CN116693515A - 一种gst蛋白抑制剂、其制备方法、药用组合物及其用途 - Google Patents
一种gst蛋白抑制剂、其制备方法、药用组合物及其用途 Download PDFInfo
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
本发明涉及一种GST抑制剂、其制备方法、药用组合物及其用途。具体地,本发明提供了一类式I所示结构的化合物,其中各基团和取代基的定义如说明书中所述;本发明还公开了所述式I化合物的制备方法及其在预防和/或治疗GST异常活性相关疾病方面的用途。
Description
技术领域
本发明涉及药物领域,具体地涉及一种GST抑制剂、其制备方法、药用组合物及其用途。
背景技术
谷胱甘肽转移酶(GSTS)是由23-29KDa的不同亚基构成的同源或异源二聚体胞浆酶家族,在机体中分布广泛,催化还原型谷胱甘肽(GSH)与各种具有亲电性外源物的结合反应,以实现细胞内解毒、氧化应激反应、介导机体潜在的和外源性有害物质的排泄,保护机体免受毒性反应的多种功能。研究显示,GST在一些具有多药耐药性的肿瘤细胞中过度表达,诱发抗肿瘤药物代谢失活。已有许多针对开发谷胱甘肽抑制剂和谷胱甘肽激活的前药,以此作为具有耐药性的癌细胞治疗的手段。
GST蛋白的酶活性位点由GSH结合位点(G-位点)和疏水底物结合位点(H-位点)组成。报道的占据G-位点的抑制剂通常和GSH具有类似的结构,这类抑制剂的选择性较好,但抑制作用较弱,而体内GST水平通常较高,限制了该类抑制剂的临床应用。而另一类占据H-位点的底物,如利尿剂乙炔酸(Ethacrynic acid,EA)具有较好的抑制活性,已在临床试验中作为化疗的佐剂。它不仅通过抑制谷胱甘肽S-转移酶的活性,还可能通过抑制多药耐药蛋白将药物的GSH偶联产物输出到肿瘤细胞,从而调节肿瘤细胞的耐药性。但该类抑制剂通常对靶点的选择性较差,会产生其他副作用。因此开发兼具选择性和抑制活性的GST抑制剂仍具有重要意义。
因此,本领域迫切需要开发新型的GST蛋白抑制剂。
发明内容
本发明的目的是提供一种新型的GST蛋白抑制剂。
本发明的第一方面,提供了一种如下式I所示的化合物、或其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物,
其中,
选自下组:C6-C12芳基、5-8元杂环基、或5-8元杂芳基、C5-C8环烷基并C6-C12芳基、含有1-3个选自N、O和S的杂原子的5-8元杂环基、或5-8元杂芳基并C6-C12芳基;
R1为一个或多个位于A环上的取代基,且R1选自下组:-H、-OH、-COR4、-COOR4、-CONHR4、-SO2NHR4、卤素、C1-C6烷基、C1-C6烷氧基、5-10元杂环基、或5-10元杂芳基;
X选自下组:-(CHR)n-;其中,n为0、1、2、3、4;
R各自独立地选自下组:-H、-OH、-Me、-COOH;
R2选自下组:-H、-COOR4、氨基酸残基(即,氨基酸通过官能团与分子中其他部分相连形成的基团)、C1-C4烷基、-NHR4、C5-C8环烷基、C5-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基;
R3选自下组:-H、-OH、-Me、-CONHR4、-SO2NHR4、卤素、C1-C6烷基、C1-C6烷氧基、C6-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基;且所述的R3被一个或多个R5取代基取代,所述的R5选自下组:-Cl、-COOH、OH、-CONH2、C1-C6烷基、C1-C6烷氧基、5-8元杂环基、或5-8元杂芳基;
R4选自下组:-H、C1-C4烷基、C6-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基;
上述各式中,杂环基含有1-3个选自N、O、S的杂原子;除非特别说明,各个所述的芳基、杂环基或杂芳基可任选被1-3个下组取代基取代:-Cl、-COOH、OH、-CONH2、C1-C6烷基、C1-C6烷氧基、杂环基或5-8元杂芳基。
在另一优选例中,所述化合物具有式I’所示的结构
其中,
R’1的定义同R1;
n’为1、2、3、4或5;
X、A、R1、R2、R3的定义如上所述。
在另一优选例中,所述化合物具有式I”所示的结构
其中,X、A、R1、R2、R3的定义如上所述。
在另一优选例中,选自下组:C6-C10芳基、5-6元杂环基、或5-6元杂芳基、C5-C8环烷基并苯基、含有1-3个选自N、O和S的杂原子的5-6元杂环基、或5-6元杂芳基并苯基;
R1选自下组:-H、-OH、-Me、-COOR4、-CONHR4、-SO2NHR4、卤素、C1-C6烷基、C1-C6烷氧基、5-6元杂环基、或5-6元杂芳基。
R4选自下组:-H、C1-C4烷基、C6-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基。在另一优选例中,X选自下组:-(CHR)n-;其中,n为1、2或3;
R各自独立地选自下组:-H、-OH、-Me、-COOH;
R2选自下组:-H、-COOR4、-NHR4、C5-C8环烷基、C5-C6芳基、5-8元杂环基、或5-8元杂芳基。
在另一优选例中,R3选自下组:苯基、5-8元杂芳基;且所述的R3被一个或多个R5取代基取代,所述的R5选自下组:-Cl、-COOH、OH、-CONH2、C1-C6烷基、C1-C6烷氧基、
在另一优选例中,选自下组:C6-C12芳基、5-8元杂环基、或5-8元杂芳基、C5-C8环烷基并C6-C12芳基、含有1-3个选自N、O和S的杂原子的5-8元杂环基、或5-8元杂芳基并C6-C12芳基。
在另一优选例中,R3选自下组:C6-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基;且所述的R3被一个或多个R5取代基取代,所述的R5选自下组:-Cl、-COOH、OH、-CONH2、C1-C6烷基、C1-C6烷氧基、5-8元杂环基、或5-8元杂芳基。
在另一优选例中,X选自下组:-(CHR)n-;其中,n为0、1、2、3、4;
R各自独立地选自下组:-H、-OH、-Me、-COOH;
R2选自下组:-H、-COOR4、氨基酸残基(即,氨基酸通过官能团与分子中其他部分相连形成的基团)、C1-C4烷基、-NHR4、C5-C8环烷基、C5-C12芳基、C5-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基;
R3选自下组:C6-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基;且所述的R3被一个或多个R5取代基取代,所述的R5选自下组:-Cl、-COOH、OH、-CONH2、C1-C6烷基、C1-C6烷氧基、5-8元杂环基、或5-8元杂芳基;
上述各式中,杂环基含有1-3个选自N、O、S的杂原子;除非特别说明,各个所述的芳基、杂环基或杂芳基可任选被1-3个下组取代基取代:-Cl、-COOH、OH、-CONH2、C1-C6烷基、C1-C6烷氧基、杂环基或5-8元杂芳基。
