CN103288738B - 具有11β-羟基类固醇脱氢酶I型抑制活性的含氮杂环衍生物 - Google Patents

具有11β-羟基类固醇脱氢酶I型抑制活性的含氮杂环衍生物 Download PDF

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CN103288738B
CN103288738B CN201310211279.3A CN201310211279A CN103288738B CN 103288738 B CN103288738 B CN 103288738B CN 201310211279 A CN201310211279 A CN 201310211279A CN 103288738 B CN103288738 B CN 103288738B
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增田功嗣
小川知行
中谷卓二
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Abstract

本发明公开了用作11β-羟基类固醇脱氢酶I型抑制剂的化合物。具体公开了由以下式(I)表示的化合物、其药学上可接受的盐或其溶剂合物:其中环A表示(II);环B表示任选取代的杂芳基(排除任选取代的异唑)或任选取代的杂环;R1表示氢或任选取代的烷基,R2表示-OR5、-SR5、卤素、卤代烷基等,R3表示任选取代的烷基等,R4表示任选取代的烷基等,R5表示任选取代的烷基等,R6表示氢等,R7和R8独立表示氢等,R10和R11独立表示氢等,R12表示任选取代的烷基等,m和p独立表示1-3的整数。

Description

具有11β-羟基类固醇脱氢酶I型抑制活性的含氮杂环衍生物
本申请是申请日为2008年5月7日、申请号为200880025349.3、发明名称为“具有11β-羟基类固醇脱氢酶I型抑制活性的含氮杂环衍生物”的发明专利申请的分案申请。
发明领域
本发明涉及一种对11β-羟基类固醇脱氢酶I型(下文中称作11β-HSD-1)具有抑制活性的在药学上有用的化合物。
背景技术
11β-HSD-1为将为非活性类固醇的11β-脱氢类固醇转化为活性类固醇的酶,被认为在生物基础代谢(biologicalbasalmetabolism)中具有重大意义(非专利文献1)。并且,敲除了11β-HSD-1的小鼠对肥胖和紧张诱导的高血糖症具有抗性(非专利文献2)。同样,在人体中,当给予为11β-HSD-1抑制剂的甘珀酸时,观察到类似的现象(非专利文献3)。
这些事实表明该酶的选择性抑制剂作为非胰岛素依赖型糖尿病和肥胖治疗药物的可能性(非专利文献4)。
专利文献1公开了对11β-HSD-1具有抑制活性的化合物,但是限于异唑衍生物,且未公开本发明化合物。
专利文献2、3和4公开了对11β-HSD-1具有抑制活性的金刚烷衍生物,但是未公开被烷氧基取代的杂芳基衍生物如本发明化合物。
专利文献5公开了对11β-HSD-1具有抑制活性的吡唑衍生物,但是未公开本发明化合物。
专利文献6公开了对11β-HSD-1具有抑制活性的吡唑衍生物,但是吡唑的3-位上的取代基限于氨基甲酰基,且未公开本发明化合物。
专利文献7公开了用作除草剂的吡唑衍生物,但是吡唑的1-位上的取代基限于氢、烷基或芳烷基,且未公开本发明化合物。
专利文献8公开了具有CB2受体激动剂活性的吡唑衍生物,但是吡唑的2-位上的取代基限于2-(4-吗啉代)乙氧基、2-(二烯丙基氨基)乙氧基、2-、3-或4-吡啶基甲氧基、2-(二乙基氨基)乙氧基、1-甲基哌啶基-2-甲氧基、苄氧基和4-取代的苄氧基,且未公开本发明化合物。
专利文献9公开了具有NK-3受体调节剂活性的吡唑衍生物,但是吡唑的4-位上的氨基甲酰基的取代基限于芳基烷基、杂芳基烷基或苯氧基烷基,且未公开本发明化合物。
专利文献10公开了对11β-HSD-1具有抑制活性的吡唑衍生物,但是吡唑的1-位上的取代基限于烷基、羟基、羟基烷基等,并且未公开“任选取代的链烯基”,例如本发明化合物。
[专利文献1]WO2006/132197
[专利文献2]WO2006/074330
[专利文献3]WO2006/024627
[专利文献4]WO2005/016877
[专利文献5]WO2007/058346
[专利文献6]WO2005/016877
[专利文献7]WO2001/023358
[专利文献8]WO98/41519
[专利文献9]WO2005/061462
[专利文献10]WO2007/107470
[非专利文献1]Clin.Endocrinol,1996,第44卷,第493页
[非专利文献2]Proc.Nat.Acad.Sci.USA,1997,第94卷,第14924页
[非专利文献3]J.Clin.Endocrinol.Metab.,1995,第80卷,第3155页
[非专利文献4]Lancet,1997,第349卷,第1210页
发明公开
本发明待解决的问题
本发明提供了有用的11β-羟基类固醇脱氢酶I型抑制剂。
本发明提供了:
(1)
式(I)表示的化合物:
[式1]
、其药学上可接受的盐或其溶剂合物,
其中环A为下式表示的基团:
[式2]
环B为任选取代的杂芳基,条件是任选取代的异唑基被排除在外,或为任选取代的杂环,
R1为氢或任选取代的烷基,
R2为-OR5、-SR5、卤素、卤代烷基、卤代烷氧基、羟基、氰基、硝基、羧基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基、任选取代的杂环、
下式表示的基团:-NR5AR6A
其中R5A和R6A各自独立为氢、羟基、烷氧基、任选取代的烷基、任选取代的链烯基、任选取代的氨基甲酰基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环,或R5A和R6A与它们所连接的相邻氮原子一起可形成任选取代的环,
下式表示的基团:-S(=O)x-R7A
其中x为1或2的整数,R7A为任选取代的烷基、任选取代的链烯基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环,
下式表示的基团:-C(=O)NR5AR6A
其中R5A和R6A如上定义,或
下式表示的基团:-(CR8AR9A)y-O-(CR10AR11A)z-CR12AR13AR14A
其中y和z各自独立为0至5的整数,
R8A、R9A、R10A、R11A、R12A、R13A和R14A各自独立为氢、羟基、卤素、卤代烷基、卤代烷氧基、烷氧基、氰基、羧基、任选取代的烷基、任选取代的链烯基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环,
R3为任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环,
下式表示的基团:-CH=CH-C(RaRb)-Rc-Rd
下式表示的基团:-(CReRf)m-C(RaRb)-Rc-Rd
其中Ra和Rb各自独立为氢、任选取代的烷基或卤素,或Ra和Rb与它们所连接的相邻碳原子一起可形成任选取代的环,
Rc为-(CH2)n-,其中n为0至3的整数,
Rd为氢、卤素、羟基、羧基、氰基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环,
下式表示的基团:-C(=O)-NRgRh
下式表示的基团:-NRiRj
Re和Rf各自独立为氢、卤素或任选取代的烷基,
Rg和Rh各自独立为氢、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、任选取代的烷基磺酰基、任选取代的环烷基磺酰基、任选取代的芳基磺酰基、任选取代的杂芳基磺酰基、任选取代的杂环磺酰基、任选取代的烷氧基、任选取代的氨基甲酰基,或Rg和Rh与它们所连接的相邻氮原子一起可形成任选取代的环,
Ri和Rj各自独立为氢、羧基、羟基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、任选取代的酰基、任选取代的氨基甲酰基、任选取代的硫代氨基甲酰基、任选取代的烷基磺酰基、任选取代的环烷基磺酰基、任选取代的芳基磺酰基、任选取代的杂芳基磺酰基、任选取代的杂环磺酰基、任选取代的烷氧基羰基、任选取代的环烷氧基羰基、任选取代的芳氧基羰基、任选取代的杂芳氧基羰基、任选取代的杂环氧基羰基、任选取代的烷基羰基、任选取代的环烷基羰基、任选取代的芳基羰基、任选取代的杂芳基羰基、任选取代的杂环羰基、任选取代的氨基磺酰基,或Ri和Rj与它们所连接的相邻氮原子一起可形成任选取代的环,
R4为任选取代的烷基、任选取代的链烯基、-OR6、-CONR7R8、-NR9CONR7R8、-NR9SO2NR7R8、-(CR10R11)pOH、-(CR10R11)pOCONR7R8、-NR9COR12、-NR9C(=O)OR12、-(CR10R11)pNR9COR12、-C(=O)NR9OR12、-CONR9CONR7R8、-CN、-COOH、卤素或-NR7R8
R5为任选取代的烷基、任选取代的链烯基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环,
R6为氢、任选取代的烷基、任选取代的链烯基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、-SO2R5、-SO2NR7R8或-CONR7R8
R7和R8各自独立为氢、任选取代的烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环或-SO2R5,或R7和R8与它们所连接的相邻氮原子一起可形成任选取代的环,
R9为氢或任选取代的烷基,
R10和R11各自独立为氢、卤素或任选取代的烷基,
R12为任选取代的烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环,
m和p各自独立为1至3的整数,
条件是,当环B为吡唑基,R2为卤素、卤代烷基、任选取代的烷基、任选取代的杂芳基、
下式表示的基团:-NR5AR6A
其中R5A和R6A如上定义或
下式表示的基团:-(CR8AR9A)y-O-(CR10AR11A)z-CR12AR13AR14A
其中R8A-R14A、y和z如上定义,
R3为任选取代的链烯基或下式表示的基团:-CH=CH-C(RaRb)-Rc-Rd
条件是,当环B为哌啶基或吡咯烷基,R2为任选取代的烷基时,R3为任选取代的链烯基或下式表示的基团:-CH=CH-C(RaRb)-Rc-Rd,且
条件是,如下所示的化合物被排除在外,
[式3]
[式4]
[式5]
[式6]
(2)
上述第(1)项的化合物、其药学上可接受的盐或其溶剂合物,其中R2为-OR5或-SR5,其中R5如上述第(1)项中所定义。
(3)
上述第(2)项的化合物、其药学上可接受的盐或其溶剂合物,其中式(I)表示的化合物为式(II)表示的化合物:
[式7]
其中环A、R1、R2和R3如上面第(1)项中所定义。
(4)
根据上述第(1)项至第(3)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R6为任选取代的烷基、任选取代的链烯基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环或-CONR7R8,其中R7和R8如上面第(1)项中所定义。
(5)
根据上述第(1)项至第(4)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中环A为式(III)表示的基团:
[式8]
其中R4如上述第(1)项中所定义,R6为任选取代的烷基、任选取代的链烯基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环或-CONR7R8,其中R7和R8如上面第(1)项中所定义。
(6)
上述第(1)、(2)、(4)或(5)项的化合物、其药学上可接受的盐或其溶剂合物,其中环B为任选取代的杂芳基,条件是任选取代的异唑被排除在外。
(7)
根据上述第(1)项至第(6)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R1为氢。
(8)
根据上述第(1)项至第(7)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R2为-OR5,其中R5如上述第(1)项中所定义。
(9)
根据上述第(1)项至第(7)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R2为-SR5,其中R5如上述第(1)项中所定义。
(10)
根据上述第(1)项至第(9)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R5为任选取代的烷基。
(11)
根据上述第(1)项至第(10)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R3为任选取代的烷基或任选取代的链烯基。
(12)
上述第(11)项的化合物、其药学上可接受的盐或其溶剂合物,其中R3为下式表示的基团:-CH=CH-C(RaRb)-Rc-Rd或下式表示的基团:-(CReRf)m-C(RaRb)-Rc-Rd,其中Ra至Rf和m如上面第(1)项中所定义。
(13)
上述第(12)项的化合物、其药学上可接受的盐或其溶剂合物,其中Ra和Rb各自独立为任选取代的烷基。
(14)
上述第(12)或(13)项的化合物、其药学上可接受的盐或其溶剂合物,其中Rc为-(CH2)n-,其中n为0或1的整数。
(15)
根据上述第(12)项至第(14)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中Rd为卤素、羟基、氰基、任选取代的杂芳基或任选取代的杂环。
(16)
根据上述第(12)项至第(14)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中Rd为下式表示的基团:-C(=O)-NRgRh,其中Rg和Rh各自独立为氢、任选取代的烷基、任选取代的烷氧基或任选取代的氨基甲酰基。
(17)
根据上述第(12)项至第(14)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中Rd为下式表示的基团:-NRiRj,其中Ri和Rj各自独立为氢、任选取代的烷基磺酰基、任选取代的烷氧基羰基、任选取代的烷基羰基或任选取代的杂环羰基。
(18)
根据上述第(1)项至第(17)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R4为-OR6、-CONR7R8、-NR9CONR7R8、-(CR10R11)POH、-(CR10R11)POCONR7R8、-NR9COR12、-NR9C(=O)OR12、-(CR10R11)PNR9COR12、-C(=O)NR9OR12、-CONR9CONR7R8或-CN,其中R6至R12和p如上面第(1)项中所定义。
(19)
上述第(18)项的化合物、其药学上可接受的盐或其溶剂合物,其中R7和R8各自独立为氢或任选取代的烷基。
(20)
上述第(18)或(19)项的化合物、其药学上可接受的盐或其溶剂合物,其中R9为氢。
(21)
根据上述第(18)项至第(20)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R10和R11各自独立为氢。
(22)
根据上述第(18)项至第(21)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R12为任选取代的烷基。
(23)
如下定义的化合物、其药学上可接受的盐或其溶剂合物,
[式9]
[式10]
[式11]
[式12]
[式13]
[式14]
[式15]
(24)
一种药物组合物,所述药物组合物包含根据上述第(1)项至第(23)项中任一项的化合物、其药学上可接受的盐或其溶剂合物。
(25)
根据上述第(24)项的药物组合物,所述药物组合物具有11β-羟基类固醇脱氢酶I型抑制活性。
此外,本发明包括:
(26)
一种用于预防或治疗糖尿病的方法,所述方法包括给予根据上述第(1)项至第(23)项中任一项的化合物、其药学上可接受的盐或其溶剂合物。
(27)
根据上述第(1)项至第(23)项中任一项的化合物、其药学上可接受的盐或其溶剂合物在制备治疗和/或预防糖尿病的药物中的用途。
此外,本发明包括:
(28)
根据上述第(1)项、第(4)项至第(22)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R2为卤素、卤代烷基、卤代烷氧基、羟基、氰基、硝基、羧基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基、任选取代的杂环、
下式表示的基团:-NR5AR6A
其中R5A和R6A各自独立为氢、羟基、烷氧基、任选取代的烷基、任选取代的链烯基、任选取代的氨基甲酰基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环,或R5A和R6A与它们所连接的相邻氮原子一起可形成任选取代的环,
下式表示的基团:-S(=O)x-R7A
其中x为1或2的整数,R7A为任选取代的烷基、任选取代的链烯基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环,
下式表示的基团:-C(=O)NR5AR6A
其中R5A和R6A具有如上定义的相同含义,或
下式表示的基团:-(CR8AR9A)y-O-(CR10AR11A)z-CR12AR13AR14A
其中y和z各自独立为0至5的整数,
R8A、R9A、R10A、R11A、R12A、R13A和R14A各自独立为氢、羟基、卤素、卤代烷基、卤代烷氧基、烷氧基、氰基、羧基、任选取代的烷基、任选取代的链烯基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环。
(29)
一种药物组合物,所述药物组合物包含上述第(28)项的化合物、其药学上可接受的盐或其溶剂合物。
(30)
上述第(29)项的药物组合物,所述药物组合物具有11β-羟基类固醇脱氢酶I型抑制活性。
(31)
一种用于预防或治疗糖尿病的方法,所述方法包括给予根据上述第(28)项的化合物、其药学上可接受的盐或其溶剂合物。
(32)
上述第(28)项的化合物、其药学上可接受的盐或其溶剂合物在制备治疗和/或预防糖尿病的药物中的用途。
(A1)
式(I)表示的化合物、其药学上可接受的盐或其溶剂合物,
[式16]
其中环A为下式的基团:
[式17]
环B为任选取代的杂芳基,条件是任选取代的异唑被排除在外,或为任选取代的杂环,
R1为氢或任选取代的烷基,
R2为-OR5或-SR5
R3为任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、
下式表示的基团:-CH=CH-C(RaRb)-Rc-Rd
下式表示的基团:-(CReRf)m-C(RaRb)-Rc-Rd
其中Ra和Rb各自独立为氢、任选取代的烷基或卤素,或Ra和Rb与它们所连接的相邻碳原子一起可形成任选取代的环,
Rc为-(CH2)n-,n为0-3的整数,
Rd为氢、卤素、羟基、羧基、氰基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环、
下式表示的基团:-C(=O)-NRgRh
下式表示的基团:-NRiRj
Re和Rf各自独立为氢、卤素或任选取代的烷基,
Rg和Rh各自独立为氢、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、任选取代的烷基磺酰基、任选取代的环烷基磺酰基、任选取代的芳基磺酰基、任选取代的杂芳基磺酰基、任选取代的杂环磺酰基、任选取代的烷氧基、任选取代的氨基甲酰基,或Rg和Rh与它们所连接的相邻氮原子一起可形成任选取代的环,
Ri和Rj各自独立为氢、羧基、羟基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、任选取代的酰基、任选取代的氨基甲酰基、任选取代的硫代氨基甲酰基、任选取代的烷基磺酰基、任选取代的环烷基磺酰基、任选取代的芳基磺酰基、任选取代的杂芳基磺酰基、任选取代的杂环磺酰基、任选取代的烷氧基羰基、任选取代的环烷氧基羰基、任选取代的芳氧基羰基、任选取代的杂芳氧基羰基、任选取代的杂环氧基羰基、任选取代的烷基羰基、任选取代的环烷基羰基、任选取代的芳基羰基、任选取代的杂芳基羰基、任选取代的杂环羰基、任选取代的氨基磺酰基,或Ri和Rj与它们所连接的相邻氮原子一起可形成任选取代的环,
R4为任选取代的烷基、任选取代的链烯基、-OR6、-CONR7R8、-NR9CONR7R8、-NR9SO2NR7R8、-(CR10R11)pOH、-(CR10R11)pOCONR7R8、-NR9COR12、-NR9C(=O)OR12、-(CR10R11)pNR9COR12、-C(=O)NR9OR12、-CONR9CONR7R8、-CN、-COOH、卤素或-NR7R8
R5为任选取代的烷基、任选取代的链烯基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环,
R6为氢、任选取代的烷基、任选取代的链烯基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、-SO2R5、-SO2NR7R8或-CONR7R8
R7和R8各自独立为氢、任选取代的烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环或-SO2R5
R9为氢或任选取代的烷基,
R10和R11各自独立为氢、卤素或任选取代的烷基,
R12为任选取代的烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环,
m和p各自独立为1至3的整数,
条件是,如下所示的化合物被排除在外,
[式18]
[式19]
[式20]
[式21]
(A2)
上述第(A1)项的化合物、其药学上可接受的盐或其溶剂合物,其中R6为任选取代的烷基、任选取代的链烯基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环或-CONR7R8,其中R7和R8如上面第(A1)项中所定义。
(A3)
上述第(A1)或(A2)项的化合物、其药学上可接受的盐或其溶剂合物,其中环A为下式表示的基团:
[式22]
其中R4如上述第(A1)项中所定义,R6为任选取代的烷基、任选取代的链烯基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环或-CONR7R8,其中R7和R8如上面第(A1)项中所定义。
(A4)
根据上述第(A1)项至第(A3)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中环B为任选取代的杂芳基,条件是任选取代的异唑被排除在外。
(A5)
根据上述第(A1)项至第(A4)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R1为氢。
(A6)
根据上述第(A1)项至第(A5)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R2为-OR5,其中R5如上述第(A1)项中所定义。
(A7)
根据上述第(A1)项至第(A6)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R5为任选取代的烷基。
(A8)
根据上述第(A1)项至第(A7)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R3为任选取代的烷基或任选取代的链烯基。
(A9)
上述第(A8)项的化合物、其药学上可接受的盐或其溶剂合物,其中R3为下式表示的基团:-CH=CH-C(RaRb)-Rc-Rd或下式表示的基团:-(CReRf)m-C(RaRb)-Rc-Rd,其中Ra至Rf如上面第(A1)项中所定义。
(A10)
上述第(A9)项的化合物、其药学上可接受的盐或其溶剂合物,其中Ra和Rb各自独立为任选取代的烷基。
(A11)
上述第(A9)项或第(A10)项的化合物、其药学上可接受的盐或其溶剂合物,其中Rc为-(CH2)n-,其中n为0或1的整数。
(A12)
根据上述第(A9)项至第(A11)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中Rd为卤素、羟基、氰基、任选取代的杂芳基或任选取代的杂环。
(A13)
根据上述第(A9)项至第(A11)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中Rd为下式表示的基团:-C(=O)-NRgRh,其中Rg和Rj各自独立为氢、任选取代的烷基、任选取代的烷氧基或任选取代的氨基甲酰基。
(A14)
根据上述第(A9)项至第(A11)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中Rd为下式表示的基团:-NRiRj,其中Ri和Rj各自独立为氢、任选取代的烷基磺酰基、任选取代的烷氧基羰基、任选取代的烷基羰基或任选取代的杂环羰基。
(A15)
根据上述第(A1)项至第(A14)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R4为-OR6、-CONR7R8、-NR9CONR7R8、-(CR10R11)nOH、-(CR10R11)nOCONR7R8、-NR9COR12、-NR9C(=O)OR12、-(CR10R11)nNR9COR12、-C(=O)NOR12、-CONR9CONR7R8或-CN,其中R6至R12如上面第(A1)项中所定义。
(A16)
上述第(A15)项的化合物、其药学上可接受的盐或其溶剂合物,其中R7和R8各自独立为氢或任选取代的烷基。
(A17)
上述第(A15)项或第(A16)项的化合物、其药学上可接受的盐或其溶剂合物,其中R9为氢。
(A18)
根据上述第(A15)项至第(A17)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R10和R11各自独立为氢。
(A19)
根据上述第(A15)项至第(A18)项中任一项的化合物、其药学上可接受的盐或其溶剂合物,其中R12为任选取代的烷基。
(A20)
如下定义的化合物、其药学上可接受的盐或其溶剂合物,
[式23]
[式24]
[式25]
[式26]
[式27]
[式28]
[式29]
(A21)
一种药物组合物,所述药物组合物包含根据上述第(A1)项至第(A20)项中任一项的化合物、其药学上可接受的盐或其溶剂合物。
(A22)
根据上述第(A21)项的药物组合物,所述药物组合物为11β-羟基类固醇脱氢酶I型抑制剂。
(A23)
一种用于预防或治疗糖尿病的方法,所述方法包括给予根据上述第(A1)项至第(A20)项中任一项的化合物、其药学上可接受的盐或其溶剂合物。
(A24)
根据上述第(A1)项至第(A20)项中任一项的化合物、其药学上可接受的盐或其溶剂合物在制备治疗和/或预防糖尿病的药物中的用途。
发明效果
由于本发明化合物对11β-羟基类固醇脱氢酶I型具有抑制活性,包含本发明化合物的药物组合物作为药物非常有用,特别是作为治疗和/或预防高血脂症、糖尿病、肥胖症、动脉硬化、动脉粥样硬化、高血糖症和/或X综合征的药物非常有用。此外,本发明化合物选择性地抑制11β-羟基类固醇脱氢酶I型,且为具有其他作为药物的应用的化合物。在本文中,作为药物的应用包括高代谢稳定性、弱药物代谢酶诱导、代谢其他药物的药物代谢酶的弱抑制、高口服吸收、低清除率、足以显现药物效力的长半衰期等等。
实施本发明的最佳方式
在下文中,将解释本发明说明书中使用术语的含义。在该说明书中当各术语单独使用或与其他术语一起使用时有相同的含义。
“卤素”包括氟、氯、溴或碘。特别是,优选氟、氯和溴。
“烷基”是指C1至C10直链或支链烷基,其实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、正庚基、正辛基、正壬基、正癸基等。优选为C1至C6或C1至C4烷基,其实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基或异己基。
“链烯基”是指在上述“烷基”中具有一个或多个双键的C2至C8直链或支链链烯基,其实例包括乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1,3-丁二烯基、3-甲基-2-丁烯基等。
“炔基”是指在上述“烷基”中具有一个或多个叁键的C2至C8直链或支链炔基,其实例包括乙炔基、丙炔基、丁炔基等。
“环烷基”是指C3至C15环状饱和烃基,其实例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、桥连环状烃基、螺烃基等。优选为环丙基、环丁基、环戊基、环己基或桥连环状烃基。
“螺烃基”包括从由共用一个碳原子的两个烃环组成的环去掉一个氢原子衍生的基团。其实例包括螺[3.4]辛基等。
“桥连环状烃基”包括从由共用两个或更多个原子的两个或多个环组成的C5至C8脂环去掉一个氢原子衍生的基团。其实例包括二环[2.1.0]戊基、二环[2.2.1]庚基、二环[2.2.2]辛基、二环[3.2.1]辛基、三环[2.2.1.0]庚基、以下基团等:
[式30]
“环烯基”是指C3至C15环状不饱和脂族烃基,其实例包括环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基等。优选为环丙烯基、环丁烯基、环戊烯基或环己烯基。环烯基还包括环中具有不饱和健的桥连环状烃基。其实例包括在在上述“环烷基”中例举的桥连环状烃基的环中具有一个或两个双键的基团。
“芳基”是指单环芳族烃基(例如苯基)和多环芳族烃基(例如1-萘基、2-萘基、1-蒽基、2-蒽基、9-蒽基、1-菲基、2-菲基、3-菲基、4-菲基或9-菲基)。优选为苯基或萘基(1-萘基或2-萘基)。
“杂芳基”是指单环芳族杂环基或稠合的芳族杂环基。单环芳族杂环基是指从环中可包含1-4个氧、硫和/或氮原子的5-至8-元芳环衍生的基团,且可在可取代的任意位置具有键。
稠合的芳族杂环基是指其中环中任选包含1至4个氧、硫和/或氮原子的5-至8-元芳环与1至4个5-至8-元芳族碳环或其他5-至8-元芳族杂环稠合的基团,且可在可取代的任意位置具有键。
“杂芳基”的实例包括呋喃基(例如2-呋喃基或3-呋喃基)、噻吩基(例如2-噻吩基或3-噻吩基)、吡咯基(例如1-吡咯基、2-吡咯基或3-吡咯基)、咪唑基(例如1-咪唑基、2-咪唑基或4-咪唑基)、吡唑基(例如1-吡唑基、3-吡唑基或4-吡唑基)、三唑基(例如1,2,4-三唑-1-基、1,2,4-三唑-3-基或1,2,4-三唑-4-基)、四唑基(例如1-四唑基、2-四唑基或5-四唑基)、唑基(例如2-唑基、4-唑基或5-唑基)、异唑基(例如3-异唑基、4-异唑基或5-异唑基)、噻唑基(例如2-噻唑基、4-噻唑基或5-噻唑基)、噻二唑基、异噻唑基(例如3-异噻唑基、4-异噻唑基或5-异噻唑基)、吡啶基(例如2-吡啶基、3-吡啶基或4-吡啶基)、哒嗪基(例如3-哒嗪基或4-哒嗪基)、嘧啶基(例如2-嘧啶基、4-嘧啶基或5-嘧啶基)、呋咱基(例如3-呋咱基)、吡嗪基(例如2-吡嗪基)、二唑基(例如1,3,4-二唑-2-基)、苯并呋喃基(例如2-苯并[b]呋喃基、3-苯并[b]呋喃基、4-苯并[b]呋喃基、5-苯并[b]呋喃基、6-苯并[b]呋喃基或7-苯并[b]呋喃基)、苯并噻吩基(例如2-苯并[b]噻吩基、3-苯并[b]噻吩基、4-苯并[b]噻吩基、5-苯并[b]噻吩基、6-苯并[b]噻吩基或7-苯并[b]噻吩基)、苯并咪唑基(例如1-苯并咪唑基、2-苯并咪唑基、4-苯并咪唑基或5-苯并咪唑基)、苯并噻唑基、二苯并呋喃基、苯并唑基、喹喔啉基(例如2-喹喔啉基、5-喹喔啉基或6-喹喔啉基)、噌啉基(例如3-噌啉基、4-噌啉基、5-噌啉基、6-噌啉基、7-噌啉基或8-噌啉基)、喹唑啉基(例如2-喹唑啉基、4-喹唑啉基、5-喹唑啉基、6-喹唑啉基、7-喹唑啉基或8-喹唑啉基)、喹啉基(例如2-喹啉基、3-喹啉基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基或8-喹啉基)、酞嗪基(例如1-酞嗪基、5-酞嗪基或6-酞嗪基)、异喹啉基(例如1-异喹啉基、3-异喹啉基、4-异喹啉基、5-异喹啉基、6-异喹啉基、7-异喹啉基或8-异喹啉基)、puryl、蝶啶基(例如2-蝶啶基、4-蝶啶基、6-蝶啶基或7-蝶啶基)、咔唑基、菲啶基、吖啶基(例如1-吖啶基、2-吖啶基、3-吖啶基、4-吖啶基或9-吖啶基)、吲哚基(例如1-吲哚基、2-吲哚基、3-吲哚基、4-吲哚基、5-吲哚基、6-吲哚基或7-吲哚基)、异吲哚基、phenadinyl(例如1-phenadinyl或2-phenadinyl)、phenothiadinyl(例如1-phenothiadinyl、2-phenothiadinyl、3-phenothiadinyl或4-phenothiadinyl)等。
“杂环”是指环中可包含1至4个氧、硫和/或氮原子的非芳族杂环基团,且可在可取代的任意位置具有键。此外,所述非芳族杂环基团可与C1至C4烷基链桥连,或可与环烷烃(优选为5-至6-元环)或苯环稠合。杂环可为饱和或不饱和的,只要其为非芳族的。优选为5-至8-元环。其实例包括1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、1-吡咯烷基、2-吡咯烷基、3-吡咯烷基、1-咪唑啉基、2-咪唑啉基、4-咪唑啉基、1-咪唑烷基、2-咪唑烷基、4-咪唑烷基、1-吡唑啉基、3-吡唑啉基、4-吡唑啉基、1-吡唑烷基、3-吡唑烷基、4-吡唑烷基、哌啶子基、2-哌啶基、3-哌啶基、4-哌啶基、1-piperadinyl、2-piperadinyl、2-吗啉基、3-吗啉基、吗啉代、四氢吡喃基、以下基团等:
[式31]
“烷氧基”、“烷基磺酰基”、“烷氧基羰基”、“烷基羰基”和“烷氧基”的烷基部分是指上述“烷基”。
“环烷基磺酰基”、“环烷基氧基羰基”和“环烷基羰基”的环烷基部分是指上述“环烷基”。
“芳基磺酰基”、“芳氧基羰基”和“芳基羰基”的芳基部分是指上述“芳基”。
“杂芳基磺酰基”、“杂芳氧基羰基”和“杂芳基羰基”的杂芳基部分是指上述“杂芳基”。
“杂环磺酰基”、“杂环氧基羰基”和“杂环羰基”的杂环部分是指上述“杂环”。
“Ra和Rb与它们所连接的相邻碳原子一起形成的环”是指3-至15-元饱和或不饱和烃环或所述烃环中包含1至4个氧、硫和/或氮原子的3-至15-元饱和或不饱和杂环。优选为非芳族环,其实例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环丙烯、环丁烯、环戊烯、环己烯、环庚烯、在上述烃环中含1至4个氧、硫和/或氮原子的饱和或不饱和杂环。
例如,作为式-C(RaRb)-的基团,其中Ra和Rb与它们所连接的相邻碳原子一起可形成任选取代的环,例举了以下基团。
[式32]
“Rg和Rh与它们所连接的相邻氮原子一起形成的环”和“Ri和Rj与它们所连接的相邻氮原子一起形成的环”是指除了环中上述氮原子外还可包含1至4个氧、硫和/或氮原子的3-至15-元非芳族杂环。此外,所述非芳族杂环可与C1至C4烷基链桥连,或可与环烷烃(优选为5-至6-元环)或苯环稠合。所述环可为饱和或不饱和的,只要其为非芳族的。优选为5-至8-元环。例如,作为式-C(=O)-NRgRh的基团,其中Rg和Rh与它们所连接的相邻氮原子一起可形成任选取代的环,式-NRiRj的基团,其中Ri和Rj与它们所连接的相邻氮原子一起可形成任选取代的环,例举了1-吡咯啉基、1-吡咯烷基、1-咪唑啉基、1-咪唑烷基、1-吡唑啉基、1-吡唑烷基、哌啶子基,吗啉代和以下基团。
[式33]
“R5A和R6A与它们所连接的相邻氮原子一起形成的环”和“R7和R8与它们所连接的相邻氮原子一起形成的环”是指除了环中上述氮原子外还可包含1至4个氧、硫和/或氮原子的3-至15-元芳族杂环或非芳族杂环。所述环包括单环或稠环,例如可与环烷烃(优选为5-至6-元环)或苯环稠合。此外,所述非芳族杂环可与C1至C4烷基链桥连。优选为5-至8-元环。例如,包括以下实例:
[式34]
“任选取代的烷基”、“任选取代的链烯基”、“任选取代的炔基”、“任选取代的环烷基”、“任选取代的环烯基”、“任选取代的芳基”、“任选取代的杂芳基”、“任选取代的杂环”、“任选取代的烷基磺酰基、“任选取代的环烷基磺酰基”、“任选取代的芳基磺酰基”、“任选取代的杂芳基磺酰基”、“任选取代的杂环磺酰基”、“任选取代的烷氧基”、“任选取代的酰基”、“任选取代的烷氧基羰基”、“任选取代的环烷氧基羰基”、“任选取代的芳氧基羰基”、“任选取代的杂芳氧基羰基”、“任选取代的杂环氧基羰基”、“任选取代的烷基羰基”、“任选取代的环烷基羰基”、“任选取代的芳基羰基”、“任选取代的杂芳基羰基”、“任选取代的杂环羰基”、“Ra和Rb与它们所连接的相邻碳原子一起形成的环”、“Rg和Rh与它们所连接的相邻氮原子一起形成的环”、“Ri和Rj与它们所连接的相邻氮原子一起形成的环”、“R5A和R6A与它们所连接的相邻氮原子一起形成的环”和“R7和R8与它们所连接的相邻氮原子一起形成的环”可被1至4个选自以下的取代基取代,例如
羟基、羧基、卤素、卤代烷基(例如-CF3、-CH2CF3或-CH2CCl3)、硝基、亚硝基、氰基,
烷基(例如甲基、乙基、异丙基或叔丁基),
链烯基(例如乙烯基)、炔基(例如乙炔基),
环烷基(例如环丙基或金刚烷基)、羟基烷基(例如羟基甲基)、环烷基烷基(例如环己基甲基或金刚烷基甲基),
环烯基(例如环丙烯基)、芳基(例如苯基或萘基),
芳基烷基(例如苄基或苯乙基)、杂芳基(例如吡啶基或呋喃基)、杂芳基烷基(例如吡啶基甲基)、杂环(例如哌啶基)、杂环烷基(例如吗啉基甲基)、烷氧基(例如甲氧基、乙氧基、丙氧基或丁氧基)、卤代烷氧基(例如OCF3)、链烯基氧基(例如乙烯氧基或烯丙氧基)、芳氧基(例如苯氧基)、烷氧基羰基(例如甲氧基羰基、乙氧基羰基或叔丁氧基羰基)、芳基烷氧基(例如苄氧基)、氨基(例如烷基氨基(例如甲基氨基、乙基氨基或二甲基氨基)、酰基氨基(例如乙酰基氨基或苯甲酰基氨基)、芳基烷基氨基(例如苄基氨基或三苯甲基氨基)、羟基氨基、烷基氨基烷基(例如二乙基氨基甲基)、氨基磺酰基等。
“羟基烷基”的烷基部分是指上述“烷基”。
“链烯基氧基”的链烯基部分是指上述“链烯基”。
“芳基烷氧基”的芳基烷基部分是指上述“芳基烷基”。
“芳氧基”的芳基部分是指上述“芳基”。
“卤代烷基”、“卤代烷基氧基”和“卤代烷氧基”的烷基部分和卤素部分与上文所述相同。
“任选取代的氨基”、“任选取代的氨基甲酰基”、“任选取代的硫代氨基甲酰基和“任选取代的氨基磺酰基”的取代基的实例包括烷基、链烯基、芳基、杂芳基、烷基羰基、芳基羰基、杂芳基羰基、杂环羰基、烷氧基羰基、芳氧基羰基、杂芳氧基羰基、杂环氧基羰基、氨基磺酰基、烷基磺酰基、氨基甲酰基、环烷基磺酰基、芳基磺酰基、杂芳基磺酰基、杂环磺酰基、酰基、羟基、磺酰基、亚磺酰基、氨基等。
在本发明的化合物中,优选以下实施方案。
环A为下式表示的基团:
[式35]
环A优选为下式表示的基团:
[式36]
特别是,环A优选下式表示的基团:
[式37]
环A包括顺式和反式异构体。
环B为任选取代的杂芳基,条件是任选取代的异唑基被排除在外,或为任选取代的杂环。
优选为呋喃基、噻吩基、吡咯基、吡唑基、三唑基、唑基、噻唑基、异噻唑基、吡啶基、吗啉代、吗啉基、哌啶基、哌啶子基、piperadinyl、吡咯烷基或四氢噻吩基。
特别是,环B优选为吡唑基。
此外,环B可具有不为R2和R3的取代基。
R1为氢或任选取代的烷基。优选为氢、甲基、乙基、正丙基或异丙基。特别是,优选为氢。
R2为-OR5、-SR5、卤素、卤代烷基、卤代烷氧基、羟基、氰基、硝基、羧基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基、任选取代的杂环、
下式表示的基团:-NR5AR6A
其中R5A和R6A各自独立为氢、羟基、烷氧基、任选取代的烷基、任选取代的链烯基、任选取代的氨基甲酰基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环,或R5A和R6A与它们所连接的相邻氮原子一起可形成任选取代的环,
下式表示的基团:-S(=O)x-R7A
其中x为1或2的整数,R7A为任选取代的烷基、任选取代的链烯基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环、
下式表示的基团:-C(=O)NR5AR6A
其中R5A和R6A如上定义,或
下式表示的基团:-(CR8AR9A)y-O-(CR10AR11A)z-CR12AR13AR14A
其中y和z各自独立为0至5的整数,
R8A、R9A、R10A、R11A、R12A、R13A和R14A各自独立为氢、羟基、卤素、卤代烷基、卤代烷氧基、烷氧基、氰基、羧基、任选取代的烷基、任选取代的链烯基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环。
R2优选为-OR5、-SR5、卤代烷基、氰基、任选取代的烷基、任选取代的芳基、任选取代的杂芳基、
下式表示的基团:-NR5AR6A,或
下式表示的基团:-(CR8AR9A)y-O-(CR10AR11A)z-CR12AR13AR14A
更优选为-OR5或-SR5
特别是,优选为-OR5
R5A和R6A各自独立为氢、羟基、烷氧基、任选取代的烷基、任选取代的链烯基、任选取代的氨基甲酰基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环,或R5A和R6A与它们所连接的相邻氮原子一起可形成任选取代的环。
优选为氢、任选取代的烷基或任选取代的氨基甲酰基,或由R5A和R6A与它们所连接的相邻氮原子一起形成的任选取代的环。
x为1或2的整数。
R7A为任选取代的烷基、任选取代的链烯基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环。
R8A、R9A、R10A、R11A、R12A、R13A和R14A各自独立为氢、羟基、卤素、卤代烷基、卤代烷氧基、烷氧基、氰基、羧基、任选取代的烷基、任选取代的链烯基、任选取代的芳基、任选取代的环烷基、任选取代的环烯基、任选取代的杂芳基或任选取代的杂环。
优选为氢、羟基、卤素、任选取代的烷基。
更优选为氢。
y为0至5的整数。
优选为0至3的整数。更优选为1。
z为0至5的整数。
优选为0至3的整数。更优选为0。
R3为任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、
下式表示的基团:-CH=CH-C(RaRb)-Rc-Rd
下式表示的基团:-(CReRf)m-C(RaRb)-Rc-Rd
其中Ra和Rb各自独立为氢、任选取代的烷基或卤素,或Ra和Rb与它们所连接的相邻碳原子一起可形成任选取代的环,
Rc为-(CH2)n-,其中n为0至3的整数,
Rd为氢、卤素、羟基、羧基、氰基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、
下式表示的基团:-C(=O)-NRgRh
下式表示的基团:-NRiRj
Re和Rf各自独立为氢、卤素或任选取代的烷基,
Rg和Rh各自独立为氢、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、任选取代的烷基磺酰基、任选取代的环烷基磺酰基、任选取代的芳基磺酰基、任选取代的杂芳基磺酰基、任选取代的杂环磺酰基、任选取代的烷氧基、任选取代的氨基甲酰基,或者Rg和Rh与它们所连接的相邻氮原子一起可形成任选取代的环,
Ri和Rj各自独立为氢、羧基、羟基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、任选取代的酰基、任选取代的氨基甲酰基、任选取代的硫代氨基甲酰基、任选取代的烷基磺酰基、任选取代的环烷基磺酰基、任选取代的芳基磺酰基、任选取代的杂芳基磺酰基、任选取代的杂环磺酰基、任选取代的烷氧基羰基、任选取代的环烷氧基羰基、任选取代的芳氧基羰基、任选取代的杂芳氧基羰基、任选取代的杂环氧基羰基、任选取代的烷基羰基、任选取代的环烷基羰基、任选取代的芳基羰基、任选取代的杂芳基羰基、任选取代的杂环羰基、任选取代的氨基磺酰基,或者Ri和Rj与它们所连接的相邻氮原子一起可形成任选取代的环。
R3优选为下式表示的基团:-CH=CH-C(RaRb)-Rc-Rd或下式表示的基团:-(CReRf)m-C(RaRb)-Rc-Rd
更优选R3为下式表示的基团:-CH=CH-C(RaRb)-Rc-Rd
Ra和Rb各自独立为氢、任选取代的烷基或卤素,或Ra和Rb与它们所连接的相邻碳原子一起可形成任选取代的环。
优选为氢、任选取代的烷基或卤素。
