CN101421240A - 氨基甲基吡啶衍生物、它们的制备和在治疗中的应用 - Google Patents
氨基甲基吡啶衍生物、它们的制备和在治疗中的应用 Download PDFInfo
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- CN101421240A CN101421240A CNA2007800131701A CN200780013170A CN101421240A CN 101421240 A CN101421240 A CN 101421240A CN A2007800131701 A CNA2007800131701 A CN A2007800131701A CN 200780013170 A CN200780013170 A CN 200780013170A CN 101421240 A CN101421240 A CN 101421240A
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- 238000000034 method Methods 0.000 title claims description 20
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- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 43
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Abstract
本发明涉及式1的化合物,其中,Z表示N(R3)XR4,N(R3)COOR或OCON(R3)R5;X表示基团-CO-,-SO2-,-CON(R6)-或CSN(R6)-;-R1和R2各自独立表示氢原子或(C1-C7)烷基或与跟它们连接的氮原子一起形成饱和或不饱和杂环基团;R3和Rg表示氢原子或(C1-C4)烷基;-R4表示:(C3-C10)烷基/碳环基;杂环基;吲哚基;四氢萘基,萘基;苯并噻吩基或苯并脲基;苯基;苯并二氧基;苯氧亚甲基,苯氧亚乙基;苯基环丙基;R5表示苯基;Ar1和Ar2各自独立表示取代或非取代苯基;n表示0,1或2;AIk表示(C1-C7)烷基;呈碱或酸加成盐状态,以及呈水合物或溶剂化物状态。
Description
本发明涉及氨基甲基吡啶的衍生物、它们的制备和它们在治疗中的应用。
国际专利申请WO03/082191描述了下式的吡啶的衍生物:
其中取代基r1-r7具有不同的值。
专利US5916905描述了下式的吡啶衍生物:
其中R3和R4可以表示芳基和R2可以表示烷基羰基氨基烷基基团。
专利申请WO2002/055502描述了下式的化合物:
专利申请WO2006/113704描述了下式的化合物:
其中B可以表示氮原子,A和C表示碳原子。
专利申请WO2004/111034描述了下式的吡嗪衍生物:
这些化合物作为受体CB1的改性剂进行了描述。
专利申请WO2006/042955描述了下式的吡啶衍生物(大麻素受体CB1的拮抗剂):
人们如今已找到新的氨基甲基吡啶衍生物,其具有拮抗位于中心和/或周围水平(niveau)的大麻素受体CB1的性质。
本发明的目的是对应于下式的化合物:
其中,
-Z表示N(R3)XR4,N(R3)COOR5或OCON(R3)R5;
-X表示基团-CO-,-SO2-,-CON(R6)-或-CSN(R6)-;
-R1和R2各自独立表示氢原子或(C1-C7)烷基或R1和R2与跟它们连接的氮原子一起组成饱和或不饱和的3-8个链节的杂环基团,其可以包括一个或多个选自氧、硫、或氮原子的其他杂原子,所述基团是未被取代的或被一个或多个(C1-C4)烷基基团取代;
-R3表示氢原子或C1-C4烷基;
-R4表示:
.未被取代的或被CF3取代的(C3-C10)烷基;
.非芳族(C3-C12)碳环基团,其是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:(C1-C4)烷基,羟基,(C1-C4)烷氧基,(C1-C4)烷硫基,氰基;
.含氧、硫或氮的3-8个原子的杂环基团,其是饱和或不饱和的,未被取代的或被一个或多个相同或不同的选自以下的取代基取代的:卤原子、(C1-C4)烷基、羟基、三氟甲基、(C1-C4)烷氧基、三氟甲氧基、三氟甲硫基、(C1-C4)烷硫基、氰基、硝基或氧基(groupe oxo);
.吲哚基,其是未被取代的或被卤原子或被(C1-C4)烷基、三氟甲基、羟基、(C1-C4)烷氧基、三氟甲氧基、三氟甲硫基、(C1-C4)烷硫基、氰基、硝基取代;
.四氢萘基;萘基;
.苯并苯硫基或苯并呋喃基;
.苯基,其是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基(alcanoyle)、苯基、S(O)nAlk、OS(O)nAlk或NR7R8基团;
.苯并二氧基(benzodioxyle);
.苯氧基亚甲基,1-苯氧基亚乙基,所述苯基是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基、苯基、S(O)nAlk、OS(O)nAlk或NR7R8基团;所述亚甲基或亚乙基是未被取代的或被(C1-C4)烷基或被(C3-C7)环烷基取代一次或多次;
.苯基环丙基,该苯基是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基、苯基、S(O)nAlk、OS(O)nAlk或NR7R8基团;
.(C1-C2)亚烷基,其被一个或两个相同或不同的选自以下的取代基取代:
(i)未被取代的或被(C1-C4)烷基取代一次或多次的非芳族C3-C12碳环基;
(ii)未被取代的或被一个或多个相同或不同的选自以下的取代基取代的苯基:卤原子、(C1-C4)烷基、羟基、三氟甲基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲氧基、三氟甲硫基、(C1-C4)链烷酰基、氰基、硝基、苯基、S(O)nAlk,OS(O)nAlk或NR7R8基团;
(iii)含氧、含硫或含氮的3-8个原子的杂环基团,其是饱和或不饱和的,未被取代或被一个或多个相同或不同的选自以下的基团取代的:卤原子、(C1-C4)烷基、羟基、三氟甲基、(C1-C4)烷氧基、三氟甲氧基、三氟甲硫基、(C1-C4)烷硫基、氰基、硝基;
.而且,当X表示基团-CON(R6)-或-CSN(R6)-,R4可以表示(C1-C6)链烷酰基或苯甲酰基或苯甲基羰基,所述基团的苯基是未被取代的或被相同或不同的选自以下的取代基取代:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基、苯基、S(O)nAlk,OS(O)nAlk或NR7R8基团;
-R5表示未被取代的或被相同或不同的选自以下的取代基取代一次或多次的苯基:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、氰基、硝基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、S(O)nAlk,OS(O)nAlk或NR7R8基团;
-R6表示氢原子或(C1-C4)烷基;
-或R4和R6与跟它们连接的氮原子一起构成3-8个原子的杂环基团,其包含或不包含选自氧、硫或氮原子的第二杂原子,其是未被取代的或被选自以下的取代一次或多次:(C1-C4)烷基;(C1-C4)链烷酰基;NR7R8或CONR7R8基团;苯基,其是未被取代的或被选自以下的基团取代一次或多次:卤原子、(C1-C4)烷基、(C1-C4)烷氧基或三氟甲基、(C1-C4)烷硫基、三氟甲氧基、三氟甲硫基、S(O)nAlk、OS(O)nAlk或NR7R8基团;
