1H,J=13.7,6.0Hz),7.03(d,1H,J=8.3Hz),6.87(t,1H,J=7.5Hz),2.77(t,2H,J=7.5Hz),1.87–1.73(m,2H),0.98(t,3H,J=7.3Hz).
KQ67:1HNMR(400MHz,CD3OD,ppm)δ7.79(d,1H,J=7.8Hz),7.72(s,1H),7.29(t,1H,J=7.8Hz),7.00(d,1H,J=8.3Hz),6.94(t,1H,J=7.6Hz),3.37(t,2H,J=7.2Hz),1.73–1.60(m,2H),1.00(t,3H,J=7.4Hz).
KQ68:1HNMR(400MHz,CDCl3,ppm)δ10.64(s,1H),7.62(d,1H,J=7.7Hz,),7.27(t,1H,J=7.4Hz,),7.11(d,1H,J=8.2Hz,),6.97(t,1H,J=7.5Hz,),6.46(s,1H),2.64(t,2H,J=7.6Hz,),1.79–1.63(m,2H),0.99(t,3H,J=7.3Hz).13CNMR(101MHz,CDCl3,ppm)δ155.78,152.16,144.94,129.07,126.54,119.48,117.00,116.93,100.12,27.48,22.34,13.72.
KQ69:1HNMR(400MHz,CDCl3,ppm)δ7.56(dd,1H,J=7.7,1.5Hz),7.25–7.17(m,1H),7.02(dd,1H,J=8.2,0.7Hz),6.94–6.86(m,1H),6.45(s,1H),2.75(q,2H,J=7.6Hz),1.34(t,3H,J=7.6Hz).
KQ70:1HNMR(400MHz,CDCl3,ppm)δ8.48(d,1H,J=2.7Hz),8.11(dd,1H,J=9.1,2.7Hz),7.07(d,1H,J=9.1Hz),6.58(s,1H),2.73(t,2H,J=7.5Hz),1.86–1.66(m,2H),1.03(t,3H,J=7.4Hz).13CNMR(101MHz,CDCl3,ppm)δ161.96,150.73,145.57,140.52,125.07,122.86,117.67,117.09,100.94,27.60,22.37,13.83.
KQ71:1HNMR(400MHz,CD3Cl,ppm)δ9.98(brs,2H),7.50(d,1H,J=2.4Hz),7.14(dd,1H,J=2.4Hz,8.6Hz),6.95(d,1H,J=8.8Hz),6.42(s,1H),2.68(t,2H,J=7.6Hz),1.77-1.70(m,2H),1.00(t,2H,J=7.2Hz).
KQ72:1HNMR(400MHz,CD3Cl,ppm)δ9.41(brs,2H),7.24-7.21(m,1H),6.97-6.88(m,2H),6.39(s,1H),2.68(t,2H,J=7.6Hz),1.77-1.69(m,2H),1.00(t,3H,J=7.6Hz).
KQ73:1HNMR(400MHz,CDCl3)δ6.89-6.84(m,1H),6.59(s,1H),6.37-6.34(m,1H),2.66(t,J=7.2Hz,2H),1.72-1.69(m,2H),0.98(t,J=7.2Hz,3H);13CNMR(400MHz,CDCl3)δ152.0,148.3,147.3,145.6,145.0,133.1,132.9,114.9,114.7,133.1,132.9,114.9,114.7,106.5,105.3,105.2,103.2,27.8,22.4,13.9.
KQ74:1HNMR(400MHz,d6-DMSO)δ11.68(s,1H),11.54(s,1H),7.96-7.93(m,1H),7.51-7.47(m,1H),6.61-6.56(m,1H),3.95(t,J=6.0Hz,2H),3.33-3.30(m,2H),1.72(s,3H);13CNMR(400MHz,d-DMSO)δ169.9,167.5,160.5,150.0,140.6,137.0,109.1,105.2,100.8,36.7,23.0.