在另一优选例中,选自:H、/>
在另一优选例中,选自:/>
在另一优选例中,R3选自:-COOH、/>
在另一优选例中,所述式(I)化合物选自下组:
在另一优选例中,所述化合物为实施例中所示化合物。
本发明的第二方面,提供了一种本发明第一方面所述的化合物在制备治疗GST异常活性相关疾病的药物中的用途。
在另一优选例中,所述GST异常活性相关疾病选自下组:胃肠癌、宫颈癌、膀胱癌、喉癌、肝癌、乳腺癌、肺癌、口腔癌、卵巢癌、糖尿病、炎症、肺部功能絮乱、疼痛(包括但不限于复杂性局部疼痛综合症)、黄斑退化及相关功能絮乱、皮肤疾病、免疫缺陷型疾病、中枢神经系统的损伤及功能絮乱。
本发明的第三方面,提供了一种药物组合物,所述的药物组合物包括治疗有效量的如本发明第一方面所述的化合物,或其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物;以及药学上可接受的载体。
在另一优选例中,所述的药物组合物预防和/或治疗GST异常活性相关疾病。
在另一优选例中,所述GST异常活性相关疾病包括但不限于选自下组的疾病:皮肤癌症(如黑色素瘤)、淋巴系统癌症、乳腺癌、宫颈癌、子宫癌、消化道癌症、肺癌、卵巢癌、前列腺癌、结肠癌、直肠癌、口腔癌、脑瘤、头颈部癌、咽喉癌、睾丸癌、肾癌、胰腺癌、脾癌、肝癌、膀胱癌、喉癌以及与艾滋病相关的癌症。
在另一优选例中,所述GST异常活性相关疾病包括但不限于选自下组的疾病:肿瘤多药耐药性。
在另一优选例中,所述血液瘤为急慢性白血病。
在另一优选例中,所述骨髓瘤为多发性骨髓瘤。
在另一优选例中,所述化合物用于预防或治疗原发肿瘤和转移性肿瘤。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1示出了化合物对GST酶活性抑制率曲线。
具体实施方式
本发明人经过长期而深入的研究,制备并提供了一种以喹唑啉酮为主要结构骨架的DEL,并基于所述DEL筛选得到一类GST抑制剂,所述抑制剂可有效抑制GST活性,与抗肿瘤药物联用有望减小因过表达的GST对抗肿瘤药物的清除造成的多因耐药,为抗肿瘤化学疗法提供了新的思路。在此基础上,发明人完成了本发明。
术语
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
在本发明中,术语“卤素”指F、Cl、Br或I。
在本发明中,“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。
在本发明中,术语“C2-C6烯基”是指具有2-6个碳原子的含有一个双键的直链或支链烯基,非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中,术语“C2-C6炔基”是指具有2-6个碳原子的含有一个三键的直链或支链炔基,非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中,术语“C3-C8环烷基”是指在环上具有3-8个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
在本发明中,术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。
在本发明中,术语“杂环基”为含1、2或3个选自N、O、S的杂原子的4-8元杂环基,包括(但并不限于)如下基团:环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基。
在本发明中,术语“芳环”或“芳基”具有相同的含义,优选为“C6-C10芳基”。术语“C6-C10芳基”是指在环上不含杂原子的具有6-10个碳原子的芳香族环基,如苯基、萘基等。
在本发明中,术语“芳香杂环”或“杂芳基”具有相同的含义,指包含一个到多个杂原子的杂芳族基团。例如“C3-C10杂芳基”是指含有1~4个选自氧、硫和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括:呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中,术语“卤代”是指被卤素取代。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中,术语1-6个指1、2、3、4、5或6个。其他类似术语各自独立地具有类似含义。
术语“互变异构体”是指容易通过互为异构体的化学反应互变的结构异构体,该反应一般导致伴随单键和相邻双键转变的氢原子或质子的形式移动。
术语“对映体”是指互为镜像而不可重叠的立体异构体。
术语“非对映体”是指具有两个或者两个以上的手性中性,并且不成镜像的立体异构体。
“消旋体”是指两个互为镜像的立体异构体,旋光性相反,可以互相抵消旋光性。
“代谢前体”是指在体外无活性或者活性较小,在体内经过体内代谢途径的转化释放出活性药物而发挥药效的一类化合物。
“可药用的盐”是指药物分子与对应的有机酸、无机酸或者有机碱、无机碱形成相应的盐,例如盐酸、甲酸、三氟乙酸、琥珀酸、甲磺酸盐等。
“前药”是指在体外无活性或者活性较小,在体内经过酶或者非酶的转化释放出活性药物而发挥药效的一类化合物。
“水合物”是指含有水的化合物。
应理解,当某一基团同时存在于化合物的多个不同位置时,其在各位置的定义是相互独立的,可以相同也可以不同。亦即,术语“选自下组:”与术语“各独立地选自下组:”具有相同含义。
合成方法一:
其中,X为Br、I;
步骤a:化合物1A与三光气反应得到化合物1B。
合成方法二:
其中,R1,R2,R3,n,A,X的定义与上述相同;
步骤b:化合物1B,化合物2A与化合物2B在乙酸催化条件下环化反应得到化合物2C;
步骤c:化合物2C在加入DDQ条件下芳香化得到化合物2D;
步骤d:化合物2D与化合物2E在四三苯基磷钯催化条件下通过suzuki偶联反应得到化合物2F。
合成方法三:
其中,Y为XX或R3;
步骤e:化合物1A与化合物2A通过缩合反应得到化合物3A;
步骤f:化合物3A与化合物2B在乙酸催化条件下环化反应得到化合物2C。
合成方法四:
步骤g:化合物1A与二碳酸二叔丁酯反应得到化合物4A;
步骤h:化合物4A与化合物2E在四三苯基膦钯条件下通过suzuki偶联反应得到化合物4B;
步骤i:化合物4B与化合物2A在四三苯基膦钯条件下通过suzuki偶联反应得到化合物4C;
步骤j:化合物4C在三氟乙酸和二氯甲烷的条件下得到化合物4D;
步骤k:化合物4D与化合物2B在乙酸催化下得到化合物4E;
步骤l:化合物4E在加入DDQ条件下芳香化得到化合物4F。
GST抑制剂
本发明提供了通式I所示的化合物、或其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物,
其中,各基团如上文所定义。
如本文所用,术语“药学上可接受的盐”或“可药用的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