-R7和R8各自相互独立表示氢原子、(C1-C4)烷基,或者R7和R8与跟它们连接的氮原子一起构成4-8个原子的饱和杂环基团,其可以包含选自氮、氧、或硫原子的其他杂原子;
-Ar1和Ar2各自相互独立表示苯基,其是未被取代的或被以下取代:卤原子、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、三氟甲基、三氟甲氧基、三氟甲硫基、氰基、硝基或S(O)nAlk、OS(O)nAlk或NR7R8基团;
-n表示0,1或2;
-Alk表示(C1-C7)烷基;其呈碱或加成盐形式,以及水合物或溶剂化物形式。
本发明尤其特别地涉及式(I)的化合物,其中:
-Z表示基团N(R3)XR4,N(R3)COOR5或OCON(R3)R5;
-X表示基团-CO-,-SO2-,-CON(R6)-或-CSN(R6)-;
-R1和R2各自相互独立表示氢原子或(C1-C7)烷基,或者R1和R2与跟它们连接的氮原子一起构成饱和或不饱和的3-8个链节的杂环基团,其可以包含一个或多个选自氧、硫、或氮原子的其他杂原子,所述基团是未被取代的或被一个或多个(C1-C4)烷基取代;
-R3表示氢原子或(C1-C4)烷基;
-R4表示:
.未被取代的或被CF3基团取代的(C3-C10)烷基;
.未被取代的或被相同或不同的选自以下的取代基取代一次或多次的非芳族(C3-C12)碳环基:(C1-C4)烷基,羟基,(C1-C4)烷氧基,(C1-C4)烷硫基,氰基;
.含氧、硫、氮的4-8个原子的杂环基团,其是饱和或不饱和的,是未被取代的或被一个或多个相同或不同的选自以下的取代基取代:卤原子、(C1-C4)烷基、羟基、三氟甲基、(C1-C4)烷氧基、三氟甲氧基、(C1-C4)烷硫基、氰基、硝基;
.吲哚基,其是未被取代的或被选自以下的取代基取代:卤原子或(C1-C4)烷基,三氟甲基、羟基、(C1-C4)烷氧基、三氟甲氧基、(C1-C4)烷硫基、氰基、硝基;
.四氢萘基-1或-2;萘基-1或-2;
.苯并苯硫基或苯并呋喃基;
.苯基,其是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基、苯基、S(O)nAlk、OS(O)nAlk或NR7R8基团;
.苯并二氧基;
.苯氧基亚甲基、1-苯氧基亚乙基,所述苯基是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基、苯基、S(O)nAlk、OS(O)nAlk或NR7R8基团;所述亚甲基或亚乙基是未被取代的或被(C1-C4)烷基或被(C3-C7)环烷基取代;
.苯基环丙基,所述苯基是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基、苯基、S(O)nAlk、OS(O)nAlk或NR7R8基团;
.(C1-C2)亚烷基,其被一个或两个相同或不同的选自以下的取代基取代:
(i)非芳族C3-C12碳环基,其是未被取代的或被(C1~C4)烷基取代;
(ii)苯基,其是未被取代的或被一个或多个相同或不同的选自以下的取代基取代:卤原子、(C1-C4)烷基、羟基、三氟甲基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲氧基、三氟甲硫基、(C1-C4)链烷酰基、氰基、硝基、苯基、S(O)nAlk、OS(O)nAlk或NR7R8基团;
(iii)含氧、硫、氮的4-8个原子的杂环基团,其是饱和或不饱和的,是未被取代的或被一个或多个相同或不同的选自以下的取代基取代:卤原子、(C1-C4)烷基、羟基、三氟甲基、(C1-C4)烷氧基、三氟甲氧基、(C1-C4)烷硫基、氰基、硝基;
.而且当X表示-CON(R6)-或-CSN(R6)-时,R4可以表示(C1-C6)链烷酰基或苯甲酰基或苯甲基羰基,所述基团的苯基是未被取代的或被相同或不同的选自以下的取代基取代:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基、苯基、S(O)nAlk、OS(O)nAlk或NR7R8基团;
-R5表示苯基,其是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、氰基、硝基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、S(O)nAlk、OS(O)nAlk;
-R6表示氢原子或(C1-C4)烷基;
-或者R4和R6与跟它们连接的氮原子一起构成4-8个原子的杂环基团,其包含或不包含选自氧、硫、或氮原子的第二杂原子,其是未被取代的或被选自以下的取代一次或多次:(C1-C4)烷基;(C1-C4)链烷酰基;NR7R8或CONR7R8基团;苯基,其是未被取代的或被选自以下的基团取代一次或多次:卤原子、(C1-C4)烷基、(C1-C4)烷氧基、三氟甲基、(C1-C4)烷硫基、三氟甲氧基、三氟甲硫基或S(O)nAlk、OS(O)nAlk基团;
-R7和R8各自相互独立表示氢原子、(C1-C4)烷基,或者R7和R8与跟它们连接的氮原子一起构成4-8个原子的饱和杂环基团,其可以包含选自氮、氧、或硫原子的其他杂原子;
-Ar1和Ar2各自相互独立表示苯基,其是未被取代的或被选自以下取代:卤原子、(C1-C6)烷基、(C1-C6)烷氧基、三氟甲基、三氟甲氧基、三氟甲硫基、氰基、硝基或S(O)nAlk或OS(O)nAlk基团;
-n表示0,1或2;
-Alk表示(C1-C4)烷基;其呈碱或加成盐形式,以及呈水合物或溶剂化物形式。
在本发明的目的式(I)的化合物中,指出:
-式(IA)的化合物,其中Z表示基团-N(R3)COR4并且R1-R4,Ar1和Ar2为如对(I)所定义;
-式(IB)的化合物,其中Z表示基团-N(R3)SO2R4并且R1-R4,Ar1和Ar2为如对(I)所定义;
-式(IC)的化合物,其中Z表示基团-N(R3)CON(R6)R4并且R1-R4,Ar1和Ar2为如对(I)所定义;
-式(ID)的化合物,其中Z表示基团-N(R3)CSN(R6)R4并且R1-R4,Ar1和Ar2为如对(I)所定义;
-式(IE)的化合物,其中Z表示基团-N(R3)COOR5并且R1-R4,Ar1和Ar2为如对(I)所定义;
-式(IF)的化合物,其中Z表示基团-O-CO-NR3R5并且R1-R4,Ar1和Ar2为如对(I)所定义。
更特别地,本发明涉及下式的化合物:
其中:
-X表示-CO-,-SO2-或-CON(R6)-;
-R1和R2为如对(I)所定义;
-R3表示氢原子或(C1-C4)烷基;
-R4表示:
.(C3-C10)烷基;
.非芳族(C3-C12)碳环基团,其是未被取代的或被(C1-C4)烷基取代一次或多次;
.含氮、氧、或硫的饱和或不饱和的4-8个原子的杂环基团,其是未被取代的或被一个或多个相同或不同的选自以下的取代基取代:卤原子、(C1-C4)烷基、羟基、三氟甲基、(C1-C4)烷氧基、三氟甲氧基、(C1-C4)烷硫基、氰基、硝基;
.吲哚基,其是未被取代的或在氮原子上被卤原子、(C1-C4)烷基、(C1-C4)烷氧基取代;
.苯基,其是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、(C1-C4)链烷酰基、苯基或者S(O)nAlk或OS(O)nAlk基团;
