CN1564811A - 作为类固醇硫酸酯酶抑制剂的酰基磺酰胺化合物 - Google Patents
作为类固醇硫酸酯酶抑制剂的酰基磺酰胺化合物 Download PDFInfo
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- CN1564811A CN1564811A CNA028197577A CN02819757A CN1564811A CN 1564811 A CN1564811 A CN 1564811A CN A028197577 A CNA028197577 A CN A028197577A CN 02819757 A CN02819757 A CN 02819757A CN 1564811 A CN1564811 A CN 1564811A
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- Prior art keywords
- substituted
- alkyl
- group
- phenyl
- compound
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- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 20
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- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 10
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 12
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Abstract
可用作药物的式I化合物,其中R1是卤代烷基、链烯基、苯基、噻吩基、吡啶、苯并噻唑基、色满基(1,2-二氢苯并吡喃基)或(C6-18)芳基,且R1或R2彼此独立地为被取代的(C4-8)环烷基、被取代的桥连环烷基系、被取代的哌啶、被取代的四氢吡啶或被取代的桥连杂环系。
Description
本发明涉及酰基磺酰胺化合物,所述化合物可例如用于治疗由类固醇硫酸酯酶的作用所介导的病症。
一方面,本发明提供了式I化合物
其中
R1是(C1-6)卤代烷基、未被取代的(C2-6)链烯基、被苯基取代的(C2-6)链烯基、未被取代或者被1-5个取代基取代的
-噻吩基、吡啶、苯并噻唑基、色满基(即1,2-二氢苯并吡喃基)或(C6-18)芳基,其中所述取代基选自
-卤素、硝基、二(C1-4)烷基氨基、氰基、(C1-6)烷基、(C1-4)卤代烷基、未被取代的苯基羰基氨基(C1-4)烷基、(C1-4)烷氧基、(C1-4)卤代烷氧基、氨基羰基、二(C1-4)烷基氨基羰基、(C1-4)烷基羰基、(C1-4)烷氧基羰基、未被取代的苯基、羧基、和在苯基上被取代的苯基羰基氨基(C1-4)烷基或被取代的苯基,其中所述苯基的取代基选自
-卤素、硝基、二(C1-4)烷基氨基、氰基、(C1-6)烷基、(C1-4)卤代烷基、(C1-4)烷氧基、(C1-4)卤代烷氧基、氨基羰基、二(C1-4)烷基氨基羰基、(C1-4)烷基羰基、(C1-4)烷氧基羰基和羧基,或者
R1是下式所示的基团
R2是下式所示的基团
R3和R13彼此独立地为氢、羟基、卤素、氰基、(C1-4)烷基、(C1-4)烷氧基、苯基或苯氧基,
对于下述两种组合:
-R4和R5与它们所连接的碳原子,
-R11和R12与它们所连接的碳原子,
它们当中至少有一个彼此独立地为被取代的
-桥连环烷基系,
-(C4-8)环烷基,
-哌啶、四氢吡啶或
-桥连杂环系,
其中所述取代基选自
(C1-6)烷氧基羰基氨基,
(C1-6)烷氧基羰基((C1-4)烷基)氨基,
(C1-6)烷氧基羰基((C2-4)链烯基)氨基,
(C3-8)环烷基羰基氨基,
(C3-8)环烷基羰基((C1-4)烷基)氨基,
(C3-8)环烷基羰基((C2-4)链烯基)氨基,
(C1-6)烷氧基羰基氧基,
苯基(C1-4)烷基羰基氧基,其中所述苯基是未被取代或被取代的,并且其中的取代基如上文关于被取代的苯基所定义,
苯基磺酰基,其中所述苯基是未被取代或被取代的,并且其中的取代基如上文关于被取代的苯基所定义,
(C4-8)烷基,例如(C5-8)烷基,
(C1-4)羟基烷基,
被苯基取代的(C1-4)羟基烷基,其中所述苯基是未被取代或被取代的,并且其中的取代基如上文关于被取代的苯基所定义,
(C1-6)烷氧基羰基(C1-4)烷基,
(C3-8)环烷氧基羰基(C1-4)烷基,
(C1-6)烷氧基羰基氨基(C1-4)烷基,
(C3-8)环烷基羰基氨基(C1-4)烷基,
苯基或被取代的苯基,其中取代基如上文关于被取代的苯基所定义,具有5或6个环原子和1-4个选自N、O、S的杂原子的杂环基,例如噁二唑基,
(C3-8)环烷氧基羰基,
(C3-8)环烷基(C1-4)烷基羰基,其中所述环烷基未被取代或者被羟基取代,苯基羰基,其中所述苯基是未被取代或被取代的,并且其中的取代基如上文关于被取代的苯基所定义,
(C3-8)环烷基氨基羰基,
(C3-8)环烷基((C1-4)烷基)氨基羰基,
(C3-8)环烷基((C2-4)链烯基)氨基羰基,和
(C1-8)烷氧基羰基,
R3、R8、R13和R18彼此独立地为氢、羟基、卤素、氰基、(C1-4)烷基、(C1-4)烷氧基、苯基或苯氧基,
其中,或者
R8或R18分别彼此独立地为氢、羟基、卤素、氰基、(C1-4)烷基、(C1-4)烷氧基、苯基或苯氧基,并且对于下述两种组合:
-R9和R10与它们所连接的碳原子,
-R16和R17与它们所连接的碳原子,
它们当中至少有一个彼此独立地具有如上文关于R4和R5与它们所连接的碳原子所定义的含义,
或者
对于下述两种组合:
-R9和R10与它们所连接的碳原子,
-R16和R17与它们所连接的碳原子,
它们当中至少有一个是(C3-8)环烷基,并且
R8或R18分别彼此独立地为被取代的
-桥连环烷基系、(C4-8)环烷基、被取代的哌啶、四氢吡啶或桥连杂环系,
其中所述取代基如上文关于相应的基团所定义,
R6和R15彼此独立地为(C1-6)卤代烷基、未被取代或被取代的(C6-18)芳基,
其中所述芳基的取代基如上所定义,或被取代的
-桥连环烷基系、(C4-8)环烷基、哌啶、四氢吡啶或桥连杂环系,
其中所述取代基如上文关于相应的基团所定义,或者
R6和R15彼此独立地为氨基,所述氨基被下列基团取代:被取代的
-桥连环烷基系、(C4-8)环烷基、哌啶、四氢吡啶或桥连杂环系,
其中所述取代基如上文关于相应的基团所定义,
R7和R14彼此独立地为被取代的
-桥连环烷基系、(C4-8)环烷基、哌啶、四氢吡啶或桥连杂环系,
其中所述取代基如上文关于相应的基团所定义,
或者R7和R14彼此独立地为氨基,所述氨基被下列基团取代:被取代的
-桥连环烷基系、(C4-8)环烷基、哌啶、四氢吡啶或桥连杂环系,
其中所述取代基如上文关于相应的基团所定义,
m是0、1、2、3或4,例如0或1,
n是0、1、2、3或4,例如0或1,并且
如果
m和/或n不是0,
则
-R1-如果m不是0-和R2-如果n不是0-彼此独立地具有如上所定义的含义,并且还可以是被取代的哌嗪,其中取代基如上文关于被取代的哌啶所定义;并且
-被取代的桥连环烷基系如上文关于被取代的桥连环烷基系所述被取代,并且还可以被氧代基团和/或(C1-4)烷基取代;和
如果
R1是被取代的
-桥连环烷基环系、(C4-8)环烷基、哌啶、四氢吡啶或桥连杂环基环系,其中所述取代基如上文关于相应的基团所定义,或者如果R1是哌嗪,如果m不是0,
则
R2具有如上所定义的含义,并且还可以是(C1-6)卤代烷基、未被取代的(C2-6)链烯基、被苯基取代的(C2-6)链烯基,未被取代或者被1-5个取代基取代的-噻吩基、吡啶、苯并噻唑基、色满基(即1,2-二氢苯并吡喃基)或(C6-18)芳基,其中所述取代基如上文关于相应的基团所定义,和
如果
m是0,n是0,且R2是被取代的(C4-8)环烷基或被取代的桥连环烷基环系,其中取代基如上所定义,
则
R1不是(C1-6)卤代烷基。
在式I化合物中,存在至少一个选自下列的取代基:被取代的桥连环烷基环系、被取代的(C4-8)环烷基、被取代的哌啶、被取代的四氢吡啶、被取代的哌嗪或被取代的桥连杂环基环系,其中的取代基如上文关于相应的基团所定义。在式I化合物中,m优选为0或1,且n优选为0或1。
除非另有说明,则
-环烷基包括例如非桥连的(C3-8)环烷基,例如(C4-8)环烷基,
-杂环基包括具有5-6个环原子和1-4个选自N、S或O的杂原子的杂环基,所述杂环基可任选地与另外的环(系)稠合,例如哌啶、四氢吡啶、吡啶、哌嗪、噻吩基、吡啶、苯并噻唑基、色满基、噁二唑基,芳基包括(C6-18)芳基,例如(C6-12)芳基,例如萘基、苯基。
在式I化合物中,连接在环己基、哌啶、四氢吡啶或哌嗪环上的取代基可以在相对于也连接在所述环上的磺酰胺基团或基团-(CH2)m-或-(CH2)n-的任何位置上,例如在2、3或4位,优选在3或4位。
桥连环烷基系包括桥连(C5-12)环烷基,例如(C6-8)环烷基,其中的桥任选地包含杂原子例如N,例如包括与另一个环系稠合,例如与(C5-12)环烷基如十氢萘和/或苯基稠合的环烷基,例如包括
-通过烷基,例如甲基桥连的十氢萘,例如金刚烷基,
-通过(C1-4)烷基桥连,例如通过-CH2-CH2-桥连的环己基或环庚基,
-通过胺基团桥连的环庚基或环辛基,
-通过被杂原子例如氮间断的烷基链如(C2-4)烷基链,例如-CH2-NH-CH2-桥连的环己基或环庚基,
-通过被杂原子例如氮间断的烷基链如(C2-4)烷基链,例如-CH2-NH-CH2-桥连的环庚基,其中所述桥连的环庚基还与苯基稠合。
桥连取代的桥连杂环系包括例如通过(C1-4)亚烷基如亚乙基桥连的哌啶。
萘基包括例如未被取代或者被例如二(C1-4)烷基氨基取代的萘-1-基、萘-2-基。噻吩基包括例如未被取代或者被例如1-3个卤素取代的噻吩-2-基和噻吩-3-基。苯并噻唑基包括例如被例如(C1-4)烷氧基取代的苯并噻唑-2-基。色满基包括例如被例如(C1-4)烷基取代的色满-6-基。吡啶包括被卤素取代的吡啶,并且经由碳原子连接在式I化合物的(任选的(CH2)m或n)羰基或(任选的(CH2)m或n)磺酰基上。
另一方面,本发明提供了定义如下的式I化合物,其中
-R4和R5与它们所连接的碳原子,
-R9和R10与它们所连接的碳原子,
-R11和R12与它们所连接的碳原子,
-R16和R17与它们所连接的碳原子,
-R6,
-R7,
-R14,或
-R15
当中至少有一个是被取代的桥连环烷基系,并且其它取代基如上所定义,例如下文中所定义的式IP3、IP4、IP5、IP11或IP12的化合物。
另一方面,本发明提供了定义如下的式I化合物,其中
-R4和R5与它们所连接的碳原子,
-R9和R10与它们所连接的碳原子,
-R11和R12与它们所连接的碳原子,
-R16和R17与它们所连接的碳原子,
-R6,
-R7,
-R14,或
-R15
当中至少有一个是被取代的(C4-8)环烷基,并且其它取代基如上所定义,例如下文中所定义的式IP2、IP6、IP7或IP10的化合物。
另一方面,本发明提供了定义如下的式I化合物,其中
-R4和R5与它们所连接的碳原子,
-R9和R10与它们所连接的碳原子,
-R11和R12与它们所连接的碳原子,
-R16和R17与它们所连接的碳原子,
-R6,
-R7,
-R14,或
-R15
当中至少有一个是被取代的哌啶、被取代的四氢吡啶或被取代的桥连杂环系,并且如果m不是0和/或n不是0,还可以是哌嗪,并且其它取代基如上所定义,例如下文中所定义的式IP1、IP4、IP5、IP8、IP9、IP12、IP13或IP14的化合物。
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中R1P1具有如上文定义R1所述的含义,并且R16P1和R17P1与它们所连接的碳原子一起是被取代的哌啶或被取代的四氢吡啶,其中取代基如上文关于被取代的哌啶所定义。