此外,本发明化合物还包括所述化合物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的,当用适当的方法服用后,其在人体内进行代谢或化学反应而转变成所述化合物,或所述化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
本发明也包含这里公布的任何一种新的中间体。
药物组合物和施用方法
本发明还提供了包含式Ⅱ化合物、或其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物的药物组合物。
由于本发明化合物具有优异的抗肿瘤活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与肿瘤相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
与现有技术相比,本发明具有以下主要优点:
(1)本申请所述式II化合物具有优异的GST抑制活性(如优异选择抑制性),可用于预防和/或治疗与GST异常活性相关疾病;
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
1HNMR由Bruker AvanceⅢ-500型核磁共振仪记录,化学位移以δ(ppm)表示;质谱由MS质谱HPLC-MS(ESI)测定:其中采用Agilent 6230TOF-ESI离子源表征DNA产物;采用Agilent 1260Infinity II高效液相色谱表征小分子产物;采用EasySep-1050半制备高效液相色谱纯化小分子产物;乙腈、三氟乙酸、石油醚、乙酸乙酯、二氯甲烷等用于柱层析流动相的溶剂均购置于国药集团化学试剂有限公司;反应检测中使用的薄层层析硅胶板(HSGF254)来自国药集团化学试剂有限公司;化合物分离选用国药集团化学试剂有限公司的200-300目硅胶;反应用96孔板或384孔板购于生工生物工程(上海)股份有限公司;四三苯基膦钯、琼脂糖、染色剂、配制缓冲液的试剂等试剂购买于国药集团化学试剂有限公司,建库用胺试剂、芳香羧酸醛、硼试剂、邻氨基芳香酸等试剂购买于上海韶远试剂有限公司及砌块化学科技(上海)有限公司;所用蛋白GST蛋白购自金斯瑞GenScript公司(货号Z02039);谷胱甘肽S-转移酶(GST)比色法测试盒购自Elabscience公司(货号:E-BC-K278-S);实验用水为Millipore-Q纯水。透明96孔板购自Corning公司(货号:CLS3340);检测仪器为TECAN Infinite M200 Pro多功能酶标仪。
EtOH:乙醇;DCM:二氯甲烷;TFA:三氟乙酸;MeOH:甲醇;NaOH:氢氧化钠;TEA:三乙胺;H2O:水;HATU:N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲;DMF:N,N-二甲基甲酰胺;DME:N,N-二甲基乙酰胺;THF:四氢呋喃;Pd(PPh3)4:四三苯基膦钯;金属清除剂Scavenger:二乙基二硫代氨基甲酸钠(三水)AcOH:醋酸;Na2CO3:碳酸钠;LiOH:氢氧化锂;DIPEA:N,N-二异丙基乙胺;(Boc)2O:二碳酸二叔丁酯;EA:乙酸乙酯;NaHCO3:碳酸氢钠;HCOOH:甲酸;piperdine:哌啶;MeCN:乙腈;DMSO:二甲基亚砜;GSH:谷胱甘肽;CDNB:1-氯-2,4-二硝基苯.
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实施例1:化合物G001的制备
化合物2.1的制备:参考报道方法2,将三光气(2.98g,10mmol)分批加入到2-氨基-5-碘苯甲酸(5.2g,20mmol)在四氢呋喃(30.0mL)溶液中,磁力搅拌1小时。然后将水/冰/碳酸氢钠溶液的混合物分批加入混合物中,进行重结晶,回收固体,依次用水和乙醚洗涤,干燥得到6-碘-1H-苯并[d][1,3]恶嗪-2,4-二酮,产量4.91g,白色固体,收率85%。LC-MS(ESI):分子式C8H5IN2O2[M-H+]:286.9
化合物2.2的制备:等量混合化合物2.1(2.88g,10mmol),3-氨基-2-(4-氯苄基)丙酸(2.13g,10mmol)和5-氯噻吩-2-甲醛(1.46g,10mmol)溶解在乙醇/乙酸(1:1)的溶液中(20.0mL),90℃加热回流,5~10小时,TIC监测反应完全。(石油醚:乙酸乙酯1:1),减压蒸馏移除溶剂,加入冰水,有固体析出,用乙酸乙酯(200mL)分三次萃取,有机相用饱和碳酸氢钠溶液洗涤,去除乙酸,经Na2SO4干燥过滤,真空旋干,粗品物用乙酸乙酯重结晶,减压过滤,依次用水和乙醚洗涤,得到产物,浅黄色固体,产量3.51g,收率60%。LC-MS(ESI):分子式C22H17Cl2IN2O3S[M+H+]理论值为:588.1
化合物2.3的制备:将化合物2.2(2.93g,5.0mmol)溶解于DME中,加入当量的2,3-二氯-5,6-二氰基-1,4-苯醌,室温下搅拌1小时,加入水淬灭反应,用乙酸乙酯分三次萃取,有机相减压旋蒸后,通过硅胶柱层析纯化(PE/EA 5:1至1:1梯度洗脱),产物为浅黄色固体,产量2.62g,产率90%。LC-MS(ESI):分子式C22H15Cl2IN2O3S[M+H+]理论值为:586.2
化合物G001的制备:将所得化合物2.2(116.0mg,0.2mmol)、(2-(1H-四唑-5-基)苯基)硼酸(45.4mg,0.2mmol)和2M的碳酸钠溶液(0.25mL)溶解在DME(3mL)和水(2mL),加入四三苯基膦钯(11.0mg,9.8μmol)。将所得混合物脱气并在氮气保护下加热至90℃ 7小时。用饱和柠檬酸中和过量的碱,析出固体经乙酸乙酯萃取,液相色谱纯化,得到终产物G001,白色固体。产量90.6mg,收率76%。1H NMR(500MHz,DMSO)δ7.86(d,J=1.8Hz,1H),7.76(d,J=7.4Hz,1H),7.71(t,J=7.4Hz,1H),7.65–7.58(m,2H),7.51(d,J=8.4Hz,1H),7.46(dd,J=5.8,2.9Hz,2H),7.24(d,J=8.3Hz,2H),7.14(d,J=3.9Hz,1H),7.10(d,J=8.3Hz,2H),4.62(dd,J=14.2,9.1Hz,1H),4.35(dd,J=14.2,5.9Hz,1H),3.00(dt,J=14.5,7.3Hz,1H),2.85(dd,J=13.9,7.4Hz,1H),2.66(dd,J=13.9,7.1Hz,1H).13C NMR(126MHz,DMSO)δ173.65,161.31,148.72,145.49,140.11,138.49,137.28,135.45,135.41,132.29,131.21,131.04,130.84,130.65,130.46,130.13,128.40,128.18,127.32,126.94,126.38,119.63,45.93,44.67,34.57.13C NMR DEPT(126MHz,DMSO)δ135.86,131.66,131.29,131.10,130.91,130.58,128.85,128.63,127.77,127.39,126.83,46.38,45.12,35.02.LC-MS(ESI):分子式C29H20Cl2N6O3S[M+H+]理论值为:603.1;实测值:603.1