特别是,Ra和Rb优选为任选取代的烷基。
Rc为-(CH2)n-,其中n为0至3的整数。
n优选为0或1。
Rd为氢、卤素、羟基、羧基、氰基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、
下式表示的基团:-C(=O)-NRgRh
下式表示的基团:-NRiRj
其中Rg和Rh各自独立为氢、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、任选取代的烷基磺酰基、任选取代的环烷基磺酰基、任选取代的芳基磺酰基、任选取代的杂芳基磺酰基、任选取代的杂环磺酰基、任选取代的烷氧基、任选取代的氨基甲酰基,或者Rg和Rh与它们所连接的相邻氮原子一起可形成任选取代的环,
Ri和Rj各自独立为氢、羧基、羟基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、任选取代的酰基、任选取代的氨基甲酰基、任选取代的硫代氨基甲酰基、任选取代的烷基磺酰基、任选取代的环烷基磺酰基、任选取代的芳基磺酰基、任选取代的杂芳基磺酰基、任选取代的杂环磺酰基、任选取代的烷氧基羰基、任选取代的环烷氧基羰基、任选取代的芳氧基羰基、任选取代的杂芳氧基羰基、任选取代的杂环氧基羰基、任选取代的烷基羰基、任选取代的环烷基羰基、任选取代的芳基羰基、任选取代的杂芳基羰基、任选取代的杂环羰基、任选取代的氨基磺酰基,或者Ri和Rj与它们所连接的相邻氮原子一起可形成任选取代的环。
Rd优选为卤素、羟基、氰基、任选取代的杂芳基、
下式表示的基团:-C(=O)-NRgRh
下式表示的基团:-NRiRj
特别是,优选为下式表示的基团:-C(=O)-NRgRh或下式表示的基团:-NRiRj
Rg和Rh各自独立为氢、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、任选取代的烷基磺酰基、任选取代的环烷基磺酰基、任选取代的芳基磺酰基、任选取代的杂芳基磺酰基、任选取代的杂环磺酰基、任选取代的烷氧基、任选取代的氨基甲酰基,或者Rg和Rh与它们所连接的相邻氮原子一起可形成任选取代的环。
优选为氢、任选取代的氨基甲酰基、任选取代的烷基或任选取代的烷氧基。
Ri和Rj各自独立为氢、羧基、羟基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、任选取代的环烷基、任选取代的环烯基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、任选取代的酰基、任选取代的氨基甲酰基、任选取代的硫代氨基甲酰基、任选取代的烷基磺酰基、任选取代的环烷基磺酰基、任选取代的芳基磺酰基、任选取代的杂芳基磺酰基、任选取代的杂环磺酰基、任选取代的烷氧基羰基、任选取代的环烷氧基羰基、任选取代的芳氧基羰基、任选取代的杂芳氧基羰基、任选取代的杂环氧基羰基、任选取代的烷基羰基、任选取代的环烷基羰基、任选取代的芳基羰基、任选取代的杂芳基羰基、任选取代的杂环羰基、任选取代的氨基磺酰基,或者Ri和Rj与它们所连接的相邻氮原子一起可形成任选取代的环。
优选为氢、任选取代的烷氧基羰基、任选取代的烷基羰基、任选取代的烷基磺酰基、任选取代的环烷基羰基、任选取代的烷基、任选取代的杂环羰基。
Re和Rf各自独立为氢、卤素或任选取代的烷基。
优选为氢或卤素。特别是,优选为氢。
R4为任选取代的烷基、任选取代的链烯基、-OR6、-CONR7R8、-NR9CONR7R8、-NR9SO2NR7R8、-(CR10R11)pOH、-(CR10R11)pOCONR7R8、-NR9COR12、-NR9C(=O)OR12、-(CR10R11)pNR9COR12、-C(=O)NR9OR12、-CONR9CONR7R8、-CN、-COOH、卤素或-NR7R8
优选为-OR6、-CONR7R8、-NR9CONR7R8、-(CR10R11)pOH、-(CR10R11)pOCONR7R8、-NR9COR12、-CN、-NR9C(=O)OR12、-(CR10R11)pNR9COR12、-C(=O)NR9OR12、-CONR9CONR7R8
特别是,优选为-OR6或-(CR10R11)pOCONR7R8
R5为任选取代的烷基、任选取代的链烯基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环。
优选为任选取代的烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环。
特别是,优选为任选取代的烷基。
R6为氢、任选取代的烷基、任选取代的链烯基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环、-SO2R5、-SO2NR7R8或-CONR7R8
优选为氢或-CONR7R8
R7和R8各自独立为氢、任选取代的烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环或-SO2R5,或R7和R8与它们所连接的相邻氮原子一起可形成任选取代的环。
优选为氢或任选取代的烷基。
特别是,优选为氢。
R9为氢或任选取代的烷基。优选为氢。
R10和R11各自独立为氢、卤素或任选取代的烷基。
优选为氢。
R12为任选取代的烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂芳基或任选取代的杂环。
优选为任选取代的烷基。
m和p各自独立为1至3的整数。m优选为1或2。p优选为1。
作为本发明化合物的药学上可接受的盐,可包括以下盐。
作为碱加成盐,其实例包括碱金属盐如钠盐或钾盐;碱土金属盐如钙盐或镁盐;铵盐;脂族胺盐如三甲基胺盐、三乙基胺盐、二环己胺盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、普鲁卡因盐、葡甲胺盐、二乙醇胺盐或乙二胺盐;芳烷基胺盐如N,N-二苄基乙二胺盐或苯乙苄胺盐;杂环芳族胺盐如吡啶盐、甲基吡啶盐、喹啉盐或异喹啉盐;季铵盐如四甲基铵盐、四乙基铵盐、苄基三甲基铵盐、苄基三乙基铵盐、苄基三丁基铵盐、甲基三辛基铵盐或四丁基铵盐;碱加成氨基酸盐如精氨酸盐或赖氨酸盐等。
作为酸加成盐,其实例包括无机酸盐如盐酸盐、硫酸盐、硝酸盐、磷酸盐、碳酸盐、碳酸氢盐或高氯酸盐;有机酸盐如乙酸盐、丙酸盐、乳酸盐、马来酸盐、富马酸盐、酒石酸盐、羟丁二酸盐、柠檬酸盐或抗坏血酸盐;磺酸盐如甲磺酸盐、羟乙磺酸盐、苯磺酸盐或对甲苯磺酸盐;酸加成氨基酸盐如天冬氨酸盐或谷氨酸盐等。
术语“溶剂合物”是指本发明化合物或其药学上可接受的盐的溶剂合物,其实例包括醇(例如乙醇)合物、水合物等。水合物的实例包括一水合物、二水合物等。
下文示例性地给出制备本发明化合物的通用方法。同时可按照在通常有机化学实验中实施的程序来进行萃取、纯化等。
(各化合物,其中R2=-OR5)
[式38]
其中上述流程中的各符号具有与上文相同的意义,对于化合物(II-A),可使用已知化合物,或者可使用通过通常方法衍生自已知化合物的化合物。Pro为保护基团。作为保护基团,其实例包括烷基等。
步骤1
步骤1为制备式(II-B)表示的化合物的方法,所述方法包括使式(II-A)表示的化合物与肼反应。
作为溶剂,其实例包括N-二甲基甲酰胺、二甲亚砜、芳烃(例如甲苯、苯、二甲苯等)、饱和烃(例如环己烷、己烷等)、卤代烃(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、醚(例如四氢呋喃、乙醚、二氧六环、1,2-二甲氧基乙烷等)、酯(例如乙酸甲酯、乙酸乙酯等)、酮(例如丙酮、甲乙酮等)、腈(例如乙腈等)、醇(例如甲醇、乙醇、叔丁醇等)、水、其混合溶剂等。优选可使用醇(例如甲醇、乙醇、叔丁醇等)。更优选可使用Pro-OH。反应可在从室温至所用溶剂的回流温度的温度范围下进行0.5至48小时。
步骤2
步骤2为制备式(II-C)表示的化合物的方法,所述方法包括使式(II-B)表示的化合物与式R5X表示的化合物在碱存在下反应。作为溶剂,可使用在步骤1中所述的溶剂。优选可使用酮(例如丙酮、甲乙酮等)或N-二甲基甲酰胺。
作为碱,其实例包括金属氢化物(例如氢化钠等)、金属氢氧化物(例如氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钡等)、金属碳酸盐(例如碳酸钠、碳酸钙、碳酸钾、碳酸铯等)、金属醇盐(例如甲醇钠、乙醇钠、叔丁醇钾等)、碳酸氢钠、金属钠、有机胺(例如三乙胺、二异丙基乙基胺、DBU、2,6-二甲基吡啶等)、吡啶、烷基锂(n-BuLi、sec-BuLi、tert-BuLi等)等。优选可使用金属碳酸盐(例如碳酸钠、碳酸钙、碳酸钾、碳酸铯等)。反应可在从室温至所用溶剂的回流温度的温度范围下进行0.5至48小时。
步骤3
步骤3为制备式(II-D)表示的化合物的方法,所述方法包括水解式(II-C)表示的化合物。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用醚(例如四氢呋喃、乙醚、二氧六环、1,2-二甲氧基乙烷等)、醇(例如甲醇、乙醇、叔丁醇等)、水、其混合溶剂等。作为碱,可使用在步骤2中所述的碱。优选可使用金属氢氧化物(例如氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钡等)。反应可在-20至40℃下进行0.5至24小时。
步骤4
步骤4为制备式(I-A)表示的化合物的方法,所述方法包括使式(II-D)表示的化合物与式(环A-NH-R1)表示的化合物反应。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用醚(例如四氢呋喃、乙醚、二氧六环、1,2-二甲氧基乙烷等)或N-二甲基甲酰胺。作为碱,可使用在步骤2中所述的碱。优选可使用有机胺(例如三乙胺、二异丙基乙基胺、DBU、2,6-二甲基吡啶等)。1-乙基-3-(3′-二甲基氨基丙基)碳二亚胺(WSCI)或1,3-二环己基碳二亚胺(DCCD)可用作缩合剂。N-羟基苯并三唑(HOBt)或N-羟基琥珀酰亚胺(HOSu)可用作添加剂。反应可在从-20℃至所用溶剂的回流温度的温度范围下进行0.5至24小时。
(各化合物,其中R2=-SR5)
[式39]
步骤5
步骤5为制备式(II-E)表示的化合物的方法,所述方法包括将式(II-B)表示的化合物中的羟基转化为氯。
作为溶剂,可使用磷酰氯(POCl3)。反应可在从-20℃至磷酰氯的回流温度的温度范围下进行0.5至24小时。
步骤6
步骤6为制备式(II-F)表示的化合物的方法,所述方法包括使式(II-E)表示的化合物与式R5SH表示的化合物在碱存在下反应。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用酮(例如丙酮、甲乙酮等)或N-二甲基甲酰胺。作为碱,可使用在步骤2中所述的碱。优选可使用金属氢化物(例如氢化钠等)、金属碳酸盐(例如碳酸钠、碳酸钙、碳酸钾、碳酸铯等)等。反应可在从室温至所用溶剂的回流温度的温度范围下进行0.5至48小时。
步骤7
步骤7为制备式(II-F)表示的化合物的方法,所述方法包括水解式(II-E)表示的化合物。
反应可在与上述步骤3相同的条件下进行。
步骤8
步骤8为制备式(I-B)表示的化合物的方法,所述方法包括使式(II-F)表示的化合物与式(环A-NH-R1)表示的化合物反应。
反应可在与上述步骤4相同的条件下进行。
[式40]
其中上述流程中的各符号具有与上文相同的意义,且对于化合物(II-G),可使用已知化合物,或者可使用通过通常方法衍生自已知化合物的化合物。
步骤9
步骤9为制备式(I-C)表示的化合物的方法,所述方法包括使式(II-G)表示的化合物与式(环A-NH-R1)表示的化合物反应。
反应可在与上述步骤4相同的条件下进行。
[式41]
其中上述流程中的各符号具有与上文相同的意义,且对于化合物(II-H),可使用已知化合物,或者可使用通过通常方法衍生自已知化合物的化合物。Pro和Pro’为保护基。作为Pro和Pro’,其实例包括甲基、乙基、苄基、苯甲酰基、叔丁基等。Hal为卤素。
步骤10
步骤10为制备式(II-I)表示的化合物的方法,所述方法包括使式(II-H)表示的化合物与肼反应。
反应可在与上述步骤1相同的条件下进行。
步骤11
步骤11为制备式(II-J)表示的化合物的方法,所述方法包括氧化式(II-I)表示的化合物。
作为氧化剂,可使用IBX(2-碘酰基苯甲酸)、铬、锰、银的金属盐或金属氧化物等,或者可用有机氧化剂。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用乙腈或酯(例如乙酸甲酯、乙酸乙酯等)。
反应可在从室温至所用溶剂的回流温度的温度范围下进行0.5至24小时。
氧化反应可在Swern氧化反应条件、TEMPO氧化反应条件等条件下进行。
步骤12
步骤12为制备式(II-L)表示的化合物的方法,所述方法包括对式(II-J)表示的化合物和式(II-K)表示的化合物进行Wittig反应。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用酯(例如乙酸甲酯、乙酸乙酯等)或醚(例如四氢呋喃、乙醚、二氧六环、1,2-二甲氧基乙烷等)。
作为碱,可使用在步骤2中所述的碱。优选可使用有机胺(例如三乙胺、二异丙基乙基胺、DBU、2,6-二甲基吡啶等)。反应可在-20至40℃下进行0.5至48小时。
步骤13
步骤13为制备式(II-M)表示的化合物的方法,所述方法包括使式(II-L)表示的化合物与式Rb-Hal表示的化合物在碱存在下反应。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用醚(例如四氢呋喃、乙醚、二氧六环、1,2-二甲氧基乙烷等)。
作为碱,可使用在步骤2中所述的碱。优选可使用金属醇盐(例如甲醇钠、乙醇钠、叔丁醇钾等)或LDA。反应可在-78至40℃下进行0.5至24小时。
步骤14
步骤14为制备式(II-N)表示的化合物的方法,所述方法包括使式(II-M)表示的化合物在强酸性条件下脱保护。
例如,三氯乙酸或硫酸可用作强酸。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用卤代烃(例如二氯甲烷、氯仿、1,2-二氯乙烷等)。反应可在-78至40℃下进行0.5至24小时。
步骤15
步骤15为制备式(II-O)表示的化合物的方法,所述方法包括使式(II-N)表示的化合物与胺反应。
反应可在与上述步骤4相同的条件下进行。
步骤16
步骤16为制备式(II-P)表示的化合物的方法,所述方法包括使式(II-O)表示的化合物脱保护。
反应可在与上述步骤3相同的条件下进行。
步骤17
步骤17为制备式(I-D)表示的化合物的方法,所述方法包括使式(II-P)表示的化合物与式(II-Q)表示的化合物反应。
反应可在与上述步骤4相同的条件下进行。
步骤18
步骤18为制备式(I-E)表示的化合物的方法,所述方法包括还原式(I-D)表示的化合物。
反应可采用过渡金属催化剂通过催化氢化进行。
作为过渡金属催化剂,可使用铂、钯、铑、钌、镍等。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用醇(例如甲醇、乙醇、叔丁醇等)、醚(例如四氢呋喃、乙醚、二氧六环、1,2-二甲氧基乙烷等)、水、其混合溶剂等。反应可在氢和过渡金属催化剂存在下在20至50℃下进行0.5至48小时。
[式42]
其中上述流程中的各符号具有与上文相同的意义,且对于化合物(II-R),可使用已知化合物,或者可使用通过通常方法衍生自已知化合物的化合物。Pro为保护基团。作为保护基团,其实例包括甲基、乙基、苄基、苯甲酰基、叔丁基等。
步骤19
步骤19为制备式(II-S)表示的化合物的方法,所述方法包括对式(II-R)表示的化合物进行酸水解。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用水。作为酸,可使用强酸如硫酸、硝酸、盐酸等。反应可在-20至100℃下进行0.5至48小时。
步骤20
步骤20为将式(II-S)表示的化合物转化为式(II-T)表示的化合物的方法。
该方法为当Ri和Rj之一为氢,Ri和Rj中的另一个为任选取代的烷基磺酰基、任选取代的环烷基磺酰基、任选取代的芳基磺酰基、任选取代的杂芳基磺酰基、任选取代的杂环磺酰基、任选取代的烷基羰基、任选取代的环烷基羰基、任选取代的芳基羰基、任选取代的杂芳基羰基或任选取代的杂环羰基时的反应方法。反应可通过使式(II-S)表示的化合物与相应的酰氯、酸酐或磺酰氯反应来进行。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用醚(例如四氢呋喃、乙醚、二氧六环、1,2-二甲氧基乙烷等)、N-二甲基甲酰胺或卤代烃(例如二氯甲烷、氯仿、1,2-二氯乙烷等)。
作为碱,可使用在步骤2中所述的碱。优选可使用有机胺(例如三乙胺、二异丙基乙基胺、DBU、2,6-二甲基吡啶等)或吡啶。
反应可在从-20℃至所用溶剂的回流温度的温度范围下进行0.5至24小时。
这是制备式(II-U)表示的化合物的方法,所述方法包括使式(II-T)表示的化合物脱保护。
反应可在与上述步骤3相同的条件下进行。
这是制备式(I-F)表示的化合物的方法,所述方法包括使式(II-U)表示的化合物与式(II-Q)表示的化合物反应。
反应可在与上述步骤4相同的条件下进行。
这是制备式(I-G)表示的化合物的方法,所述方法包括将式(I-F)表示的化合物还原。
反应可在与上述步骤18相同的条件下进行。
[式43]
其中上述流程中的各符号具有与上文相同的意义,且对于化合物(II-R),可使用已知化合物,或者可使用通过通常方法衍生自已知化合物的化合物。Pro为保护基团。作为保护基团,其实例包括甲基、乙基、苄基、苯甲酰基、叔丁基等。
步骤24
步骤24为将式(II-R)表示的化合物转化为式(II-T)表示的化合物的方法。
该方法为当Ri和Rj之一为氢,Ri和Rj中的另一个为任选取代的氨基甲酰基、任选取代的烷氧基羰基、任选取代的环烷氧基羰基、任选取代的芳氧基羰基、任选取代的杂芳氧基羰基、任选取代的杂环氧基羰基时的反应方法。反应可通过使式(II-R)表示的化合物与相应的醇或胺反应来进行。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用芳烃(例如甲苯、苯、二甲苯等)或醚(例如四氢呋喃、乙醚、二氧六环、1,2-二甲氧基乙烷等)。反应可在从-20℃至所用溶剂的回流温度的温度范围下进行0.5至24小时。
[式44]
其中上述流程中的各符号具有与上文相同的意义,且对于化合物(II-N),可使用已知化合物,或者可使用通过通常方法衍生自已知化合物的化合物。Pro为保护基团。作为保护基团,其实例包括甲基、乙基、苄基、苯甲酰基、叔丁基等。Hal为卤素。
步骤25
步骤25为制备式(II-V)表示的化合物的方法,所述方法包括还原式(II-N)表示的化合物。
反应可通过使式(II-N)表示的化合物与氯碳酸乙酯反应以制备活性酯、随后与还原剂反应来进行。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用醚(例如四氢呋喃、乙醚、二氧六环、1,2-二甲氧基乙烷等)。
作为还原剂,可使用三乙酰氧基硼氢化钠、硼氢化钠、四氢硼酸锂、吡啶硼烷络合物、四氢呋喃硼烷络合物、二甲基硫醚-硼烷络合物或2-甲基吡啶硼烷络合物。优选可使用硼氢化钠。
反应可在-20至50℃下进行0.5至24小时。
步骤26
步骤26为制备式(II-W)表示的化合物的方法,所述方法包括使式(II-V)表示的化合物脱保护。
反应可在与上述步骤3相同的条件下进行。
步骤27
步骤27为制备式(I-H)表示的化合物的方法,所述方法包括使式(II-W)表示的化合物与式(II-Q)表示的化合物反应。
反应可在与上述步骤4相同的条件下进行。
步骤28
步骤28为制备式(I-J)表示的化合物的方法,所述方法包括还原式(I-H)表示的化合物。
反应可在与上述步骤18相同的条件下进行。
步骤29
步骤29为制备式(I-K)表示的化合物的方法,所述方法包括卤化式(I-H)表示的化合物。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用卤代烃(例如二氯甲烷、氯仿、1,2-二氯乙烷等)。
作为卤化剂,可使用DAST((二乙基氨基)三氟化硫)、NCS(N-氯代琥珀酰亚胺)、NBS(N-溴代琥珀酰亚胺)、CBr4、PBr3或PBr5
反应可在从-78℃至所用溶剂的回流温度的温度范围下进行0.5至24小时。
步骤30
步骤30为制备式(I-L)表示的化合物的方法,所述方法包括卤化式(I-J)表示的化合物。
反应可在与上述步骤29相同的条件下进行。
[式45]
(各化合物,其中Rd=-CN)
其中Rg和Rh为氢,上述流程中的其他各符号具有与上文相同的意义,且对于化合物(II-O),可使用已知化合物,或者可使用通过通常方法衍生自已知化合物的化合物。Pro为保护基团。作为保护基团,其实例包括甲基、乙基、苄基、苯甲酰基、叔丁基等。
步骤31
步骤31为制备式(II-X)表示的化合物的方法,所述方法包括使式(II-O)表示的化合物脱水。
反应可通过使式(II-O)表示的化合物与无水三氟乙酸和吡啶在卤代烃(例如二氯甲烷、氯仿、1,2-二氯乙烷等)中在-20至40℃下反应0.5至10小时来进行。
步骤32
步骤32为制备式(II-Y)表示的化合物的方法,所述方法包括使式(II-X)表示的化合物脱保护。
反应可在与上述步骤18相同的条件下进行。
步骤33
步骤33为制备式(I-M)表示的化合物的方法,所述方法包括使式(II-Y)表示的化合物与式(II-Q)表示的化合物反应。
反应可在与上述步骤4相同的条件下进行。
步骤34
步骤34为制备式(I-N)表示的化合物的方法,所述方法包括还原式(I-M)表示的化合物。
反应可在与上述步骤18相同的条件下进行。
[式46]
其中上述流程中的各符号具有与上文相同的意义,且对于化合物(II-A),可使用已知化合物,或者可使用通过通常方法衍生自已知化合物的化合物。Pro为保护基团。作为保护基团,其实例包括甲基、乙基、苄基、苯甲酰基、叔丁基等。Pro”为保护基团。作为保护基团,其实例包括叔丁基、三苯甲基、苄基、对甲氧基苄基、甲硅烷基、甲磺酰基、酰基等。
步骤35
步骤35为制备式(II-AA)表示的化合物的方法,所述方法包括使式(II-A)表示的化合物与式(II-Z)表示的化合物反应。
反应可在与上述步骤1相同的条件下进行。
步骤36
步骤36为制备式(II-AB)表示的化合物的方法,所述方法包括卤化式(II-AA)表示的化合物。