在式IP1化合物中,优选地
R1P1是被取代或未被取代的噻吩基、苯并噻唑基、色满基、苯基或萘基,R16P1和R17P1与它们所连接的碳原子一起是哌啶或四氢吡啶,优选哌啶,
其
a)在环氮原子上被选自下列的取代基取代:
-(C1-6)烷氧基羰基,例如BOC(即叔丁氧基羰基),
-(C1-6)烷氧基羰基(C1-4)烷基,例如叔丁氧基羰基甲基,
-未被取代或被取代的苯基,其中取代基如上文关于苯基所定义,
-(C1-6)烷基羰基或苯基羰基、(C3-8)环烷基(C1-4)烷基羰基,
-杂环基,例如吡啶,如吡啶-2-基,例如其被硝基取代,
更优选在氮原子上被BOC或未被取代或被取代的苯基取代的哌啶,和任选地
b)还在环碳原子上被(C1-4)烷基取代,
且
R18P1是氢、苯基或(C1-4)烷基,更优选是氢或苯基。
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中R1P2具有如上文所定义的R1的含义,R16P2和R17P2与它们所连接的碳原子一起是取代的(C4-7)环烷基,其中取代基如上文关于被取代的环烷基所定义,且R18P2具有如上文所定义的R18的含义。
在式IP2化合物中,优选地
-R1P2是被取代或未被取代的苯基、萘基、链烯基(例如被苯基取代)或噻吩基,
-R16P2和R17P2与它们所连接的碳原子一起是环己基,所述环己基被下列基团取代:
(C1-6)烷氧基羰基氨基(C1-4)烷基、(C1-6)烷氧基羰基氨基、(C1-6)烷氧基羰基-((C1-4)烷基)氨基、(C1-6)烷氧基羰基((C2-4)链烯基)氨基、(C3-8)环烷基羰基-((C1-4)烷基)氨基、(C3-8)环烷基羰基氨基(C1-4)烷基、(C1-6)烷基羰基氨基-(C1-4)烷基、(C3-8)环烷基(C1-4)烷基-羰基氧基、(C3-8)环烷基(C1-4)烷基羰基氧基、(C3-8)环烷基((C1-4)烷基)氨基羰基、苯基羰基,或具有5或6个环原子和1-4个选自N、O、S的杂原子的杂环基,例如噁二唑基,
所述环己基更优选被(C1-6)烷氧基羰基氨基(C1-4)烷基或(C1-6)烷氧基羰基氨基取代,
R18P2是氢。
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中R1P3具有如上文所定义的R1的含义,R16P3和R17P3与它们所连接的碳原子一起是被取代的桥连环烷基环系,其中取代基如上文关于桥连环烷基环系所定义,且R18P3具有如上文所定义的R18的含义。
在式IP3化合物中,优选地
-R1P3是未被取代或被取代的苯基或噻吩基,
-R16P3和R17P3与它们所连接的碳原子一起是桥连环烷基环系,所述桥连环烷基环系被下列基团取代:
-(C4-12)烷基,
-被羟基、苯基取代的(C1-6)烷基,
-未被取代的苯基和被取代的苯基,其中取代基如上文关于苯基所定义,
-(C1-6)烷氧基羰基氨基,例如叔丁氧基羰基氨基,
-(C1-6)烷氧基羰基(C1-6)烷基,
-(C3-8)环烷基羰基(C1-6)烷基,
-(C3-8)环烷氧基羰基(C1-6)烷基,
-(C1-6)烷基羰基,其中所述烷基未被取代或被取代,例如被羟基取代,
-(C3-8)环烷基,
-(C3-8)环烷基氨基(C1-6)烷基,
所述桥连环烷基环系更优选被下列基团取代:(C1-6)烷氧基羰基例如BOC,(C4-8)烷基例如戊基,或(C1-6)烷氧基羰基氨基例如叔丁氧基羰基氨基,
-R18P3是氢,例如下式所示的化合物
或下式所示的化合物
包括下式所示纯的异构体
及其混合物。
包含下式所示基团的化合物
通常是以式EX217化合物的构型获得的。
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中
R1P4具有如上文所定义的R1的含义,R16P4和R17P4与它们所连接的碳原子一起是被取代的桥连环烷基环系或被取代的哌啶、被取代的桥连杂环系、被取代的哌嗪或被取代的四氢吡啶,其中取代基如上文关于相应的基团所定义,并且其中哌嗪被如上文关于取代的哌啶所定义的基团取代,
R18P4具有如上文所定义的R18的含义,且
mP4是1、2、3或4。
在式IP4化合物中,优选地
R1P4是未被取代或被取代的苯基或噻吩基,
R16P4和R17P4与它们所连接的碳原子一起是被取代的桥连环烷基环系、被取代的哌啶或被取代的桥连哌啶,更优选是被取代的桥连环烷基环系或被取代的哌啶,
其中取代基选自
a)-(C1-6)烷氧基羰基,例如BOC,
-(C1-6)烷氧基羰基(C1-4)烷基,例如叔丁氧基羰基甲基,
-(C1-4)烷基羰基氧基(C1-4)烷基,例如其未被取代或被苯基取代,
-未被取代或被取代的苯基,其中取代基如上文关于苯基所定义,
-(C1-6)烷基羰基或苯基羰基,
(C3-8)环烷基(C1-4)烷基羰基,
-杂环基,例如吡啶,如吡啶-2-基,例如其被硝基取代,和任选地
b)在环碳原子上的(C1-4)烷基,
取代基更优选选自(C1-6)烷氧基羰基,例如BOC,苯基、未取代的苯基和取代的苯基,例如苯基被如上文关于取代的苯基所定义的基团,例如硝基、(C1-4)烷基、(C1-4)卤代烷基如三氟甲基、氨基羰基取代,
-R18P4是氢或羟基,更优选氢,
-mP4是1,例如下式所示的化合物
或下式所示的化合物
或下式所示化合物
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中
R1P5具有如上文所定义的R1的含义,
R13P5具有如上文所定义的R13的含义,且
R11P5和R12P5与它们所连接的碳原子具有如上文所定义的R11和R12的含义。
在式IP5化合物中,优选地
-R1P5是未被取代或被取代的苯基或噻吩基,
-R11P5和R12P5与它们所连接的碳原子一起是哌啶、甲基哌啶或桥连环烷基环系,其被下列基团取代:
-(C1-6)烷氧基羰基,例如叔丁氧基羰基;
-未被取代或被取代的苯基,其中取代基如上文关于苯基所定义,
-(C1-8)烷基羰基氧基,例如叔丁基-甲基羰基氧基,
取代基更优选选自(C1-8)烷氧基羰基,例如BOC,或(C1-6)烷基-羰基氧基例如叔丁基甲基羰基氧基,
-R3P5是氢、卤素或氰基。
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中
R1P6具有如上文所定义的R1的含义,
R16P6和R17P6与它们所连接的碳原子一起是被取代的(C4-8)环烷基,
R18P6具有如上文所定义的R18的含义,且
mP6是1、2、3或4。
在式IP6化合物中,优选地
-R1P6是未被取代或被取代的苯基或噻吩基,
-R16P6和R17P6与它们所连接的碳原子一起是被(C1-6)烷氧基羰基氧基或(C1-6)烷氧基羰基氨基取代的环己基,
-mP6是1。
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中
R1P7具有如上文所定义的R1的含义,
R16P7和R17P7与它们所连接的碳原子一起是被取代的(C4-8)环烷基,
R18P7具有如上文所定义的R18的含义,且
mP7是1、2、3或4。
在式IP7化合物中,优选地
-R1P7是未被取代或被取代的苯基,
-R16P7和R17P7与它们所连接的碳原子一起是被(C1-6)烷氧基羰基氨基(C1-4)烷基或(C1-6)烷氧基羰基氨基取代的环己基,其中所述氨基可任选被(C1-4)烷基取代,
-R18P7是氢,且
-mP7是1。
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中
R1P8具有如上文所定义的R1的含义,
R16P8和R17P8与它们所连接的碳原子一起是被取代的哌啶、四氢吡啶或哌嗪,其中取代基如上文关于哌啶所定义,
R18P8具有如上文所定义的R18的含义,
mP8是1,且nP8是1。
在式IP8化合物中,优选地
-R1P8是未被取代或被取代的苯基,
-R16P8和R17P8与它们所连接的碳原子一起是被(C1-6)烷氧基羰基取代的哌啶,
-R18P8是氢,
-mP8是1,
-nP8是1。
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中R1P9、R6P9和R7P9分别具有如上所定义的R1、R6和R7的相应含义。
在式IP9化合物中,优选地
-R1P9是未被取代或被取代的苯基,
-R6P9和R7P9彼此独立地为(C1-6)卤代烷基,未被取代或被取代的苯基,被(C3-8)环烷基氨基羰基或(C1-6)烷氧基羰基取代的哌啶基,或被取代的哌啶取代的氨基。
另一方面,本发明提供了下式所示的化合物
其中
R1P10具有R1的含义,
R8P10具有R8的含义,且
R9P10和R10P10与它们所连接的碳原子一起是(C4-8)环烷基。
在式IP10化合物中,优选地
-R1P10是被取代或未被取代的苯基,
-R8P10是被(C1-6)烷氧基羰基取代的哌啶或未被取代或被取代的苯基,
-R9P10和R10P10与它们所连接的碳原子一起是(C4-7)环烷基。
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中
R1P11具有R1的含义,
R11P11和R12P11与它们所连接的碳原子一起具有R11和R12与它们所连接的碳原子所具有的含义,
R13P11具有R13的含义,且
mP11是1、2、3或4。
在式IP11化合物中,优选地
-R1P11是被取代或未被取代的苯基,
-R11P11和R12P11与它们所连接的碳原子一起是被取代的桥连环烷基环系,-mP11是1。
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中
R2P12具有如上所定义的R8的含义,并且还可以是未被取代或被取代的(C6-18)芳基,其中取代基如上文关于芳基的取代基所定义,
R8P12具有如上所定义的R8的含义,
R9P12和R10P12具有如上所定义的R9和R10的含义,且
mP11是1、2、3或4。
在式IP12化合物中,优选地
-R2P12是被取代或未被取代的苯基,
-R8P12是氢或羟基,
-R9P12和R10P12与它们所连接的碳原子一起是
-A)在环氮原子上被下列基团取代的哌啶:(C1-6)烷氧基羰基、(C3-8)环烷基(C1-4)烷基羰基或未被取代或被取代的苯基,
-B)桥连环烷基环系,所述环系被例如氧代基团和(C1-4)烷基取代,
-mP12是1,例如下式所示的化合物
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中
R2P13具有如上所定义的R2的含义,并且还可以是未被取代或被取代的(C6-18)芳基,其中取代基如上文关于芳基的取代基所定义,
R11P13和R12P13具有如上所定义的R11和R12的含义,且
R13P13具有如上所定义的R13的含义。
在式IP13化合物中,优选地
-R2P13是未被取代或被取代的苯基,
-R11P13和R12P13与它们所连接的碳原子一起是哌啶,所述哌啶被下列基团取代:未被取代或被取代的苯基或(C1-6)烷氧基羰基,
-R13P13是氢。
另一方面,本发明提供了这样的式I化合物,其是下式所示的化合物
其中R1P14是(C6-18)芳基,且R2P14是(C6-18)芳基磺酰基(sulfondioxide)氨基。
在式IP14化合物中,优选地
-R1P14是被三氟甲基或卤素取代的苯基,
-R2P14是(C3-18)芳基磺酰基氨基例如苯基磺酰基氨基,所述基团未被取代或被下列取代基取代:(C1-6)烷基、或卤代(C1-3)烷基、(C1-3)烷氧基、卤代(C1-3)烷氧基或卤素。
式I化合物包括式IP1、IP2、IP3、IP4、IP5、IP6、IP7、IP8、IP9、IP10、IP11、IP12、IP13和IP14化合物。本发明所提供的化合物在下文中称为“本发明化合物”。本发明化合物包括任何形式,例如游离形式、盐形式、溶剂化物形式以及盐和溶剂化物形式的化合物。在本发明化合物中,除非另有说明,所指出的取代基是未被取代的。上文在式I化合物中定义的每个单独取代基自身可独立于其它所定义的取代基而是优选的取代基。