.苯甲基,其是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、三氟甲硫基、(C1-C4)烷氧基、氰基、苯基,或者S(O)nAlk或OS(O)nAlk基团;
-R6表示氢原子或(C1-C4)烷基;
-或R4和R6与跟它们连接的氮原子一起构成4-8个原子的杂环基团,其包含或不包含选自氧、硫或氮原子的第二杂原子,其是未被取代的或被选自以下的取代一次或多次:(C1-C4)烷基;(C1-C4)链烷酰基;NR7R8或CONR7R8基团;苯基,其是未被取代的或被选自以下的基团取代一次或多次:卤原子、(C1-C4)烷基、(C1-C4)烷氧基或三氟甲基;
-R7和R8各自相互独立表示氢原子、(C1-C4)烷基,或者R7和R8与跟它们连接的氮原子一起构成杂环基团,其选自哌啶基、吡咯烷基、哌嗪基、N-甲基哌嗪基、azépinyl或吗啉基;
-Ar1和Ar2各自相互独立表示苯基,其是未被取代的或被以下取代:卤原子、(C1-C6)烷基、(C1-C6)烷氧基、三氟甲基、三氟甲硫基、三氟甲氧基或者S(O)nAlk或OS(O)nAlk基团;
-n表示0,1或2;
-Alk表示(C1-C4)烷基;其呈碱或加成盐形式,以及水合物或溶剂化物形式。
还更特别地,本发明涉及下式的化合物:
其中:
-R1和R2各自相互独立表示氢原子或(C1-C7)烷基,或者R1和R2与跟它们连接的氮原子一起构成选自以下的基团:azéridinyle、吖丁啶基(azétidinyle)、吡咯烷基、哌啶基、吖庚因基(azépinyle)、哌嗪基、N-甲基哌嗪基、吗啉基、咪唑基、吡唑基、四唑基、三唑基;
-R3表示氢原子或甲基;
-R4表示:
.(C5-C10)烷基;
.(C5-C7)环烷基,其是未被取代的或被甲基取代一次或多次;
.含氧、硫、氮的4-8个原子的饱和杂环基团,其是未被取代的或被甲基取代一次或多次;
.苯基,其被卤原子或独立选自以下的基团取代一次或多次:三氟甲基、三氟甲氧基、三氟甲硫基、(C1-C4)烷氧基、(C1-C4)烷硫基、SO2Alk或OSO2Alk;
-Ar1和Ar2各自相互独立表示苯基,其被一个或两个独立选自以下的取代基取代:卤原子、甲氧基、甲硫基、三氟甲硫基、三氟甲氧基、SO2Alk、OSO2Alk;其呈碱或加成盐形式,以及呈水合物或溶剂化物形式。
还更特别地,本发明涉及下式的化合物:
其中:
-R1和R2各自相互独立表示氢原子或(C1-C7)烷基,或者R1和R2与跟它们连接的氮原子一起构成选自以下的基团:azéridinyle、吖丁啶基、吡咯烷基、哌啶基、吖庚因基、哌嗪基、N-甲基哌嗪基、吗啉基、咪唑基、吡唑基、四唑基、三唑基;
-R3表示氢原子或甲基;
-R4表示:
.(C5-C10)烷基;
.(C5-C7)环烷基,其是未被取代的或被甲基取代一次或多次;
.含氧、硫、氮的4-8个原子的饱和杂环基团,其是未被取代的或被甲基取代一次或多次;
.苯基,其被独立选自以下的基团取代一次或多次:卤原子、三氟甲基、三氟甲氧基、三氟甲硫基、(C1-C4)烷氧基、(C1-C4)烷硫基、SO2Alk或OSO2Alk;
-R6表示氢原子或甲基
-Ar1和Ar2各自相互独立表示苯基,其被一个或两个独立选自以下的取代基取代:卤原子、甲氧基、甲硫基、三氟甲硫基、三氟甲氧基、SO2Alk、OSO2Alk;
该化合物呈碱或加成盐形式,以及呈水合物或溶剂化物形式。
式(I)的化合物可以包括一个或多个不对称的碳原子。因此它们可以以对映体或对映异构体形式存在。这些对映体或非对映异构体以及它们的混合物(包括外消旋混合物)构成本发明的一部分。
式(I)的化合物可以以碱或酸的加成盐形式存在。上述这些加成盐构成本发明的一部分。
这些盐可以使用药物可接受的酸进行制备,但是其他有用酸(例如用于式(I)的化合物的纯化或分离)的盐也构成本发明的一部分。
式(I)的化合物还可以以水合物或溶剂化物形式存在,即呈与一个或多个水分子或与溶剂结合或化合的形式。上述这些水合物或溶剂化物构成本发明的一部分。
在本发明的范围内,以下应当理解为:
-卤原子:氟、氯、溴或碘;
-(C1-C4)烷基或分别地(C1-C6)烷基、(C1-C7)烷基、(C3-C10)烷基、(C5-C10)烷基:分别地是饱和的直链或支链的(C1-C4)或(C1-C6)、(C1-C7)、(C3-C10)或(C5-C10)脂肪基团。举例而言,可以提及甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、1-乙基丙基、1-丙基丁基、2-丙基戊基、5-甲基壬基、4-甲基庚基、4-甲基-2,6-二甲基庚基等;
-(C1-C4)烷氧基或分别地(C1-C6)烷氧基:O-烷基,其中该烷基如前所定义。
上述非芳族C3-C12碳环基包括单-或多环基,其是稠合的或桥联的。所述单环基团包括环烷基,例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基;环己基环庚基是优选的。上述稠合的、桥联的或螺旋状的(spiranique)二-或三环基包括,例如降冰片基、冰片基、异冰片基、将金刚烷基(noradamantyle)、金刚烷基,螺[5.5]十一烷基,双环[2.2.1]庚基,双环[3.2.1]辛基;双环[3.1.1]庚基。
由两个取代基与跟它们连接的氮原子一起形成的3-8个链节的含氮杂环基包括饱和基团,如azéridinyle、吖丁啶基、吡咯烷基、哌啶基、全氢吖庚因基、全氢吖辛基(perhydroazocinyle);上述饱和的和不饱和基团还包括选自氧、硫或氮原子的第二杂原子,如,咪唑烷基、吡唑烷基、哌嗪基、吗啉基、硫代吗啉基、咪唑基、吡唑基、异噻唑基、异噁唑基、三唑基、四唑基、噁唑基、噻唑基。不饱和的含氮的3-8个链节的杂环基还包括一个或多个杂原子,其包括咪唑基、吡咯基、吡唑基(pyrazolyle)、异噻唑基、异噁唑基。
含氧、硫或氮的饱和或不饱和的3-8个链节的杂环基团特别地包括呋喃基、四氢呋喃基、噻吩基、吡咯基。尤其特别地,指出式(IA)的化合物,其中:
-Z表示NHCOR4;
-R1和R2各自相互独立表示(C1-C7)烷基,或者R1和R2与跟它们连接的氮原子一起构成基团,其选自:azéridinyle、吖丁啶基,吡咯烷基、哌啶基、吖庚因基、哌嗪基,N-甲基哌嗪基、吗啉基、咪唑基、吡唑基、四唑基、三唑基;
-R4表示2-丙基戊基,1-丙基丁基,5-甲基壬基,4-甲基庚基,4-甲基-2,6-二甲基庚基,环戊基,四甲基环戊基,环己基,四氢呋喃基,吡咯烷基,1,1,4,4-四甲基环戊基,2,2,5,5-四甲基呋喃基,2,2,5,5-四甲基吡咯烷基,苯基,其是未被代的或被卤原子、三氟甲基、三氟甲氧基、三氟甲硫基或被SO2Alk或OSO2Alk取代;
-和/或Ar1和Ar2各自相互独立表示苯基,其被独立选自以下的取代基取代:氯、溴原子或甲氧基、甲硫基;其呈碱或加成盐形式,以及水合物或溶剂化物形式。
还应当指出式(IC)的化合物,其中:
-Z表示基团-NHCONHR4;
-R1和R2彼此独立地表示(C1-C7)烷基或者R1和R2与跟它们连接的氮原子一起构成选自以下的基团:azéridinyle,吖丁啶基,吡咯烷基、哌啶基、吖庚因基、哌嗪基,N-甲基哌嗪基、吗啉基、咪唑基、吡唑基、四唑基、三唑基;
-R4表示环己基、未被取代的或被以下基团取代的苯基:卤原子、甲氧基、三氟甲基、三氟甲氧基或三氟甲硫基;
-Ar1和Ar2各自相互独立表示苯基,其是未被取代的或被独立选自以下的取代基取代一次或多次:氯原子、溴原子、甲氧基或甲硫基;其呈碱或加成盐形式,以及水合物或溶剂化物形式。
在本发明描述的化合物中,尤其可以提及以下化合物:
N-{[6-(4-氯苯基)-5-(2,4-二氯苯基)-2-(吡咯烷-1-基甲基)吡啶-3-基]甲基}-4-(三氟甲氧基)苯甲酰胺;
N-{[6-(4-溴苯基)-5-(2,4-二氯苯基)-2-(四唑-2-基甲基)吡啶-3-基]甲基}-4-(三氟甲基)苯甲酰胺;
N-{[6-(4-溴苯基)-5-(2,4-二氯苯基)-2-[1,2,4]三唑-1-基甲基-吡啶-3-基]甲基}-4-(三氟甲基)苯甲酰胺;
N-{[6-(4-氯苯基)-5-(2,4-二氯苯基)-2-(吡咯烷-1-基甲基)吡啶-3-基]甲基}-2-丙基戊酰胺;
N-{[6-(4-氯苯基)-5-(2,4-二氯苯基)-2-(吡咯烷-1-基甲基)吡啶-3-基]甲基}-4-((三氟甲基)硫基)苯甲酰胺;
N-{[6-(4-氯苯基)-5-(2,4-二氯苯基)-2-(哌啶-1-基]甲基)吡啶-3-基]甲基}-4-(三氟甲氧基)苯甲酰胺;
N-{[6-(4-氯苯基)-5-(2,4-二氯苯基)-2-(吗啉-4-基]甲基)吡啶-3-基]甲基}-4-(三氟甲氧基)苯甲酰胺;
N-{[6-(4-溴苯基)-5-(2,4-二氯苯基)-2-吡唑-1-基]甲基)吡啶-3-基j甲基}-4-(三氟甲氧基)苯甲酰胺;其呈碱或加成盐形式,以及水合物或溶剂化物形式。
根据本发明,可以根据特征在于使用以下物质处理下式的化合物的方法制备通式(I)的化合物,其中Z表示基团N(R3)XR4或N(R3)COOR5:
其中取代基R1-R3和Ar1,Ar2为如对(I)所定义:
-当希望制备式(IA)的化合物(其中X表示基团-CO-)时,或者使用式R4CO2H(III)的酸(在该式中R4为如对(I)所定义),或者使用所述酸的活性衍生物;或者
-当希望制备式(IB)的化合物(其中X表示-SO2-基团)时,使用式R4SO2Hal(IV)的磺酰基卤化物,在该式中R4是如在(I)所定义,Hal表示卤原子,优选地是氯;或者
-为了制式(IC)的化合物(其中X表示基团-CONH-),使用式R4-N=C=O(VII)的异氰酸酯(isocyanate),其中R4为如对(I)所定义;或者
-为了制备式(ID)的化合物(其中X表示基团-CSNH-),使用式R4-N=C=S(VII bis)的异硫氰酸酯(isothiocyanate),其中R4为如对(I)所定义;或者
-当希望制备式(IE)的化合物(其中Z表示基团N(R3)COOR5)时,使用式HalCOOR5的芳氧基羰基卤化物,其中R5如在式(I)所定义。
或者,当希望制备式(IC)的化合物时,其中X表示基团-CON(R6)-,可以使用式HalCOOR5的芳氧基羰基卤化物处理如在上面定义的(II)的化合物(其中R5为如对(I)所定义),以获得下式的中间化合物:
其中取代基R1-R5为如对(I)所定义,然后用式R4R6NH(VI)的胺对其进行处理,其中R4和R6为如对(I)所定义。
根据本发明,式(IF)的化合物(其中Z表示基团OCONHR5)通过一种方法进行制备,该方法特征在于使用式R5-N=C=O的异氰酸酯处理下式的化合物:
必要时,可以通过本领域技术人已知的方法烷基化式(I)的化合物(其中R3和/或R6是氢原子)来制备式(I)的化合物(其中R3和/或R6表示(C1-C4)烷基)。
任选地,将如此获得的式(I):(IA),(IB),(IC),(DD),(IE)或(IF)的化合物转化为它们的酸加成盐的一种。
在式(IA)的化合物制备期间(其中X表示-CO-),可以使用式(III)的酸的活化衍生物,如酸的卤化物或用以下物质活化的酸:N,N-二环己基碳二亚胺或苯并三唑-1-基氧基三(二甲基胺)鏻六氟磷酸盐(BOP),苯并三唑-1-基氧基三(四氢吡咯并)鏻六氟磷酸盐(PyBOP)或2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(TBTU)。
在式(IB)的化合物制备期间(其中X表示-SO2-),反应在碱(如三乙基胺或二异丙基乙基胺)存在下在溶剂(如二氯甲烷或四氢呋喃)中在环境温度和溶剂回流温度之间的温度下进行。
上述式(IV)的化合物可以通过商业或通过在文献中描述的那样获得,或者可以根据如在以下文献中描述的方法进行制备:J.Org.Chem.USSR,1970,6,2454-2458;J.Am.Chem.Soc,1952,74,2008;J.Med.Chem,1977,20(10),1235-1239;EP0469984;WO95/18105。
例如,式(IV)的化合物可以使用对应的磺酸或它们的盐(例如,它们的钠盐或钾盐)的卤化反应进行制备。在卤化剂(如氯氧化磷、亚硫酰氯、三氯化磷、三溴化磷或五氯化磷)存在下,在没有溶剂或在溶剂(如,卤代烃或N,N-二甲基甲酰胺)中和在-10℃-200℃之间的温度下进行反应。
在式(V)的化合物的制备中使用的芳氧基羰基卤是已知的或通过已知的方法进行制备。
上述式(II)的化合物根据以下反应方案进行制备:
反应方案1
Alk’表示(C1-C4)烷基或苯甲基。
在步骤a1,使用还原剂如LiAlH4以将式(VI)的酯转化为式(VII)的醇。
在步骤b1,在酞酰亚胺存在下,将带有羟甲基的式(VII)的化合物加入到Mitsunobu反应中以获得式(VIII)的化合物,其在下一步c1期间使用水合肼进行处理获得所希望的(II)化合物。
式(VI)的化合物可以根据以下反应方案进行制备:
反应方案2
在AIBN和苯甲酰过氧化物存在下,在UV照射下和在溶剂(如CCl4)中,使用N-溴代琥珀酰亚胺(NBS)进行步骤a2的溴化反应。
在步骤b2中,在碱(如三乙基胺)存在下,在溶剂(如乙腈)中,使用胺HNR1R2处理单溴化衍生物以获得式(VI)的化合物。
在步骤c2中,在乙酸钠存在下,在溶剂(如水/THF的混合物)中,使用硝酸银进行二溴化衍生物的水解。
在步骤d2中,在NaBH(OAc)3存在下,使用式HNR1R2的胺进行处理以获得式(VI)的化合物。
式(X)的化合物根据已知的方法进行制备,所述方法为如在WO03/082191和WO2005/00817中描述的方法。
式(VII)的化合物还可以根据以下反应方案进行制备:
反应方案3
在步骤a3,皂化反应在碱性介质(例如在钾碱存在下)中进行。然后在还原剂(如BH3)存在下进行步骤b3。
使用苯甲酰氯(c3)的酯化反应可以保护醇官能。
在步骤d3中,使用氧化剂(如,间氯过苯甲酸)以制备式(XVII)的吡啶N-氧化衍生物,然后通过重排反应(根据B.H.Lipshutz等人,Tetraheron,1998,54,6999-7012),苯磺酰氯的作用可以制备式(XVIII)的含氯衍生物,利用该衍生物可以制备在胺官能上不同取代的式(VII)化合物。
下式的化合物:
其中:
-R1-R3,Ar1和Ar2为如对(I)所定义,它们是新的并构成本发明的后一方面。
下式的化合物:
其中:
-R1、R2,Ar1和Ar2为如对(I)所定义,它们是新的并构成本发明的后一方面。
式(VII)的化合物如在方案1中所指出的那样使用式(VI)的化合物进行制备或如在方案3中所指出地使用式(XVIII)的化合物进行制备。
根据本发明,当基团NR1R2对还原剂敏感时,还可以通过一种方法制备通式(I)的化合物,其中Z表示基团N(R3)XR4,该方法的特征在于:
a)处理下式的化合物:
其中取代基Ar1,Ar2和R3为如对(I)所定义:
-使用式R4CO2H(III)的酸,其中R4为如对(I)所定义,或使用所述酸的活性衍生物;或者
-使用式R4SO2Hal(IV)的磺酰卤,其中R4为如对(I)所定义,和Hal表示卤原子,优选地是氯;或者
-使用式R4-N=C=O(VII)的异氰酸酯,其中R4为如对(I)所定义;或者