例如,卤化可参考WO2007/058346中的实施例3来进行。
氯化可用磷酰氯在-20℃至磷酰氯的回流温度的温度范围内进行0.5至24小时。该反应可在步骤1中所述的溶剂中进行,或者可在没有任何溶剂下进行。
溴化可用PBr3在与上述相同的条件下进行。氟衍生物可通过使相应的氯衍生物与氟化钾反应来得到。
步骤37
步骤37为由式(II-AB)表示的化合物制备式(I-O)表示的化合物的方法。
反应可按照本说明书中描述的通用方法进行。
[式47]
其中上述流程中的各符号具有与上文相同的意义,且对于化合物(II-AB),可使用已知化合物,或者可使用通过通常方法衍生自已知化合物的化合物。Pro为保护基团。作为保护基团,其实例包括甲基、乙基、苄基、苯甲酰基、叔丁基等。Pro”为保护基团。作为保护基团,其实例包括叔丁基、三苯甲基、苄基、对甲氧基苄基、甲硅烷基、甲磺酰基、酰基等。Hal为卤素。作为X’,其实例包括=N-或=CRY-,其中RY为氢、C1-C6烷基或卤素。
步骤38
步骤38为制备式(II-AD)表示的化合物的方法,所述方法包括使式(II-AB)表示的化合物与式(II-AC)表示的化合物在碱存在下反应。
作为碱,可使用在步骤2中所述的碱。优选可使用金属氢化物(例如氢化钠等)或LDA。
作为溶剂,可使用在步骤1中所述的溶剂。优选可使用醚(例如四氢呋喃、乙醚、二氧六环、1,2-二甲氧基乙烷等)。
反应可在-78至50℃下进行0.5至24小时。
步骤39
步骤39为由式(II-AD)表示的化合物制备式(I-P)表示的化合物的方法。
反应可按照本说明书中描述的通用方法进行。
步骤40
步骤40为制备式(II-AF)表示的化合物的方法,所述方法包括使式(II-AB)表示的化合物与式(II-AE)表示的化合物反应。
作为溶剂,可使用在步骤1中所述的溶剂。反应还可在不存在溶剂下进行。
反应可在80至150℃下进行0.5至48小时。
此外,微波也可用于该反应。
步骤41
步骤41为由式(II-AF)表示的化合物制备式(I-Q)表示的化合物的方法。
反应可按照本说明书中描述的通用方法进行。
[式48]
其中上述流程中的各符号具有与上文相同的意义,且对于化合物(II-AG),可使用已知化合物,或者可使用通过通常方法衍生自已知化合物的化合物。
步骤42
步骤42为制备式(II-AH)表示的化合物的方法,所述方法包括使式(II-AG)表示的化合物与肼反应。
反应可在与上述步骤1相同的条件下进行。
步骤43
步骤43为制备式(II-AI)表示的化合物的方法,所述方法包括卤化式(II-AH)表示的化合物。
例如,卤化可通过Sandmeye反应进行。
溴化反应可用CuBr在-20℃至所用溶剂的回流温度的温度范围内进行0.5至24小时。
氯化反应可在如上所述的相同条件下用CuCl进行。同时,在如上所述的相同条件下,可用碘化钠进行碘化,可用四氟硼酸银进行氟化。
步骤44
步骤44为式(II-AI)表示的化合物制备式(II-AJ)或(II-AK)表示的化合物的方法。
反应可按照本说明书中描述的通用方法进行。
其中上式(II-AJ)或(II-AK)表示的化合物的卤素基团被各种取代基取代的化合物可通过使上式(II-AJ)或(II-AK)表示的化合物在如以上步骤6、步骤38或步骤40中所述的相同条件下反应制备。
本发明化合物中的各种取代基可通过参考以下文献来引入:(1)AlanR.Katriszly等,ComprehensiveHeterocyclicChemistry(高等杂环化学);(2)AlanR.Katriszly等,ComprehensiveHeterocyclicChemistry(高等杂环化学)II;(3)RODD′SCHEMISTRYOFCARBONCOMPOUNDSVOLUMEIVHETEROCYCLICCOMPOUNDS等。
本发明化合物对11β-羟基类固醇脱氢酶I型具有优异的抑制活性。因此,本发明化合物可用于治疗或预防与11β-羟基类固醇脱氢酶I型相关的疾病,特别是,疾病如高血脂症、糖尿病、肥胖症、动脉硬化、动脉粥样硬化、高血糖症和/或X综合征。本发明化合物特别可用于治疗或预防糖尿病。
本发明所用化合物可口服给药或胃肠外给药。在口服给药的情况下,本发明所用化合物可以以任何剂型使用,所述剂型包括常规制剂,例如,固体制剂如片剂、散剂、颗粒剂、胶囊等;水性制剂;油质混悬剂;或液体制剂如糖浆或酏剂。在胃肠外给药的情况下,本发明所用化合物可以以注射用水性或油性混悬液或鼻用溶液形式使用。在这类制剂的制备中,可任选使用常规的赋形剂、粘合剂、润滑剂、水性溶剂、油性溶剂、乳化剂、悬浮剂、防腐剂、稳定剂等。特别是,优选以口服制剂形式使用。
本发明所用化合物的制剂可通过将治疗有效量的本发明所用化合物与药学上可接受的载体或稀释剂结合(例如混合)来制备。本发明所用化合物的制剂可采用众所周知的易得成分通过公知方法制备。
本发明所用化合物的剂量随患者的给药途径、年龄、体重、身体状况和疾病类型而异,且通常对于成年人为每天约0.05mg至3000mg并优选约0.1mg至1000mg,在口服给药的情况下,可按需以分剂量给药。在胃肠外给药的情况下,对于成年人可每天给予约0.01mg至1000mg且优选约0.05mg至500mg。在给药中,可与其他药物一起使用。
下文将通过实施例更详细地描述本发明,但是这些实施例并非意欲限制本发明的范围。
此外,式(III’)表示的基团:
[式49]
等于以下基团:
[式50]
[实施例1]
[式51]
经15分钟往化合物(II-1)(乙氧基亚甲基丙二酸二乙基酯,10g)在N,N-二甲基甲酰胺(50ml)中的溶液中滴加在N,N-二甲基甲酰胺(50ml)中的80%肼/乙醇(4.4g)。往得到的溶液中加入碳酸钾(6.4g),在80℃下将反应混合物搅拌2小时。往该混合物中加入异丁基溴(7.6mL),将整个混合物在120℃下搅拌1.5小时。在反应终止后,将反应混合物倾入0.5MHCl水溶液,用乙酸乙酯萃取。有机层依次用饱和NaHCO3水溶液和盐水洗涤,经硫酸钠干燥并浓缩。将残余物溶解于少量乙酸乙酯,在冰冷却下往得到的溶液中加入己烷,得到晶体。过滤收集晶体并干燥,得到化合物II-2(4.6g)。
往化合物II-2(5.7g)在乙酸乙酯(160ml)中的溶液中加入IBX(7.5g),随后将得到的混合物回流6小时。在反应终止后,过滤除去不溶性物质,浓缩滤液,得到化合物II-3(5.6g)。得到的产物无需进一步纯化用于下一反应。
往化合物II-3(5.6g)在四氢呋喃(40ml)中的溶液中加入磷盐(13.5g)。经20分钟往该溶液中滴加三乙胺(3.4g),随后将整个混合物在室温下搅拌3小时。在反应终止后,往该混合物中加入水(40ml),随后用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸镁干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物II-4(5.2g)。
将二异丙基胺(1.3ml)在四氢呋喃(60ml)中的溶液冷却到-78℃,随后往该溶液中滴加正丁基锂(3.25ml,2.8M,在己烷中)。在-78℃下搅拌30分钟后,往该溶液中加入在四氢呋喃(40ml)中的化合物II-4(2.8g)并将整个混合物搅拌30分钟。往该混合物中加入碘甲烷(1.4ml),随后让整个混合物逐渐温热至0℃。3小时后,该混合物用饱和NH4Cl水溶液稀释并用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸镁干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物II-5(2.42g)。
往化合物II-5(19.4g)在二氯甲烷(100ml)中的溶液中加入三氟乙酸(50ml),随后将反应混合物在室温下搅拌3小时。在反应终止后,除去溶剂,残余物用H2O(100ml)稀释并用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸镁干燥并浓缩,得到化合物II-6(16.6g)。
在0℃下往化合物II-6(237mg)在四氢呋喃(3ml)中的溶液中加入三乙胺(152μl)和氯碳酸乙酯(84μl),随后将反应化合物在室温下搅拌1小时。在0℃下往该混合物中加入硼氢化钠(69mg)和水(1ml)且将整个混合物搅拌20分钟。在反应终止后,将HCl水溶液加入该混合物中。用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸钠干燥并浓缩。残余物经硅胶柱层析纯化,得到II-7(185mg)。
在-78℃下往化合物II-7(185mg)在二氯甲烷(5ml)的溶液中加入DAST(102μl),随后在同一温度下将反应混合物搅拌30分钟。在反应终止后,将饱和NH4Cl水溶液加入该混合物中。用乙酸乙酯萃取。有机层经硫酸钠干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物II-8(62mg)。
往化合物II-8(61.6mg)在四氢呋喃(1ml)-甲醇(1ml)中的溶液中加入2NNaOH水溶液(1ml),随后将反应混合物在室温下搅拌14小时。在反应终止后,该混合物用2NHCl水溶液酸化并用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸钠干燥并浓缩,得到化合物II-9(60.1mg)。得到的产物无需进一步纯化用于下一反应。
往化合物II-9(60.1mg)在二甲基甲酰胺(3ml)中的溶液中加入羟基金刚烷胺(38.8mg)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺·盐酸盐(48.5mg)、1-羟基苯并三唑(8.5mg)和三乙胺(50μl),随后将反应混合物在室温下搅拌18小时。在反应终止后,该混合物用2NHCl水溶液酸化并用乙酸乙酯萃取。有机层依次用饱和NaHCO3水溶液和盐水洗涤,经硫酸钠干燥。残余物经硅胶柱层析纯化,得到化合物II-10(62mg)。
在-45℃下往化合物II-10(54mg)在四氢呋喃(1.2ml)中的溶液中加入氯磺酰基异氰酸酯(22μl),随后将反应混合物在-30℃下搅拌2小时。将固体NaHCO3(74mg)和水(24μl)加入该溶液并将整个混合物在室温下搅拌2小时。在反应终止后,将水加入该混合物,随后用乙酸乙酯萃取。有机层用盐水洗涤并经硫酸钠干燥。残余物经硅胶柱层析纯化,得到化合物I-1(51mg)。
(化合物I-1)
NMR(DMSO-d6);δ(ppm)0.95(d,J=6.6Hz,6H),1.30(s,3H),1.36(s,3H),1.41(d,J=12.4Hz,2H),1.94-2.10(m,12H),2.46-2.53(m,2H),3.94(s,1H),4.10(d,J=6.3Hz,2H),6.08-6.16(m,1H),6.20(br,2H),6.92(d,J=14.2Hz,1H),7.50(d,J=6.6Hz,1H),7.94(s,1H)
以下所示的各化合物按照类似的方法合成。
对于每个化合物,公开了NMR或logk’的测定结果。
logk’为表示亲脂特性程度的数值,通过下式计算。
logk’=log(tR-t0)/t0
tR:在梯度洗脱条件下化合物的保留时间
t0:不保留在柱中的标准物的保留时间
用XTerraMSC185μm,2.1×100mm柱(Waters制造)进行测定。洗脱按照乙腈/pH6.8缓冲液的线性梯度进行(5∶95~95∶5/20分钟),流速为0.25mL/分钟。
[实施例2]
[式52]
(化合物I-2)logk’=1.014
[实施例3]
[式53]
(化合物I-3)logk’=1.066
[实施例4]
[式54]
(化合物I-4)NMR(CDCl3);δ(ppm)1.10(d,J=6.7Hz,6H),1.36-1.84(m,8H),1.54(s,6H),1.95(s,3H),2.10-2.35(m,5H),2.64-2.76(m,1H),3.98(d,J=6.8Hz,2H),4.23-4.28(m,1H),5.32(br,1H),5.47(s,1H),5.50(br,1H),6.38(d,J=14.1Hz,1H),6.46(d,J=8.0Hz,1H),6.86(d,J=14.1Hz,1H),7.83(s,1H)
[实施例5]
[式55]
(化合物I-5)logk’=0.795
[实施例6]
[式56]
(化合物I-6)NMR(DMSO-d6);δ(ppm)0.96(t,J=7.5Hz,3H),0.97(d,J=6.6Hz,6H),1.32-1.36(m.2H),1.40(s,6H),1.58-1.75(m,6H),1.89-2.11(m,8H),3.86-3.91(m,1H),4.07(d,J=6.3Hz,2H),4.42(s,1H),6.35(d,J=14.1Hz,1H),6.76(d,J=14.1Hz,1H),7.38(d,J=6.9Hz,1H),7.67(s,1H),7.95(s,1H)
[实施例7]
[式57]
(化合物I-7)NMR(DMSO-d6);δ(ppm)0.98(d,J=6.8Hz,6H),1.42(d,J=13.1Hz,2H),1.52(s,6H),1.95-2.11(m,12H),3.96(s,1H),4.15(d,J=6.3Hz,2H),6.20(br,2H),6.24(d,J=14.2Hz,1H),7.10(d,J=14.2Hz,1H),7.55(d,J=6.1Hz,1H),8.04(s,1H)
[实施例8]
[式58]
(化合物I-8)logk’=0.883
[实施例9]
[式59]
(化合物I-9)NMR(DMSO-d6);δ(ppm)0.97(d,J=6.6Hz,6H),1.40-1.44(m,8H),1.94-2.10(m,12H),2.90(s,3H),3.94-3.96(m,1H),4.11(d,J=6.3Hz,2H),6.20(br,2H),6.33(d,J=14.4Hz,1H),6.92(d,J=14.4Hz,1H),7.24(s,1H),7.50(d,J=6.8Hz,1H),7.98(s,1H)
[实施例10]
[式60]
(化合物I-10)logk’=0.798
[实施例11]
[式61]
(化合物I-11)logk’=0.831
[实施例12]
[式62]
(化合物I-12)logk’=0.763
[实施例13]
[式63]
(化合物I-13)logk’=0.822
[实施例14]
[式64]
(化合物I-14)logk’=0.981
[实施例15]
[式65]
(化合物I-15)NMR(CDCl3);δ(ppm)1.08(d,J=6.8Hz,6H),1.51(s,6H),1.58-1.85(m,6H),2.02-2.11(m,6H),2.12(m,1H),2.92-3.04(m,1H),3.62(s,3H),3.97(d,J=7.0Hz,2H),4.07-4.10(m,1H),4.83(s,1H),5.35(br,1H),5.51(br,1H),6.37(d,J=14.1Hz,1H),6.46(d,J=7.6Hz,1H),6.87(d,J=14.1Hz,1H),7.83(s,1H)
[实施例16]
[式66]
(化合物I-16)logk’=0.842
[实施例17]
[式67]
(化合物I-17)logk’=0.916
[实施例18]
[式68]
(化合物I-18)logk’=0.866
[实施例19]
[式69]
(化合物I-19)logk’=0.907
[实施例20]
[式70]
(化合物I-20)logk’=0.845
[实施例21]
[式71]
(化合物I-21)logk’=0.909
[实施例22]
[式72]
(化合物I-22)logk’=0.879
[实施例23]
[式73]
(化合物I-23)logk’=0.864
[实施例24]
[式74]
(化合物I-24)logk’=0.876
[实施例25]
[式75]
(化合物I-25)logk’=0.87
[实施例26]
[式76]
(化合物I-26)logk’=0.895
[实施例27]
[式77]
(化合物I-27)logk’=0.903
[实施例28]
[式78]
(化合物I-28)logk’=0.927
[实施例29]
[式79]
(化合物I-29)NMR(CDCl3);δ(ppm)1.39(d,J=6.3Hz,6H),1.51(s,6H),1.55-2.11(m,13H),3.62(s,3H),3.73(s,2H),4.14-4.16(m,1H),4.61(br,2H),4.67-4.75(m,1H),4.83(m,1H),6.36(d,J=14.2Hz,1H),6.53(d,J=7.3Hz,1H),6.83(d,J=14.2Hz,1H),7.86(s,1H)
[实施例30]
[式80]
(化合物I-30)NMR(CDCl3);δ(ppm)1.39(d,J=6.3Hz,6H),1.54(s,6H),1.59-1.78(m,4H),1.96(s,3H),2.13-2.29(m,9H),4.20-4.23(m,1H),4.43(br,2H),4.67-4.75(m,1H),5.46(s,1H),6.36(d,J=14.2Hz,1H),6.47(d,J=7.6Hz,1H),6.81(d,J=14.2Hz,1H),7.85(s,1H)
[实施例31]
[式81]
(化合物I-31)logk’=0.819
[实施例32]
[式82]
(化合物I-32)NMR(CDCl3);δ(ppm)1.39(d,J=6.3Hz,6H),1.54(s,6H),1.56-2.10(m,13H),1.96(s,3H),3.73(s,2H),4.14-4.16(m,1H),4.63(br,2H),4.67-4.75(m,1H),5.48(s,1H),6.36(d,J=14.2Hz,1H),6.56(d,J=7.8Hz,1H),6.82(d,J=14.2Hz,1H),7.86(s,1H)
[实施例33]
[式83]
(化合物I-33)logk’=0.955
[实施例34]
[式84]
(化合物I-34)logk’=0.877
[实施例35]
[式85]
(化合物I-35)logk’=0.921
[实施例36]
[式86]
(化合物I-36)NMR(DMSO-d6):δ(ppm)1.08(d,J=6.6Hz,6H),1.47-1.74(m,19H),1.54(s,3H),1.64(s,3H),1.89-1.98(m,2H),2.10-2.24(m,6H),3.98(d,J=6.9Hz,2H),4.14-4.20(m,1H),5.42(s,1H),6.38(d,J=14.4Hz,1H),6.38(s,1H),6.86(d,J=14.4Hz,1H),7.80(s,1H).
[实施例37]
[式87]
(化合物I-37)
[实施例38]
[式88]
(化合物I-38)
[实施例39]
[式89]
(化合物I-39)
[实施例40]
[式90]
(化合物I-40)
[实施例41]
[式91]
(化合物I-41)
[实施例42]
[式92]
(化合物I-42)logk’=0.805
[实施例43]
[式93]
(化合物I-43)logk’=0.851
[实施例44]
[式94]
(化合物I-44)NMR(CDCl3);δ(ppm)1.08(d,J=6.7Hz,6H),1.51(s,6H),1.58-2.06(m,13H),2.07-2.20(m,1H),2.24-2.36(m,1H),3.41(d,J=6.2Hz,2H),3.62(s,3H),3.98(d,J=6.7Hz,2H),3.99-4.02(m,1H),4.82(s,1H),6.37(d,J=14.2Hz,1H),6.49(d,J=7.6Hz,1H),6.87(d,J=14.2Hz,1H),7.82(s,1H)
[实施例45]
[式95]
(化合物I-45)logk’=0.865
[实施例46]
[式96]
(化合物I-46)logk’=0.913
[实施例47]
[式97]
(化合物I-47)NMR(CDCl3):δ(ppm)1.08(d,J=6.6Hz,6H),1.51-1.84(m,8H),1.58(s,3H),1.66(s,3H),1.88-1.98(m,2H),2.06-2.24(m,4H),3.41(s,3H),3.80(s,2H),3.98(d,J=6.6Hz,2H),4.14-4.20(m,1H),6.35(d,J=8.1Hz,1H),6.41(d,J=14.1Hz,1H),6.52(s,1H),6.87(d,J=14.1Hz,1H),7.81(s,1H).
[实施例48]
[式98]
(化合物I-48)NMR(DMSO-d6):δ(ppm)0.85(t,J=7.2Hz,3H),0.96(d,J=6.6Hz,6H),1.35-1.56(m,4H),1.40(s,6H),1.90-2.16(m,14H),3.91-3.98(m,1H),4.07(d,J=6.3Hz,2H),6.21(br,2H),6.35(d,J=14.4Hz,1H),6.76(d,J=14.4Hz,1H),7.47(d,J=6.3Hz,1H),7.72(s,1H).
[实施例49]
[式99]
(化合物I-49)logk’=0.945
[实施例50]
[式100]
(化合物I-50)logk’=0.989
[实施例51]
[式101]
(化合物I-51)logk’=0.882
[实施例52]
[式102]
(化合物I-52)NMR(CDCl3):δ(ppm)1.07(d,J=6.6Hz,6H),1.51-1.84(m,8H),1.60(s,3H),1.62(s,3H),1.88-1.98(m,2H),2.05-2.24(m,4H),3.99(d,J=6.6Hz,2H),4.14-4.20(m,1H),4.39(s,2H),6.36(d,J=7.5Hz,1H),6.44(d,J=14.4Hz,1H),6.58(s,1H),6.86-6.96(m,3H),7.00-7.06(m,1H),7.28-7.36(m,2H),7.81(s,1H).
[实施例53]
[式103]
(化合物I-53)NMR(CDCl3):δ(ppm)1.09(d,J=6.9Hz,6H),1.38-1.84(m,8H),1.47(s,3H),1.63(s,3H),1.88-2.00(m,2H),2.08-2.26(m,4H),2.42(t,J=7.5Hz,2H),2.93(t,J=7.5Hz,2H),3.99(d,J=6.9Hz,2H),4.12-4.20(m,1H),5.29(s,1H),6.33(d,J=14.1Hz,1H),6.39(s,1H),6.84(d,J=14.1Hz,1H),7.14-7.32(m,5H),7.82(s,1H).