另一方面,本发明提供了盐形式,例如盐形式并且是溶剂化物形式,或溶剂化物形式的本发明化合物。
本发明化合物的盐包括可药用盐,例如包括金属盐、酸加成盐或胺盐。金属盐包括例如碱金属或碱土金属盐;酸加成盐包括式I化合物与酸例如HCl形成的盐;胺盐包括式I化合物与胺形成的盐。
可将游离形式的本发明化合物转化成相应的盐形式的化合物;反之亦然。可将游离形式或盐形式并且是溶剂化物形式的本发明化合物转化成相应的非溶剂化形式的游离形式或盐形式的化合物;反之亦然。
本发明化合物可以以异构体及其混合物的形式存在。本发明化合物可例如含有不对称碳原子,并因此可以以非对映异构体及其混合物的形式存在。在非芳环中的取代基可以彼此呈顺式或反式构型。例如,如果R1或R2包括可以在其环的碳原子上被另外的取代基取代的被取代的哌啶或四氢吡啶,则所述另外的取代基可以与也连接在所述哌啶或四氢吡啶上的(任选-(CH2)m-或-(CH2)n)磺酰胺基团呈顺式或反式构型关系;如果R1或R2包括被取代的环己基,则所述取代基可以与也连接在所述环己基环上的(任选-(CH2)m-或-(CH2)n)磺酰胺基团呈顺式或反式构型关系。可按照需要,例如依据常规方法将异构体混合物分离,以获得纯的异构体。本发明包括任何异构体形式以及任何异构体混合物形式的本发明化合物。
任何本文所述化合物,例如本发明化合物均可适当地制得,例如可按照常规方法或类似于常规方法的方法或如本文所具体描述的方法制得。
另一方面,本发明提供了制备式I化合物的方法,所述方法包括将式VIII化合物
其中R1和n如上所定义,
与式IX化合物反应,
其中R2和m如上所定义,
例如,所述反应物可以以活化的形式进行反应,例如和/或所述反应可在偶联剂存在下进行;从所得反应混合物中分离出其中R1、R2、m和n如上所述的式I化合物,例如
如果式I化合物包含式II或式V所示的基团,则可将式VIII化合物与式X或XI化合物反应
其中取代基如上所定义,
例如,所述反应物可以以活化的形式进行反应,例如和/或所述反应可在偶联剂存在下进行,以获得其中取代基如上所定义的式I化合物。
上述反应是酰化反应,并且可适当地进行,例如在合适的溶剂中于适当温度下进行,例如按照常规方法,例如按照类似于常规方法的方法,或按照本文所述的方法,例如按照类似于本文所述方法的方法进行。
如果在式I化合物中,哌啶、四氢吡啶或哌嗪或者在桥中包含氮原子的桥连环烷基环系是未被取代的,则这样的环可以例如在氮原子上被取代,例如通过酰化引入包含羰基的残基,例如通过与含有氟的苯基反应(其中氟起离去基团的作用)进行N-苯基化(类似地,使用被作为离去基团的氯取代的相应杂环,可将杂环基连接在氮上)。可将通过反应步骤获得的酯基皂化以获得羧酸基团,反之亦然。
式VIII、IX、X和XI的化合物是已知的,或者可适当地制得,例如按照常规方法,例如按照类似于常规方法的方法,或按照本文所述的方法制得。
例如,式VIII化合物可通过用NH3(水溶液)处理而由式XII化合物获得
例如,式X或XI化合物可这样制得:将化合物R2-H,其中R2是在(桥连)环系的一个碳原子上携带氧代基团的式II或式V所示的基团,与下列化合物反应
-(RO)2OP-CHRx-COO-R,其中R是烷基,例如(C1-4)烷基如甲基或乙基,且Rx是如上所定义的R3或R8,所述反应在溶剂例如四氢呋喃中,在碱例如氢化钠存在下进行;或
-Ph3-P-CRx-COO-C2H5,其中Rx如上所定义,所述反应在溶剂例如甲苯中于例如高于室温的温度下进行,或者
-如果Rx是氢,与NC-CH2-COOR反应,其中R如上所定义,所述反应在溶剂例如二甲基甲酰胺中,在催化剂例如哌啶和β-丙氨酸存在下,于例如高于室温的温度下进行;
然后在溶剂例如四氢呋喃/H2O中,于例如高于室温的温度下,用NaOH或LiOH处理所得化合物。
特定组织中的类固醇激素与多种疾病,例如乳腺癌、子宫内膜癌和***癌,毛囊皮脂腺病症例如痤疮、雄激素性脱发和多毛症有关。局部产生这些类固醇激素的重要前体是类固醇3-O-硫酸酯,其在目标组织中被类固醇硫酸酯酶脱硫酸化。抑制该酶可导致相应的活性类固醇激素的局部水平降低,预计这将有治疗价值。此外,类固醇硫酸酯酶抑制剂可用作免疫抑制剂,并且证实当递送到脑中时其能提高记忆力。
痤疮是由多种因素例如遗传、皮脂、激素和细菌的相互影响而引起的多病因疾病。最重要的痤疮致病因素是皮脂生成;与具有健康皮肤的人相比,在几乎所有痤疮患者中,皮脂腺都更大,并产生更多的皮脂。皮脂腺的发育和皮脂生成的程度是由雄激素通过激素控制的;因此,雄激素在痤疮的发病机理中起决定性作用。在男性中,有两个主要来源给目标组织提供雄激素:(i)分泌睾酮的性腺,(ii)产生以硫酸酯缀合物(DHEAS)的形式分泌的脱氢表雄甾酮(DHEA)的肾上腺。在目标组织例如皮肤中,睾酮和DHEAS都被转化成活性最强的雄激素二氢睾酮(DHT)。有证据表明,这些在皮肤中局部合成DHT的途径比从循环中直接补充活性雄激素更重要。因此,用特异性抑制剂降低目标组织中内源性雄激素水平应当对于痤疮和皮脂溢有治疗益处。此外,这启示了通过局部治疗调节局部雄激素水平,而不是通过全身治疗影响循环激素水平来治疗这些病症。
雄激素性男性脱发在白种人中非常普遍,约占所有类型脱发的95%。男性模式脱发是由于头皮中进入毛发生长终期的发囊数量增加并且毛发生长终期持续更长的时间而引起的。通过雄激素引起的脱发是由遗传决定的。据报道,与未秃顶的对照相比,在秃顶男性中,血清DHEA水平增高,但睾酮水平正常,这意味着在雄激素性脱发中,目标组织雄激素生成很重要。
多毛症是病理性的毛发增厚和增强,其特征是在儿童和女性中出现男性模式的毛发生长。多毛症是由雄激素引起的,是通过增加雄激素形成或者通过增加发囊对雄激素的敏感性而导致的。因此,使得目标组织(皮肤)中雄激素和/或***的内源性水平降低的治疗应当对痤疮、雄激素性脱发和多毛症有效。
如上所述,在皮肤中,DHT-活性最强的雄激素是由大量全身存在的前体DHEAS合成的,并且在从DHEAS到DHT的代谢途径中,第一个步骤是通过类固醇硫酸酯酶的作用将DHEAS脱硫酸化,以生成DHEA。已经描述了在角质形成细胞和皮肤衍生的成纤维细胞中存在该酶。已经使用已知的类固醇硫酸酯酶抑制剂例如雌酮3-O-氨基磺酸酯和4-甲基伞形醇(umbelliferyl)-7-O-氨基磺酸酯证实了类固醇硫酸酯酶抑制剂在降低皮肤中类固醇激素内源性水平方面的可能应用。我们已经发现,胎盘类固醇硫酸酯酶的抑制剂还抑制由人角质形成细胞(HaCaT)或人皮肤衍生成纤维细胞系(1BR3GN)制备的类固醇硫酸酯酶。这些抑制剂也显示出可以阻断完整单层HaCaT角质形成细胞中的类固醇硫酸酯酶。
因此,类固醇硫酸酯酶抑制剂可用于降低皮肤中的雄激素和***水平。它们可作为类固醇硫酸酯酶抑制剂来用于局部治疗毛囊皮脂腺的雄激素依赖性病症(例如痤疮、皮脂溢、雄激素性头发、多毛症)和局部治疗鳞状细胞癌。
此外,预计非甾体类固醇硫酸酯酶抑制剂可用于治疗其中硫酸酯酶的类固醇裂解产物起作用的通过类固醇激素的作用介导的病症。这些新型抑制剂的适应症包括毛囊皮脂腺的雄激素依赖性病症(例如痤疮、皮脂溢、雄激素性脱发、多毛症);***或雄激素依赖性肿瘤,例如鳞状细胞癌和肿瘤,例如乳腺癌、子宫内膜癌和***癌;炎性和自身免疫性疾病,例如类风湿性关节炎、I型和II型糖尿病、全身性红斑狼疮、多发性硬化、重症肌无力、甲状腺炎、脉管炎、溃疡性结肠炎和局限性回肠炎、牛皮癣、接触性皮炎、移植物对抗宿主疾病、湿疹、哮喘和移植术后的器官排斥。类固醇硫酸酯酶抑制剂还可用于治疗癌症,尤其是***和雄激素依赖性癌症,例如乳腺癌、子宫内膜癌、鳞状细胞癌和***癌。类固醇硫酸酯酶抑制剂还可用于通过增加中枢神经***中的DHEAS水平来提高认知功能,尤其是治疗老年痴呆,包括阿尔茨海默氏病。
可通过下列测试***来证明本发明化合物在抑制类固醇硫酸酯酶活性中的活性:
人类固醇硫酸酯酶的纯化
在分娩后获得新鲜的人胎盘,剥去膜以及***。将该材料在-70℃冷冻以进行贮存。融化后,所有进一步的步骤都是在4℃进行,而pH值是在20℃调节的。将400g组织在1.2升缓冲液A(50mM Tris-HCl,pH7.4,0.25M蔗糖)中匀化。将所得匀浆以10,000×g离心45分钟。取出上清液,将所得离心沉淀团在500ml缓冲液A中再次匀化。离心后,将所得两份上清液合并,进行超速离心(100,000×g,1小时)。将所得离心沉淀团重悬在缓冲液A中,再次离心。将所得离心沉淀团悬浮在50ml 50mM Tris-HCl,pH7.4中,在-20℃贮存直至进一步处理。
融化后,通过超速离心(如上所述)收集微粒体,悬浮在50ml缓冲液B(10mM Tris-HCl,pH7.0,1mM EDTA,2mM 2-巯基乙醇,1%Triton X-100,0.1%抑蛋白酶肽)中。在冰上轻微搅拌1小时后,将悬浮液离心(100,000×g,1小时)。收集具有酶活性的上清液,用1M Tris将pH调节至8.0。将所得溶液装载到羟磷灰石柱(2.6×20cm)上,用缓冲液B,pH8.0平衡。用缓冲液B以2ml/分钟的流速洗涤该柱。在流出液中回收活性。将合并的所需洗脱液调节至pH7.4,在用缓冲液C(20mM Tris-HCl,pH7.4,0.1%TritonX-100,0.5M NaCl)平衡的伴刀豆球蛋白A琼脂糖柱(1.6×10cm)上进行色谱处理。用缓冲液C洗涤该柱,用10%甘露糖甲苷在缓冲液C中的溶液洗脱结合的蛋白。将活性级份合并,用缓冲液D(20mM Tris-HCl,pH8.0,1mM EDTA,0.1%Triton X-100,10%甘油(v/v))透析。将所得保留物装载到用缓冲液D平衡的蓝琼脂糖柱(0.8×10cm)上;用缓冲液D至2M NaCl在缓冲液D中的溶液的线性梯度洗脱该柱。将活性级份合并,按照需要浓缩(Centricon 10),用缓冲液D透析,并以等份试样在-20℃贮存。
人类固醇硫酸酯酶的测定
已知纯化的人类固醇硫酸酯酶不仅能裂解类固醇硫酸酯,而且还能容易地裂解硫酸芳基酯例如4-甲基伞形醇硫酸酯,其在该测试***中用作活性指示剂。通过连续地将下列溶液配送到白色微量滴定板的孔中来制备测定混合物:
1)50μl底物溶液(1.5mM 4-甲基伞形醇硫酸酯在0.1M Tris-HCl,pH7.5中的溶液)
2)50μl测试化合物在0.1M Tris-HCl,pH7.5,0.1%Triton X-100中的稀释液(测试化合物的贮备液是在DMSO中制备的;溶剂在测定混合物中的终浓度不超过1%)
3)50μl酶稀释液(约12个酶单位/ml)
我们将1个酶单位定义为:在37℃,在0.1M Tris-HCl,pH7.5,0.1%Triton X-100中,在500μM的初始底物浓度下,每小时水解1nmol 4-甲基伞形醇硫酸酯的类固醇硫酸酯酶的量。
将平板在37℃培养1小时。然后通过加入100μl 0.2M NaOH来停止反应。在λex=355nm和λem=460nm的Titertek Fluoroskan II仪器中测定荧光强度。
计算相对IC50值
由在上述人类固醇硫酸酯酶测定中在测试化合物的不同浓度(c)下获得的荧光强度数据(I),使用下述公式计算将酶活性抑制50%的浓度(IC50):
其中I100是在没有抑制剂存在的情况下观测到的强度,且s是斜率因数。使用雌酮氨基磺酸酯作为参照化合物,并且以与所有其它测试化合物平行的方式测定其IC50值。相对IC50值定义为:
根据我们的测试和计算,雌酮氨基磺酸酯表现出约60nM的IC50值。
本发明化合物在所述测定中表现出活性(相对IC50为0.0046-10)。
CHO/STS测定
将用人类固醇硫酸酯酶稳定转染的CHO细胞(CHO/STS)接种到微量滴定板内。达到约90%融合以后,将其与梯度浓度的测试物(例如本发明化合物)一起培养过夜。然后在室温用4%低聚甲醛将其固定10分钟,用PBS洗涤4次,然后与溶解在0.1M Tris-HCl,pH7.5中的100μl/孔0.5mM 4-甲基伞形醇硫酸酯(MUS)一起培养。该酶反应在37℃进行30分钟。然后加入50μl/孔停止溶液(1M Tris-HCl,pH10.4)。将该酶反应溶液转移到白色平板(Microfluor,Dynex,Chantilly,VA)内,在Fluoroskan II荧光微量滴定板读数器中读数。从总值中减去试剂空白。对于药物测试,用荧光单位(FU)除以用磺基罗丹明(sulforhodamine)B将细胞蛋白染色后的光密度读数(OD550)以校正细胞数目差异。通过在两个划界点之间进行的线性内插法来确定IC50值。在用抑制剂进行的每个测定中,都使用雌酮3-O-氨基磺酸酯作为参照化合物,并将IC50值相对于雌酮3-O-氨基磺酸酯进行归一化(相对IC50=化合物的IC50/雌酮3-O-氨基磺酸酯的IC50)。