-使用式R4-N=C=S(VII bis)的异硫氰酸酯其中R4为如上面对(I)所定义;
b)使用脱烷剂如BBr3或氢溴酸处理如此获得的下式的化合物:
c)使用式HNR1R2的胺处理如此获得的下式的化合物:
步骤c)可以通过Mitsonobu反应进行,例如在偶氮二甲酸二乙酯和三苯基膦存在下进行。
还可以间接地(intermédiairement)制备下式的化合物:
其中L表示离去基团(groupe partant)然后用胺HNR1R2通过本领域技术人员已知的方法进行取代以得到式(I)的化合物。后者方法特别地适合制备式(IA),(IB),(IC)或(ID)的化合物,其中NR1R2表示四唑基、三唑基。
式(XX)的化合物根据在国际专利申请WO2006/042955中描述的方法进行制备。
下面的实施例描述了符合本发明的某些化合物的制备。这些实施例是非限制性的仅仅举例说明本发明。
在制备中和在这些实施例中使用以下简写:
AcOEt:乙酸乙酯
AcONa:乙酸钠
AIBN:2,2′-偶氮二(2-甲基丙腈)
APTS:对甲苯磺酸
DCM:二氯甲烷
DEAD:偶氮二羧酸二乙酯
缓冲溶液pH=2:16.66g的KHSO4和32.32g的K2SO4在1升水中的溶液
DMSO:二甲基亚砜
DIPEA:二异丙基乙胺
DMF:N,N-二甲基甲酰胺
Et2O:醚:二乙基醚
氯化醚2N:盐酸在二乙基醚中的溶液2N
异醚(éther iso):二异丙基醚
NaBH(OAc)3:三乙酰氧基硼氢化钠
NaHMDS:六亚甲基二硅氮烷钠
NBS:N-溴代琥珀酰亚胺
PyBOP:苯并三唑-1-基氧基三(吡咯烷并)鏻六氟磷酸盐
TA:环境温度
TBTU:2-(1H-苯并三唑-1-基)基氧基三(吡咯烷并)鏻四氟硼酸盐
TEA:三乙基胺
THF:四氢呋喃
根据本发明的化合物使用LC/UV/MS(液相色谱/UV检测/质谱)联用进行分析。测定了分子峰(MH+)和以分钟表示的保留时间(tr)(mn)。
条件A:
洗脱液组成如下:
.溶剂A:0.005%在水中的三氟乙酸(TFA)
.溶剂B:0.005%在乙腈中的TFA。
梯度:在10分钟内溶剂B的百分比从0变到90%,在90%B稳定5分钟。
在210nm-220nm之间进行UV检测,以大气压正电喷雾电离模式(ESI)进行质量检测。
条件B:
洗脱液组成如下:
.溶剂A:0.005%在水中的三氟乙酸(TFA)
.溶剂B:0.005%在乙腈中的TFA。
梯度:在20分钟内溶剂B的百分比从0变到90%,在90%B稳定10分钟。
在210nm-220nm之间进行UV检测,以大气压正电喷雾电离模式(ESI)进行质量检测。
条件C:
洗脱液组成如下:
.溶剂A:10mM的乙酸铵(pH约7)
.溶剂B:乙腈。
梯度:在10分钟内溶剂B的百分比从0变到90%,在90%B稳定5分钟。
在220nm进行UV检测,以大气压正电喷雾电离模式(ESI)进行质量检测。
除非另有说明,条件A为用于LC/MS的条件。
制备1
A)6-(4-氯苯基)-2-(二溴甲基)-5-(2,4-二氯苯基)烟酸乙酯(nicotinated’ethyle)和6-(4-氯苯基)-2-(溴甲基)-5-(2,4-二氯苯基)烟酸乙酯。
将6-(4-氯苯基)-5-(2,4-二氯苯基)-2-甲基烟酸乙酯置于在20ml的CCl4中的溶液中,然后加入4.8g的NBS,0.69g的苯甲酰过氧化物和0.35g的AIBN在UV射线下回流加热。一周后,在真空下浓缩该反应介质,然后残留物用200ml的DCM再溶解。有机相用2×200ml的水洗涤,用Na2SO4干燥,过滤和干燥,得到6.12g粗产物。该粗产物通过用环己烷/AcOEt在二氧化硅上进行纯化2次。回收2个主要级分:
.1.1g二溴化衍生物
.3.42g单溴化衍生物。
LC/MS(条件B):MH+=575.6;tr=21.84mn.
LC/MS(条件B):MH+=497.8;tr=21.20mn.
B)6-(4-氯苯基)-5-(2,4-二氯苯基)-2-甲酰烟酸酯。
将6.4g在步骤A中获得的二溴化合物、7.8g乙酸钠和30.25g硝酸银放置于600ml的THF/水(5/1;v/v)的混合物中。回流加热24小时。反应如下进行处理:通过过滤将无机固体去除,然后蒸发掉溶剂,使粗产物在二氧化硅上使用在环己烷中的5-12%的AcOEt洗脱1小时进行色谱分离。合并纯化的级分并进行干燥浓缩,得到1.98g的希望产物。
LC/MS:MH+=433.8;tr=12.02mn。
C)6-(4-氯苯基)-5-(2,4-二氯苯基)-2-吡咯烷-1-基甲基)烟酸乙酯
将1.98g在步骤B中获得的化合物、0.42ml的吡咯烷和1.93g的NaBH(OAc)3放置于45.5ml的DCM中,然后在TA搅拌2小时。该介质用50ml蒸馏水稀释然后用100ml的DCM萃取;有机相用Na2SO4干燥,过滤并干燥,获得2.38g的希望产物。
LC/MS:MH+=488.9;tr=8.46mn。
D)6-(4-氯苯基)-5-(2,4-二氯苯基)-2-吡咯烷-1-基甲基)烟酸乙酯
将3g在步骤A中获得单溴化合物放置于100ml的乙腈中。加入0,50ml的吡咯烷和0.92ml的TEA。在TA搅拌2小时。蒸发掉溶剂,用100ml的DCM重新溶解并用NaHCO3饱和溶液洗涤。在Na2SO4上干燥有机相,过滤并干燥。获得2.4g希望的产物,根据CCM(薄层色谱法)分析,其与在步骤C中获得的产物相同。
E)6-(4-氯苯基)-5-(2,4-二氯苯基)-2-吡咯烷-1-基甲基)吡啶-3-基)甲醇。
将2.38g在步骤C中获得的化合物放置于20ml的乙醚(éther)中,然后在0℃用小药刀(petites spatulées)加入0.27g的LiAlH4。搅拌2小时。该介质在0进行处理,用100ml乙醚进行稀释,然后加入0.28ml蒸馏水、然后0.28ml的NaOH 4N和0.84ml蒸馏水直到产生沉淀。在TA下搅拌混合物1小时,过滤形成的固体,用50ml的DCM、然后50ml的MeOH进行洗涤。通过蒸发除去溶剂,然后将残留物用100ml的DCM再溶解,有机相用100ml蒸馏水洗涤,用Na2SO4干燥,过滤并干燥,获得1.92g的希望产物。
LC/MS(条件B):MH+=446.9;tr=11.29mn。
F)2-(6-(4-氯苯基)-5-(2,4-二氯苯基)-2-(吡咯烷-1-基甲基)吡咯烷-
3-基)甲基-1H-异吲哚-1,3-(2H)-二酮。
将1.92g在前面步骤中获得的化合物,1.1g的三苯基膦和0.64g的酞酰亚胺放置于71.5ml的THF中。在-10℃,滴加0.76g的DEAD,然后在TA过夜。该反应介质用200ml乙醚稀释。有机相用100ml的pH=2缓冲液、100ml的NaCl的饱和溶液洗涤,用Na2SO4干燥,过滤和干燥。获得5.85g的粗制的希望产物。该粗产物在二氧化硅上通过0-3%的DCM/MeOH洗涤1小时进行纯化。合并包含纯化的产物的级分并进行干燥,得到510mg希望化合物。LC/MS:MH+=575.9;tr=8.56mn。
G)1-(6-(4-氯苯基)-5-(2,4-二氯苯基)-2-(吡咯烷-1-基甲基)吡啶-3-基)甲胺。
将0.51g在前面获得的化合物和0.09ml的单水合肼放置于8.84ml的MeOH中并回流3小时。干燥该反应介质,并再加入100ml蒸馏水和100ml的DCM。有机相用100ml的NaHCO3饱和溶液和100ml的NaCl饱和溶液洗涤,用Na2SO4干燥,过滤并干燥,得到423mg希望化合物,其用于后面步骤中。
LC/MS:MH+=445.9;tr=6.28mn。
制备2
A)6-(4-溴苯基)-5-(2,4-二氯苯基)-2-甲基烟酸.