参照实例2的合成路线,制备得化合物G005的制备:1H NMR(500MHz,DMSO)δ7.86(d,J=2.0Hz,1H),7.76–7.70(m,2H),7.63(dt,J=4.5,2.6Hz,2H),7.59–7.45(m,8H),7.18(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,2H),4.28(dd,J=13.9,9.0Hz,1H),4.06(dd,J=14.0,5.8Hz,1H),2.87–2.77(m,1H),2.64(dd,J=13.9,8.1Hz,1H),2.44(dd,J=14.1,6.6Hz,1H).13C NMR(126MHz,DMSO)δ173.76,161.55,156.38,146.10,140.42,138.31,137.38,135.44,135.08,131.59,131.11,131.09,130.83,130.51,130.00,128.63,128.52,128.37,127.31,126.42,123.64,120.18,46.65,44.86,34.70.13C NMR DEPT(126MHz,DMSO)δ135.18,131.33,130.83,130.58,130.26,129.75,128.37,128.26,128.12,127.05,126.16,46.40,44.60,39.85,39.69,39.52,39.35,39.19,34.45.LC-MS(ESI):分子式C31H23ClN6O3[M+H+]理论值为:563.0;实测值:561.1实施例3
化合物3.1的制备:将2-氨基-5-碘苯甲酸(2.6g,10mmol)与O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基六氟磷酸盐(HATU)(4.1g,11mmol)溶解在DMF(20mL)中,随后滴加DIPEA(102μL,11mmol)。混合物在室温下搅拌10分钟,加入3-氨基丙酸乙酯(1.2g,10mmol),继续搅拌2小时。将反应混合物稀释到乙酸乙酯中,依次用饱和碳酸氢钠和盐水洗涤,用硫酸钠干燥。旋转蒸发除去溶剂得到化合物3.1,产量3.6g,收率98%。1H NMR(400MHz,DMSO)δ8.66(d,J=29.6Hz,1H),7.88(s,1H),7.75(s,1H),7.57(d,J=8.4Hz,1H),6.97(s,2H),6.58(d,J=8.4Hz,1H),6.58(d,J=8.4Hz,1H),6.19(s,1H),5.35–4.93(m,1H),4.78(s,1H),4.43–4.19(m,1H),4.04(d,J=6.9Hz,4H),3.23(dt,J=13.6,6.9Hz,1H),2.68(dd,J=15.5,7.2Hz,1H),1.16(t,J=6.7Hz,3H).LC-MS(ESI):分子式C12H15IN2O3[M+H+]理论值为:362.01;实测值:363.0
化合物3.2的制备:将所得化合物3.1与5-氯噻吩-2-甲醛(1.46g,10mmol)溶解在乙醇/乙酸(1:1)的溶液中(20.0mL),90℃加热回流,5小时,TIC监测反应。减压蒸馏移除溶剂,加入冰水,有固体析出,用乙酸乙酯(200mL)分三次萃取,有机相用饱和碳酸氢钠溶液洗涤,去除乙酸,经Na2SO4干燥过滤,真空旋干,粗品物用乙酸乙酯重结晶,减压过滤,依次用水和乙醚洗涤,得到产物,浅黄色固体,产量4.8g,收率97%。LC-MS(ESI):分子式C17H16ClIN2O3S[M+H+]理论值为:491.0
化合物3.3的制备参见化合物(2.3)的制备方法。LC-MS(ESI):分子式C17H14ClIN2O3S[M+H+]理论值为:489.72;实测值:489.7
化合物G007的制备:将所得化合物2.2(97.6mg,0.2mmol)、3-羧基苯硼酸(39.6mg,0.2mmol)和2M的碳酸钠溶液(0.25mL)溶解在DME(3mL)和水(2mL),加入四三苯基膦钯(11.0mg,9.8μmol)。将所得混合物脱气并在氮气保护下加热至90℃ 7小时。用饱和柠檬酸中和过量的碱,析出固体经乙酸乙酯萃取,液相色谱纯化,得到终产物G001,淡化色固体。产量77.2mg,收率85%。1H NMR(500MHz,DMSO)δ8.15(d,J=2.1Hz,1H),8.06(s,1H),7.98(dd,J=8.5,2.2Hz,1H),7.80(dd,J=24.0,7.7Hz,2H),7.54(d,J=8.5Hz,1H),7.45(t,J=7.7Hz,1H),7.34(d,J=4.0Hz,1H),7.05(d,J=4.0Hz,1H),4.25–4.19(m,2H),2.57(t,J=7.6Hz,2H),2.32–2.29(m,2H).13C NMR(126MHz,DMSO)δ172.14,167.26,161.53,148.95,146.15,139.04,137.96,136.00,133.36,132.80,131.84,131.27,129.94,129.24,128.11,127.79,127.45,126.89,123.79,120.37,42.00,32.44.13C NMR DEPT(126MHz,DMSO)δ133.35,131.27,129.94,129.78,128.10,127.79,127.45,126.89,123.79,41.99,32.44.LC-MS(ESI):分子式C22H15ClN2O5S[M+H+]理论值为:455.0;实测值:455.0
参照实例2和实例3的合成路线,制备得化合物G002:1H NMR(500MHz,DMSO)δ7.87(s,1H),7.77–7.69(m,2H),7.66–7.60(m,2H),7.54(d,J=8.4Hz,1H),7.52–7.47(m,2H),7.28(d,J=8.2Hz,2H),7.22(d,J=4.0Hz,1H),7.08(d,J=8.1Hz,2H),4.41–4.32(m,2H),2.97–2.93(m,2H).13C NMR(126MHz,DMSO)δ161.12,148.77,145.55,140.08,138.38,136.81,135.62,135.41,132.41,131.36,131.26,130.80,130.65,130.40,129.70,128.50,127.46,127.04,126.30,123.64,119.72,46.37,33.04.LC-MS(ESI):分子式C27H18Cl2N6OS[M+H+]理论值为:544.1;实测值:545.0