本发明化合物在所述测定中表现出活性(相对IC50为0.05至10)。
使用人皮肤匀浆的测定
使用锋利的剪刀将冷冻的人尸体皮肤样本(每个样本约100mg)切成小片(约1×1mm)。将所得皮肤片悬浮在10倍体积(w/w)的含有0.1%TritonX-100的缓冲液(20mM Tris-HCl,pH7.5)中。用在乙醇或DMSO内的贮备液加入梯度浓度的测试化合物(例如本发明化合物)。然后加入作为底物的DHEAS(1μC/ml [3H]DHEAS,比活度:约60Ci/mmol,和20μM未标记的DHEAS)。将样本在37℃培养18小时。培养结束时,加入50μl 1M Tris,pH10.4和3ml甲苯。取出1ml等份试样的有机相,进行液体闪烁计数。将在等份试样中测定的dpm值转化成每小时每克皮肤裂解的DHEA的nmol数。
本发明化合物在所述测定中表现出活性(IC50为0.03-10μM)。
本发明化合物在如上所定义的测试***中表现出活性。盐和/或溶剂化物形式的本发明化合物表现出与游离和/或非溶剂化形式的本发明化合物相同数量级的活性。
因此,本发明化合物可作为类固醇硫酸酯酶抑制剂用于治疗由类固醇硫酸酯酶的作用所介导的病症,例如包括毛囊皮脂腺的雄激素依赖性病症,例如痤疮、皮脂溢、雄激素性脱发、多毛症;癌症,例如***和雄激素依赖性癌症;和认知功能障碍,例如老年痴呆,包括阿尔茨海默氏病。治疗包括治疗和预防。
优选的本发明化合物包括实施例208的化合物、实施例217和218的化合物、实施例248的化合物、实施例249的化合物、实施例251的化合物和实施例379的化合物。这些化合物在人类固醇硫酸酯酶测定中表现出的相对IC50为0.0046-0.29,在CHO/STS测定中表现出的相对IC50为0.05-0.18,在使用人皮肤匀浆的测定中表现出的IC50为0.03-0.27μM,因此是高活性的类固醇硫酸酯酶抑制剂。甚至更优选的化合物是实施例217和实施例218的化合物,它们在人类固醇硫酸酯酶测定中表现出的相对IC50为0.29,在CHO/STS测定中表现出的相对IC50为0.08,在使用人皮肤匀浆的测定中表现出的IC50为0.27μM。
另一方面,本发明提供了用作药物,例如用作治疗由类固醇硫酸酯酶的作用介导的病症的药物的式I化合物。
另一方面,本发明提供了用于制备治疗由类固醇硫酸酯酶的作用介导的病症的药物的式I化合物。
另一方面,本发明提供了治疗由类固醇硫酸酯酶的作用介导的病症的方法,包括给需要这种治疗的个体施用治疗有效量的式I化合物。
对于这样的应用,所用剂量当然会根据例如使用的特定化合物、给药方式和所需的治疗而有所不同。然而,一般情况下,如果化合物以约0.1mg/kg-约100mg/kg动物体重的日剂量给药,例如每天分2-4次给药,可获得令人满意的结果。对于大型哺乳动物,总日剂量为约5mg-约5000mg,例如每天分最多4次进行给药,或者以延迟的形式给药。单位剂型包括例如约1.25mg-约2000mg本发明化合物以及与其混和的至少一种可药用赋形剂例如载体、稀释剂。本发明化合物可以以可药用盐,例如酸加成盐、金属盐、胺盐的形式;或以游离形式;任选以溶剂化物的形式给药。本发明化合物可以按照类似于已知用于这类适应症的准则的方式给药。可将本发明化合物与常规例如可药用赋形剂如载体和稀释剂以及任选另外的赋形剂混和。本发明化合物可以以例如药物组合物的形式给药,
-口服给药,例如以片剂、胶囊的形式口服给药;
-非胃肠道给药、静脉内给药,例如以液体如溶液、混悬液的形式给药;
-局部给药,例如以膏剂、霜剂的形式局部给药。
活性物质在药物组合物中的浓度当然会根据例如所用的化合物、所需治疗和所用组合物的性质而有所不同。一般情况下,在局部给药用组合物中约0.05-约5%,例如约0.1-约1%w/w的浓度,在口服、非胃肠道给药或静脉内给药用组合物中约1%w/w-约90%w/w的浓度可获得令人满意的结果。
另一方面,本发明提供了药物组合物,其中包含药物有效量的至少一种本发明化合物和至少一种可药用赋形剂。
本发明药物组合物可包含一种或多种,例如至少一种本发明化合物,和一种或多种其它药物活性剂作为活性组分。因此,本发明化合物可单独用于药物治疗,或者与一种或多种另外的药物活性剂联合用于治疗。所述另外的药物活性剂包括例如类维生素A,例如视黄酸,如异维A酸;维A酸(Roche);阿达帕林(6-[3-(1-金刚烷基)-4-甲氧基苯基]-2-萘甲酸);口服避孕药,例如19-去甲-17a-孕-1,3,5(10)-三烯-20-炔-3,17-二醇、6-氯-17-羟基-1a,2a-亚甲基-4,6-孕二烯-3,20-二酮,例如Diane(Schering);抗生素,例如红霉素类,包括红霉素A,阿奇霉素、克拉霉素、罗红霉素;四环素类,林可酰胺类抗生素,例如克林霉素(甲基7-氯-6,7,8-三去氧-6-(反式-1-甲基-4-丙基-L-2-吡咯烷-甲酰氨基)-1-硫代-L-苏型-a-D-半乳-吡喃辛糖苷)、壬二酸、那氟沙星;过氧化苯甲酰。
联合用药物包括
-固定的联合用药物,其中两种或多种药物活性剂在同一药物组合物中,
-药盒,其中两种或多种药物活性剂在单独的组合物中,这些组合物在同一包装内销售,例如具有关于联合给药的说明书;和
-自由的联合用药物,其中药物活性剂单独包装,但是给予有关同时或顺序给药的说明书。
另一方面,本发明提供了与至少一种其它药物活性剂联合用作药物的本发明化合物,所述药物是例如药物组合物,其中包含至少一种本发明化合物和与其联合使用的至少一种其它药物活性剂以及至少一种可药用赋形剂。
在下列实施例中,所有温度都是摄氏度,并且是未校正的。
使用下列缩写:
DIEA:二异丙基乙胺
DMA:N,N-二甲基乙酰胺
DMAP:N,N-二甲基氨基吡啶
DMF:N,N-二甲基甲酰胺
DMSO:二甲亚砜
EDC:盐酸盐形式的1-乙基-3-(3′-二甲基氨基丙基)碳二亚胺
EtAc:乙酸乙酯
EX:实施例
HEX:正己烷
c-HEX:环己烷
m.p.:熔点
PPA:丙烷膦酸酐
RT:室温
THF:四氢呋喃
操作方法
实施例A
4-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基羰基)-哌啶-1-甲酸叔丁酯(实施例1的化合物)
a.4-溴-2,5-二氯-噻吩-3-磺酰胺
在室温将90ml氨水溶液(32%)加到8.88g 4-溴-2,5-二氯-噻吩-3-磺酰氯在120ml乙酸乙酯内的溶液中。将所得混合物搅拌约15小时。分离所获得的两相,将有机层用1N HCl和H2O洗涤,并干燥。将有机相的溶剂蒸发。得到4-溴-2,5-二氯-噻吩-3-磺酰胺,为白色粉末。m.p.113-117℃;13C-NMR(CDCl3):=108.287;125.342;130.404;135.716。
b.4-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基羰基)-哌啶-1-甲酸叔丁酯
将60mg DMAP、130mg DIEA和192mg EDC加到155mg 4-溴-2,5-二氯-噻吩-3-磺酰胺和230mg 1-(叔丁氧基羰基)-哌啶-4-甲酸在8ml DMF内的溶液中。将所得混合物在约30℃搅拌约16小时,将溶剂蒸发,将蒸发的残余物用乙酸乙酯处理。将所得混合物用1N盐酸、饱和碳酸氢钠水溶液和盐水洗涤,并干燥。将溶剂从所得有机相中蒸发出去,通过色谱法纯化蒸发的残余物。得到4-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基羰基)-哌啶-1-甲酸叔丁酯,并从1,4-二氧杂环己烷中冷冻干燥。
实施例B
4-(3,5-二-三氟甲基-苯磺酰基氨基羰基)-顺式-3-甲基-哌啶-1-甲酸叔丁酯(实施例72的化合物)和
4-(3,5-二-三氟甲基-苯磺酰基氨基羰基)-反式-3-甲基-哌啶-1-甲酸叔丁酯(实施例73的化合物)
在0℃,将18ml二(三甲基甲硅烷基)氨基钠的THF溶液(2M)加到12.4g甲氧基甲基三苯基氯化鏻在25ml无水THF内的悬浮液中。向所得混合物中缓慢地加入在25ml THF内的5.87g 3-甲基-4-氧代-哌啶-1-甲酸叔丁酯,将所得混合物在0℃搅拌,用乙酸乙酯稀释,用1M盐酸、饱和碳酸氢钠水溶液和盐水萃取。将所得有机层干燥,并将溶剂蒸发。将所得蒸发残余物经由硅胶过滤,将所得滤液的溶剂蒸发。将3.6g所得过滤残余物溶解在150ml CH3CN中,加入1.68g三氯化铈七水合物和337mg碘化钠,将所得混合物在40℃搅拌过夜。从所得混合物中蒸除溶剂,用乙酸乙酯处理所得蒸发残余物。用1M盐酸、饱和碳酸氢钠水溶液和盐水萃取所得混合物。将所得有机层干燥,蒸除溶剂,将所得蒸发残余物经由硅胶过滤,将所得滤液的溶剂蒸发。将494mg所得蒸发残余物与1.18g单过氧邻苯二甲酸镁六水合物在36ml EtOH/H2O(1∶1)中于室温搅拌,用乙酸乙酯稀释。用1M盐酸萃取所得混合物。将所得有机层干燥,蒸除溶剂,将蒸发残余物过滤,将所得滤液的溶剂蒸发。向60mg所得蒸发残余物的溶液中加入在2mlDMF内的71mg 3,5-二(三氟甲基)苯基磺酰胺、94mg EDC和30mg DMAP以及84μl DIEA,将所得混合物在室温振摇。将溶剂从所得混合物中除去,在RP-18柱上通过制备HPLC纯化所得浓缩残余物(CH3CN/H2O(0.1%TFA))。得到4-(3,5-二-三氟甲基-苯磺酰基氨基羰基)-顺式-3-甲基-哌啶-1-甲酸叔丁酯和4-(3,5-二-三氟甲基-苯磺酰基-氨基羰基)-反式-3-甲基-哌啶-1-甲酸叔丁酯。
实施例C
N-[1-(2-硝基-苯基)-哌啶-4-羰基]-3,5-二-三氟甲基-苯磺酰胺(实施例81的化合物)
a.盐酸盐形式的N-(哌啶-4-羰基)-3,5-二-三氟甲基-苯磺酰胺
将2g 4-(3,5-二-三氟甲基-苯磺酰基氨基羰基)-哌啶-1-甲酸叔丁酯溶解在1ml MeOH与9ml CH2Cl2的混合物中。将所得混合物在室温用20ml 3NHCl在(C2H5)2O中的溶液处理约16小时。将溶剂蒸发,得到盐酸盐形式的N-(哌啶-4-羰基)-3,5-二-三氟甲基-苯磺酰胺。m.p.285-291℃。
b.N-[1-(2-硝基-苯基)-哌啶-4-羰基]-3,5-二-三氟甲基-苯磺酰胺
将0.13g DIEA和0.07g 1-氟-2-硝基苯加到0.22g盐酸盐形式的N-(哌啶-4-羰基)-3,5-二-三氟甲基-苯磺酰胺在4ml DMSO内的溶液中。将所得混合物在80℃搅拌约18小时,将溶剂蒸发,将蒸发的残余物进行快速硅胶色谱纯化(洗脱剂∶乙酸乙酯)。得到N-[1-(2-硝基-苯基)-哌啶-4-羰基]-3,5-二-三氟甲基-苯磺酰胺。
实施例D
反式-[4-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基羰基)-环己基甲基]-氨基甲酸叔丁酯(实施例109的化合物)
a.4-溴-2,5-二氯-噻吩-3-磺酰胺
在室温将90ml氨水溶液(32%)加到8.88g 4-溴-2,5-二氯-噻吩-3-磺酰氯在120ml乙酸乙酯内的溶液中。将所得混合物搅拌约15小时,分离所获得的两相。将有机层用1N HCl和H2O洗涤,并干燥。将所得有机溶液的溶剂蒸发。得到4-溴-2,5-二氯-噻吩-3-磺酰胺,为白色粉末。
m.p.113-117℃,13C-NMR:δ=108.287;125.342;130.404;135.716。
b.反式-[4-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基羰基)-环己基甲基]-氨基甲酸
叔丁酯