将103g的6-(4-溴苯基)-5-(2,4-二氯苯基)-2-甲基烟酸的乙基酯和67g的钾碱放置于200ml乙醇中。在搅拌2小时后,蒸发至干然后用Et2O洗涤,用水萃取。酸化水相并用Et2O萃取产物,然后用Na2SO4干燥,过滤并干燥溶液。获得90g希望的酸。
LC/MS:MH+=436;tr=10.95mn.
B)6-(4-溴苯基)-5-(2,4-二氯苯基)-2-(甲基吡啶-3-基)甲醇。
将171.5ml的在THF1N中的BH3溶液稀释在200ml的补充THF中,在0℃在其中加入30g在前面步骤中制备的并稀释在THF中的酸。在环境温度下在搅拌12小时后,在环境温度下滴加100ml的MeOH。冷却至0℃,加入100ml的氯化醚(éther chlorhydrique)然后再搅拌3小时。蒸发至干,用NaHCO3饱和溶液洗涤然后用DCM萃取。用Na2SO4干燥,过滤并干燥滤液,得到29g希望化合物。
LC/MS:MH+=422;tr=9.71mn。
C)6-(4-溴苯基)-5-(2,4-二氯苯基)-2-(甲基吡啶-3-基)甲基苯甲酸酯
在环境温度下,将58g在前面步骤中获得的化合物,19.6g苯甲酰氯和38.1ml三乙基胺放置于200ml的DCM并搅拌4小时。用NaHCO3饱和溶液洗涤,然后用DCM萃取。用Na2SO4干燥,过滤并干燥滤液,获得55g希望化合物。
LC/MS:MH+=526;tr=12.74mn。
D)(6-(4-溴苯基)-5-(2,4-二氯苯基)-2-甲基-1-oxido吡啶-3-基)甲基苯甲酸酯
在环境温度下,将55g在前面步骤中获得的化合物和72g间氯过苯甲酸放置于200ml的DCM中并搅拌12小时。该反应介质用NaHCO3饱和溶液,然后用水进行洗涤。用DCM萃取水相并将合并的有机相用Na2SO4进行干燥,然后过滤浓缩干燥获得55g希望化合物。
LC/MS(条件C):MH+=542;tr=11.09mn。
E)(6-(4-溴苯基)-2-(氯甲基)-5-(2,4-二氯苯基)吡啶-3-基)甲基苯甲酸酯
将55g前面获得的产物稀释在100ml甲苯中并在80℃加热。然后在15分钟内加入35.8g稀释在30ml甲苯中的苯磺酰氯并在80℃下搅拌72小时。将反应介质冷却到0℃,用5%的HCl、Na2CO3饱和溶液然后用水洗涤溶液。用甲苯萃取,用Na2SO4干燥,过滤并干燥滤液,获得36g希望化合物。
LC/MS:MH+=560;tr=13.18mn。
F)(6-(4-溴苯基)-5-(2,4-二氯苯基)-2-((二乙基氨基)甲基)吡啶-3-基)甲基苯甲酸酯
将6g在前面步骤中获得的化合物、2.7g的二乙基胺和5.9g的K2CO3放置于100ml乙腈中并在回流中搅拌3小时。蒸发至干,用水洗涤,然后用DCM萃取。用Na2SO4干燥,过滤然后浓缩该溶液至干,获得2.7g希望的产物。
制备3
(6-(4-溴苯基)-5-(2,4-二氯苯基)-2-((4-甲基哌嗪-1-基)甲基)吡啶-3-基)甲基苯甲酸酯
将6g在制备2,步骤E中获得的化合物和1g的N-甲基哌嗪放置于100ml含有1.49ml的TEA的DCM中,在40℃搅拌10小时。用水洗涤该反应介质并用DCM进行萃取。用Na2SO4干燥,过滤然后将溶液浓缩至干,获得2.5g希望的化合物。
LC/MS:MH+=624;tr=8.56mn。
制备4
A)(6-(4-溴苯基)-5-(2,4-二氯苯基)-2-(1H-吡唑-1-基甲基)吡啶-3-基)甲基苯甲酸酯
将1.45g吡唑放置于50ml含有0.85g NaH的THF中并在环境温度下搅拌2小时;加入6g在制备2,步骤E中获得的化合物,在70℃搅拌3小时。用水洗涤该反应介质并用AcOEt进行萃取。用Na2SO4干燥,过滤然后将溶液浓缩至干,获得3g希望的化合物。
LC/MS:MH+=592;tr=12.49mn。
B)(6-(4-溴苯基)-5-(2,4-二氯苯基)-2-(1H-吡唑-1-基甲基)吡啶-3-基)甲醇
将3g在前面步骤中获得的化合物和1.4g钾碱放置于100ml乙醇中,在环境温度下搅拌1小时。蒸干,用水洗涤和用DCM萃取。用Na2SO4干燥,过滤然后将溶液浓缩至干,获得3g希望的化合物。
C)1-(6-(4-溴苯基)-5-(2,4-二氯苯基)-2-(1H-吡唑-1-基甲基)吡啶-3-基)甲胺
这种化合物根据在制备1的步骤F和G中描述的操作方法进行制备。
LC/MS:MH+=487;tr=7.54mn。
使用在制备2和3中获得的式(XIX)的化合物制备式(VII)的化合物,然后相应的(II)的化合物。这些化合物描述在下面表I和II中。
因此,下面的表举例说明了根据本发明的化合物的某些中间体的化学结构和物理性质。在这些表中,Me表示甲基。
表I
表II
制备5
通过根据描述在WO2006/042955中的方法进行操作,制备了:N-{[6-(4-溴苯基)-5-(2,4-二氯苯基)-2-(甲氧基甲基)吡啶-3-基]甲基}-4-(三氟甲基)苯甲酰胺。
实施例1:化合物N°1
N-{[6-(4-氯苯基)-5-(2,4-二氯苯基)-2-(吡咯烷-1-基甲基)吡啶-3-基]甲基}-4-(三氟甲氧基)苯甲酰胺。
将在制备1的步骤G中获得的化合物在DCM中制成溶液并加入TEA,然后滴加0.14g的4-三氟甲氧基苯磺酰氯。在TA下,搅拌2小时。该反应介质用100ml的DCM稀释,有机相用100ml蒸馏水洗涤,然后用Na2SO4干燥,过滤并干燥,得到450mg的粗产物。该粗产物使用色谱用0-2%的DCM/MeOH洗脱1小时在二氧化硅上进行纯化。合并包含经纯化的产物的级分并干燥,获得300mg呈碱形式的希望的化合物。经纯化的产物根据标准方法被盐化为盐酸盐。得到214mg希望的二盐酸盐(dichlorhydrate)。
LCMS:MH+=633.9;tr=9.03mn。
实施例2:化合物N°26A)N-{[6-(4-溴苯基)-5-(2,4-二氯苯基)-2-(甲氧基甲基)吡啶-3-基]甲基}-4-(三氟甲基)苯甲酰胺。
该化合物根据WO2006/042955进行制备。
LC/MS:MH+=623;tr=12.2mn。
B)N-{[6-(4-溴苯基)-5-(2,4-二氯苯基)-2-(羟甲基)吡啶-3-基]甲基}-4-(三氟甲基)苯甲酰胺。