参照实例3的合成路线,制备得化合物G008:1H NMR(500MHz,DMSO)δ8.37(s,1H),8.27(s,1H),8.18(d,J=8.4Hz,1H),8.03(d,J=7.5Hz,1H),7.98(d,J=7.6Hz,1H),7.86(d,J=4.9Hz,1H),7.75(d,J=8.4Hz,1H),7.67–7.61(m,2H),7.26–7.21(m,1H),4.42–4.33(m,2H),2.74(d,J=7.7Hz,2H).13C NMR(126MHz,DMSO)δ171.88,167.06,161.39,150.06,146.17,138.89,137.60,136.32,133.05,131.74,131.02,130.14,129.65,129.53,128.69,127.95,127.59,127.26,123.58,120.21,41.94,32.35.LC-MS(ESI):分子式C22H16N2O5S[M+H+]理论值为:421.1;实测值:421.1
参照实例2和实例3的合成路线,制备得化合物G009:1H NMR(500MHz,DMSO)δ12.84(s,2H),8.45(s,1H),8.26(dd,J=24.0,8.1Hz,3H),8.06(d,J=7.5Hz,1H),8.02–7.95(m,2H),7.83–7.76(m,2H),7.68–7.60(m,1H),4.08(t,J=6.6Hz,2H),2.62(t,J=7.0Hz,2H).13C NMR(126MHz,DMSO)δ172.31,167.62,161.53,151.65,149.36,148.12,146.87,139.46,138.99,134.21,133.78,133.01,132.29,131.81,130.23,129.31,128.78,127.94,124.22,123.41,121.57,118.68,42.61,32.85.13C NMR DEPT(126MHz,DMSO)δ133.65,133.40,132.53,131.30,129.67,128.94,128.36,127.52,123.80,118.25,42.18,32.41.LC-MS(ESI):分子式C24H16N4O6[M+H+]理论值为:457.1;实测值:457.1
参照实例3的合成路线,制备得化合物G010:1H NMR Spectrum(in dDMSO,500MHz)1H NMR(500MHz,DMSO)δ8.38(d,J=2.0Hz,1H),8.26(s,1H),8.18(dd,J=8.5,2.1Hz,1H),7.99(dd,J=16.0,7.8Hz,2H),7.79(d,J=8.5Hz,1H),7.66–7.57(m,2H),6.75(d,J=1.9Hz,1H),4.20(t,J=7.3Hz,2H),3.92(s,3H),2.65(t,J=7.4Hz,2H).13C NMR(126MHz,DMSO)δ172.11,167.19,161.14,147.58,145.98,138.97,138.38,137.89,135.25,133.18,131.86,131.22,129.63,128.91,128.32,127.46,123.69,121.02,107.76,41.99,37.68,32.11.13C NMR DEPT(126MHz,DMSO)δ137.89,133.18,131.22,129.63,128.91,128.31,127.46,123.69,107.76,41.99,37.68,32.11.LC-MS(ESI):分子式C22H18N4O5[M+H+]理论值为:419.1;实测值:419.1
参照实例2和实例3的合成路线,制备得化合物G011:1H NMR(500MHz,DMSO)δ8.38(s,1H),7.91(d,J=2.1Hz,1H),7.78–7.67(m,2H),7.65–7.60(m,2H),7.57(d,J=8.4Hz,1H),7.44(dd,J=8.4,2.1Hz,1H),4.15(t,J=6.7Hz,2H),2.75(t,J=6.8Hz,2H).13C NMR(126MHz,DMSO)δ172.43,160.11,148.79,147.10,140.23,138.07,134.95,131.37,130.93,130.67,128.45,127.05,126.08,123.52,121.37,42.84,32.51.LC-MS(ESI):分子式C18H14N6O3[M+H+]理论值为:363.1;实测值:363.1
参照实例3的合成路线,制备得化合物G012:1H NMR(500MHz,DMSO)δ8.33(d,J=20.5Hz,1H),8.25(d,J=22.2Hz,1H),8.20–8.09(m,1H),7.99(s,2H),7.74–7.53(m,3H),7.26(d,J=18.3Hz,1H),4.31(d,J=6.0Hz,2H),4.12–3.90(m,2H),2.04(s,3H),1.90(d,J=9.7Hz,2H).13C NMR(126MHz,DMSO)δ170.18,167.02,161.37,148.57,146.02,138.91,137.74,135.93,133.10,132.85,131.72,131.09,129.90,129.56,128.79,127.90,127.75,127.33,123.74,120.20,61.70,42.68,27.20,20.47.LC-MS(ESI):分子式C24H19ClN2O5S[M+H+]理论值为:483.1;实测值:483.1
参照实例3的合成路线,制备得化合物G013:1H NMR(500MHz,DMSO)δ8.33(s,1H),8.23(s,1H),8.14(d,J=7.5Hz,1H),7.97(dd,J=16.1,7.5Hz,2H),7.70(d,J=8.4Hz,1H),7.64–7.56(m,2H),7.21(d,J=3.9Hz,1H),4.27(d,J=6.9Hz,2H),3.11(t,J=11.2Hz,2H),1.36(d,J=12.6Hz,2H),1.18–1.13(m,2H).13C NMR(126MHz,DMSO)δ167.24,161.70,148.76,145.99,139.03,138.03,136.20,133.33,132.77,131.81,131.23,130.34,129.74,128.93,128.10,127.88,127.46,124.09,120.22,66.58,49.14,34.43,30.14.LC-MS(ESI):分子式C25H21ClN2O4S[M+H+]理论值为:481.1;实测值:481.1