将60mg DMAP、130mg DIEA和192mg EDC加到155mg 4-溴-2,5-二氯-噻吩-3-磺酰胺和257mg反式-1-(叔丁氧基羰基-氨基甲基)环己烷-4-甲酸在8ml DMF内的溶液中,将所得混合物在约30℃搅拌约16小时。从所得混合物中蒸除溶剂,将所得蒸发残余物溶解在乙酸乙酯中。将所得溶液用1N HCl、饱和碳酸氢钠溶液和盐水洗涤,并干燥。将溶剂从所得有机相中蒸发出来,通过色谱法纯化所得蒸发的残余物。得到反式-[4-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基羰基)-环己基甲基]-氨基甲酸叔丁酯。
实施例E
4-氯-N-(4-戊基-二环[2.2.2]辛烷-1-羰基)-苯磺酰胺(实施例186的化合物)
将0.42g 4-氯苯基磺酰胺、60mg DMAP和0.42g EDC加到0.5g 4-戊基-二环[2.2.2]辛烷-1-甲酸在8ml DMF内的溶液中,将所得混合物在室温搅拌约16小时,从所得混合物中蒸除溶剂。将所得蒸发残余物溶解在乙酸乙酯中,用1N HCl、饱和碳酸氢钠溶液和盐水洗涤,将所得有机相干燥。将所得有机相的溶剂蒸发,通过色谱法纯化所得蒸发残余物。得到4-氯-N-(4-戊基-二环[2.2.2]辛烷-1-羰基)-苯磺酰胺,为白色粉末;
实施例F
10-(3,5-二-三氟甲基-苯磺酰基氨基羰基)-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯(实施例217的化合物)
a.10-氧代-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯
将25g氢溴酸盐形式的8-甲基-8-氮杂-二环[4.3.1]癸-10-酮溶解在H2O中,通过加入氢氧化钠水溶液将pH调节至约11。用(C2H5)2O萃取所得混合物。将所得有机层干燥,将溶剂蒸发。将所得蒸发残余物溶解在50ml二氯乙烷中,在0℃加入23.7ml氯甲酸1-氯乙酯。将所得混合物在80℃搅拌,冷却至室温,加入50ml MeOH。将所得混合物在60℃搅拌,将溶剂蒸发,将所得蒸发残余物与18g K2CO3和28.4g二碳酸二叔丁酯一起用240ml THF/H2O(5∶1)处理,在室温搅拌。将所得混合物减压浓缩,用乙酸乙酯稀释。将所得混合物用H2O、1M盐酸、饱和碳酸氢钠溶液和盐水萃取。将所得有机层干燥,并将溶剂蒸发。将蒸发残余物经由硅胶过滤,用乙酸乙酯/c-Hex(1∶3)洗涤。得到10-氧代-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯。m.p.:50-52℃;13C-NMR:211.99,154.82,80.20,48.70,28.44,26.40。
b.10-甲氧基亚甲基-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯
在0℃、搅拌下,向9.54g甲氧基甲基三苯基氯化鏻在25ml无水THF内的悬浮液中加入13.8ml二(三甲基甲硅烷基)氨基钠的THF溶液(2M)。
向所得混合物中缓慢地加入在25ml THF内的5.40g 10-氧代-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯,并继续在0℃搅拌。将所得混合物用乙酸乙酯稀释,用1M盐酸、饱和碳酸氢钠水溶液和盐水萃取。将所得有机层干燥,并将溶剂蒸发。将所得蒸发残余物经由硅胶过滤,用乙酸乙酯/c-Hex(1∶9)洗涤。得到10-甲氧基亚甲基-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯。
13C-NMR:155.54,142.46,118.38,79.58,59.82,52.17,50.89,49.54,36.93,35.53,34.91,33.80,33.50,32.08,28.94,27.30,27.18。
c.10-甲酰基-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯
将4.8g 10-甲氧基亚甲基-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯溶解在180ml CH3CN中,加入1.94g三氯化铈七水合物和390mg碘化钠,将所得混合物在40℃搅拌过夜。从所得混合物中蒸除溶剂,将所得蒸发残余物溶解在乙酸乙酯中。用1M盐酸、饱和碳酸氢钠水溶液和盐水萃取所得混合物。将所得有机层干燥,将溶剂蒸发,将所得蒸发残余物经由硅胶过滤,用乙酸乙酯/c-Hex(1∶4->1∶2)洗涤。得到10-甲酰基-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯。m.p.:55-60℃;13C-NMR:204.53,155.28,78.00,55.40,32.44,32.12,30.06,28.89,27.29。
d.8-氮杂-二环[4.3.1]癸烷-8,10-二甲酸8-叔丁酯
将2.86g 10-甲酰基-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯和5.8g单过氧邻苯二甲酸镁六水合物在170ml EtOH/H2O(1∶1)中于室温搅拌。用乙酸乙酯稀释所得混合物。用1M盐酸和盐水萃取所得混合物。将所得有机层干燥,蒸除溶剂,将蒸发的残余物从MeOH/H2O中结晶。得到8-氮杂-二环[4.3.1]癸烷-8,10-二甲酸8-叔丁酯。m.p.:218-222℃;13C-NMR:179.88,155.31,80.00,52.43,50.98,47.63,33.14,32.31,28.91,27.06。
e.10-(3,5-二-三氟甲基-苯磺酰基氨基羰基)-8-氮杂-二环[4.3.1]癸烷-8-甲酸
叔丁酯
将6.1ml 50%PPA的DMF溶液、633mg DMAP的50ml二甲胺溶液和1.8ml DIEA加到1.5g 8-氮杂-二环[4.3.1]癸烷-8,10-二甲酸8-叔丁酯、2.3g3,5-二(三氟甲基)苯基磺酰胺的溶液中,将所得混合物在40℃搅拌,用乙酸乙酯稀释。用1M NaHSO4水溶液、饱和碳酸氢钠溶液和盐水萃取所得混合物。从所得混合物中蒸除溶剂。经由硅胶过滤来纯化所得蒸馏残余物,用乙酸乙酯/c-Hex/MeOH(5∶5∶1)洗涤,将纯化的残余物从CH3CN∶H2O(4∶6)中结晶。得到钠盐形式的10-(3,5-二-三氟甲基苯磺酰基氨基-羰基)-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯,将其溶解在乙酸乙酯和1M盐酸以及H2O中,分离所得各相,将所得有机层干燥,并将溶剂蒸发。得到10-(3,5-二-三氟甲基-苯磺酰基氨基羰基)-8-氮杂-二环[4.3.1]癸烷-8-甲酸叔丁酯。
实施例G
2-{4-[2-(3,5-二-三氟甲基-苯磺酰基氨基)-2-氧代-乙基]-哌啶-1-基}-4-三氟甲基-苯甲酰胺(实施例241的化合物)
a.3,5-二-(三氟甲基)苯-磺酰胺
在室温下将氨水溶液(32%)加到3,5-二(三氟甲基)-苯磺酰氯的乙酸乙酯溶液中。搅拌所得混合物并将所得到两相分离。将有机层用1N HCl和H2O洗涤并干燥。将所得有机溶液的溶剂蒸发。得到3,5-二-三氟甲基-苯磺酰胺。
b.2-{4-[2-(3,5-二-三氟甲基-苯磺酰基氨基)-2-氧代-乙基]-哌啶-1-基}-4-三氟
甲基-苯甲酰胺
将0.46g 2-氟-4-(三氟甲基)苯甲酰胺加到1.8g K2CO3和0.8g哌啶-4-基乙酸盐酸盐在12ml DMSO内的悬浮液中,将所得混合物在150℃搅拌4小时,将溶剂蒸发,将所得蒸发残余物悬浮在MeOH中,过滤。将所得滤液浓缩,通过硅胶色谱纯化。得到[1-(2-氨基甲酰基-5-三氟甲基-苯基)-哌啶-4-基]-乙酸。将300mg EDC加到260mg[1-(2-氨基甲酰基-5-三氟甲基-苯基)-哌啶-4-基]-乙酸、230mg 3,5-二-三氟甲基-苯磺酰胺、200mg DIEA和90mg DMAP在4ml DMF内的溶液中。将所得混合物在室温搅拌3天,将溶剂真空蒸发,用乙酸乙酯处理所得蒸发残余物。将所得混合物用1N HCl、饱和碳酸氢钠水溶液和盐水洗涤,干燥,真空浓缩,通过硅胶色谱纯化。得到2-{4-[2-(3,5-二-三氟甲基-苯磺酰基氨基)-2-氧代-乙基]-哌啶-1-基}-4-三氟甲基-苯甲酰胺。
实施例H
3-[2-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基)-2-氧代-乙基]-9-氮杂-二环[3.3.1]壬
烷-9-甲酸叔丁酯(实施例242的化合物)
a.3-氧代-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯
将19.1g盐酸盐形式的9-甲基-9-氮杂-二环[3.3.1]壬-3-酮悬浮在150ml二氯乙烷中,在0℃缓慢地加入26ml DIEA。将所得混合物在0℃搅拌1小时,向所得混合物中加入27ml氯甲酸1-氯乙酯,将所得混合物在80℃搅拌8小时,然后冷却至室温。向所得混合物中加入100ml MeOH,将所得混合物在60℃搅拌5小时,并将溶剂蒸发。将所得蒸发残余物、18g K2CO3和28.4g二碳酸二叔丁酯用250ml THF/H2O处理,将所得混合物在室温搅拌3小时,减压浓缩,用乙酸乙酯稀释。将所得混合物用H2O、1M HCl、饱和碳酸氢钠溶液和盐水洗涤,将所得有机层干燥,并将溶剂蒸发。将所得蒸发残余物经由硅胶过滤。得到3-氧代-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯,为油状物,将其结晶。13C-NMR:209.94,168.09,154.33,80.56,48.90,47.58,45.81,45.61,30.95,30.67,28.81,16.67。
b.3-乙氧基羰基亚甲基-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯
在0℃,将0.54ml(二乙氧基-磷酰基)-乙酸乙酯滴加到108mg NaH(55%矿物油悬浮液)在5ml THF内的悬浮液中。将所得混合物搅拌,缓慢地加入在5ml THF中的650mg 3-氧代-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯。将所得混合物在60℃搅拌3天,用环己烷稀释,用1M NaH2PO4水溶液和饱和碳酸氢钠水溶液洗涤。将所得有机层干燥,将溶剂蒸发,通过硅胶色谱法纯化所得蒸发残余物。得到3-乙氧基羰基亚甲基-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯,为油状物。13C-NMR:171.79,154.45,154.27,133.38,132.77,127.11,126.30,79.64,79.54,61.03,61.00,48.59,47.20,46.81,45.22,42.72,33.61,33.42,32.59,32.17,30.73,30.07,28.87,28.57,28.13,16.48,14.59。
c.3-乙氧基羰基甲基-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯
将390mg 3-乙氧基羰基亚甲基-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯溶解在50ml EtOH中,并在100mg PtO2催化剂的存在下氢化(50巴,RT)。将催化剂从所得混合物中过滤出来,得到3-乙氧基羰基甲基-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯,为顺式和反式异构体的混合物。13C-NMR:172.95,172.88,155.55,154.44,79.46,79.42,60.63,47.40,45.96,45.88,44.60,43.77,40.69,37.01,36.63,32.24,32.03,31.40,31.02,29.61,29.21,29.17,27.43,20.60,14.65,14.07。