[实施例54]
[式104]
(化合物I-54)logk’=0.886
[实施例55]
[式105]
(化合物I-55)NMR(DMSO-d6);δ(ppm)0.97(d,J=6.6Hz,6H),1.27(s,6H),1.35(d,J=12.1Hz,2H),1.61-1.72(m,6H),1.89-2.04(m,6H),2.57(d,J=4.3Hz,3H),3.87-3.91(m,1H),4.10(d,J=6.3Hz,2H),4.44(s,1H),6.33(d,J=14.2Hz,1H),6.78(d,J=14.7Hz,1H),7.39(d,J=6.1Hz,1H),7.52-7.56(m,1H),7.98(s,1H)
[实施例56]
[式106]
(化合物I-56)logk’=0.838
[实施例57]
[式107]
(化合物I-57)logk’=0.852
[实施例58]
[式108]
(化合物I-58)logk’=0.899
[实施例59]
[式109]
(化合物I-59)logk’=0.833
[实施例60]
[式110]
(化合物I-60)logk’=0.813
[实施例61]
[式111]
(化合物I-61)logk’=0.841
[实施例62]
[式112]
(化合物I-62)logk’=0.794
[实施例63]
[式113]
(化合物I-63)NMR(DMSO-d6);δ(ppm)0.98(d,J=6.8Hz,6H),1.27(s,6H),1.39-1.51(m,8H),1.87-2.03(m,6H),3.00(d,J=5.6Hz,2H),3.88(s,1H),4.10(d,J=6.3Hz,2H),4.37(t,J=5.6Hz,1H),6.37(d,J=14.4Hz,1H),6.81(d,J=14.4Hz,1H),6.95(s,1H),7.15(s,1H),7.41(d,J=7.1Hz,1H),7.98(s,1H)
[实施例64]
[式114]
(化合物I-64)logk’=0.814
[实施例65]
[式115]
(化合物I-65)logk’=0.838
[实施例66]
[式116]
(化合物I-66)logk’=0.886
[实施例67]
[式117]
(化合物I-67)logk’=0.82
[实施例68]
[式118]
(化合物I-68)logk’=0.85
[实施例69]
[式119]
(化合物I-69)logk’=0.866
[实施例70]
[式120]
(化合物I-70)logk’=0.882
[实施例71]
[式121]
(化合物I-71)logk’=0.868
[实施例72]
[式122]
(化合物I-72)NMR(DMSO-d6);δ(ppm)0.96-1.01(m,9H),1.27(s,6H),1.34(d,J=12.1Hz,2H),1.61-1.72(m,6H),1.89-2.04(m,6H),3.03-3.08(m,2H),3.89(s,1H),4.10(d,J=6.6Hz,2H),4.44(s,1H),6.34(d,J=14.4Hz,1H),6.78(d,J=14.4Hz,1H),7.39(d,J=6.6Hz,1H),7.57(t,J=5.4Hz,1H),7.98(s,1H)
[实施例73]
[式123]
(化合物I-73)logk’=0.876
[实施例74]
[式124]
(化合物I-74)logk’=0.896
[实施例75]
[式125]
(化合物I-75)logk’=0.95
[实施例76]
[式126]
(化合物I-76)logk’=0.946
[实施例77]
[式127]
(化合物I-77)logk’=0.926
[实施例78]
[式128]
(化合物I-78)logk’=0.955
[实施例79]
[式129]
(化合物I-79)logk’=0.818
[实施例80]
[式130]
(化合物I-80)logk’=0.852
[实施例81]
[式131]
(化合物I-81)logk’=0.813
[实施例82]
[式132]
(化合物I-82)logk’=0.682
[实施例83]
[式133]
(化合物I-83)logk’=0.87
[实施例84]
[式134]
在-11℃下经20分钟往化合物II-11(3-(二甲基氨基)丙烯酸乙酯,6.9g)在甲苯(100ml)中的溶液中滴加无水三氟乙酸(6.7ml),随后将反应混合物在室温下搅拌4小时。在反应终止后,将二氯甲烷和H2O加入该混合物中并将整个混合物搅拌20分钟,随后分离。水层用二氯甲烷萃取。合并有机层,经硫酸镁干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物II-12(10.1g)。
往化合物II-12(10.1g)在乙腈(100ml)中的溶液中滴加80%肼/乙醇(3.72ml),将反应混合物在50℃下搅拌1小时。在反应终止后,除去溶剂并将H2O加入残余物中,用二氯甲烷萃取。有机层经硫酸镁干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物II-13(8.36g)。
往化合物II-13(7.82g)在乙酸乙酯(156ml)中的溶液中加入TEMPO(242mg)、溴化钾(738mg)、固体NaHCO3(6.51g)和H2O(15.6ml)。在-7℃下经8分钟将5%NaClO水溶液(48.5ml)滴加至得到的混合物中,随后在同一温度下将反应混合物搅拌1小时。在证实生成了醛后,将盐(14.62g)和三乙胺(5.2ml)加至该混合物中,随后将整个混合物在室温下搅拌30分钟。在反应终止后,将H2O加入反应混合物中,随后用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸镁干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物II-14(9.2g)。
往化合物II-14(9.2g)在四氢呋喃(92ml)中的溶液中加入碘甲烷(1.9ml),将得到的溶液冷却至-30℃。将乙醇钠(1.9g)加入该溶液中,随后反应混合物在-25℃下搅拌2小时。在反应终止后,反应混合物用1NHCl水溶液酸化并用乙酸乙酯萃取。有机层依次用10%Na2S2O3水溶液和盐水洗涤,经硫酸镁干燥。除去溶剂,得到化合物II-15(9.4g)。得到的产物无需进一步纯化用于下一反应。
在0℃下往化合物II-15(9.4g)在甲酸(14.1ml)中的溶液中加入H2SO4(1.41ml)。在0℃下搅拌1小时后,将反应混合物在室温下搅拌1小时。在反应终止后,将反应混合物倾入冰冷却的水中并用乙酸乙酯萃取。有机层用盐水洗涤并除去溶剂。将NaHCO3水溶液加至残余物中,该混合物用二异丙基醚洗涤。有机层用NaHCO3水溶液萃取并与水层合并。整个混合物用HCl水溶液酸化并用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸镁干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物II-16(7.04g)。
往化合物II-16(1.5g)在甲苯(7.5ml)中的溶液中加入三乙胺(718μl)和二苯基磷酰基叠氮化物(1.06ml),随后将反应混合物在80℃下搅拌3小时。在证实原料消失后,在0℃下将甲醇(285μl)加入混合物中,将整个混合物在80℃下搅拌1小时。在反应终止后,将2NNaOH水溶液加至混合物中并用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸镁干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物II-17(1.13g)。
往化合物II-17(1.13g)在甲醇(4.5ml)-H2O(2.3ml)中的溶液中加入4NLiOH水溶液(1.62ml),随后将反应混合物在室温下搅拌1.5小时。在反应终止后,混合物用2NHCl水溶液酸化并用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸镁干燥并浓缩。用乙酸乙酯-己烷结晶,得到化合物II-18(677mg)。
往化合物II-18(100mg)在二甲基甲酰胺(1.5ml)中的溶液中加入羟基金刚烷胺·盐酸盐(76mg)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺·盐酸盐(78mg)、1-羟基苯并三唑(12.6mg)和三乙胺(108μl),随后将反应混合物在室温下搅拌6小时。在反应终止后,该混合物用2NHCl水溶液酸化并用乙酸乙酯萃取。有机层依次用饱和NaHCO3水溶液和盐水洗涤,经硫酸钠干燥。残余物经硅胶柱层析纯化,得到化合物I-84(139mg)。
(化合物I-84)NMR(d6-DMSO);δ(ppm)1.28-1.35(m,2H),1.40(s,6H),1.58-2.03(m,11H),3.50(s,3H),3.87-3.92(m,1H),4.43(s,1H),6.57(d,J=13.6Hz,1H),6.88(d,J=13.6Hz,1H),7.35(s,1H),7.95(s,1H),8.28(d,J=6.8Hz,1H)
在-30℃下往化合物I-84(117mg)在四氢呋喃(4.7ml)中的溶液中加入氯磺酰基异氰酸酯(33μl),随后将得到的溶液在-30℃下搅拌2小时。将固体NaHCO3(104mg)和H2O(157μl)加入该溶液中并将整个混合物在室温下搅拌2小时。在反应终止后,将H2O加入该混合物中并用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸钠干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物I-85(116mg)。
(化合物I-85)NMR(d6-DMSO);δ(ppm)1.40(s,8H),1.88-2.13(m,11H),3.50(s,3H),3.94-3.99(m,1H),6.05-6.35(s,2H),6.58(d,J=13.6Hz,1H),6.88(d,J=13.6Hz,1H),7.35(s,1H),7.96(s,1H),8.33(d,J=6.8Hz,1H)
以类似的方法合成如下所示的各化合物。
[实施例85]
[式135]
(化合物I-86)NMR(d6-DMSO);δ(ppm)1.40(s,8H),1.72-2.03(m,14H),3.50(s,3H),3.91-3.97(m,1H),6.58(d,J=13.6Hz,1H),6.88(d,J=13.6Hz,1H),7.31-7.39(m,2H),7.95(s,1H),8.33(d,J=7.2Hz,1H)
[实施例86]
[式136]
往化合物II-16(1.5g)在甲苯(7.5ml)中的溶液中加入三乙胺(718μl)、二苯基磷酰基叠氮化物(1.06ml),随后将反应混合物在80℃下搅拌30分钟。在证实原料消失后,在0℃下将硫酸(374μl)加入该化合物中,随后将整个混合物在80℃下搅拌1小时。在反应终止后,用2NNaOH水溶液将该混合物碱化,用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸镁干燥并浓缩。得到的产物无需进一步纯化用于下一反应。
按照上述方法,将得到的残余物溶解于二氯甲烷(14ml),将三乙胺(1.74ml)和乙酸酐(0.59ml)加至得到的溶液中。将反应混合物在室温下搅拌3小时。在反应终止后,往该混合物中加入1NHCl水溶液并用乙酸乙酯萃取。有机层依次用饱和NaHCO3水溶液和盐水洗涤,经硫酸镁干燥并浓缩。得到的产物无需进一步纯化用于下一反应。
按照上述方法,将得到的残余物溶解于甲醇(5.5ml)-H2O(2.8ml)中,将4NLiOH(2.08ml)水溶液加至得到的溶液中。将反应混合物在室温下搅拌1.5小时。在反应终止后,整个混合物用2NHCl水溶液酸化并用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸镁干燥并浓缩。用氯仿结晶,得到化合物II-21(1.09g)。
按照上述实施例由化合物II-21合成下述化合物。
[实施例87]
[式137]
(化合物I-87)NMR(d6-DMSO);δ(ppm)1.28-1.35(m,2H),1.42(s,6H),1.58-2.03(m,14H),3.87-3.91(m,1H),4.43(s,1H),6.64(d,J=13.6Hz,1H),6.86(d,J=13.6Hz,1H),7.85(s,1H),7.94(s,1H),8.27(d,J=7.2Hz,1H)
[实施例88]
[式138]
(化合物I-88)NMR(d6-DMSO);δ(ppm)1.37-1.43(m,8H),1.78-2.11(m,14H),3.93-3.98(m,1H),6.05-6.35(s,2H),6.64(d,J=13.6Hz,1H),6.86(d,J=13.6Hz,1H),7.85(s,1H),7.95(s,1H),8.32(d,J=6.0Hz,1H)
[实施例89]
[式139]
(化合物I-89)NMR(d6-DMSO);δ(ppm)1.34-1.45(m,8H),1.72-2.02(m,17H),3.90-3.97(m,1H),6.64(d,J=13.6Hz,1H),6.86(d,J=13.6Hz,1H),7.37(s,1H),7.85(s,1H),7.95(s,1H),8.31(d,J=7.2Hz,1H)
[实施例90]
[式140]
在冰冷却下往化合物II-16(1g)在四氢呋喃(10ml)中的溶液中加入二甲基甲酰胺(24μl)和草酰氯(396μl),随后将得到的混合物在室温下搅拌1小时。在冰冷却下将得到的酰氯滴加至40%甲胺水溶液(2.42g)中,将反应混合物在室温下搅拌3小时。在反应终止后,往该混合物中加入H2O,用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸镁干燥并浓缩。得到的产物无需进一步纯化用于下一反应。
按照上述方法,将得到的残余物溶解于甲醇(4.1ml)-H2O(2ml)中,将4NLiOH(1.54ml)水溶液加至得到的溶液。将反应混合物在室温下搅拌30分钟。在反应终止后,整个混合物用水稀释,用乙酸乙酯洗涤。水层用HCl水溶液酸化,用乙酸乙酯萃取,经硫酸镁干燥。除去溶剂,得到化合物II-23(929mg)。
按照上述实施例由化合物II-23合成下述化合物。
[实施例91]
[式141]
(化合物I-90)NMR(d6-DMSO);δ(ppm)1.25-1.37(m,8H),1.57-2.06(m,11H),2.58(d,J=4.4Hz,3H),3.85-3.91(m,1H),4.44(s,1H),6.62(d,J=13.6Hz,1H),6.87(d,J=13.6Hz,1H),7.61(d,J=4.4Hz,1H),7.97(s,1H),8.27(d,J=6.8Hz,1H)
[实施例92]
[式142]
(化合物I-91)NMR(d6-DMSO);δ(ppm)1.30(s,6H),1.35-1.46(m,2H),1.87-2.13(m,11H),2.55-2.61(m,3H),3.92-3.98(m,1H),6.00-6.35(s,2H),6.62(d,J=14.0Hz,1H),6.88(d,J=14.0Hz,1H),7.61(s,1H),7.98(s,1H),8.32(d,J=6.4Hz,1H)
[实施例93]
[式143]
(化合物I-92)NMR(d6-DMSO);δ(ppm)1.30(s,6H),1.34-1.43(m,2H),1.80-2.21(m,11H),2.58(d,J=4.4Hz,3H),3.91-3.98(m,1H),6.62(d,J=13.6Hz,1H),6.88(d,J=13.6Hz,1H),7.58-7.66(m,1H),7.99(s,1H),8.33(d,J=6.4Hz,1H)
[实施例94]
[式144]
(化合物I-93)NMR(d6-DMSO);δ(ppm)1.30(s,6H),1.35-1.43(m,2H),1.72-2.03(m,14H),2.58(d,J=4.4Hz,3H),3.91-3.97(m,1H),6.62(d,J=13.6Hz,1H),6.88(d,J=13.6Hz,1H),7.37(s,1H),7.61(d,J=4.0Hz,1H),7.97(s,1H),8.31(d,J=7.2Hz,1H)
[实施例95]
[式145]
(化合物I-94)NMR(d6-DMSO);δ(ppm)1.00(t,J=7.2Hz,3H),1.23-1.35(m,8H),1.55-2.05(m,11H),3.04-3.12(m,2H),3.87-4.02(m,1H),4.44(s,1H),6.62(d,J=13.6Hz,1H),6.87(d,J=13.6Hz,1H),7.62-7.69(m,1H),7.97(s,1H),8.28(d,J=7.2Hz,1H)
[实施例96]
[式146]
(化合物I-95)NMR(d6-DMSO);δ(ppm)1.00(t,J=6.8Hz,3H),1.30(s,6H),1.36-1.44(m,2H),1.87-2.13(m,11H),3.04-3.12(m,2H),3.93-3.99(m,1H),6.00-6.40(s,2H),6.63(d,J=13.6Hz,1H),6.87(d,J=13.6Hz,1H),7.62-7.69(m,1H),7.98(s,1H),8.33(d,J=6.8Hz,1H)
[实施例97]
[式147]
(化合物I-96)NMR(d6-DMSO);δ(ppm)1.00(t,J=7.2Hz,3H),1.30(s,6H),1.35-1.43(m,2H),1.72-2.03(m,14H),3.03-3.13(m,2H),3.90-3.96(m,1H),6.62(d,J=13.6Hz,1H),6.87(d,J=13.6Hz,1H),7.37(s,1H),7.62-7.69(m,1H),7.97(s,1H),8.32(d,J=6.8Hz,1H)
[实施例98]
[式148]
经10分钟往化合物II-24(4-甲氧基-3-氧代丁酸甲酯,9.87g)在甲苯(99ml)中的溶液中滴加1,1-二甲氧基-N,N-二甲基甲胺(26.9ml),随后将反应混合物回流2小时。在反应终止后,将混合物浓缩。得到的产物用于下一反应。
按照上述程序,将得到的残余物溶解于乙腈溶液(136ml),往得到的溶液中加入80%肼乙醇(6.58g)。反应混合物在50℃下搅拌1小时。在反应终止后,将混合物浓缩。往残余物中加入1NHCl水溶液,用乙酸乙酯萃取。有机层依次用饱和NaHCO3水溶液和盐水洗涤,经硫酸镁干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物II-26(9.74g)。
按照上述实施例由化合物II-26合成下述化合物。
[实施例99]
[式149]
(化合物I-97)NMR(d6-DMSO);δ(ppm)1.28-1.43(m,8H),1.58-2.09(m,11H),3.26(s,3H),3.50(s,3H),3.86-3.92(m,1H),4.41(s,1H),4.82(s,2H),6.48(d,J=14.0Hz,1H),6.99(d,J=14.0Hz,1H),7.24(s,1H),7.59(d,J=6.4Hz,1H),8.14(s,1H)
[实施例100]
[式150]
(化合物I-98)NMR(d6-DMSO);δ(ppm)1.35-1.48(m,8H),1.90-2.18(m,11H),3.26(s,3H),3.50(s,3H),3.95-4.01(m,1H),4.83(s,2H),6.00-6.35(s,2H),6.49(d,J=14.0Hz,1H),7.00(d,J=14.0Hz,1H),7.26(s,1H),7.65(d,J=6.8Hz,1H),8.15(s,1H)
[实施例101]
[式151]
(化合物I-99)NMR(d6-DMSO);δ(ppm)1.30-1.47(m,8H),1.56-2.09(m,14H),3.26(s,3H),3.88-3.95(m,1H),4.41(s,1H),4.82(s,2H),6.55(d,J=14.0Hz,1H),6.98(d,J=14.0Hz,1H),7.59(d,J=6.4Hz,1H),7.77(s,1H),8.13(s,1H)
[实施例102]
[式152]
(化合物I-100)NMR(d6-DMSO);δ(ppm)1.35-1.56(m,8H),1.77-2.05(m,14H),3.01(d,J=5.6Hz,2H),3.27(s,3H),3.88-3.95(m,1H),4.36(t,J=5.6Hz,1H),4.83(s,2H),6.55(d,J=14.0Hz,1H),6.98(d,J=14.0Hz,1H),7.63(d,J=6.8Hz,1H),7.78(s,1H),8.14(s,1H)
[实施例103]
[式153]
(化合物I-101)NMR(d6-DMSO);δ(ppm)1.35-1.56(m,8H),1.77-2.05(m,14H),3.01(d,J=5.6Hz,2H),3.27(s,3H),3.88-3.95(m,1H),4.36(t,J=5.6Hz,1H),4.83(s,2H),6.55(d,J=14.0Hz,1H),6.98(d,J=14.0Hz,1H),7.63(d,J=6.8Hz,1H),7.78(s,1H),8.14(s,1H)
采用类似的方法合成下述化合物。
[实施例104]
[式154]
(化合物I-102)NMR(DMSO-d6);δ(ppm)1.00(t,J=7.1Hz,3H),1.27-2.03(m,28H),3.05-3.11(m,2H),3.70-3.77(m,1H),3.93(brs,1H),6.42(d,J=13.9Hz,1H),6.94(d.J=13.9Hz,1H),7.36(s,1H),7.56-7.61(m,2H),7.93(s,1H)
[实施例105]
[式155]
(化合物I-103)NMR(DMSO-d6);δ(ppm)1.27(d,J=7.3Hz,6H),1.32-2.05(m,19H),3.50(s,3H),3.76-3.83(m,1H),3.88(brs,1H),4.41(s,1H),6.38(d,J=13.9Hz,1H),6.96(d,J=13.9Hz,1H),7.27(s,1H),7.56(d,J=6.3Hz,1H),7.93(s,1H)
[实施例106]
[式156]
(化合物I-104)NMR(DMSO-d6);δ(ppm)1.27(d,J=7.1Hz,6H),1.38-2.13(m,19H),3.50(s,3H),3.76-3.83(m,1H),3.95(brs,1H),6.18(brs,2H),6.38(d,J=13.9Hz,1H),6.96(d,J=13.9Hz,1H),7.26(s,1H),7.62(d,J=6.1Hz,1H),7.94(s,1H)
[实施例107]
[式157]
(化合物I-105)NMR(DMSO-d6);δ(ppm)1.28(d,J=71Hz,6H),1.36-2.05(m,19H),3.01(d,J=5.6Hz,2H),3.50(s,3H),3.77-3.84(m,1H),3.88(brs,1H),4.35(t,J=5.6Hz,1H),6.38(d,J=13.6Hz,1H),6.96(d,J=13.6Hz,1H),7.25(s,1H),7.57(d,J=6.6Hz,2H),7.94(s,1H)
[实施例108]
[式158]
(化合物I-106)NMR(DMSO-d6);δ(ppm)1.28(d,J=7.1Hz,6H),1.38-2.06(m,19H),3.50(s,3H),3.56(s,2H),3.77-3.84(m,1H),3.90(brs,1H),6.38(d,J=13.6Hz,1H),6.40(brs,2H),6.96(d,J=13.6Hz,1H),7.25(s,1H),7.61(d,J=6.3Hz,1H),7.94(s,1H)
[实施例109]
[式159]
(化合物I-107)NMR(DMSO-d6);δ(ppm)1.27(d,J=7.1Hz,6H),1.38-2.03(m,22H),3.49(s,3H),3.76-3.84(m,1H),3.92(brs,1H),6.38(d,J=13.9Hz,1H),6.96(d,J=13.9Hz,1H),7.27(s,1H),7.36(s,1H),7.60(d,J=6.6Hz,1H),7.94(s,1H)
[实施例110]
[式160]
(化合物I-108)NMR(DMSO-d6);δ(ppm)1.26-2.08(m,28H),3.74-3.81(m,1H),3.88(brs,1H),4.41(s,1H),6.44(d,J=13.6Hz,1H),6.94(d,J=13.6Hz,1H),7.56(d,J=6.3Hz,1H),7.77(s,1H),7.93(s,1H)
[实施例111]
[式161]
(化合物I-109)NMR(DMSO-d6);δ(ppm)1.27(d,J=7.1Hz,6H),1.38-2.12(m,22H),3.74-3.81(m,1H),3.94(brs,1H),6.19(brs,2H),6.44(d,J=13.9Hz,1H),6.94(d,J=13.9Hz,1H),7.61(d,J=5.8Hz,1H),7.77(s,1H),7.93(s,1H)
[实施例112]
[式162]
(化合物I-110)NMR(DMSO-d6);δ(ppm)1.27(d,J=7.1Hz,6H),1.35-2.05(m,22H),3.00(d,J=5.3Hz,2H),3.75-3.82(m,1H),3.87(brs,1H),4.36(t,J=5.3Hz,1H),6.44(d,J=13.9Hz,1H),6.94(d,J=13.9Hz,1H),7.58(d,J=6.3Hz,1H),7.78(s,1H),7.93(s,1H)