参照实例3的合成路线,制备得化合物G016:1H NMR(500MHz,DMSO)δ8.37(s,1H),8.26(s,1H),8.20(d,J=8.4Hz,1H),8.02(d,J=7.6Hz,1H),7.97(d,J=7.6Hz,1H),7.77(d,J=8.5Hz,1H),7.63(t,J=7.7Hz,1H),7.33(t,J=7.5Hz,2H),7.26(t,J=7.2Hz,1H),7.18–7.13(m,3H),7.10(d,J=4.0Hz,1H),5.51(s,2H).13C NMR(126MHz,DMSO)δ167.10,161.55,148.90,146.18,138.91,137.95,136.50,136.13,133.40,133.18,131.75,131.14,129.67,129.62,128.86,128.08,127.78,127.37,127.23,125.75,124.01,120.13,48.52.13C NMR DEPT(126MHz,DMSO)δ133.40,131.14,129.67,129.62,128.86,128.08,127.78,127.37,127.24,125.75,124.01,48.52.LC-MS(ESI):分子式C26H17ClN2O3S[M+H+]理论值为:474.1;实测值:474.1
参照实例3的合成路线,制备得化合物G017:1H NMR(500MHz,DMSO)δ8.24(d,J=8.4Hz,1H),8.14(s,1H),8.04(dd,J=26.3,7.7Hz,1H),7.96–7.82(m,2H),7.77–7.37(m,4H),7.12(s,1H),4.37(s,2H),3.35(s,2H),2.39(s,2H),0.89(t,J=52.1Hz,9H).13C NMR(126MHz,DMSO)δ167.12,161.45,154.21,148.71,146.13,138.91,137.96,136.18,135.81,133.27,132.39,131.78,131.08,130.14,130.00,129.64,127.50,127.34,123.87,120.35,78.57,46.86,42.71,27.71,27.41.13C NMR DEPT(126MHz,DMSO)δ133.68,131.50,130.55,130.06,129.28,127.92,127.75,124.28,47.28,43.13,34.48,33.73,28.13,27.83.LC-MS(ESI):分子式C27H26ClN3O5S[M+H+]理论值为:540.2;实测值:540.2
参照实例3的合成路线,制备得化合物G019:1H NMR(500MHz,DMSO)δ12.77(s,2H),8.44(s,1H),8.29(s,1H),8.23(d,J=8.3Hz,1H),8.06(d,J=7.0Hz,1H),7.99(d,J=7.2Hz,1H),7.87(dd,J=8.0,2.5Hz,1H),7.81(dd,J=8.4,3.6Hz,1H),7.78–7.74(m,1H),7.66(td,J=7.6,3.6Hz,1H),7.59(td,J=7.9,3.8Hz,1H),4.24(dd,J=8.9,4.8Hz,1H),3.74–3.65(m,1H),2.59(d,J=4.9Hz,2H).13C NMR(126MHz,DMSO)δ171.69,167.09,160.85,152.61,146.31,138.98,138.40,135.83,133.36,132.13,132.04,131.75,131.32,129.65,129.55,129.04,128.89,128.29,127.47,123.73,121.07,41.46,32.02.13C NMR(126MHz,DMSO)δ133.36,132.04,131.32,129.65,129.05,128.90,128.29,127.47,123.73,41.46,32.02.LC-MS(ESI):分子式C24H16Cl2N2O5[M+H+]理论值为:483.0;实测值:483.0
参照实例3的合成路线,制备得化合物G020:1H NMR(600MHz,DMSO)δ8.44(d,J=1.5Hz,1H),8.28(s,1H),8.21(d,J=9.9Hz,2H),7.92(t,J=8.8Hz,2H),7.74(d,J=8.4Hz,1H),7.58(t,J=7.7Hz,1H),7.55(d,J=4.0Hz,1H),7.46(s,1H),7.26(d,J=4.0Hz,1H),4.48–4.38(m,2H),2.84–2.71(m,2H).13C NMR(151MHz,DMSO)δ172.52,168.15,161.90,149.22,146.46,139.04,138.65,136.45,135.58,133.80,133.12,130.29,130.00,129.73,128.31,128.18,127.75,126.19,124.28,120.74,42.36,32.82.LC-MS(ESI):分子式C22H16ClN3O4S[M+H+]理论值为:454.9;实测值:454.0
实施例4
化合物G014的制备:将醋酸钯(2mol%)和Xantphos(2mol%)转移到一个充满氮气的烘干管中。向反应管中加入甲苯(1.0mL)、Et N(1.0mmol)、化合物3.2(0.5mmol,244mg)、tBuOH(1.5mmol)。将甲酸(1.0mmol)和乙酸酐(1.0mmol)的混合物在30℃下搅拌1.5小时,然后加入反应管中。关闭管子。在80℃下搅拌混合物12小时。反应完成后过滤反应混合物。真空移除溶剂。液相色谱纯化产物,得到化合物G014,白色固体,产量140mg,收率74%。1H NMR(500MHz,DMSO)δ8.65(s,1H),8.26(d,J=7.2Hz,1H),7.67(d,J=8.4Hz,1H),7.57(s,1H),7.26(s,1H),4.40(s,2H),2.76(d,J=4.7Hz,2H).13C NMR(126MHz,DMSO)δ172.09,166.72,161.29,150.27,149.06,135.84,134.66,133.22,130.25,128.05,127.85,127.28,119.54,42.01,32.36.13C NMR DEPT(126MHz,DMSO)δ172.09,166.72,161.29,150.27,149.06,135.84,134.66,133.22,130.25,128.05,127.85,127.28,119.54,42.01,32.36.LC-MS(ESI):分子式C16H11ClN2O5S[M+H+]理论值为:379.0;实测值:379.0
实施例5