d.3-羧基甲基-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯
将10ml 1M氢氧化钠水溶液加到3-乙氧基羰基甲基-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯的20ml THF溶液中,在室温搅拌所得混合物。向所得混合物中加入10ml盐水和70ml乙酸乙酯,用1M盐酸洗涤所得混合物。将所得有机层干燥,并将溶剂蒸发。得到3-羧基甲基-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯,为油状物。13C-NMR:178.47,177.28,155.61,154.50,79.70,79.63,47.39,45.88,43.39,40.31,36.92,32.22,31.98,31.37,30.99,30.74,30.64,30.08,29.59,29.20,21.15,20.60,14.05。
e.3-[2-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基)-2-氧代-乙基]-9-氮杂-二环[3.3.1]
壬烷-9-甲酸叔丁酯
将69μl DIEA加到57mg 3-羧基甲基-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯、93mg 2,4,5-三氯-噻吩-3-磺酸酰胺、233μl PPA和24mg DMAP在2mlDMA内的溶液中,将所得混合物在室温搅拌48小时。从所得混合物中蒸除溶剂,在RP-18柱上通过制备HPLC纯化所得蒸发残余物,然后从二氧杂环己烷中冷冻干燥。得到粉末状3-[2-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基)-2-氧代-乙基]-9-氮杂-二环[3.3.1]壬烷-9-甲酸叔丁酯。
实施例J
9-[1-氟-2-氧代-2-(2,4,5-三氯-噻吩-3-磺酰基氨基)-亚乙基]-3-氮杂-二环[3.3.1]壬烷-3-甲酸叔丁酯(实施例288的化合物)
a.9-氧代-3-氮杂-二环[3.3.1]癸烷-3-甲酸叔丁酯
将20g 3-甲基-3-氮杂-二环[3.3.1]癸-10-酮草酸盐溶解在H2O中,通过加入1M氢氧化钠水溶液将pH调节至约11。用(C2H5)2O萃取所得混合物。将所得有机层干燥,并将溶剂蒸发。将所得蒸发残余物溶解在100ml二氯乙烷中,在0℃加入22.5ml氯甲酸1-氯乙酯,将所得混合物在80℃搅拌,冷却至室温,加入100ml MeOH。将所得混合物在60℃搅拌,并将溶剂蒸发。将所得蒸发残余物、14.8g K2CO3和23.4g二碳酸二叔丁酯用300mlTHF/H2O处理并在室温搅拌。将所得混合物减压浓缩,用乙酸乙酯稀释,用H2O、1M HCl、饱和碳酸氢钠水溶液和盐水洗涤。将所得有机层干燥,将溶剂蒸发,将蒸发残余物经由硅胶过滤,用乙酸乙酯/c-HEX洗涤。得到结晶形式的9-氧代-3-氮杂-二环[3.3.1]癸烷-3-甲酸叔丁酯。13C-NMR:216.58,154.49,80.36,51.00,50.15,47.11,34.08,28.45,19.49。
b.9-(氟-乙氧基羰基亚甲基)-3-氮杂-二环[3.3.1]壬烷-3-甲酸叔丁酯
在0℃,将1.14ml(二乙氧基-磷酰基)-氟-乙酸乙酯滴加到244mg NaH(55%矿物油悬浮液)在THF内的悬浮液中,搅拌所得混合物,缓慢地加入在10ml THF中的918mg 9-氧代-3-氮杂-二环[3.3.1]癸烷-3-甲酸叔丁酯,并将所得混合物在室温搅拌过夜。用c-HEX稀释所得混合物,将所得稀释的混合物用1M NaH2PO4水溶液和饱和碳酸氢钠水溶液洗涤。将所得有机层干燥,通过蒸馏除去溶剂,通过硅胶色谱纯化所得蒸馏残余物。得到油状的9-(氟-乙氧基羰基亚甲基)-3-氮杂-二环[3.3.1]-壬烷-3-甲酸叔丁酯。
13C-NMR:161.43,161.15,154.65,139.95,139.4,137.97,79.79,61.15,50.33,49.98,48.97,48.53,31.39,31.04,30.98,28.54,28.49,19.70,14.14。
c.9-(羧基-氟-亚甲基)-3-氮杂-二环[3.3.1]壬烷-3-甲酸叔丁酯
将10ml 1M氢氧化钠水溶液加到9-(氟-乙氧基羰基亚甲基)-3-氮杂-二环[3.3.1]壬烷-3-甲酸叔丁酯在20ml THF内的溶液中,在40℃搅拌所得混合物,加入10ml盐水,用乙酸乙酯稀释所得混合物。将所得稀释的混合物用1M盐酸洗涤,将所得有机层干燥,并将溶剂蒸发。得到9-(羧基-氟-亚甲基)-3-氮杂-二环[3.3.1]壬烷-3-甲酸叔丁酯,为油状物。
13C-NMR:165.25,164.96,154.81,142.21,139.37,137.42,80.23,50.39,50.03,49.37,49.05,33.21,33.10,32.94,32.81,31.74,31.73,31.37,31.31,28.51,19.64。
d.9-[1-氟-2-氧代-2-(2,4,5-三氯-噻吩-3-磺酰基氨基)-亚乙基]-3-氮杂-二环
[3.3.1]壬烷-3-甲酸叔丁酯
将69μl DIEA加到60mg 9-(羧基-氟-亚甲基)-3-氮杂-二环[3.3.1]壬烷-3-甲酸叔丁酯71mg 2,4,5-三氯-噻吩-3-磺酰胺、233μl PPA和24mg DMAP在2ml DMA内的溶液中,将所得混合物在40℃搅拌过夜。将所得混合物用10ml乙酸乙酯/c-HEX稀释,用1M NaHSO4溶液洗涤。将所得有机层干燥,并将溶剂蒸发。在硅胶和Sephadex LH20(MeOH)上通过色谱法纯化所得蒸发残余物,将得自色谱纯化的相关级分从二氧杂环己烷中冷冻干燥。得到粉末状的9-[1-氟-2-氧代-2-(2,4,5-三氯-噻吩-3-磺酰基氨基)-亚乙基]-3-氮杂-二环[3.3.1]壬烷-3-甲酸叔丁酯。
实施例K
3-[2-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基)-1-氰基-2-氧代-亚乙基]-8-氮杂-二环[3.2.1]辛烷-8-甲酸叔丁酯(实施例289的化合物)
a.3-(氰基-甲氧基羰基-亚甲基)-8-氮杂-二环[3.2.1]辛烷-8-甲酸叔丁酯
将2g 3-氧代-8-氮杂-二环[3.2.1]辛烷-8-甲酸叔丁酯、1.2ml氰基-乙酸甲酯、130μl哌啶和38mg β-丙氨酸在4ml DMF中的溶液于70℃搅拌48小时,将所得混合物用乙酸乙酯稀释,用H2O和盐水洗涤,将所得有机层干燥,真空除去溶剂,通过硅胶色谱纯化所得残余物。得到油状的3-(氰基-甲氧基羰基-亚甲基)-8-氮杂-二环[3.2.1]辛烷-8-甲酸叔丁酯。13C-NMR:174.13,162.27,153.68,115.37,107.45,80.70,53.92,53.08,28.81。
b.3-(羧基-氰基-亚甲基)-8-氮杂-二环[3.2.1]辛烷-8-甲酸叔丁酯
按照类似于实施例J,c)中描述的方法将3-(氰基-甲氧基羰基-亚甲基)-8-氮杂-二环[3.2.1]辛烷-8-甲酸叔丁酯皂化。得到3-(羧基-氰基-亚甲基)-8-氮杂-二环[3.2.1]辛烷-8-甲酸叔丁酯,为泡沫状物。13C-NMR:165.14,153.83,115.12,107.51,81.23,28.82。
c.3-[2-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基)-1-氰基-2-氧代-亚乙基]-8-氮杂-
二环[3.2.1]辛烷-8-甲酸叔丁酯
将120μl DIEA加到102mg 3-(羧基-氰基-亚甲基)-8-氮杂-二环[3.2.1]辛烷-8-甲酸叔丁酯、162mg 4-溴-2,5-二氯-噻吩-3-磺酰胺、583μl PPA的DMF溶液(50%)和43mg DMAP的4ml DMA溶液中,将所得混合物在室温搅拌48小时。将溶剂从所得混合物中真空除去,在RP-18柱上通过制备HPLC纯化所得残余物。得到3-[2-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基)-1-氰基-2-氧代-亚乙基]-8-氮杂-二环[3.2.1]辛烷-8-甲酸叔丁酯,为泡沫状物。
实施例L
3,3-二甲基-丁酸4-[2-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基)-1-氟-2-氧代-亚乙基]-金刚烷-1-基酯(实施例290的化合物)
a.3,3-二甲基-丁酸4-氧代-金刚烷-1-基酯
将1.03g 5-羟基-2-金刚烷酮、1.83g DMAP和1.9ml 3,3-二甲基丁酰氯在10ml CH2Cl2中的溶液于40℃搅拌48小时,加入6ml 1M KH2PO4水溶液,搅拌所得混合物。分离所得各层,从所得有机层中蒸除溶剂,通过色谱法纯化所得蒸发残余物。得到3,3-二甲基-丁酸4-氧代-金刚烷-1-基酯,为油状物。13C-NMR:215.61,171.52,49.10,47.02,41.38,39.93,38.17,30.74,29.79,29.62。
b.3,3-二甲基-丁酸4-(氟-乙氧基羰基-亚甲基)-金刚烷-1-基酯
在0℃,将1.48ml(二乙氧基-磷酰基)-氟-乙酸乙酯滴加到317mg NaH(55%矿物油悬浮液)在30ml THF内的悬浮液中。搅拌所得混合物,缓慢地加入在10ml THF中的1.37g 3,3-二甲基-丁酸4-氧代-金刚烷-1-基酯,并将所得混合物在室温下搅拌过夜。用乙酸乙酯稀释所得混合物,将所得稀释的混合物用1M NaH2PO4水溶液和饱和碳酸氢钠水溶液洗涤。将所得有机层干燥,将溶剂蒸发,通过硅胶色谱纯化所得蒸发残余物。得到3,3-二甲基-丁酸4-(氟-乙氧基羰基-亚甲基)-金刚烷-1-基酯,为油状物。
13C-NMR:171.54,161.64,140.78,140.66,139.92,137.45,78.28,61.06,49.23,41.82,41.80,41.46,40.27,37.78,37.54,32.41,32.39,32.19,30.72,30.20,29.63,14.21。
c.3,3-二甲基-丁酸4-(羧基-氟-亚甲基)-金刚烷-1-基酯
按照类似于实施例J c.中描述的方法将3,3-二甲基-丁酸4-(氟-乙氧基羰基-亚甲基)-金刚烷-1-基酯皂化,得到3,3-二甲基-丁酸4-(羧基-氟-亚甲基)-金刚烷-1-基酯,为泡沫状物。
13C-NMR:172.09,166.50,166.13,144.79,144.67,139.55,137.13,78.52,49.62,42.22,42.20,41.83,40.55,38.31,37.96,33.12,33.10,32.95,32.87,31.94,31.15,30.52,30.10,30.04。
d.3,3-二甲基-丁酸4-[2-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基)-1-氟-2-氧代-亚
乙基]-金刚烷-1-基酯
按照类似于实施例K c.中描述的方法,将3,3-二甲基-丁酸4-(羧基-氟-亚甲基)-金刚烷-1-基酯与4-溴-2,5-二氯-噻吩-3-磺酰胺偶联然后分离。得到3,3-二甲基-丁酸4-[2-(4-溴-2,5-二氯-噻吩-3-磺酰基氨基)-1-氟-2-氧代-亚乙基]-金刚烷-1-基酯。
实施例M
[4-顺式/反式-(3,5-二-(三氟甲基)-苯磺酰氨基羰基甲基)-环己基]-氨基甲酸叔丁酯(实施例331的化合物)
a.3,5-二-(三氟甲基)苯-磺酰胺
在室温下将氨水溶液(32%)加到3,5-二-(三氟甲基)苯磺酰氯在乙酸乙酯内的溶液中。搅拌所得混合物,分离所获得的两相,将所得有机层用1NHCl和H2O洗涤并干燥。将所得有机溶液的溶剂蒸发。得到3,5-二-三氟甲基-苯磺酰胺。
b.[4-顺式/反式-(3,5-二-(三氟甲基)-苯磺酰基氨基羰基甲基)-环己基]-氨基