KQ75:1HNMR(400MHz,d6-DMSO)δ11.67(s,1H),11.37(s,1H),7.48-7.43(m,1H),6.54-6.50(m,1H),3.83(t,J=7.2Hz,2H),1.62-1.56(m,2H),0.90(t,J=7.6Hz,3H);13CNMR(400MHz,d-DMSO)δ166.6,156.2,149.6,142.7,140.4,128.2,128.1,122.8,122.6,108.4,108.3,101.4,101.3,41.9,20.9,11.6.
KQ76:1HNMR(400MHz,CDCl3,ppm)6.76(t,1H,J=12Hz),6.20(s,1H),4.58(s,2H),2.59(s,2H),1.66(d,2H,J=4Hz),0.98(d,3H,J=4Hz).
KQ77:1HNMR(400MHz,CD3OD,ppm)9.12(s,1H),7.33(dd,1H,J=8.4,10.8Hz),6.97(dd,1H,J=3.6,12.4Hz),3.09(t,2H,J=7.6Hz),1.91(m,2H)1.04(t,3H,J=7.2Hz).
KQ78:1HNMR(400MHz,d6-DMSO,ppm)13.03(brs,1H),10.88(brs,1H),7.17(dd,1H,J=9.2,11.2Hz)6.57(dd,1H,J=3.6,8.8Hz),2.94(t,2H,J=7.2Hz),1.76(m,2H,)0.92(t,3H,J=7.2Hz).13CNMR(101MHz,d6-DMSO,ppm)159.57,151.03,150.32(d,J=2Hz),144.24,141.90,127.32(d,J=4Hz),115.51(d,J=19Hz),108.64,106.26,102.38,29.26,22.30,14.16.
KQ79:HRMS(EI+):found273.1276[M]+,(CalcdforC15H16FN3O:273.1277).
KQ80:HRMS(EI+):found275.1431[M]+,(CalcdforC15H18FN3O:275.1434).
KQ81:HRMS(EI+):found261.1279[M]+,(CalcdforC14H16FN3O:261.1277).
活性测试实施例
NMR化学位移扰动测试亲和力(KD):NMRHSQC滴定的方法检测被小分子化合物扰动的蛋白氨基酸残基,并通过扰动信号检测小分子和蛋白的结合亲和力。0.05mM到0.2mM的15N标记的BRM的溴结构域,与小分子化合物的摩尔比从0.0到4.0的浓度比范围内分别进行滴定。每个滴定数据点的HSQC图谱使用500MH或700MHz安捷伦核磁仪器在293K温度下采集18min。结果总结在表1中。
细胞存活率实验:小分子对细胞的存活率的影响,使用MTT法检测。细胞放置于96孔板中,分别给予不同浓度的测试小分子样品、KQ70(阴性对照)以及DMSO(空白对照),给药3~4天,之后加入MTT储液(5mg/ml,20μL)。96孔板在CO2孵育箱中在37℃继续孵育4h。在每个孔中加入DMSO(150μL),混匀直至所有的晶体都溶解。使用SpectraMaxM5(MolecularDevices,CA,USA)测试在490nm处的OD值。半抑制浓度IC50值通过非线性回归分析进行计算。细胞存活率实验分别在大细胞肺癌(属于非小细胞肺癌)H1299细胞和肺腺癌细胞(属于非小细胞肺癌)A549细胞上进行测试。H1299细胞和A549细胞均为BRG1基因缺失(BRG1-),而BRM基因(BRM+)非缺失的细胞株,该细胞株的细胞内不能表达BRG1蛋白,但可正常表达BRM蛋白。能在细胞内阻止BRM蛋白与染色体相互作用的小分子,即可阻止BRM蛋白行使细胞内的功能。根据协同致死规律,在BRG1基因缺失的细胞里,阻止BRM蛋白的功能,则会导致细胞死亡,实现小分子杀死癌细胞的作用。
按照常规检测方法,确定了各化合物(小分子)的半数抑制浓度(IC50),结果总结在表1中,在表1中,+++代表有强的抑制活性,++代表有中等抑制活性,+代表抑制活性较低,但仍具有明显优于现有已知化合物的抑制活性。
表1
由此,可以证明本发明的化合物KQ1~KQ81能够有效地治疗癌症尤其是BRG1基因缺失的非小细胞肺癌。