化合物G018的制备:将1mL三氟乙酸加入含有54mg Boc保护的化合物G017的2mL二氯甲烷溶液中。搅拌反应30分钟。真空旋干。将残留物溶解在DME中,滤除固体杂质,液相纯化。1H NMR(500MHz,DMSO)δ8.84(s,1H),8.35(s,1H),8.25(s,1H),8.21–8.16(m,1H),7.99(dd,J=12.4,7.7Hz,2H),7.74(d,J=8.4Hz,1H),7.63(t,J=7.7Hz,1H),7.57(d,J=4.0Hz,1H),7.23(d,J=3.9Hz,1H),4.56(t,J=5.8Hz,2H),3.31(t,J=5.7Hz,2H),3.00(s,1H),2.58(s,3H).13C NMR(126MHz,DMSO)δ167.09,162.23,148.29,146.02,138.89,137.93,135.45,133.33,133.09,131.84,131.05,130.30,129.66,128.86,127.97,127.82,127.37,123.81,120.39,47.07,43.67,41.63,33.05.13CNMR DEPT(126MHz,DMSO)δ133.77,131.48,130.73,130.09,129.30,128.40,128.25,127.80,124.24,47.51,42.07,33.49.LC-MS(ESI):分子式C22H18ClN3O3S[M+H+]理论值为:440.1;实测值:440.1
实施例6
参照实例6化合物3.1的合成路线,以2-氯-5-甲酰基噻吩-3-羧酸和吗啡啉为原料制备化合物7.1,为无色油状物,LC-MS(ESI):分子式C10H10ClNO3S[M+H+]理论值为:260.7;实测值:260.7
参照实例6,制备化合物G004:1H NMR(500MHz,DMSO)δ7.86(s,1H),7.73(t,J=8.5Hz,2H),7.63(d,J=7.1Hz,2H),7.59(s,1H),7.56(d,J=8.4Hz,1H),7.49(d,J=8.2Hz,1H),4.38–4.31(m,2H),3.07(dd,J=14.1,7.0Hz,2H),2.75–2.70(m,2H),1.16(t,J=7.2Hz,2H).13C NMR(126MHz,DMSO)δ172.19,161.84,161.26,148.72,145.71,140.24,138.73,135.61,134.36,131.51,130.97,130.76,130.09,128.69,127.18,126.36,119.97,66.46,66.09,47.14,45.96,42.07,32.43.13C NMR DEPT(126MHz,DMSO)δ135.61,131.51,130.98,130.76,128.69,127.18,126.37,66.47,66.09,47.30,45.92,42.06,32.43.LC-MS(ESI):分子式C27H22ClN7O5S[M+H+]理论值为:592.1;实测值:594.2
实施例7
化合物G003的制备:以2-((叔丁氧羰基)氨基)-5-碘苯甲酸为起始原料,经实例2中化合物G001合成路线的suzuki偶联操作制得化合物8.2。LC-MS(ESI):分子式C17H23IN2O5[M-H+]:592.1;实测值:461.2,再经实例3中化合物3.1的合成方法制得化合物8.3。LC-MS(ESI):分子式C22H24N6O5[M-H+]:480.2;实测值:480.1将该中间体通过实例5中的脱Boc保护操作制备化合物8.4,经环化及芳构化处理,液相色谱纯化,得到化合物G003,为黄色油状物。1H NMR(500MHz,DMSO)δ7.83(d,J=1.8Hz,1H),7.70(dd,J=13.3,7.5Hz,2H),7.61(dd,J=7.1,4.4Hz,2H),7.52(dd,J=10.9,6.2Hz,2H),7.46(dd,J=8.4,1.8Hz,1H),7.23(d,J=4.0Hz,1H),4.37(t,J=7.5Hz,2H),3.98(q,J=7.1Hz,2H),2.76(t,J=7.5Hz,2H),1.08(t,J=7.1Hz,3H).13CNMR(126MHz,DMSO)δ170.89,161.66,149.31,146.13,140.61,138.82,136.17,135.87,133.06,131.76,131.27,131.08,130.37,128.90,128.13,127.44,126.67,120.12,60.80,42.16,32.79,14.39.13C NMR DEPT(126MHz,DMSO)δ135.87,131.76,131.27,131.08,130.37,128.90,128.13,127.44,126.67,60.80,42.16,40.56,40.40,40.23,40.06,39.89,32.79,14.39.LC-MS(ESI):理论值C24H19ClN6O3S[M+H+]理论值为:507.1;实测值:507.1
参照实例7的合成路线,制备得化合物G006:1H NMR(500MHz,DMSO)δ7.86(d,J=2.1Hz,1H),7.79(s,1H),7.74(d,J=7.3Hz,1H),7.69(t,J=7.0Hz,1H),7.61(t,J=7.2Hz,2H),7.55(d,J=8.4Hz,1H),7.48(d,J=8.4Hz,1H),4.40(t,J=7.4Hz,2H),3.56(s,3H),2.82(t,J=7.4Hz,2H).13C NMR(126MHz,DMSO)δ170.93,162.07,161.12,155.72,148.36,145.52,140.03,138.93,138.11,135.56,133.83,130.94,130.80,130.65,130.61,128.41,128.00,126.94,126.23,124.46,119.79,51.71,41.73,32.12.13C NMR DEPT(126MHz,DMSO)δ135.57,130.94,130.94,130.81,130.81,130.65,130.62,130.62,128.41,128.41,128.00,128.00,126.94,126.94,126.23,126.23,51.72,41.73,32.12.LC-MS(ESI):分子式C24H17ClN6O5S[M+H+]理论值为:537.1;实测值:537.0。
实施例9化合物G001-G019对SjGST蛋白酶活性抑制率
1.实验方法
(1)10mM化合物用Millipore-Q纯水稀释10倍(最终浓度50μM),1mg/ml GST蛋白用Millipore-Q纯水稀释2倍备用。
(2)CDNB应用液提前于37℃预热10min,酶标仪提前预热至37℃。
(3)在96孔反应板中加入5μL步骤(1)中GST蛋白稀释液及5μL上述化合物稀释液,室温孵育30min。
(4)在反应板中加90μL GSH,以及10μL CDNB应用液,立即计时,迅速混匀,并于已提前预热的酶标仪连续读板5min(每30s读板一次)。
(5)根据第0s(A1)及第300s(A2)读值,得出▲A=(A2-A1)T-(A2-A1)B,T代表测试样品组,B代表空白组。
(6)根据在37℃条件下,每毫克蛋白每分钟催化1μmol CDNB与GSH结合为一个酶活单位。GST活力(U/mgprot)=[(ΔA÷(ε×d)]×106÷t×(V1÷V2)×f÷Cpr。其中:ΔA:ΔA测定-ΔA空白,ε:产物摩尔消光系数,6.22x103 L/mol/cm,d:96孔板光径(0.5cm),106:1mol=106μmol,t:反应时间(5min),V1:反应体系总体积(110μL),V2:加入反应体系中待测样本体积(5μl),Cpr:待测样本的蛋白浓度(mgprot/mL),f:样本加入检测体系之前的稀释倍数。