[实施例113]
[式163]
(化合物I-111)NMR(DMSO-d6);δ(ppm)1.27(d,J=7.1Hz,6H),1.37-2.08(m,22H),3.56(s,2H),3.75-3.83(m,1H),3.89(brs,1H),6.42(brs,2H),6.44(d,J=13.9Hz,1H),6.94(d,J=13.9Hz,1H),7.61(d,J=7.1Hz,1H),7.78(s,1H),7.94(s,1H)
[实施例114]
[式164]
(化合物I-112)NMR(DMSO-d6);δ(ppm)1.27(d,J=7.1Hz,6H),1.38-2.02(m,25H),3.75-3.82(m,1H),3.93(brs,1H),6.44(d,J=13.6Hz,1H),6.95(d,J=13.6Hz,1H),7.36(s,1H),7.60(d,J=6.3Hz,1H),7.78(s,1H),7.93(s,1H)
[实施例115]
[式165]
(化合物I-113)NMR(DMSO-d6);δ(ppm)0.84(d,J=6.6Hz,6H),1.00(t,J=7.1Hz,3H),1.29-2.04(m,20H),2.95(d,J=7.1Hz,2H),3.05-3.11(m,2H),3.90(brs,1H),4.40(s,1H),6.46(d,J=14.2Hz,1H),6.88(d,J=13.9Hz,1H),7.41(d,J=6.6Hz,1H),7.54(brs,1H),8.15(s,1H)
[实施例116]
[式166]
(化合物I-114)NMR(DMSO-d6);δ(ppm)0.85(d,J=6.6Hz,6H),1.00(t,J=7.2Hz,3H),1.30(s,6H),1.38-2.10(m,14H),2.95(d,J=7.1Hz,2H),3.04-3.11(m,2H),3.97(brs,1H),6.17(brs,2H),6.47(d,J=13.9Hz,1H),6.88(d,J=13.9Hz,1H),7.46(d,J=6.6Hz,1H),7.54(brs,1H),8.15(s,1H)
[实施例117]
[式167]
(化合物I-115)NMR(DMSO-d6);δ(ppm)0.84(d,J=6.6Hz,6H),1.32-2.04(m,20H),2.92(d,J=7.3Hz,2H),3.50(s,3H),3.90(brs,1H),4.41(s,1H),6.43(d,J=13.9Hz,1H),6.88(d,J=13.9Hz,1H),7.24(s,1H),7.42(d,J=6.3Hz,1H),8.14(s,1H)
[实施例118]
[式168]
(化合物I-116)NMR(DMSO-d6);δ(ppm)0.84(d,J=6.6Hz,6H),1.41-2.10(m,20H),2.93(d,J=6.8Hz,2H),3.50(s,3H),3.96(brs,1H),6.17(brs,2H),6.43(d,J=13.9Hz,1H),6.89(d,J=13.9Hz,1H),7.23(s,1H),7.46(d,J=6.3Hz,1H),8.14(s,1H)
[实施例119]
[式169]
(化合物I-117)NMR(DMSO-d6);δ(ppm)0.84(d,J=6.6Hz,6H),1.37-2.20(m,20H),2.93(d,J=6.8Hz,2H),3.50(s,3H),3.96(brs,1H),6.44(d,J=14.4Hz,1H),6.89(d,J=14.4Hz,1H),7.23(s,1H),7.48(d,J=6.3Hz,1H),8.14(s,1H)
[实施例120]
[式170]
(化合物I-118)NMR(DMSO-d6);δ(ppm)0.84(d,J=6.6Hz,6H),1.41-2.01(m,23H),2.93(d,J=7.1Hz,2H),3.50(s,3H),3.94(brs,1H),6.43(d,J=13.9Hz,1H),6.89(d,J=13.9Hz,1H),7.24(s,1H),7.36(s,1H),7.45(d,J=6.8Hz,1H),8.14(s,1H)
[实施例121]
[式171]
(化合物I-119)NMR(CDCl3);δ(ppm)0.95(d,J=6.6Hz,6H),1.55-2.21(m,23H),2.94(d,J=7.1Hz,2H),4.15(brs,1H),5.47(s,1H),5.89(d,J=7.8Hz,1H),6.50(d,J=13.9Hz,1H),6.88(d,J=13.9Hz,1H),7.67(s,1H)
[实施例122]
[式172]
(化合物I-120)NMR(DMSO-d6);δ(ppm)0.84(d,J=6.6Hz,6H),1.38-2.10(m,23H),2.93(d,J=6.8Hz,2H),3.96(brs,1H),6.19(brs,2H),6.50(d,J=13.6Hz,1H),6.87(d,J=13.6Hz,1H),7.46(d,J=6.3Hz,1H),7.76(s,1H),8.14(s,1H)
[实施例123]
[式173]
(化合物I-121)NMR(DMSO-d6);δ(ppm)0.84(d,J=6.6Hz,6H),1.36-2.05(m,23H),2.93(d,J=7.3Hz,2H),3.01(d,J=5.1Hz,2H),3.89(brs,1H),4.35(t,J=5.1Hz,1H),6.49(d,J=13.9Hz,1H),6.87(d,J=13.9Hz,1H),7.43(d,J=6.8Hz,1H),7.75(s,1H),8.14(s,1H)
[实施例124]
[式174]
(化合物I-122)NMR(DMSO-d6);δ(ppm)0.84(d,J=6.6Hz,6H),1.37-2.07(m,23H),2.93(d,J=7.1Hz,2H),3.56(s,2H),3.91(brs,1H),6.42(brs,2H),6.49(d,J=14.2Hz,1H),6.87(d,J=14.2Hz,1H),7.47(d,J=6.8Hz,1H),7.76(s,1H),8.14(s,1H)
[实施例125]
[式175]
(化合物I-123)NMR(CDCl3);δ(ppm)0.95(d,J=6.6Hz,6H),1.55-2.29(m,23H),2.93(d,J=7.1Hz,2H),4.18(brs,1H),5.61(s,1H),5.91(d,J=7.3Hz,1H),6.51(d,J=13.9Hz,1H),6.88(d,J=13.9Hz,1H),7.68(s,1H)
[实施例126]
[式176]
(化合物I-124)NMR(DMSO-d6);δ(ppm)0.84(d,J=6.6Hz,6H),1.32-2.04(m,20H),2.93(d,J=7.1Hz,2H),3.31(s,3H),3.76(s,2H),3.90(brs,1H),4.40(s,1H),6.51(d,J=14.2Hz,1H),6.91(d,J=14.2Hz,1H),7.36(s,1H),7.41(d,J=6.3Hz,1H),8.14(s,1H)
[实施例127]
[式177]
(化合物I-125)NMR(DMSO-d6);δ(ppm)0.84(d,J=6.6Hz,6H),1.38-2.10(m,20H),2.93(d,J=6.6Hz,2H),3.32(s,3H),3.76(s,2H),3.96(s,1H),6.19(brs,2H),6.51(d,J=14.4Hz,1H),6.91(d,J=14.4Hz,1H),7.36(s,1H),7.46(d,J=6.1Hz,1H),8.14(s,1H)
[实施例128]
[式178]
(化合物I-126)NMR(d6-DMSO);δ(ppm)1.14-1.89(m,19H),3.43(s,3H),3.76-3.81(m,1H),4.37(s,1H),6.39(d,J=14.0Hz,1H),6.46(d,J=14.0Hz,1H),6.69(d,J=6.4Hz,1H),7.15(s,1H),7.40-7.60(m,5H),8.08(s,1H)
[实施例129]
[式179]
(化合物I-127)NMR(d6-DMSO);δ(ppm)1.20-1.49(m,10H),1.85-2.08(s,9H),3.44(s,3H),3.82-3.89(m,1H),6.00-6.30(s,2H),6.39(d,J=14.0Hz,1H),6.47(d,J=14.0Hz,1H),6.79(d,J=6.8Hz,1H),7.15(s,1H),7.39-7.59(m,5H),8.10(s,1H)
[实施例130]
[式180]
(化合物I-128)NMR(d6-DMSO);δ(ppm)1.20-1.50(m,10H),1.70-2.04(m,9H),3.43(s,3H),3.81-3.88(m,1H),6.39(d,J=14.0Hz,1H),6.47(d,J=14.0Hz,1H),6.84(d,J=6.4Hz,1H),7.15(s,1H),7.39-7.59(m,5H),8.09(s,1H)
[实施例131]
[式181]
(化合物I-129)NMR(d6-DMSO);δ(ppm)1.15-1.89(m,22H),3.76-3.81(m,1H),4.37(s,1H),6.44(s,2H),6.71(d,J=6.4Hz,1H),7.40-7.69(m,6H),8.08(s,1H)
[实施例132]
[式182]
(化合物I-130)NMR(d6-DMSO);δ(ppm)1.20-1.50(m,10H),1.70(s,3H),1.85-2.07(m,9H),3.81-3.89(m,1H),6.00-6.30(s,2H),6.45(s,2H),6.82(d,J=6.8Hz,1H),7.40-7.70(m,6H),8.10(s,1H)
[实施例133]
[式183]
(化合物I-131)NMR(d6-DMSO);δ(ppm)1.19-1.80(m,22H),2.95(d,J=4.8Hz,2H),3.75-3.80(m,1H),4.34(t,J=5.2Hz,1H),6.44(s,2H),6.70(d,J=6.4Hz,1H),7.42-7.71(m,6H),8.09(s,1H)
[实施例134]
[式184]
(化合物I-132)NMR(d6-DMSO);δ(ppm)1.21-1.82(m,22H),3.51(s,2H),3.77-3.82(m,1H),6.20-6.50(m,4H),6.76(d,J=6.8Hz,1H),7.42-7.69(m,6H),8.09(s,1H)
[实施例135]
[式185]
往化合物II-27(乙氧基亚甲基氰基乙酸乙酯,50.75g)在乙醇(100ml)中的溶液中滴加80%肼乙醇(28.54g),随后反应混合物在125℃下搅拌3.5小时。在反应终止后,将混合物浓缩。残余物经硅胶柱层析纯化,得到化合物II-28(54.73g)。
在-11℃下往化合物II-28(32.42g)中加入48%氢溴酸水溶液(130ml),随后经5分钟往得到的混合物中滴加亚硝酸钠(16.91g)-H2O(33.8ml)。将该混合物在-3℃下搅拌2小时,得到重氮盐。按照上述程序,在室温下将得到的重氮盐滴加到CuBr-HBr溶液中,随后在50℃下将该混合物搅拌1小时40分钟。在反应终止后,往混合物中加入H2O,用氯仿萃取;有机层用盐水洗涤并经硫酸钠干燥。除去溶剂,得到化合物II-29(33.54g)。
*制备CuBr-HBr溶液:往H2O(270ml)中加入五水合硫酸铜(52.67g)和溴化钠(51.45g)。在60℃下经5分钟往得到的混合物中滴加在H2O(33ml)中的亚硫酸钠(21.43g),随后将该混合物在相同温度下搅拌10分钟。将混合物冷却至室温,1小时后除去上清液,得到CuBr白色沉淀。得到的白色沉淀用H2O(100ml)洗涤两次。往该白色沉淀中加入48%氢溴酸水溶液(130ml),随后将得到的混合物用于反应。
按照以上实施例,由化合物II-29合成化合物II-30。以下各化合物使用化合物II-30作为常见中间体合成。
[实施例136]
[式186]
在冰冷却下往吡唑(378mg)在二甲基甲酰胺(2ml)中的溶液中加入60%氢化钠(211mg),随后在40℃下将得到的混合物搅拌1小时。往混合物中滴加化合物II-30(1g)在二甲基甲酰胺(6ml)中的溶液,随后将整个混合物在80℃下搅拌35分钟。在反应终止后,将反应混合物倾入2NHCl水溶液,用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸钠干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物II-31(416mg)。
按照以上实施例,由化合物II-31合成化合物I-133。
(化合物I-133)NMR(d6-DMSO);δ(ppm)1.29(s,6H),1.30-2.00(m,13H),3.45(s,3H),3.80-3.87(m,1H),4.43(s,1H),6.36(s,2H),6.66(t,J=2.1Hz,1H),7.23(s,1H),7.37(d,J=7.2Hz,1H),7.98(d,J=2.1Hz,1H),8.19(s,1H),8.23(d,J=2.1Hz,1H)
采用类似的方法合成下述化合物。
[实施例137]
[式187]
(化合物I-134)NMR(CDCl3);δ(ppm)1.10(t,J=7.2Hz,3H),1.30(s,6H),1.40-2.09(m,13H),3.19-3.28(m,2H),4.05-4.10(m,1H),5.58(br,1H),6.39(d,J=14.1Hz,1H),6.46(d,J=14.1Hz,1H),6.67(t,J=2.1Hz,1H),6.80(d,J=7.5Hz,1H),7.77(d,J=2.1Hz,1H),7.94(d,J=2.1Hz,1H),8.12(s,1H)
[实施例138]
[式188]
(化合物I-135)NMR(CDCl3);δ(ppm)1.10(t,J=7.5Hz,3H),1.30(s,6H),1.45-2.23(m,13H),3.20-3.29(m,2H),4.09-4.17(m,1H),4.41(br,2H),5.58(br,1H),6.39(d,J=14.1Hz,1H),6.46(d,J=14.1Hz,1H),6.67(t,J=2.1Hz,1H),6.82(d,J=7.2Hz,1H),7.77(d,J=2.1Hz,1H),7.94(d,J=2.1Hz,1H),8.12(s,1H)
[实施例139]
[式189]
(化合物I-136)NMR(CDCl3);δ(ppm)1.10(t,J=7.2Hz,3H),1.30(s,6H),1.46-2.17(m,16H),3.19-3.29(m,2H),4.08-4.15(m,1H),5.13(br,1H),5.59(br,1H),6.39(d,J=14.1Hz,1H),6.45(d,J=14.1Hz,1H),6.67(t,J=2.1Hz,1H),6.83(d,J=7.2Hz,1H),7.77(d,J=2.1Hz,1H),7.94(d,J=2.1Hz,1H),8.12(s,1H)
[实施例140]
[式190]
(化合物I-137)NMR(CDCl3);δ(ppm)1.42(s,6H),1.48-2.23(m,13H),3.61(s,3H),4.11-4.17(m,1H),4.41(br,2H),4.77(s,1H),6.31(d,J=14.1Hz,1H),6.44(d,J=14.1Hz,1H),6.63(t,J=2.1Hz,1H),7.36(br,1H),7.85(d,J=2.1Hz,1H),7.91(d,J=2.1Hz,1H),8.12(s,1H)
[实施例141]
[式191]
(化合物I-138)NMR(CDCl3);δ(ppm)1.42(s,6H),1.46-1.96(m,13H),3.22(d,J=3.6Hz,2H),3.61(s,3H),4.05-4.08(m,1H),4.77(s,1H),6.31(d,J=14.1Hz,1H),6.44(d,J=14.1Hz,1H),6.63(t,J=2.1Hz,1H),7.36(br,1H),7.85(d,J=2.1Hz,1H),7.91(d,J=2.1Hz,1H),8.13(s,1H)
[实施例142]
[式192]
(化合物I-139)NMR(CDCl3);δ(ppm)1.42(s,6H),1.45-1.96(m,13H),3.61(s,3H),3.69(s,2H),4.03-4.10(m,1H),4.58(br,2H),4.76(s,1H),6.31(d,J=14.1Hz,1H),6.44(d,J=14.1Hz,1H),6.63(t,J=2.1Hz,1H),7.37(br,1H),7.85(d,J=2.1Hz,1H),7.91(d,J=2.1Hz,1H),8.12(s,1H)
[实施例143]
[式193]
(化合物I-140)NMR(d6-DMSO);δ(ppm)1.31(s,6H),1.54-1.98(m,16H),3.80-3.87(m,1H),4.43(s,1H),6.35(d,J=14.1Hz,1H),6.43(d,J=14.1Hz,1H),6.67(t,J=2.4Hz,1H),7.38(d,J=6.9Hz,1H),7.75(s,1H),7.98(d,J=2.4Hz,1H),8.19(s,1H),8.23(d,J=2.4Hz,1H)
[实施例144]
[式194]
(化合物I-141)NMR(CDCl3);δ(ppm)1.45(s,6H),1.48-2.23(m,16H),4.10-4.17(m,1H),4.41(br,2H),5.42(s,1H),6.31(d,J=14.1Hz),6.42(d,J=14.1Hz,1H),6.64(t,J=2.4Hz,1H),7.45(d,J=7.8Hz,),7.90(d,J=2.4Hz,2H),8.12(s,1H)
[实施例145]
[式195]
(化合物I-142)NMR(CDCl3);δ(ppm)1.45(s,6H),1.51-2.20(m,16H),4.08-4.14(m,1H),5.41(br,1H),6.32(d,J=13.8Hz,1H),6.43(d,J=13.8Hz,1H),6.65(t,J=2.1Hz,1H),7.48(d,J=7.2Hz,1H),7.90(d,J=2.1Hz,1H),7.91(d,J=2.1Hz,1H),8.13(s,1H)
[实施例146]
[式196]
(化合物I-143)NMR(CDCl3);δ(ppm)1.45(s,6H),1.51-2.16(m,19H),4.10-4.16(m,1H),5.17(s,1H),5.46(s,1H),6.31(d,J=14.1Hz,1H),6.43(d,J=14.1Hz,1H),6.64(t,J=2.1Hz,1H),7.48(d,J=7.8Hz,1H),7.90(d,J=2.1Hz,2H),8.12(s,1H)
[实施例147]
[式197]
往化合物II-30(300mg)中加入甲氧基乙基甲胺(2ml),随后在80℃下将反应混合物搅拌16小时。在反应终止后,往反应混合物中加入2NHCl水溶液,用乙酸乙酯萃取。有机层用盐水洗涤并浓缩。残余物经硅胶柱层析纯化,得到化合物II-32(257mg)。
按照以上实施例,由化合物II-32合成化合物I-144。
(化合物I-144)NMR(CDCl3);δ(ppm)1.52(s,6H),1.54-2.25(m,13H),2.94(s,3H),3.25(s,3H),3.32(t,J=4.8Hz,2H),3.41(t,J=4.8Hz,2H),3.62(s,3H),4.12-4.19(m,1H),4.84(s,1H),6.38(d,J=14.1Hz,1H),6.93(d,J=14.1Hz,1H),7.43(d,J=7.2Hz,1H),7.89(s,1H)
采用类似的方法合成下述化合物。
[实施例148]
[式198]
(化合物I-145)NMR(CDCl3);δ(ppm)1.11(t,J=7.2Hz,3H),1.21(d,J=6.3Hz,6H),1.40(s,6H),1.45-2.3(m,13H),3.26(m,2H),3.50(m,1H),4.14(brd,J=7.5Hz,1H),5.74(brs,1H),5.83(d,J=7.5Hz,1H),5.95(d,J=9.9Hz,1H),6.38(d,J=14.1Hz,1H),
6.84(d,J=14.1Hz,1H),7.58(s,1H)
[实施例149]
[式199]
(化合物I-146)NMR(CDCl3);δ(ppm)1.22(t,J=7.2Hz,3H),1.41(s,6H),1.57(s,6H),1.6-2.14(m,13H),3.27(m,2H),3.67(s,3H),4.19(m,1H),5.65(m,1H),5.97(d,J=7.5Hz,1H),6.37(d,J=14.7Hz,1H),6.93(d,J=14.1Hz,1H),7.82(s,1H),8.02(s,1H)
[实施例150]
[式200]
(化合物I-147)NMR(CDCl3);δ(ppm)111(t,J=7.2Hz,3H),1.40(s,6H),1.81(d,J=6.6Hz,6H),1.93(s,6H),1.61-2.3(m,13H),3.26(m,2H),3.49(m,1H),4.17(brd,J=7.2Hz,1H),5.16(s,1H),5.71(s,1H),5.86(d,J=7.5Hz,1H),5.94(d,J=10.2Hz,1H),6.38(d,J=14.1Hz,1H),6.84(d,J=13.8Hz,1H),7.57(s,1H)
[实施例151]
[式201]
(化合物I-148)NMR(DMSO-d6);δ(ppm)1.08(d,J=6.3Hz,6H),1.32-2.03(m,19H),3.42-3.49(m,4H),3.91(brs,1H),4.42(s,1H),6.04(d,J=9.1Hz,1H),6.25(d,J=13.9Hz,1H),6.75(d,J=13.9Hz,1H),7.25(s,1H),7.40(d,J=6.6Hz,1H),8.09(s,1H)
[实施例152]
[式202]
(化合物I-149)NMR(DMSO-d6);δ(ppm)1.09(d,J=6.3Hz,6H),1.38-2.10(m,19H),3.46-3.49(m,4H),3.97(brs,1H),6.04(d,J=6.4Hz,1H),6.19(brs,2H),6.25(d,J=14.4Hz,1H),6.75(d,J=14.4Hz,1H),7.25(s,1H),7.44(d,J=6.1Hz,1H),8.10(s,1H)
[实施例153]
[式203]
(化合物I-150)NMR(CDCl3);δ(ppm)1.21-1.89(d,J=6.6Hz,6H),1.38-2.19(m,13H),1.55(s,3H),1.57(s,3H),3.56(m,1H),4.13(m,1H),5.44(s,1H),5.82(m,1H),5.85(s,1H),6.32(d,J=14.1Hz,1H),6.81(d,J=14.1Hz,1H),7.55(s,1H)
[实施例154]
[式204]
(化合物I-151)NMR(CDCl3);δ(ppm)1.13(t,J=7.2Hz,3H),1.42(s,6H),1.48-2.29(m,13H),3.20(t,J=4.5Hz,4H),3.24-3.33(m,2H),3.84(t,J=4.5Hz,4H),4.15-4.21(m,1H),5.70(br,1H),6.48(d,J=7.5Hz,1H),6.49(d,J=14.4Hz,1H),7.12(d,J=14.4Hz,1H),7.76(s,1H)
[实施例155]
[式205]
(化合物I-152)NMR(CDCl3);δ(ppm)1.13(t,J=7.2Hz,3H),1.42(s,6H),1.62-2.31(m,13H),3.20(t,J=4.5Hz,4H),3.24-3.33(m,2H),3.83(t,J=4.5Hz,4H),4.20-4.27(m,1H),4.46(br,2H),5.70(br,1H),6.49(d,J=14.1Hz,1H),6.50(d,J=7.8Hz,1H),7.12(d,J=14.1Hz,1H),7.76(s,1H)
[实施例156]
[式206]
(化合物I-153)NMR(CDCl3);δ(ppm)1.53(s,6H),1.56-2.27(m,13H),3.20(t,J=4.5Hz,4H),3.64(s,3H),3.83(t,J=4.5Hz,4H),4.14-4.21(m,1H),4.84(s,1H),6.38(d,J=14.1Hz,1H),6.58(d,J=7.5Hz,1H),7.08(d,J=14.1Hz,1H),7.75(s,1H)
[实施例157]
[式207]
(化合物I-154)NMR(CDCl3);δ(ppm)1.53(s,6H),1.60-2.31(m,13H),3.20(t,J=4.5Hz,4H),3.64(s,3H),3.83(t,J=4.5Hz,4H),4.19-4.25(m,1H),4.44(br.s,2H),4.85(s,1H),6.38(d,J=14.1Hz,1H),6.60(d,J=7.8Hz,1H),7.07(d,J=14.1Hz,1H),7.75(s,1H)
[实施例158]
[式208]
(化合物I-155)NMR(CDCl3);δ(ppm)1.56(s,6H),1.55-2.4(m,13H),1.98(s,3H),3.21(m,4H),3.84(m,4H),4.17(brd,J=7.2Hz,1H),5.53(s,1H),6.39(d,J=14.1Hz,1H),6.63(d,J=7.2Hz,1H),7.07(d,J=14.1Hz,1H),7.75(s,1H)
[实施例159]
[式209]