将2g前面步骤的化合物放置于100ml的DCM中,然后在-30℃下将12.8ml的BBr3缓慢加入到在DCM中制成1N溶液。在环境温度下搅拌12小时。该介质在200ml水中洗涤然后再放置于100ml的DCM中。该有机相用Na2SO4进行干燥,过滤并干燥。获得的粗产品被稀释在200ml的二噁烷/水(50/50;v/v)中。在其中加入1.77g的K2CO3。在回流下搅拌5小时。蒸发至干。用水洗涤该反应介质并用DCM萃取。用Na2SO4干燥,过滤并将滤液浓缩至干。该粗产物用色谱在二氧化硅上通过用0-3%的DCM/MeOH洗脱1小时。干燥经纯化的产品得到1.5g希望的化合物。
LC/MS:MH+=609;tr=11.44mn。
C)N-{[6-(4-溴苯基)-5-(2,4-二氯苯基)-2-(1H-四唑-1-基甲基)吡啶-3-基]甲基}-4-(三氟甲氧基)苯甲酰胺。
将0.7g在前面步骤中获得的化合物、3.73ml在乙腈中3%的四唑溶液、0.31g的三苯基膦放置于100ml的THF中。在0℃,加入0.22g稀释在20ml的THF的DEAD。在0℃下搅拌3小时然后在TA下搅拌2小时。将干燥、然后用水洗涤后的反应介质放置于100ml的DCM中。有机相用Na2SO4干燥,过滤并干燥。该粗产物用色谱在二氧化硅上通过0-1%的DCM/MeOH洗脱1小时进行纯化。干燥经纯化的产物得到0.15g希望的化合物。
LC/MS:MH+=661;tr=19.1mn。
下面的表举例说明了使用上述介质进行制备的本发明的化合物的某些实例的化学结构和物理性质。在这些表中,Me表示甲基。
表III
由M.Rinaldi-Carmona等人(FEBS Letters,1994,350,240-244)描述的条件下,式(I)的化合物具有特别好的对大麻素的受体CB1的体外亲合性(IC50<5.10-7M)。
通过在腺苷酸-环化酶的抑制模型中获得的结果显示了式(I)的化合物的拮抗性质,该模型如描述在M.Bouaboula等人,J.Biol.Chem.,1995,270,13973-13980,M.Rinaldi-Carmona等人,J.Pharmacol.Exp.Ther.,1996,278,871-878和M.Bouaboula等人,J.Biol.Chem.,1997,272,22330-22339。
根据本发明的化合物与存在于大脑中的受体CB1的相互作用在小鼠体中使用[3H]-CP55940的间接体内连接试验(le test de binding exvivo)在静脉注射或口服给药后进行测定,其如描述在M.Rinaldi-Carmona等人,FEBSLetters,1994,350,240-244和M.Rinaldi-Carmona等人,LifeSciences,1995,56,1941-1947,M.Rinaldi-Carmona等人,J.Pharmacol.Exp.Ther.,2004,310,905-914和Rinaldi-CarmonaM.等人,JPET2004,310,905-914中。
根据本发明的化合物与存在于周围组织(périphérie)中的受体CB1的相互作用在小鼠体中使用在口服给药后CP55940对经肠胃通过(transit gastrointestinal)的抑制作用的回复试验进行测定,该试验如描述在M.Rinaldi-Carmona等人,J.Pharmacol.Exp.Ther.,2004,310,1905-914中。
式(I)的化合物的毒性与它们作为药物的用途是相容的。
因此,根据它们另一方面,本发明的目的是用于人的或动物医学的药物,其包含式(I)的化合物,或还包含式(I)的化合物的溶剂化物或水合物。
因此,根据本发明的化合物可以用于人或用于动物(尤其是哺乳动物,非限定性地包括狗、猫、马、牛、羊)的治疗或预防与大麻素(cannabinoides)的受体CB1有关的疾病。
例如并非限制性地,式(I)的化合物用作治疗精神病的药物,尤其用于治疗精神紊乱,包括焦虑症、抑郁症、情绪病症(troubles del′humeur),失眠,谵妄症(les troubles délirants),强迫症,常规精神病(lespsychoses en général),精神分裂症,注意力缺陷病症(les troubles dudéficit de l′attention)和在活动过度的婴儿中的活动过强疾病(TDAH)以及用于制备与使用治疗精神病物质有关的障碍,尤其在物质滥用和/或物质依赖(包括酒精依赖和烟碱依赖)的情况下也是如此。
根据本发明的式(I)的化合物可以用作治疗偏头疼、紧张,源自心身的疾病(des maladies d′origine psychosomatique),恐慌病发作(descrises d′attaques de panique),癫痫病发作(de l′épilepsie),运动病症,尤其是运动障碍或帕金森病、震颤病和张力障碍。
根据本发明的式(I)的化合物还可以用作在记忆障碍、认知障碍治疗中,尤其用于在老年性痴呆、阿尔茨海默(Alzheimer)病的药物,以及用于在注意障碍或惊醒病症的治疗中。而且,式(I)的化合物可以用作神经保护剂(neuroprotecteurs),在治疗局部缺血、脑颅创伤和急性或慢性神经变性疾病,包括舞蹈病、亨廷顿(Huntington)舞蹈病,Tourrette综合症。
根据本发明的式(I)的化合物可以用作治疗以下疼痛的药物:神经病疼痛、外周急性疼痛(les douleurs périphériques),炎症源慢性疼痛(les douleur chroniques d′origine inflammatoire),抗癌治疗引起的疼痛。