甲酸叔丁酯
将60mg DMAP、130mg DIEA和192mg EDC加到293mg 3,5-二-三氟甲基-苯磺酰胺和257mg顺式/反式-1-(叔丁氧基-羰基氨基)环己烷-4-乙酸在10ml DMF内的溶液中,将所得混合物在约30℃搅拌16小时。从所得混合物中 溶剂,将所得蒸发残余物溶解在乙酸乙酯中。将所得溶液用1N HCl、 碳酸氢钠溶液和盐水洗涤,并干燥。将溶剂从所得有机相中蒸除,通 谱法纯化所得蒸发残余物。得到异构体混合物形式的[4-顺式/反式-(3,5-二-(三氟甲基)-苯磺酰基氨基羰基乙基)-环己基]-氨基甲酸叔丁酯。
实施例N
1-[2-(3,5-二-三氟甲基-苯磺酰基氨基)-2-氧代-(4-氯-苯基)-乙基]-哌啶-4-甲酸环己基酰胺(实施例371的化合物)
在10℃,将140mg三乙胺和0.32ml 50%丙基膦酸酐(在DMF中的溶液)加到150mg(4-氯苯基)-(4-环己基氨基甲酰基-哌啶-1-基)-乙酸、174mg3,5-二(三氟甲基)-苯磺酰胺和24mg DMAP在6ml无水DMF内的溶液中。将所得混合物在室温搅拌约60小时,将溶剂蒸发,用乙酸乙酯和H2O处理所得蒸发残余物。分离所获得的两相,将所得有机层洗涤,干燥,并将溶剂蒸发。通过硅胶色谱纯化所得蒸发残余物。得到1-[2-(3,5-二-三氟甲基-苯磺酰基氨基)-2-氧代-(4-氯-苯基)-乙基]-哌啶-4-甲酸环己基酰胺。
实施例O
1-[2-苯磺酰基氨基-1-(3,5-二-三氟甲基-苯基)-2-氧代-乙基]-哌啶-4-甲酸环己基酰胺(实施例365的化合物)
在室温下,将500mg溴-(4-氯苯基)-乙酸甲酯在1.3ml CH3CN中的溶液加到288mg哌啶-4-甲酸环己基酰胺和0.239ml DIEA在4ml CH3CN内的溶液中,将所得混合物在室温搅拌约24小时,将溶剂蒸发,用乙酸乙酯和H2O处理所得蒸发残余物。将所得有机相洗涤,干燥,并将溶剂蒸发。得到1-[2-苯磺酰基氨基-1-(3,5-二-三氟甲基-苯基)-2-氧代-乙基]-哌啶-4-甲酸环己基酰胺。
实施例P(实施例375的化合物)
4-(1-羧基-环戊基)-哌啶-1-甲酸叔丁酯
a.1-吡啶-4-基-环戊烷甲酸乙酯
将25ml正丁基锂的己烷溶液(1.6M)缓慢加到2.17ml吡啶-4-基-乙酸乙酯在200ml THF内的溶液中,将所得混合物在室温搅拌30分钟,冷却至-78℃,用2.8ml 1,4-二溴丁烷在20ml THF中的溶液处理。将所得混合物温热至室温并保持过夜,用乙酸乙酯处理,将所得有机层用水、饱和碳酸氢钠溶液和盐水洗涤,干燥并蒸除溶剂。通过色谱法纯化所得蒸发残余物。得到1-吡啶-4-基-环戊烷甲酸乙酯。13C-NMR:175.05,152.68,150.15,122.44,61.63,59.18,36.19,24.06,14.33。
b.盐酸盐形式的1-哌啶-4-基-环戊烷甲酸乙酯
将1.75g 1-吡啶-4-基-环戊烷甲酸乙酯溶解在100ml MeOH与盐酸(32%)的混合物中,将所得混合物在175mg PtO2催化剂的存在下加压氢化5小时。通过过滤将催化剂从所得混合物中除去,并将溶剂蒸发。得到盐酸盐形式的1-哌啶-4-基-环戊烷甲酸乙酯。13C-NMR(CD3OD):176.73,61.33,57.71,45.08,45.00,42.14,33.80,25.49,25.43,25.36,14.58。
c.4-(1-乙氧基羰基-环戊基)-哌啶-1-甲酸叔丁酯
按照类似于实施例F,c.中描述的方法,将2.0g盐酸盐形式的1-哌啶-4-基-环戊烷甲酸乙酯转化成4-(1-乙氧基羰基-环戊基)-哌啶-1-甲酸叔丁酯。得到4-(1-乙氧基羰基-环戊基)-哌啶-1-甲酸叔丁酯。13C-NMR:177.22,155.16,79.67,60.75,58.22,44.77,44.46,33.73,28.83,28.67,25.34,14.66。
d.4-(1-羧基-环戊基)-哌啶-1-甲酸叔丁酯
将1.2g 4-(1-乙氧基羰基-环戊基)-哌啶-1-甲酸叔丁酯在100ml EtOH与50ml 1M氢氧化钠水溶液的混合物中的溶液于70℃搅拌14天,加入乙酸乙酯,分离所得两相。用盐酸将所得水层酸化(pH2-3),用乙酸乙酯萃取。将有机层用盐水洗涤,干燥,并将溶剂蒸发。得到4-(1-羰基-环戊基)-哌啶-1-甲酸叔丁酯。
实施例Q
4-[(3,5-二-三氟甲基-苯甲酰基氨基磺酰基)-甲基]-哌啶-1-甲酸叔丁酯(实施例378的化合物)
a.4-[(二苯甲基-氨基磺酰基)-甲基]-4-羟基-哌啶-1-甲酸叔丁酯
在-70℃,将28ml正丁基锂(1.6N的己烷溶液)加到5.22g N-(二苯基甲基)-甲磺酰胺在120ml THF内的溶液中。将该混合物温热至0℃,冷却至-30℃,用在15ml THF中的4g BOC-哌啶-4-酮处理。将所得混合物在室温搅拌过夜,蒸除溶剂,用乙酸乙酯处理所得蒸发残余物,用1N HCl、饱和碳酸氢钠水溶液和盐水洗涤,将所得有机层干燥,并将溶剂蒸发。通过硅胶色谱纯化所得蒸发残余物。得到粉末状4-[(二苯甲基-氨基磺酰基)-甲基]-4-羟基-哌啶-1-甲酸叔丁酯。m.p.121-123℃。
b.4-羟基-4-氨基磺酰基甲基-哌啶-1-甲酸叔丁酯
将在150ml MeOH中的5.19g 4-[(二苯甲基-氨基磺酰基)-甲基]-4-羟基-哌啶-1-甲酸叔丁酯用100μl三乙胺处理,用10%Pd/C作为催化剂将所得混合物于室温下氢化过夜。将催化剂从所得混合物中过滤出来,将溶剂蒸发,通过硅胶色谱纯化蒸发残余物。得到4-羟基-4-氨基磺酰基甲基-哌啶-1-甲酸叔丁酯。m.p.176-180℃。
c.4-[(3,5-二-三氟甲基-苯甲酰基氨基磺酰基)-甲基]-4-羟基-哌啶-1-甲酸叔
丁酯
将1510mg 3,5-二-(三氟甲基)-苯甲酸、477mg DMAP、1010mg DIEA和1500mg EDC加到1150mg 4-羟基-4-氨基磺酰基甲基-哌啶-1-甲酸叔丁酯的溶液中。将所得混合物搅拌16小时,将溶剂蒸发,用乙酸乙酯处理蒸发的残余物,用1N HCl、饱和碳酸氢钠水溶液和盐水洗涤,将所得有机层干燥,通过硅胶色谱纯化。得到4-[(3,5-二-三氟甲基-苯甲酰基氨基磺酰基)-甲基]-4-羟基-哌啶-1-甲酸叔丁酯。m.p.154-159℃。
d.4-[(3,5-二-三氟甲基-苯甲酰基氨基磺酰基)-亚甲基]-哌啶-1-甲酸叔丁酯
将1510mg Martin Sulfuran脱水剂加到在5ml CH2Cl2内的300mg4-[(3,5-二-三氟甲基-苯甲酰基氨基磺酰基)-甲基]-4-羟基-哌啶-1-甲酸叔丁酯中。将所得混合物在微波炉中于100℃搅拌15分钟,从所得混合物中蒸除溶剂,通过硅胶色谱纯化蒸发残余物。得到4-[(3,5-二-三氟甲基-苯甲酰基氨基磺酰基)-亚甲基]-哌啶-1-甲酸叔丁酯。m.p.132-136℃。
e.4-[(3,5-二-三氟甲基-苯甲酰基氨基磺酰基)-甲基]-哌啶-]-甲酸叔丁酯
将880mg 4-[(3,5-二-三氟甲基-苯甲酰基氨基磺酰基)-亚甲基]-哌啶-1-甲酸叔丁酯在100ml MeOH中的溶液氢化(10%Pd/C作为催化剂)。将催化剂从所得混合物中过滤出来并将溶剂蒸发。得到4-[(3,5-二-三氟甲基-苯甲酰基氨基磺酰基)-甲基]-哌啶-1-甲酸叔丁酯。
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示的化合物:
其中,若在表1中没有另有说明,则R18是氢,且R1和R16+R17如表1中所定义(其中m是0,n是0,且R1是式VII所示基团的式I化合物)。
除非另有说明,在表1中,13C-NMR和1H-NMR数据是在CDCl3中测定的。
表1
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示化合物:
其中R18是氢,且R1和R16+R17如表2中所定义(其中m是0,n是0,且R1是式VII所示基团的式I化合物)。除非另有说明,在表2中,1HNMR和13C-NMR数据是在CDCl3中测定的。
表2
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示化合物:
其中R18是氢,且R1和R16+R17如表3中所定义(其中m是0,n是0,且R1是式VII所示基团的式I化合物)。除非另有说明,在表3中,13C-NMR和1H-NMR数据是在CDCl3中测定的。
表3
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示化合物:
其中R1、R16+R17如表4中所定义,且R18是氢或如表4中所定义(其中m是0,n是1,且R1是式VII所示基团的式I化合物)。除非另有说明,在表4中,特征数据是1HNMR数据,并且13C-NMR和1HNMR数据是在CDCl3中测定的。
表4
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示化合物:
其中R2、R3和R4+R5如表5中所定义(其中m是0,n是0,且R1是式II所示基团的式I化合物)。除非另有说明,在表5中,1HNMR和13C-NMR数据是在CDCl3中测定的。
表5
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示的化合物:
其中R18是氢,且R1和R16+R17如表6中所定义(其中m是0,n是0,且R2是式VII所示基团的式I化合物)。除非另有说明,在表6中,13C-NMR和1HNMR数据是在DMSO-d6中测定的。
表6
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示的化合物:
其中R18是氢,且R1和R16+R17如表7中所定义(其中m是1,n是0,且R1是式VII所示基团的式I化合物)。除非另有说明,在表7中,13C-NMR和1HNMR数据是在CDCl3中测定的。
表7
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示的化合物:
其中R18是氢,且R1和R16+R17如表8中所定义(其中m是1,n是1,且R2是式VII所示基团的式I化合物)。
表8
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示的化合物:
其中R1、R14和R15如表9中所定义(其中m是0,n是0,且R1是式VI所示基团的式I化合物)。除非另有说明,在表9中,13C-NMR和1HNMR数据是在DMSO-d6中测定的。
表9
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示的化合物:
其中R1、R16+R17和R18如表10中所定义(其中m是0,n是0,且R2是式VII所示基团的式I化合物)。
表10
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示的化合物:
其中R13是氢,且R1和R11+R12如表11中所定义(其中m是1,n是0,且R2是式V所示基团的式I化合物)。
表11
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示的化合物:
其中R8是氢或如表12中所定义,且R2和R9+R10如表12中所定义(其中m是0,n是1,且R1是式VII所示基团的式I化合物)。
表12
按照类似于操作方法(实施例A-Q)中描述的方法,但是使用合适的原料,得到下式所示的化合物:
其中R3是氢,且R2和R4+R5如表13中所定义(其中m是0,n是0,R1是式II所示的基团,且R2是(C6-18)芳基的式I化合物)。
表13
Claims (10)
1.式I化合物
其中
R1是(C1-6)卤代烷基、未被取代的(C2-6)链烯基、被苯基取代的(C2-6)链烯基、未被取代或者被1-5个取代基取代的
-噻吩基、吡啶、苯并噻唑基、色满基(即1,2-二氢苯并吡喃基)或(C6-18)芳基,其中所述取代基选自