(化合物I-156)NMR(CDCl3);δ(ppm)1.55(s,6H),1.55-2.15(m,13H),1.97(s,3H),3.21(brs,4H),3.25(s,2H),3.83(brs,4H),4.13(m,1H),5.66(s,1H),6.38(d,J=14.1Hz,1H),6.77(brd,J=7.2Hz,1H),7.06(d,J=14.1Hz,1H),7.76(s,1H)
[实施例160]
[式210]
(化合物I-157)NMR(CDCl3);δ(ppm)1.55(s,6H),16-1.85(m,8H),1.92(s,3H),1.9-2.25(m,6H),1.97(s,3H),3.19(m,4H),3.49(s,1H),3.83(m,4H),4.20(brd,J=6.6Hz,1H),5.21(brs,1H),5.52(brs,1H),6.38(d,J=14.1Hz,1H),6.67(d,J=7.5Hz,1H),7.06(d,J=14.1Hz,1H),7.75(s,1H)
[实施例161]
[式211]
(化合物I-158)NMR(CDCl3);δ(ppm)1.51(s,6H),1.58-2.23(m,13H),3.34-3.44(m,2H),3.39(s,3H),3.52(t,J=4.8Hz,2H),3.61(s,3H),4.12-4.18(m,1H),4.85(s,1H),5.96(d,J=7.5Hz,1H),6.19(t,J=6.6Hz,1H),6.30(d,J=14.1Hz,1H),6.98(d,J=14.1Hz,1H),7.57(s,1H)
[实施例162]
[式212]
(化合物I-159)NMR(DMSO-d6);δ(ppm)0.90-0.96(m,6H),1.36-2.10(m,19H),3.48(s,3H),3.97(brs,1H),4.33-4.40(m,1H),6.21(brs,2H),6.40-6.42(m,3H),6.66(d,J=13.6Hz,1H),7.24(d,J=8.1Hz,1H),7.31(s,1H),7.96(s,1H)
[实施例163]
[式213]
在冰冷却下往丙-2-硫醇(413μl)在二甲基甲酰胺(8ml)中的溶液中加入60%氢化钠(169mg),随后在室温下将反应混合物搅拌1小时。将化合物II-30(800mg)在二甲基甲酰胺(8ml)中的溶液滴加至混合物中,随后将整个混合物搅拌2小时。在反应终止后,将反应混合物倾入1NHCl水溶液,用乙酸乙酯萃取。有机层依次用饱和NaHCO3水溶液和盐水洗涤,经硫酸钠干燥并浓缩。残余物经硅胶柱层析纯化,得到化合物II-33(738mg)。
按照以上实施例,由化合物II-33合成化合物I-160。
(化合物I-160)NMR(CDCl3);δ(ppm)1.28(d,J=6.8Hz,6H),1.53-2.20(m,19H),3.30-3.37(m,1H),3.63(s,3H),4.25(d,J=7.3Hz,1H),4.91(s,1H),6.56(d,J=14.2Hz,1H),7.40(d,J=14.2Hz,1H),7.96(d,J=7.6Hz,1H),8.20(s,1H)
采用类似的方法合成下述化合物。
[实施例164]
[式214]
(化合物I-161)NMR(CDCl3);δ(ppm)1.12(t,J=7.2Hz,3H),1.29(d,J=6.8Hz,6H),1.43(s,6H),1.58-2.22(m,13H),3.24-3.34(m,3H),4.26(brs,1H),5.76(brs,1H),6.64(d,J=14.2Hz,1H),7.42(d,J=14.2Hz,1H),7.92(d,J=7.8Hz,1H),8.22(s,1H)
[实施例165]
[式215]
(化合物I-162)NMR(CDCl3);δ(ppm)1.12(t,J=7.2Hz,3H),1.29(d,J=6.6Hz,6H),1.43(s,6H),1.64-2.28(m,13H),3.24-3.34(m,3H),4.30(brs,1H),4.55(s,2H),5.74(s,1H),6.64(d,J=13.9Hz,1H),7.42(d,J=13.9Hz,1H),7.92(d,J=7.6Hz,1H),8.22(s,1H)
[实施例166]
[式216]
(化合物I-163)NMR(CDCl3);δ(ppm)1.12(t,J=7.2Hz,3H),1.29(d,J=6.6Hz,6H),1.43(s,6H),1.66-2.22(m,16H),3.24-3.32(m,3H),4.29(brs,1H),5.26(s,1H),5.70(brs,1H),6.64(d,J=14.4Hz,1H),7.42(d,J=14.4Hz,1H),7.95(d,J=8.3Hz,1H),8.21(s,1H)
[实施例167]
[式217]
(化合物I-164)NMR(CDCl3);δ(ppm)1.28(d,J=6.6Hz,6H),1.54(s,6H),1.64-2.28(m,13H),3.30-3.37(m,1H),3.63(s,3H),4.30(d,J=7.1Hz,1H),4.57(s,2H),4.96(s,1H),6.56(d,J=13.9Hz,1H),7.39(d,J=13.9Hz,1H),7.95(d,J=7.8Hz,1H),8.20(s,1H)
[实施例168]
[式218]
(化合物I-165)NMR(d6-DMSO);δ(ppm)1.17(d,J=6.4Hz,6H),1.38-1.56(m,8H),1.77-2.18(m,14H),3.32-3.40(m,1H),4.00-4.07(m,1H),6.00-6.40(s,2H),6.55(d,J=14.0Hz,1H),7.29(d,J=14.0Hz,1H),7.79-7.90(m,2H),8.07(s,1H)
[实施例169]
[式219]
(化合物I-166)NMR(d6-DMSO);δ(ppm)1.18(d,J=6.8Hz,6H),1.38-1.58(m,8H),1.77-2.18(m,14H),3.02(d,J=5.6Hz,2H),3.32-3.40(m,1H),3.93-4.00(m,1H),4.39(t,J=5.6Hz,1H),6.55(d,J=14.0Hz,1H),7.29(d,J=14.0Hz,1H),7.84(s,1H),7.91(d,J=7.2Hz,1H),8.07(s,1H)
[实施例170]
[式220]
(化合物I-167)NMR(d6-DMSO);δ(ppm)1.18(d,J=5.6Hz,6H),1.44(s,6H),1.50-2.07(m,16H),3.32-3.40(m,1H),3.98-4.10(m,3H),6.55(d,J=14.0Hz,1H),7.09(s,1H),7.29(d,J=14.0Hz,1H),7.66(s,1H),7.85(s,1H),7.92(d,J=6.0Hz,1H),8.08(s,1H),8.33(s,1H)
[实施例171]
[式221]
(化合物I-168)NMR(CDCl3);δ(ppm)1.29(d,J=6.6Hz,6H),1.57-2.20(m,22H),3.31-3.38(m,1H),4.25(d,J=6.6Hz,1H),5.59(s,1H),6.55(d,J=14.2Hz,1H),7.39(d,J=14.2Hz,1H),7.96(d,J=7.8Hz,1H),8.19(s,1H)
按照以上实施例,合成下述化合物。
[实施例172]
[式222]
(化合物I-169)NMR(DMSO-d6);δ(ppm)1.25-2.03(m,25H),2.58(d,J=4.3Hz,3H),3.90(brs,1H),4.42(s,1H),4.88-4.94(m,1H),6.35(d,J=14.2Hz,1H),6.77(d,J=14.2Hz,1H),7.30(d,J=6.8Hz,1H),7.52(brs,1H),8.03(s,1H)
[实施例173]
[式223]
(化合物I-170)NMR(DMSO-d6);δ(ppm)1.00(t,J=7.1Hz,3H),1.25-2.03(m,25H),3.04-3.10(m,2H),3.89(brs,1H),4.42(s,1H),4.89-4.94(m,1H),6.35(d,J=14.4Hz,1H),6.77(d,J=14.4Hz,1H),7.31(d,J=6.8Hz,1H),7.57(t,J=5.2Hz,1H),8.02(s,1H)
[实施例174]
[式224]
(化合物I-171)NMR(DMSO-d6);δ(ppm)1.26-2.10(m,25H),2.58(d,J=4.6Hz,3H),3.97(brs,1H),4.89-4.96(m,1H),6.19(brs,2H),6.35(d,J=14.4Hz,1H),6.77(d,J=14.4Hz,1H),7.38(d,J=6.3Hz,1H),7.53(brs,1H),8.04(s,1H)
[实施例175]
[式225]
(化合物I-172)NMR(DMSO-d6);δ(ppm)1.00(t,J=7.2Hz,3H),1.25-2.10(m,25H),3.04-3.11(m,2H),3.96(brs,1H),4.90-4.97(m,1H),6.20(brs,2H),6.35(d,J=14.4Hz,1H),6.77(d,J=14.4Hz,1H),7.38(d,J=7.1Hz,1H),7.57(t,J=5.4Hz,1H),8.04(s,1H)
[实施例176]
[式226]
(化合物I-173)NMR(DMSO-d6);δ(ppm)0.87(t,J=7.3Hz,3H),1.24(d,J=6.1Hz,6H),1.33-2.07(m,23H),3.88(brs,1H),4.42(s,1H),4.87-4.93(m,1H),6.35(d,J=14.4Hz,1H),6.75(d,J=14.4Hz,1H),7.31(d,J=7.3Hz,1H),7.69(s,1H),8.00(s,1H)
[实施例177]
[式227]
(化合物I-174)NMR(DMSO-d6);δ(ppm)0.87(t,J=7.3Hz,3H),1.24(d,J=6.1Hz,6H),1.40-2.10(m,23H),3.96(brs,1H),4.89-4.95(m,1H),6.20(brs,2H),6.36(d,J=14.4Hz,1H),6.75(d,J=14.4Hz,1H),7.38(d,J=6.6Hz,1H),7.69(s,1H),8.01(s,1H)
[实施例178]
[式228]
(化合物I-175)NMR(d6-DMSO);δ(ppm)1.43(s,6H),1.81(s,6H),1.86-2.21(m,13H),2.17(m,1H),3.96(brs,1H),6.59(d,J=10.8Hz,1H),7.00(d,J=10.5Hz,1H),7.64(brd,J=4.5Hz,1H),7.83(s,1H),8.21(s,1H),8.31(brs,1H)
[实施例179]
[式229]
(化合物I-176)NMR(d6-DMSO);δ(ppm)1.34-2.10(m,13H),1.43(s,3H),1.44(s,3H),1.81(s,3H),3.92(m,1H),4.44(m,1H),6.72(d,J=10.5Hz,1H),6.99(d,J=10.5Hz,1H),7.89(s,1H),8.21(s,1H),8.47(s,1H)
[实施例180]
[式230]
(化合物I-177)NMR(CDCl3);δ(ppm)1.55(s,6H),1.61-2.20(m,13H),1.96(s,3H),3.1(m,1H),3.29(brs,1H),4.19(m,1H),6.59(d,J=14.1Hz,1H),6.72(brd,J=6.9Hz,1H),7.03(d,J=13.8Hz,1H),8.06(s,1H)
[实施例181]
[式231]
(化合物I-178)NMR(CDCl3);δ(ppm)1.5-2.3(m,13H),1.97(s,3H),4.27(brd,J=7.8Hz,1H),4.41(brs,2H),5.46(s,1H),6.50(d,J=7.2Hz,1H),6.60(d,J=13.2Hz,1H),7.04(d,J=13.8Hz,1H),8.07(s,1H)
[实施例182]
[式232]
(化合物I-179)NMR(DMSO-d6);δ(ppm)1.25(d,J=6.1Hz,6H),1.35-2.03(m,19H),3.31(s,3H),3.76(s,2H),3.89(brs,1H),4.43(s,1H),4.86-4.93(m,1H),6.39(d,J=14.4Hz,1H),6.79(d,J=14.4Hz,1H),7.31(d,J=7.1Hz,1H),7.40(s,1H),8.01(s,1H)
[实施例183]
[式233]
(化合物I-180)NMR(DMSO-d6);δ(ppm)1.25(d,J=6.1Hz,6H),1.41-2.10(m,19H),3.31(s,3H),3.76(s,2H),3.95(brs,1H),4.87-4.94(m,1H),6.19(brs,2H),6.39(d,J=14.4Hz,1H),6.79(d,J=14.4Hz,1H),7.36-7.40(m,2H),8.02(s,1H)
按照以上实施例,合成作为本发明化合物的下述化合物。
[式234]
[式235]
[式236]
[式237]
[式238]
[式239]
[式240]
此外,可合成作为本发明化合物的下述化合物。
具体地,列出由式(IV)定义的化合物。
[式241]
用于式(IV)中的环A的缩写如下。
[式242]
用于式(IV)中的R3的缩写如下。
[式243]
用于式(IV)中的R2的缩写如下。
[式244]
(化合物编号,环A、R2、R3)=(I-P1,A-1,R2-1,R3-1),(I-P2,A-1,R2-1,R3-2),(I-P3,A-1,R2-1,R3-3),(I-P4,A-1,R2-1,R3-4),(I-P5,A-1,R2-1,R3-5),(I-P6,A-1,R2-1,R3-6),(I-P7,A-1,R2-1,R3-7),(I-P8,A-1,R2-1,R3-8),(I-P9,A-1,R2-1,R3-9),(I-P10,A-1,R2-1,R3-10),(I-P11,A-1,R2-1,R3-11),(I-P12,A-1,R2-1,R3-12),(I-P13,A-1,R2-1,R3-13),(I-P14,A-1,R2-1,R3-14),(I-P15,A-1,R2-1,R3-15),(I-P16,A-1,R2-1,R3-16),(I-P17,A-1,R2-1,R3-17),(I-P18,A-1,R2-1,R3-18),(I-P19,A-1,R2-1,R3-19),(I-P20,A-1,R2-1,R3-20),(I-P21,A-1,R2-1,R3-21),(I-P22,A-1,R2-1,R3-22),(I-P23,A-1,R2-1,R3-23),(I-P24,A-1,R2-1,R3-24),(I-P25,A-1,R2-1,R3-25),(I-P26,A-1,R2-1,R3-26),(I-P27,A-1,R2-1,R3-27),(I-P28,A-1,R2-1,R3-28),(I-P29,A-1,R2-1,R3-29),(I-P30,A-1,R2-1,R3-30),(I-P31,A-1,R2-1,R3-31),(I-P32,A-1,R2-1,R3-32),(I-P33,A-1,R2-1,R3-33),(I-P34,A-1,R2-1,R3-34),(I-P35,A-1,R2-2,R3-1),(I-P36,A-1,R2-2,R3-2),(I-P37,A-1,R2-2,R3-3),(I-P38,A-1,R2-2,R3-4),(I-P39,A-1,R2-2,R3-5),(I-P40,A-1,R2-2,R3-6),(I-P41,A-1,R2-2,R3-7),(I-P42,A-1,R2-2,R3-8),(I-P43,A-1,R2-2,R3-9),(I-P44,A-1,R2-2,R3-10),(I-P45,A-1,R2-2,R3-11),(I-P46,A-1,R2-2,R3-12),(I-P47,A-1,R2-2,R3-13),(I-P48,A-1,R2-2,R3-14),(I-P49,A-1,R2-2,R3-15),(I-P50,A-1,R2-2,R3-16),(I-P51,A-1,R2-2,R3-17),(I-P52,A-1,R2-2,R3-18),(I-P53,A-1,R2-2,R3-19),(I-P54,A-1,R2-2,R3-20),(I-P55,A-1,R2-2,R3-21),(I-P56,A-1,R2-2,R3-22),(I-P57,A-1,R2-2,R3-23),(I-P58,A-1,R2-2,R3-24),(I-P59,A-1,R2-2,R3-25),(I-P60,A-1,R2-2,R3-26),(I-P61,A-1,R2-2,R3-27),(I-P62,A-1,R2-2,R3-28),(I-P63,A-1,R2-2,R3-29),(I-P64,A-1,R2-2,R3-30),(I-P65,A-1,R2-2,R3-31),(I-P66,A-1,R2-2,R3-32),(I-P67,A-1,R2-2,R3-33),(I-P68,A-1,R2-2,R3-34),(I-P69,A-1,R2-3,R3-1),(I-P70,A-1,R2-3,R3-2),(I-P71,A-1,R2-3,R3-3),(I-P72,A-1,R2-3,R3-4),(I-P73,A-1,R2-3,R3-5),(I-P74,A-1,R2-3,R3-6),(I-P75,A-1,R2-3,R3-7),(I-P76,A-1,R2-3,R3-8),(I-P77,A-1,R2-3,R3-9),(I-P78,A-1,R2-3,R3-10),(I-P79,A-1,R2-3,R3-11),(I-P80,A-1,R2-3,R3-12),(I-P81,A-1,R2-3,R3-13),(I-P82,A-1,R2-3,R3-14),(I-P83,A-1,R2-3,R3-15),(I-P84,A-1,R2-3,R3-16),(I-P85,A-1,R2-3,R3-17),(I-P86,A-1,R2-3,R3-18),(I-P87,A-1,R2-3,R3-19),(I-P88,A-1,R2-3,R3-20),(I-P89,A-1,R2-3,R3-21),(I-P90,A-1,R2-3,R3-22),(I-P91,A-1,R2-3,R3-23),(I-P92,A-1,R2-3,R3-24),(I-P93,A-1,R2-3,R3-25),(I-P94,A-1,R2-3,R3-26),(I-P95,A-1,R2-3,R3-27),(I-P96,A-1,R2-3,R3-28),(I-P97,A-1,R2-3,R3-29),(I-P98,A-1,R2-3,R3-30),(I-P99,A-1,R2-3,R3-31),(I-P100,A-1,R2-3,R3-32),(I-P101,A-1,R2-3,R3-33),(I-P102,A-1,R2-3,R3-34),(I-P103,A-1,R2-4,R3-1),(I-P104,A-1,R2-4,R3-2),(I-P105,A-1,R2-4,R3-3),(I-P106,A-1,R2-4,R3-4),(I-P107,A-1,R2-4,R3-5),(I-P108,A-1,R2-4,R3-6),(I-P109,A-1,R2-4,R3-7),(I-P110,A-1,R2-4,R3-8),(I-P111,A-1,R2-4,R3-9),(I-P112,A-1,R2-4,R3-10),(I-P113,A-1,R2-4,R3-11),(I-P114,A-1,R2-4,R3-12),(I-P115,A-1,R2-4,R3-13),(I-P116,A-1,R2-4,R3-14),(I-P117,A-1,R2-4,R3-15),(I-P118,A-1,R2-4,R3-16),(I-P119,A-1,R2-4,R3-17),(I-P120,A-1,R2-4,R3-18),(I-P121,A-1,R2-4,R3-19),(I-P122,A-1,R2-4,R3-20),(I-P123,A-1,R2-4,R3-21),(I-P124,A-1,R2-4,R3-22),(I-P125,A-1,R2-4,R3-23),(I-P126,A-1,R2-4,R3-24),(I-P127,A-1,R2-4,R3-25),(I-P128,A-1,R2-4,R3-26),(I-P129,A-1,R2-4,R3-27),(I-P130,A-1,R2-4,R3-28),(I-P131,A-1,R2-4,R3-29),(I-P132,A-1,R2-4,R3-30),(I-P133,A-1,R2-4,R3-31),(I-P134,A-1,R2-4,R3-32),(I-P135,A-1,R2-4,R3-33),(I-P136,A-1,R2-4,R3-34),(I-P137,A-1,R2-5,R3-1),(I-P138,A-1,R2-5,R3-2),(I-P139,A-1,R2-5,R3-3),(I-P140,A-1,R2-5,R3-4),(I-P141,A-1,R2-5,R3-5),(I-P142,A-1,R2-5,R3-6),(I-P143,A-1,R2-5,R3-7),(I-P144,A-1,R2-5,R3-8),(I-P145,A-1,R2-5,R3-9),(I-P146,A-1,R2-5,R3-10),(I-P147,A-1,R2-5,R3-11),(I-P148,A-1,R2-5,R3-12),(I-P149,A-1,R2-5,R3-13),(I-P150,A-1,R2-5,R3-14),(I-P151,A-1,R2-5,R3-15),(I-P152,A-1,R2-5,R3-16),(I-P153,A-1,R2-5,R3-17),(I-P154,A-1,R2-5,R3-18),(I-P155,A-1,R2-5,R3-19),(I-P156,A-1,R2-5,R3-20),(I-P157,A-1,R2-5,R3-21),(I-P158,A-1,R2-5,R3-22),(I-P159,A-1,R2-5,R3-23),(I-P160,A-1,R2-5,R3-24),(I-P161,A-1,R2-5,R3-25),(I-P162,A-1,R2-5,R3-26),(I-P163,A-1,R2-5,R3-27),(I-P164,A-1,R2-5,R3-28),(I-P165,A-1,R2-5,R3-29),(I-P166,A-1,R2-5,R3-30),(I-P167,A-1,R2-5,R3-31),(I-P168,A-1,R2-5,R3-32),(I-P169,A-1,R2-5,R3-33),(I-P170,A-1,R2-5,R3-34),(I-P171,A-1,R2-6,R3-1),(I-P172,A-1,R2-6,R3-2),(I-P173,A-1,R2-6,R3-3),(I-P174,A-1,R2-6,R3-4),(I-P175,A-1,R2-6,R3-5),(I-P176,A-1,R2-6,R3-6),(I-P177,A-1,R2-6,R3-7),(I-P178,A-1,R2-6,R3-8),(I-P179,A-1,R2-6,R3-9),(I-P180,A-1,R2-6,R3-10),(I-P181,A-1,R2-6,R3-11),(I-P182,A-1,R2-6,R3-12),(I-P183,A-1,R2-6,R3-13),(I-P184,A-1,R2-6,R3-14),(I-P185,A-1,R2-6,R3-15),(I-P186,A-1,R2-6,R3-16),(I-P187,A-1,R2-6,R3-17),(I-P188,A-1,R2-6,R3-18),(I-P189,A-1,R2-6,R3-19),(I-P190,A-1,R2-6,R3-20),(I-P191,A-1,R2-6,R3-21),(I-P192,A-1,R2-6,R3-22),(I-P193,A-1,R2-6,R3-23),(I-P194,A-1,R2-6,R3-24),(I-P195,A-1,R2-6,R3-25),(I-P196,A-1,R2-6,R3-26),(I-P197,A-1,R2-6,R3-27),(I-P198,A-1,R2-6,R3-28),(I-P199,A-1,R2-6,R3-29),(I-P200,A-1,R2-6,R3-30),(I-P201,A-1,R2-6,R3-31),(I-P202,A-1,R2-6,R3-32),(I-P203,A-1,R2-6,R3-33),(I-P204,A-1,R2-6,R3-34),(I-P205,A-1,R2-7,R3-1),(I-P206,A-1,R2-7,R3-2),(I-P207,A-1,R2-7,R3-3),(I-P208,A-1,R2-7,R3-4),(I-P209,A-1,R2-7,R3-5),(I-P210,A-1,R2-7,R3-6),(I-P211,A-1,R2-7,R3-7),(I-P212,A-1,R2-7,R3-8),(I-P213,A-1,R2-7,R3-9),(I-P214,A-1,R2-7,R3-10),(I-P215,A-1,R2-7,R3-11),(I-P216,A-1,R2-7,R3-12),(I-P217,A-1,R2-7,R3-13),(I-P218,A-1,R2-7,R3-14),(I-P219,A-1,R2-7,R3-15),(I-P220,A-1,R2-7,R3-16),(I-P221,A-1,R2-7,R3-17),(I-P222,A-1,R2-7,R3-18),(I-P223,A-1,R2-7,R3-19),(I-P224,A-1,R2-7,R3-20),(I-P225,A-1,R2-7,R3-21),(I-P226,A-1,R2-7,R3-22),(I-P227