对于本领域技术人员显而易见的是,本公开内容并不限于前述说明性实施例,而且可以体现在其它具体形式中而又不偏离其实质特性。因此,预期各实施例在所有方面都被视作说明性的且非限制性的,应参照所附权利要求书,而不是前述实施例,因此,在所附权利要求书等同内容的含义和范围内的所有变化都包括在本文中。
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一定指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何的一个或多个实施例或示例中以合适的方式结合。
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不脱离本发明的原理和宗旨的情况下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 (10)
1.一种化合物,其为如式(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,消旋体,氮氧化物,水合物,溶剂化物,代谢产物以及药学上可接受的盐或前药:
其中,Q表示C或N,
R1表示H,或任选被C1~5烷基、C1~5烷基酯基取代的五元含氮杂环,R6为键,H,C1~5亚烷基,任选被C1~5亚烷基取代的五元含氮杂环,或任选被C1~5亚烷基取代的亚氨基,R7为H,C1~5烷基,或者任选被C1~5烷基、C1~5烷氧基、C1~5亚烷基环烷基、C1~5亚烷基环烯基、芳基、亚烷基芳基、六元杂环、亚烷基六元杂环、氰基、氰基亚氨基C1~5烷基取代的亚氨基或次氨基;以及R2、R3、R4、R5和R6的每一个分别独立地为H、卤素、羟基、C1~5烷氧基、胺基、C1~5羰基亚氨基或者亚氨基、芳基、硝基或者氰基,前提是R2、R3、R4、R5和R6不同时为H;
或者
R1~R6中相邻的两个连同与其所连接的碳原子构成任选被C1~5烷基、芳基、任选含有氧、硫和氮至少之一的五~七元环或者稠合双环。
2.根据权利要求1所述的化合物,其特征在于,R1为任选取代的亚氨基羰基、次氨基羰基或者五元含氮杂环。
3.根据权利要求1所述的化合物,其特征在于,所述卤素为F或者Cl。
4.根据权利要求1所述的化合物,其特征在于,R1和R2连同与其所连接的碳原子构成任选被C1~5烷基、芳基、任选含有氧、硫和氮至少之一的五~七元环或者稠合双环,或者R2和R3连同与其所连接的碳原子构成任选被C1~5烷基、芳基、任选含有氧、硫和氮至少之一的五~七元环或者稠合双环。
5.根据权利要求1所述的化合物,其特征在于,R1和R2连同与其所连接的碳原子构成任选取代的含有1~3个氮原子的五~七元环或者稠合双环,任选地所述五~七元环或者稠合双环的环上形成有至少一个羰基。
6.根据权利要求1所述的化合物,其特征在于,所述化合物为如下式所示的化合物或下式所示化合物的立体异构体,几何异构体,互变异构体,消旋体,氮氧化物,水合物,溶剂化物,代谢产物以及药学上可接受的盐或前药:
7.权利要求1~6任一项化合物在制备药物中的用途,所述药物用于治疗癌症。
8.根据权利要求7所述的用途,其特征在于,所述癌症为肺癌。
9.根据权利要求8所述的用途,其特征在于,所述肺癌为非小细胞肺癌。
10.根据权利要求9所述的用途,其特征在于,所述非小细胞肺癌为BRG1基因缺失。
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WO2020221376A1 (zh) * | 2019-04-29 | 2020-11-05 | 北京嘉林药业股份有限公司 | 一种预防和/或治疗癌症的化合物及其制备方法和应用 |
CN111848528B (zh) * | 2019-04-29 | 2022-03-11 | 北京嘉林药业股份有限公司 | 一种预防和/或治疗癌症的化合物及其制备方法和应用 |
CN111635310A (zh) * | 2020-05-21 | 2020-09-08 | 大连理工大学 | 一种用于防护铜在弱碱性介质中腐蚀的水杨酸酰胺型缓蚀剂及制备方法 |
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