2.实验结果
表4.化合物G001-G020对SjGST蛋白活性抑制结果
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实施例10化合物对SjGST蛋白酶活性抑制率
我们选取抑制率较优的化合物G001、G003、G012,进行不同浓度下对SjGST蛋白酶活性抑制试验,图1为化合物浓度区间在0.2-50μM下GST酶活性抑制率曲线,结果显示,G001的IC50为2.15μM,G003的IC50为4.50μM,G012的IC50为9.97μM,阳性化合物利尿酸(EA)的IC50为0.92μM。
基于以上化合物对SjGST蛋白酶活性抑制率测试结果,化合物G001,G003对GST蛋白酶活性具有很好的抑制作用。因此,本发明的化合物可以作为靶向GST蛋白的新型抑制剂。
表5.化合物对SjGST酶活抑制率(%)
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表6.化合物对SjGST酶活抑制的IC50值(μM)
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在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (9)
1.一种如下式I所示的化合物、或其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物,
其中,
选自下组:C6-C12芳基、5-8元杂环基、或5-8元杂芳基、C5-C8环烷基并C6-C12芳基、含有1-3个选自N、O和S的杂原子的5-8元杂环基、或5-8元杂芳基并C6-C12芳基;
R1为一个或多个位于A环上的取代基,且R1选自下组:-H、-OH、-COR4、-COOR4、-CONHR4、-SO2NHR4、卤素、C1-C6烷基、C1-C6烷氧基、5-10元杂环基、或5-10元杂芳基;
X选自下组:-(CHR)n-;其中,n为0、1、2、3、4;
R各自独立地选自下组:-H、-OH、-Me、-COOH;
R2选自下组:-H、-COOR4、氨基酸残基(即,氨基酸通过官能团与分子中其他部分相连形成的基团)、C1-C4烷基、-NHR4、C5-C8环烷基、C5-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基;
R3选自下组:-H、-OH、-Me、-CONHR4、-SO2NHR4、卤素、C1-C6烷基、C1-C6烷氧基、C6-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基;且所述的R3被一个或多个R5取代基取代,所述的R5选自下组:-Cl、-COOH、OH、-CONH2、C1-C6烷基、C1-C6烷氧基、5-8元杂环基、或5-8元杂芳基;
R4选自下组:-H、C1-C4烷基、C6-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基;
上述各式中,杂环基含有1-3个选自N、O、S的杂原子;除非特别说明,各个所述的芳基、杂环基或杂芳基可任选被1-3个下组取代基取代:-Cl、-COOH、OH、-CONH2、C1-C6烷基、C1-C6烷氧基、杂环基或5-8元杂芳基。
2.如权利要求1所述的化合物、或其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物,其特征在于,选自下组:C6-C10芳基、5-6元杂环基、或5-6元杂芳基、C5-C8环烷基并苯基、含有1-3个选自N、O和S的杂原子的5-6元杂环基、或5-6元杂芳基并苯基;
R1选自下组:-H、-OH、-Me、-COOR4、-CONHR4、-SO2NHR4、卤素、C1-C6烷基、C1-C6烷氧基、5-6元杂环基、或5-6元杂芳基;
R4选自下组:-H、C1-C4烷基、C6-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基。
3.如权利要求1所述的化合物、或其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物,其特征在于,X选自下组:-(CHR)n-;其中,n为1、2或3;
R各自独立地选自下组:-H、-OH、-Me、-COOH;
R2选自下组:-H、-COOR4、-NHR4、C5-C8环烷基、C5-C6芳基、5-8元杂环基、或5-8元杂芳基。
4.如权利要求1所述的化合物、或其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物,其特征在于,R3选自下组:苯基、5-8元杂芳基;且所述的R3被一个或多个R5取代基取代,所述的R5选自下组:-Cl、-COOH、OH、-CONH2、C1-C6烷基、C1-C6烷氧基、
5.如权利要求1所述的化合物、或其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物,其特征在于,
X选自下组:-(CHR)n-;其中,n为0、1、2、3、4;
R各自独立地选自下组:-H、-OH、-Me、-COOH;
R2选自下组:-H、-COOR4、氨基酸残基(即,氨基酸通过官能团与分子中其他部分相连形成的基团)、C1-C4烷基、-NHR4、C5-C8环烷基、C5-C12芳基、C5-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基;
R3选自下组:C6-C12芳基、含有1-3个选自N、O、S的杂原子的5-8元杂环基或5-8元杂芳基;且所述的R3被一个或多个R5取代基取代,所述的R5选自下组:-Cl、-COOH、OH、-CONH2、C1-C6烷基、C1-C6烷氧基、5-8元杂环基、或5-8元杂芳基;
上述各式中,杂环基含有1-3个选自N、O、S的杂原子;除非特别说明,各个所述的芳基、杂环基或杂芳基可任选被1-3个下组取代基取代:-Cl、-COOH、OH、-CONH2、C1-C6烷基、C1-C6烷氧基、杂环基或5-8元杂芳基。
6.如权利要求1所述的化合物、或其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物,其特征在于,所述式(I)化合物选自下组:
7.一种权利要求1-6任一所述的化合物的用途,其特征在于,用于制备治疗GST异常活性相关疾病的药物。
8.如权利要求7所述用途,其特征在于,所述GST异常活性相关疾病选自下组:胃肠癌、宫颈癌、膀胱癌、喉癌、肝癌、乳腺癌、肺癌、口腔癌、卵巢癌、糖尿病、炎症、肺部功能絮乱、疼痛(包括但不限于复杂性局部疼痛综合症)、黄斑退化及相关功能絮乱、皮肤疾病、免疫缺陷型疾病、中枢神经系统的损伤及功能絮乱。
9.一种药物组合物的用途,其特征在于,用于制备预防和/或治疗GST异常活性相关疾病的药物。
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