,A-1,R2-7,R3-23),(I-P228,A-1,R2-7,R3-24),(I-P229,A-1,R2-7,R3-25),(I-P230,A-1,R2-7,R3-26),(I-P231,A-1,R2-7,R3-27),(I-P232,A-1,R2-7,R3-28),(I-P233,A-1,R2-7,R3-29),(I-P234,A-1,R2-7,R3-30),(I-P235,A-1,R2-7,R3-31),(I-P236,A-1,R2-7,R3-32),(I-P237,A-1,R2-7,R3-33),(I-P238,A-1,R2-7,R3-34),(I-P239,A-1,R2-8,R3-1),(I-P240,A-1,R2-8,R3-2),(I-P241,A-1,R2-8,R3-3),(I-P242,A-1,R2-8,R3-4),(I-P243,A-1,R2-8,R3-5),(I-P244,A-1,R2-8,R3-6),(I-P245,A-1,R2-8,R3-7),(I-P246,A-1,R2-8,R3-8),(I-P247,A-1,R2-8,R3-9),(I-P248,A-1,R2-8,R3-10),(I-P249,A-1,R2-8,R3-11),(I-P250,A-1,R2-8,R3-12),(I-P251,A-1,R2-8,R3-13),(I-P252,A-1,R2-8,R3-14),(I-P253,A-1,R2-8,R3-15),(I-P254,A-1,R2-8,R3-16),(I-P255,A-1,R2-8,R3-17),(I-P256,A-1,R2-8,R3-18),(I-P257,A-1,R2-8,R3-19),(I-P258,A-1,R2-8,R3-20),(I-P259,A-1,R2-8,R3-21),(I-P260,A-1,R2-8,R3-22),(I-P261,A-1,R2-8,R3-23),(I-P262,A-1,R2-8,R3-24),(I-P263,A-1,R2-8,R3-25),(I-P264,A-1,R2-8,R3-26),(I-P265,A-1,R2-8,R3-27),(I-P266,A-1,R2-8,R3-28),(I-P267,A-1,R2-8,R3-29),(I-P268,A-1,R2-8,R3-30),(I-P269,A-1,R2-8,R3-31),(I-P270,A-1,R2-8,R3-32),(I-P271,A-1,R2-8,R3-33),(I-P272,A-1,R2-8,R3-34),(I-P273,A-1,R2-9,R3-1),(I-P274,A-1,R2-9,R3-2),(I-P275,A-1,R2-9,R3-3),(I-P276,A-1,R2-9,R3-4),(I-P277,A-1,R2-9,R3-5),(I-P278,A-1,R2-9,R3-6),(I-P279,A-1,R2-9,R3-7),(I-P280,A-1,R2-9,R3-8),(I-P281,A-1,R2-9,R3-9),(I-P282,A-1,R2-9,R3-10),(I-P283,A-1,R2-9,R3-11),(I-P284,A-1,R2-9,R3-12),(I-P285,A-1,R2-9,R3-13),(I-P286,A-1,R2-9,R3-14),(I-P287,A-1,R2-9,R3-15),(I-P288,A-1,R2-9,R3-16),(I-P289,A-1,R2-9,R3-17),(I-P290,A-1,R2-9,R3-18),(I-P291,A-1,R2-9,R3-19),(I-P292,A-1,R2-9,R3-20),(I-P293,A-1,R2-9,R3-21),(I-P294,A-1,R2-9,R3-22),(I-P295,A-1,R2-9,R3-23),(I-P296,A-1,R2-9,R3-24),(I-P297,A-1,R2-9,R3-25),(I-P298,A-1,R2-9,R3-26),(I-P299,A-1,R2-9,R3-27),(I-P300,A-1,R2-9,R3-28),(I-P301,A-1,R2-9,R3-29),(I-P302,A-1,R2-9,R3-30),(I-P303,A-1,R2-9,R3-31),(I-P304,A-1,R2-9,R3-32),(I-P305,A-1,R2-9,R3-33),(I-P306,A-1,R2-9,R3-34),(I-P307,A-1,R2-10,R3-1),(I-P308,A-1,R2-10,R3-2),(I-P309,A-1,R2-10,R3-3),(I-P310,A-1,R2-10,R3-4),(I-P311,A-1,R2-10,R3-5),(I-P312,A-1,R2-10,R3-6),(I-P313,A-1,R2-10,R3-7),(I-P314,A-1,R2-10,R3-8),(I-P315,A-1,R2-10,R3-9),(I-P316,A-1,R2-10,R3-10),(I-P317,A-1,R2-10,R3-11),(I-P318,A-1,R2-10,R3-12),(I-P319,A-1,R2-10,R3-13),(I-P320,A-1,R2-10,R3-14),(I-P321,A-1,R2-10,R3-15),(I-P322,A-1,R2-10,R3-16),(I-P323,A-1,R2-10,R3-17),(I-P324,A-1,R2-10,R3-18),(I-P325,A-1,R2-10,R3-19),(I-P326,A-1,R2-10,R3-20),(I-P327,A-1,R2-10,R3-21),(I-P328,A-1,R2-10,R3-22),(I-P329,A-1,R2-10,R3-23),(I-P330,A-1,R2-10,R3-24),(I-P331,A-1,R2-10,R3-25),(I-P332,A-1,R2-10,R3-26),(I-P333,A-1,R2-10,R3-27),(I-P334,A-1,R2-10,R3-28),(I-P335,A-1,R2-10,R3-29),(I-P336,A-1,R2-10,R3-30),(I-P337,A-1,R2-10,R3-31),(I-P338,A-1,R3-10,R3-32),(I-P339,A-1,R2-10,R3-33),(I-P340,A-1,R2-10,R3-34),(I-P341,A-1,R2-11,R3-1),(I-P342,A-1,R2-11,R3-2),(I-P343,A-1,R2-11,R3-3),(I-P344,A-1,R2-11,R3-4),(I-P345,A-1,R2-11,R3-5),(I-P346,A-1,R2-11,R3-6),(I-P347,A-1,R2-11,R3-7),(I-P348,A-1,R2-11,R3-8),(I-P349,A-1,R2-11,R3-9),(I-P350,A-1,R2-11,R3-10),(I-P351,A-1,R2-11,R3-11),(I-P352,A-1,R2-11,R3-12),(I-P353,A-1,R2-11,R3-13),(I-P354,A-1,R2-11,R3-14),(I-P355,A-1,R2-11,R3-15),(I-P356,A-1,R2-11,R3-16),(I-P357,A-1,R2-11,R3-17),(I-P358,A-1,R2-11,R3-18),(I-P359,A-1,R2-11,R3-19),(I-P360,A-1,R2-11,R3-20),(I-P361,A-1,R2-11,R3-21),(I-P362,A-1,R2-11,R3-22),(I-P363,A-1,R2-11,R3-23),(I-P364,A-1,R2-11,R3-24),(I-P365,A-1,R2-11,R3-25),(I-P366,A-1,R2-11,R3-26),(I-P367,A-1,R2-11,R3-27),(I-P368,A-1,R2-11,R3-28),(I-P369,A-1,R2-11,R3-29),(I-P370,A-1,R2-11,R3-30),(I-P371,A-1,R2-11,R3-31),(I-P372,A-1,R2-11,R3-32),(I-P373,A-1,R2-11,R3-33),(I-P374,A-1,R2-11,R3-34),(I-P375,A-1,R2-12,R3-1),(I-P376,A-1,R2-12,R3-2),(I-P377,A-1,R2-12,R3-3),(I-P378,A-1,R2-12,R3-4),(I-P379,A-1,R2-12,R3-5),(I-P380,A-1,R2-12,R3-6),(I-P381,A-1,R2-12,R3-7),(I-P382,A-1,R2-12,R3-8),(I-P383,A-1,R2-12,R3-9),(I-P384,A-1,R2-12,R3-10),(I-P385,A-1,R2-12,R3-11),(I-P386,A-1,R2-12,R3-12),(I-P387,A-1,R2-12,R3-13),(I-P388,A-1,R2-12,R3-14),(I-P389,A-1,R2-12,R3-15),(I-P390,A-1,R2-12,R3-16),(I-P391,A-1,R2-12,R3-17),(I-P392,A-1,R2-12,R3-18),(I-P393,A-1,R2-12,R3-19),(I-P394,A-1,R2-12,R3-20),(I-P395,A-1,R2-12,R3-21),(I-P396,A-1,R2-12,R3-22),(I-P397,A-1,R2-12,R3-23),(I-P398,A-1,R2-12,R3-24),(I-P399,A-1,R2-12,R3-25),(I-P400,A-1,R2-12,R3-26),(I-P401,A-1,R2-12,R3-27),(I-P402,A-1,R2-12,R3-28),(I-P403,A-1,R2-12,R3-29),(I-P404,A-1,R2-12,R3-30),(I-P405,A-1,R2-12,R3-31),(I-P406,A-1,R2-12,R3-32),(I-P407,A-1,R2-12,R3-33),(I-P408,A-1,R2-12,R3-34),(I-P409,A-1,R2-13,R3-1),(I-P410,A-1,R2-13,R3-2),(I-P411,A-1,R2-13,R3-3),(I-P412,A-1,R2-13,R3-4),(I-P413,A-1,R2-13,R3-5),(I-P414,A-1,R2-13,R3-6),(I-P415,A-1,R2-13,R3-7),(I-P416,A-1,R2-13,R3-8),(I-P417,A-1,R2-13,R3-9),(I-P418,A-1,R2-13,R3-10),(I-P419,A-1,R2-13,R3-11),(I-P420,A-1,R2-13,R3-12),(I-P421,A-1,R2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2-27,R3-6),(I-P15681,A-16,R2-27,R3-7),(I-P15682,A-16,R2-27,R3-8),(I-P15683,A-16,R2-27,R3-9),(I-P15684,A-16,R2-27,R3-10),(I-P15685,A-16,R2-27,R3-11),(I-P15686,A-16,R2-27,R3-12),(I-P15687,A-16,R2-27,R3-13),(I-P15688,A-16,R2-27,R3-14),(I-P15689,A-16,R2-27,R3-15),(I-P15690,A-1,6,R2-27,R3-16),(I-P15691,A-16,R2-27,R3-17),(I-P15692,A-16,R2-27,R3-18),(I-P15693,A-16,R2-27,R3-19),(I-P15694,A-16,R2-27,R3-20),(I-P15695,A-16,R2-27,R3-21),(I-P15696,A-16,R2-27,R3-22),(I-P15697,A-16,R2-27,R3-23),(I-P15698,A-16,R2-27,R3-24),(I-P15699,A-16,R2-27,R3-25),(I-P15700,A-16,R2-27,R3-26),(I-P15701,A-16,R2-27,R3-27),(I-P15702,A-16,R2-27,R3-28),(I-P15703,A-16,R2-27,R3-29),(I-P15704,A-16,R2-27,R3-30),(I-P15705,A-16,R2-27,R3-31),(I-P15706,A-16,R2-27,R3-32),(I-P15707,A-16,R2-27,R3-33),(I-P15708,A-16,R2-27,R3-34),(I-P15709,A-16,R2-28,R3-1),(I-P15710,A-16,R2-28,R3-2),(I-P15711,A-16,R2-28,R3-3),(I-P15712,A-16,R2-28,R3-4),(I-P15713,A-16,R2-28,R3-5),(I-P15714,A-16,R2-28,R3-6),(I-P15715,A-16,R2-28,R3-7),(I-P15716,A-16,R2-28,R3-8),(I-P15717,A-16,R2-28,R3-9),(I-P15718,A-16,R2-28,R3-10),(I-P15719,A-16,R2-28,R3-11),(I-P15720,A-16,R2-28,R3-12),(I-P15721,A-16,R2-28,R3-13),(I-P15722,A-16,R2-28,R3-14),(I-P15723,A-16,R2-28,R3-15),(I-P15724,A-16,R2-28,R3-16),(I-P15725,A-16,R2-28,R3-17),(I-P15726,A-16,R2-28,R3-18),(I-P15727,A-16,R2-28,R3-19),(I-P15728,A-16,R2-28,R3-20),(I-P15729,A-16,R2-28,R3-21),(I-P15730,A-16,R2-28,R3-22),(I-P15731,A-16,R2-28,R3-23),(I-P15732,A-16,R2-28,R3-24),(I-P15733,A-16,R2-28,R3-25),(I-P15734,A-16,R2-28,R3-26),(I-P15735,A-16,R2-28,R3-27),(I-P15736,A-16,R2-28,R3-28),(I-P15737,A-16,R2-28,R3-29),(I-P15738,A-16,R2-28,R3-30),(I-P15739,A-16,R2-28,R3-31),(I-P15740,A-16,R2-28,R3-32),(I-P15741,A-16,R2-28,R3-33),(I-P15742,A-16,R2-28,R3-34),(I-P15743,A-16,R2-29,R3-1),(I-P15744,A-16,R2-29,R3-2),(I-P15745,A-16,R2-29,R3-3),(I-P15746,A-16,R2-29,R3-4),(I-P15747,A-16,R2-29,R3-5),(I-P15748,A-16,R2-29,R3-6),(I-P15749,A-16,R2-29,R3-7),(I-P15750,A-16,R2-29,R3-8),(I-P15751,A-16,R2-29,R3-9),(I-P15752,A-16,R2-29,R3-10),(I-P15753,A-16,R2-29,R3-11),(I-P15754,A-16,R2-29,R3-12),(I-P15755,A-16,R2-29,R3-13),(I-P15756,A-16,R2-29,R3-14),(I-P15757,A-16,R2-29,R3-15),(I-P15758,A-16,R2-29,R3-16),(I-P15759,A-16,R2-29,R3-17),(I-P15760,A-16,R2-29,R3-18),(I-P15761,A-16,R2-29,R3-19),(I-P15762,A-16,R2-29,R3-20),(I-P15763,A-16,R2-29,R3-21),(I-P15764,A-16,R2-29,R3-22),(I-P15765,A-16,R2-29,R3-23),(I-P15766,A-16,R2-29,R3-24),(I-P15767,A-16,R2-29,R3-25),(I-P15768,A-16,R2-29,R3-26),(I-P15769,A-16,R2-29,R3-27),(I-P15770,A-16,R2-29,R3-28),(I-P15771,A-16,R2-29,R3-29),(I-P15772,A-16,R2-29,R3-30),(I-P15773,A-16,R2-29,R3-31),(I-P15774,A-16,R2-29,R3-32),(I-P15775,A-16,R2-29,R3-33),(I-P15776,A-16,R2-29,R3-34)
(测试实施例1)
11β-HSD1抑制剂的评价方法(化合物对人11β-HSD1抑制的评价)
在室温下将抑制剂在反应溶液中预培养30分钟后,加入作为底物(总量10μL)的可的松(5μM),所述反应溶液由50mM磷酸钠缓冲液(pH7.5)、小牛血清白蛋白(1mg/mL)、NADPH(0.42mg/mL)、葡萄糖-6-磷酸盐(1.26mg/mL)、葡萄糖-6-磷酸盐脱氢酶和酶组成。在37℃下反应2小时后,加入XL-665-标记的皮质甾醇溶液(5μL)和Cryptate-标记的抗-皮质甾醇抗体溶液(5μL)。在室温下将该反应进行2小时,测定荧光强度(HTRF方法)。由使用每次测定中已知浓度的皮质甾醇绘制的标准曲线计算皮质甾醇浓度。
将在不存在抑制剂时得到的皮质甾醇浓度作为对照值,抑制剂抑制11β-HSD1的50%抑制浓度(IC50值)由各浓度抑制剂的抑制率与对照值作图得到的抑制曲线计算。
(测试实施例2)
11β-HSD1抑制剂的评价方法(化合物对小鼠11β-HSD1抑制的评价)
在室温下将抑制剂在反应溶液中预培养30分钟后,加入作为底物(总量10μL)的11-去氢皮质甾酮(2μM),所述反应溶液由50mM磷酸钠缓冲液(pH7.5)、小牛血清白蛋白(1mg/mL)、NADPH(0.42mg/mL)、葡萄糖-6-磷酸盐(1.26mg/mL)、葡萄糖-6-磷酸盐脱氢酶和酶组成。在37℃下反应2小时后,加入XL-665-标记的皮质甾醇溶液(5μL)和Cryptate-标记的抗-皮质甾醇抗体溶液(5μL)。在室温下将该反应进行2小时,并测定荧光强度(HTRF方法)。
由使用每次测定中已知浓度的皮质甾酮绘制的标准曲线计算皮质甾酮浓度。
将在不存在抑制剂时得到的皮质甾酮浓度作为对照值,抑制剂抑制11β-HSD1的50%抑制浓度(IC50值)由各浓度抑制剂的抑制率与对照值作图得到的抑制曲线计算。
以下表明测试实施例1和2的结果。
化合物I-7:人IC50=3.4μM,小鼠IC50=0.41μM
化合物I-9:人IC50=11μM,小鼠IC50=1.7μM
化合物I-36:人IC50=1.2μM,小鼠IC50=1μM
化合物I-63:人IC50=1.4μM,小鼠IC50=0.21μM
化合物I-77:人IC50=0.62μM,小鼠IC50=0.23μM
化合物I-105:人IC50=147.8nM,小鼠IC50=3.6nM
化合物I-121:人IC50=154.3nM,小鼠IC50=4.9nM
化合物I-127:人IC50=88.1nM,小鼠IC50=3.0nM
化合物I-128:人IC50=62.4nM,小鼠IC50=5.5nM
化合物I-131:人IC50=20.8nM,小鼠IC50=1.4nM
化合物I-133:人IC50=75.6nM,小鼠IC50=0.52nM
化合物I-138:人IC50=35.1nM,小鼠IC50=0.28nM
化合物I-139:人IC50=64.4nM,小鼠IC50=0.37nM
(测试实施例3)
抗糖尿病的11β-HSD1抑制剂的口服吸收的材料和方法
(1)动物:购自CLEAJapan,Inc.的6周龄的雄性C57BL/6JJcl小鼠,在预先饲养1周后以7周龄用于试验。
(2)饲养条件:在以下环境中喂养小鼠:温度23±2℃,湿度55±10%,以8:00至20:00在亮处和20:00至8:00在暗处的循环。在预先饲养和试验期间,让小鼠自由进食固体饲料(CE-2,CLEAJapan,Inc.)和已灭菌自来水。
(3)个体和笼的辨别:用油墨在小鼠尾部标注个体编号来得以识别。将笼贴上标签,标签上描述有试验负责人姓名、到达数据(dataofarrival)、品种、性别和供给方名称,并在预先饲养期小鼠以20只/笼饲养。在试验开始后,将小鼠以3只/笼饲养。
(4)剂量和分组的设置:根据口服或静脉给予的剂量设置以下组。
口服给予20mg/kg(n=3)
静脉给予5mg/kg(n=3)
(5)给药液体的制备:制备方法如下所示。使用0.5%甲基纤维素(1500cP)作为口服给药赋形剂制备悬浮液。使用N,N-二甲基乙酰胺/聚乙二醇400(=1/2)作为静脉给药赋形剂制备增溶溶液。
(6)给予方式:至于口服给予,使用口用探针以10mL/kg强制将给药悬浮液给予胃中。至于静脉给药,使用玻璃注射器以2.5mL/kg将给药溶液给予尾静脉。
(7)评价项目:通过时间点血采集由心脏收集血液,并通过使用HPLC或LC/MS/MS测定血浆中药物浓度。
(8)统计分析:至于血浆浓度分布,通过使用非线性最小程序WinNonlin(已注册的商品名)计算血浆浓度-时间曲线下面积(AUC),由口服给予组和静脉给予组的AUC值计算生物利用度。
使用离体脂肪组织评价HSD1抑制活性的方法
将9-10周龄雄性ob/ob小鼠用于实验。口服给予动物测试化合物30-50mg/kg。在8和16个小时后,在水合氯醛麻醉下将内脏脂肪组织离体并测定在脂肪中HSD1活性。采用已口服给予0.5%甲基纤维素溶液的动物的脂肪组织中的HSD1活性,将类似处理作为对照值(100%),测定测试化合物的HSD1抑制活性。
往约200mg离体脂肪组织中加入三次等体积的磷酸盐缓冲液(50mM磷酸钠(pH7.5)、小牛血清白蛋白(1mg/ml)),制备匀浆溶液并用于HSD1酶活性测定。至于HSD1酶活性测定,将60μL反应溶液(50mM磷酸钠缓冲液(pH7.5)、小牛血清白蛋白(1mg/mL)、NADPH(0.42mg/mL)、葡萄糖-6-磷酸盐(1.26mg/mL)、葡萄糖-6-磷酸盐脱氢酶)和20μL脂肪匀浆溶液混合,通过加入20μL作为底物的10μM11-DHC溶液启动反应。在37℃下将该反应进行60分钟,加入200μL乙酸乙酯使反应终止。在加入作为分析用内标的10μL地塞米松溶液(20pmol/μL)后,将该混合物离心(15000rpmx3分钟,室温)并收集150μL上清液。在将上清液减压干燥后,将残余物溶解在60μL水-甲醇溶液(H2O∶甲醇=45∶55)中并通过使用HPLC测定皮质甾酮浓度。
使用地塞米松作为内标由校正曲线计算皮质甾酮浓度。
以下制剂实施例1-8仅为实例,并不意欲限制本发明的范围。术语“活性成分”意指本发明化合物、其药学上可接受的盐或其水合物。
(制剂实施例1)
使用以下成分制备硬胶囊剂:
(制剂实施例2)
使用以下成分制备片剂:
将各成分混合,并压制形成片,片重665mg。
(制剂实施例3)
制备包含以下成分的气雾剂溶液:
将活性成分和乙醇混合,随后往一部分的推进剂22中加入该混合物,冷却至-30℃,并转移至包装机中。随后,向不锈钢容器中装入必要量,用剩余的推进剂稀释。将发泡装置与容器连接。
(制剂实施例4)
以下方法制备含60mg活性成分的片剂:
使活性成分、淀粉和纤维素通过No.45目U.S.筛并充分混合。将含聚乙烯吡咯烷酮的水溶液与得到的粉末混合,随后使该混合物通过No.14目U.S.筛。将以该方法得到的颗粒在50℃下干燥并通过No.18目U.S.筛。往该颗粒中加入预先过No.60目U.S.筛的羧甲基淀粉钠、硬脂酸镁和滑石,混合,随后经压片机压制,得到片重150mg的片剂。
(制剂实施例5)
以下方法制备含80mg活性成分的胶囊:
将活性成分、淀粉、纤维素和硬脂酸镁混合,使其通过No.45目U.S.筛,并以200mg的量填充至硬明胶胶囊中。
(制剂实施例6)
以下方法制备含225mg活性成分的栓剂:
使活性成分通过No.60目U.S.筛,随后在预先最少必要加热下熔化的饱和脂肪酸甘油酯中悬浮。随后,将得到的混合物置于约2g模具,冷却。
(制剂实施例7)
以下方法制备含50mg活性成分的混悬剂:
使活性成分通过No.45目U.S.筛,并与羧甲基纤维素钠和糖浆混合形成匀浆。加入苯甲酸溶液和用部分水稀释的矫味剂,并搅拌。随后加入足量的水,得到所需体积。
(制剂实施例8)
以下方法制备静脉注射制剂:
活性成分100mg
饱和脂肪酸甘油酯1000mL
以上成分的溶液通常以1mL/分钟的速度静脉内给予患者。
[工业适用性]
由以上测试实施例显而易见,本发明化合物表现出对11β-羟基类固醇脱氢酶I型的抑制活性。因此,本发明化合物作为用于糖尿病的治疗剂是极其有用的。

Claims (5)

1.化合物、或其药学上可接受的盐,其如下定义,所述化合物为:
2.化合物、或其药学上可接受的盐,其如下定义,所述化合物为:
3.化合物、或其药学上可接受的盐,其如下定义,所述化合物为:
4.一种药物组合物,所述药物组合物包含权利要求1-3中任一项的化合物、或其药学上可接受的盐。
5.权利要求1-3中任一项的化合物、或其药学上可接受的盐在制备治疗和/或预防糖尿病的药物中的用途。
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