-卤素、硝基、二(C1-4)烷基氨基、氰基、(C1-6)烷基、(C1-4)卤代烷基、未被取代的苯基羰基氨基(C1-4)烷基、(C1-4)烷氧基、(C1-4)卤代烷氧基、氨基羰基、二(C1-4)烷基氨基羰基、(C1-4)烷基羰基、(C1-4)烷氧基羰基、未被取代的苯基、羧基、和在苯基上被取代的苯基羰基氨基(C1-4)烷基或被取代的苯基,其中所述苯基的取代基选自
-卤素、硝基、二(C1-4)烷基氨基、氰基、(C1-6)烷基、(C1-4)卤代烷基、(C1-4)烷氧基、(C1-4)卤代烷氧基、氨基羰基、二(C1-4)烷基氨基羰基、(C1-4)烷基羰基、(C1-4)烷氧基羰基和羧基,或者
R1是下式所示的基团
或
或
R2是下式所示的基团
R3和R13彼此独立地为氢、羟基、卤素、氰基、(C1-4)烷基、(C1-4)烷氧基、苯基或苯氧基,
对于下述两种组合:
-R4和R5与它们所连接的碳原子,
-R11和R12与它们所连接的碳原子,
它们当中至少有一个彼此独立地为被取代的
-桥连环烷基系,
-(C4-8)环烷基,
-哌啶、四氢吡啶或
-桥连杂环系,
其中所述取代基选自
(C1-6)烷氧基羰基氨基,
(C1-6)烷氧基羰基((C1-4)烷基)氨基,
(C1-6)烷氧基羰基((C2-4)链烯基)氨基,
(C3-8)环烷基羰基氨基,
(C3-8)环烷基羰基((C1-4)烷基)氨基,
(C3-8)环烷基羰基((C2-4)链烯基)氨基,
(C1-6)烷氧基羰基氧基,
苯基(C1-4)烷基羰基氧基,其中所述苯基是未被取代或被取代的,并且其中的取代基如上文关于被取代的苯基所定义,
苯基磺酰基,其中所述苯基是未被取代或被取代的,并且其中的取代基如上文关于被取代的苯基所定义,
(C4-8)烷基,
(C1-4)羟基烷基,
被苯基取代的(C1-4)羟基烷基,其中所述苯基是未被取代或被取代的,并且其中的取代基如上文关于被取代的苯基所定义,
(C1-6)烷氧基羰基(C1-4)烷基,
(C3-8)环烷氧基羰基(C1-4)烷基,
(C1-6)烷氧基羰基氨基(C1-4)烷基,
(C3-8)环烷基羰基氨基(C1-4)烷基,
苯基或被取代的苯基,其中取代基如上文关于被取代的苯基所定义,具有5或6个环原子和1-4个选自N、O、S的杂原子的杂环基,
(C3-8)环烷氧基羰基,
(C3-8)环烷基(C1-4)烷基羰基,其中所述环烷基未被取代或者被羟基取代,苯基羰基,其中所述苯基是未被取代或被取代的,并且其中的取代基如上文关于被取代的苯基所定义,
(C3-8)环烷基氨基羰基,
(C3-8)环烷基((C1-4)烷基)氨基羰基,
(C3-8)环烷基((C2-4)链烯基)氨基羰基,和
(C1-8)烷氧基羰基,
R3、R8、R13和R18彼此独立地为氢、羟基、卤素、氰基、(C1-4)烷基、(C1-4)烷氧基、苯基或苯氧基,
其中,或者
R8或R18分别彼此独立地为氢、羟基、卤素、氰基、(C1-4)烷基、(C1-4)烷氧基、苯基或苯氧基,并且对于下述两种组合:
-R9和R10与它们所连接的碳原子,
-R16和R17与它们所连接的碳原子,
它们当中至少有一个彼此独立地具有如上文关于R4和R5与它们所连接的碳原子所定义的含义,
或者
对于下述两种组合:
-R9和R10与它们所连接的碳原子,
-R16和R17与它们所连接的碳原子,
它们当中至少有一个是(C3-8)环烷基,并且
R8或R18分别彼此独立地为被取代的
-桥连环烷基系、(C4-8)环烷基、哌啶、四氢吡啶或桥连杂环系,其中所述取代基如上文关于相应的基团所定义,
R6和R15彼此独立地为(C1-6)卤代烷基、未被取代或被取代的(C6-18)芳基,其中所述芳基的取代基如上所定义,或被取代的
-桥连环烷基系、(C4-8)环烷基、哌啶、四氢吡啶或桥连杂环系,其中所述取代基如上文关于相应的基团所定义,或者
R6和R15彼此独立地为氨基,所述氨基被下列基团取代:被取代的
-桥连环烷基系、(C4-8)环烷基、哌啶、四氢吡啶或桥连杂环系,其中所述取代基如上文关于相应的基团所定义,
R7和R14彼此独立地为被取代的
-桥连环烷基系、(C4-8)环烷基、哌啶、四氢吡啶或桥连杂环系,其中所述取代基如上文关于相应的基团所定义,
或者R7和R14彼此独立地为氨基,所述氨基被下列基团取代:被取代的
-桥连环烷基系、(C4-8)环烷基、哌啶、四氢吡啶或桥连杂环系,其中所述取代基如上文关于相应的基团所定义,
m是0、1、2、3或4,
n是0、1、2、3或4,并且
如果
m和/或n不是0,
则
-R1-如果m不是0-和R2-如果n不是0-彼此独立地具有如上所定义的含义,并且还可以是被取代的哌嗪,其中取代基如上文关于被取代的哌啶所定义;并且
-被取代的桥连环烷基系如上文关于被取代的桥连环烷基系所述被取代,并且还可以被氧代基团和/或(C1-4)烷基取代;和
如果
R1是被取代的
-桥连环烷基环系、(C4-8)环烷基、哌啶、四氢吡啶或桥连杂环基环系,其中所述取代基如上文关于相应的基团所定义,或者如果R1是哌嗪,如果
m不是0,
则
R2具有如上所定义的含义,并且还可以是(C1-6)卤代烷基、未被取代的(C2-6)链烯基、被苯基取代的(C2-6)链烯基、未被取代或者被1-5个取代基取代的
-噻吩基、吡啶、苯并噻唑基、色满基(即1,2-二氢苯并吡喃基)或(C6-18)芳基,其中所述取代基如上文关于相应的基团所定义,和
如果
m是0,n是0,且R2是被取代的(C4-8)环烷基或被取代的桥连环烷基环系,其中取代基如上所定义,
则
R1不是(C1-6)卤代烷基。
2.权利要求1的化合物,其中对于下述组合
-R4和R5与它们所连接的碳原子,
-R9和R10与它们所连接的碳原子,
-R11和R12与它们所连接的碳原子,或
-R16和R17与它们所连接的碳原子
它们当中至少有一个是被取代的桥连环烷基系,且其它取代基如权利要求1所定义。
3.权利要求1或2的化合物,其中所述化合物是下式所示的化合物
其中R1P3具有如权利要求1中所定义的R1的含义,R16P3和R17P3与它们所连接的碳原子一起是如权利要求1中所定义的被取代的桥连环烷基环系,其中取代基如权利要求1中关于桥连环烷基环系所定义,且R18P3具有如权利要求1中所定义的R18的含义。
5.权利要求1-4任一项的化合物,其中所述化合物是盐形式。
6.用作药物的权利要求1-5任一项的化合物。
7.用于制备治疗由类固醇硫酸酯酶的作用介导的病症的药物的权利要求1-5任一项的化合物。
8.治疗由类固醇硫酸酯酶的作用介导的病症的方法,包括给需要这种治疗的个体施用治疗有效量的式I化合物。
9.药物组合物,其中包含药物有效量的至少一种权利要求1-5任一项的化合物和至少一种可药用赋形剂。
10.与至少一种其它药物活性剂联合用作药物的权利要求1-5任一项的化合物。
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2002
- 2002-10-03 AR ARP020103736A patent/AR037097A1/es unknown
- 2002-10-04 IL IL16078602A patent/IL160786A0/xx unknown
- 2002-10-04 JP JP2003534381A patent/JP4390559B2/ja not_active Expired - Fee Related
- 2002-10-04 PL PL02367411A patent/PL367411A1/xx not_active Application Discontinuation
- 2002-10-04 BR BR0213131-5A patent/BR0213131A/pt not_active IP Right Cessation
- 2002-10-04 EP EP02785159A patent/EP1436253A1/en not_active Withdrawn
- 2002-10-04 HU HU0401687A patent/HUP0401687A3/hu unknown
- 2002-10-04 US US10/490,464 patent/US7482462B2/en not_active Expired - Fee Related
- 2002-10-04 AU AU2002350490A patent/AU2002350490B2/en not_active Ceased
- 2002-10-04 WO PCT/EP2002/011140 patent/WO2003031397A1/en active Application Filing
- 2002-10-04 MX MXPA04003236A patent/MXPA04003236A/es active IP Right Grant
- 2002-10-04 PE PE2002000993A patent/PE20030548A1/es not_active Application Discontinuation
- 2002-10-04 CN CNB028197577A patent/CN100509774C/zh not_active Expired - Fee Related
- 2002-10-04 KR KR1020047004906A patent/KR100952770B1/ko not_active IP Right Cessation
- 2002-10-04 NZ NZ532072A patent/NZ532072A/en not_active IP Right Cessation
- 2002-10-04 EP EP10159985A patent/EP2228364A1/en not_active Withdrawn
- 2002-10-04 KR KR1020097024161A patent/KR20090123988A/ko not_active Application Discontinuation
- 2002-10-04 CA CA002458453A patent/CA2458453A1/en not_active Abandoned
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Also Published As
Publication number | Publication date |
---|---|
EP1436253A1 (en) | 2004-07-14 |
EP2228364A1 (en) | 2010-09-15 |
NZ532072A (en) | 2007-02-23 |
PE20030548A1 (es) | 2003-07-07 |
IL160786A0 (en) | 2004-08-31 |
CO5570700A2 (es) | 2005-10-31 |
US20050059712A1 (en) | 2005-03-17 |
KR20050033509A (ko) | 2005-04-12 |
US7482462B2 (en) | 2009-01-27 |
AU2002350490B2 (en) | 2006-07-27 |
HUP0401687A2 (hu) | 2004-11-29 |
JP4390559B2 (ja) | 2009-12-24 |
HUP0401687A3 (en) | 2008-06-30 |
BR0213131A (pt) | 2004-09-21 |
KR100952770B1 (ko) | 2010-04-14 |
AR037097A1 (es) | 2004-10-20 |
MXPA04003236A (es) | 2004-07-23 |
KR20090123988A (ko) | 2009-12-02 |
PL367411A1 (en) | 2005-02-21 |
JP2005504843A (ja) | 2005-02-17 |
WO2003031397A1 (en) | 2003-04-17 |
CA2458453A1 (en) | 2003-04-17 |
CN100509774C (zh) | 2009-07-08 |
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