根据本发明的式(I)的化合物可以被用作在治疗以下疾病中的人或动物医学中的药物:食欲病症(troubles de l′appétit)、嗜好病症(troublesde l′appétence)(对糖,碳水化合物,药物,酒精或所有吸引性物质)和/或饮食引起的疾病,尤其用于治疗肥胖症或食欲过盛以及用于治疗II型糖尿病或非胰岛素依赖性糖尿病和用于治疗血脂异常(dyslipidémies),新陈代谢综合症。以及根据本发明的式(I)的化合物用于治疗肥胖症和与肥胖症相关的危险,尤其是心血管危险。而且,根据本发明的式(I)的化合物可以用作治疗以下疾病的药物:胃肠病症、腹泻病症、溃疡、呕吐、膀胱和尿病症、内分泌源病症、心血管病症、高血压、出血性休克、感染性休克(du choc septique),慢性肝硬化、肝脂肪化、脂肪肝(stéatohépatite)、哮喘、雷诺(Raynaud)综合症、青光眼、生育病症(troubles de la fertilité),流产(de l′interruption de grossesse),早产、发炎病症、免疫系统疾病,尤其是自身免疫疾病和神经炎疾病(neuroinflammatoires)如,风湿性关节炎、反应性关节炎(arthriteréactionnelle),引起脱髓鞘、多发性硬化的疾病,传染性和病毒性疾病,如脑炎、脑血管病状(des accidents vasculaires cérébraux)以及作为用于抗癌化疗的药物,用于治疗Guillain-Barré综合症和用于治疗骨疾病和骨质疏松疾病的药物。
根据本发明,式(I)的化合物尤其特别地用于治疗精神疾病,特别地是精神分裂症、在活动过度的婴儿中的注意力障碍(troubles del′attention)和活动过强疾病(TDAH);用于治疗食欲病症和肥胖症;用于治疗记忆和认知缺陷;用于治疗酒精依赖、烟碱依赖,即用于戒酒和戒烟。
更特别地,根据本发明的式(I)的化合物用于治疗和预防食欲病症、代谢病症、胃肠病症、发炎症状、免疫系统疾病、精神病症、酒精依赖和烟碱依赖疾病。
根据它的一个方面,本发明涉及使用式(I)的化合物、其溶剂化物和水合物用于治疗上面提到的病症的用途。
根据它的另一个方面,本发明涉及药物组合物,其包括本发明的化合物作为活性成分。这些药物组合物包含有效剂量的至少一种本发明的化合物,所述化合物的溶剂化物或水合物,以及至少一种药物可接受的赋形剂。
所述赋形剂根据药物形式和希望的给药方式在本领域的技术人员已知的通常的赋形剂中进行选择。
根据本发明的药物组合物,除了式(I)的化合物,可以包含一种(或多种)其他的用于治疗上面提到的病症和疾病的活性成分。
因此,本发明还一个目的是药物组合物,其包含本发明的式(I)的化合物,其与一种(或多种)选自下面治疗种类中一种的活性成分结合:
-大麻素受体CB1的其它拮抗剂或别构效应调节剂;
-大麻素受体CB2的调节剂;
-血管收缩素II受体AT1的拮抗剂;
-转换酶抑制剂;
-钙拮抗剂;
-利尿剂;
-β-封端剂(béta-bloquant);
-抗高血脂或高血胆固醇剂;
-抗糖尿病剂;
-其它的抗肥胖症或治疗代谢疾病的药剂(aggissant);
-烟碱激动剂,部分烟酸激动剂(agoniste);
-抗抑郁剂,抗精神病药(un antispychotique),抗焦虑药;
-抗癌药或抗扩散剂(agent antiprolifératif);
-类吗啡拮抗剂;
以及:
-记忆改善剂(un agent améliorant la mémoire);
-用于治疗骨质疏松的药剂;
-非甾类或甾类抗炎药;
-抗感染药;
-镇痛药;
-抗哮喘药。
抗糖尿病药,理解为属于以下种类的一种:磺脲类(lessulfonylurées),双胍类,α-葡糖苷酶抑制剂类、噻唑烷二酮类、lesmétiglinides以及胰岛素和胰岛素类似物。
其他的抗肥胖症药剂或治疗代谢病症的药剂,可以理解为如PPAR(过氧物酶体活性受体拮抗剂)拮抗剂的化合物、多巴胺拮抗剂、瘦素的受体激动剂、5-羟色胺再摄取抑制剂,β-3激动剂,CCK-A激动剂,NPY抑制剂、MC4的受体激动剂,MCH(黑色素浓缩素)受体拮抗剂、食欲素拮抗剂、磷酸二酯酶抑制剂、11βHSD(11-β-羟基甾类脱氢酶)的抑制剂、DPP-IV(二肽基肽酶IV)的抑制剂,拮抗剂(或组胺H3反向激动剂,CNTF(睫状神经营养因子)衍生物,GHS(生长激素促分泌素)受体的激动剂,ghréline的调节剂、甘油二酯酰基转移酶抑制剂(DGAT)、磷酸二酯酶(PDE)抑制剂、甲状腺激素激动剂、糖皮质激素受体拮抗剂、硬脂酰-CoA-去饱和酶(SCD)抑制剂,磷转运蛋白、葡萄糖、脂肪酸、二羧酸酯的调节剂,5HT2拮抗剂,5HT6拮抗剂,蛙皮素激动剂。
用于治疗骨质疏松的药剂,理解为例如二膦酸酯。
根据本发明,还可以结合其他具有抗高血脂、抗高血胆固醇、抗糖尿病或抗肥胖症性质的化合物。更特别地,可以结合属于以下种类之一的化合物:PTP1B(酪氨酸蛋白磷酸酶-IB(Protein TyrosinePhosphase-1B))抑制剂、VPAC2受体激动剂、GLK调节剂、维加酸(retinoides)调节剂、糖原磷酸化酶(glycogen phosporylase)(HGLPa)抑制剂、高血糖素拮抗剂、葡萄糖-6磷酸酯抑制剂,丙酮酸脱氢酶激酶(PKD)激活剂,RXR、FXR、LXR的调节剂,SGLT(钠依赖性单糖转运体)抑制剂、CETP(胆固醇酯转运蛋白)抑制剂、角鲨烯合成酶抑制剂、角鲨烯环氧化酶抑制剂、甘油三酸酯合成抑制剂、LDL(低密度脂蛋白)受体诱导剂、IBAT抑制剂、FBP酶(果糖-1,6-二磷酸酯酶)抑制剂、CART(可卡因-苯丙胺调节转录肽)调节剂、MC4(黑素皮质激素4)调节剂,食欲素受体拮抗剂、GLP-1(胰高血糖素样肽(Glucafon Like Peptide-1))受体调节剂。
根据本发明另一方面,式(I)的化合物、其药物可接受盐的一种或它们的溶剂化物和其他结合的活性成分可以同时、分开或在时间上分期给药。
“同时使用”理解为给药本发明的组合物的化合物,它们被包含在唯一和相同药物形式中。
“分开使用”理解为本发明的组合物的两种化合物的同时给药,每种被包含在不同的药物形式中。
“时间上分期使用”理解为相继给药本发明组合物的第一化合物(被包含在一种药物形式中),然后本发明组合物的第二化合物(被包含在不同的药物形式中)。在这种情况下,在给药本发明的组合物的第一化合物和给药本发明的组合物第二化合物之间的时间间隔一般不超过24小时。
在本发明的用于口服、舌下、皮下、肌内、静脉内、体表(topique)、局部、气管内、鼻内、经皮、直肠给药的药物组合物中,上面式(I)的活性成分或它们的任选溶剂化物或水合物可以以单位给药形式(sousforme unitaire d′administration)、以传统的药物赋形剂的混合物对动物或人进行给药以预防或治疗上述病症或疾病。
合适的单位给药形式包括通过口服途径形式(如片剂、软或硬胶囊、粉剂、丸剂和口服溶液或悬浮液),舌下、口腔、气管内、眼内、鼻内(通过吸入)的给药形式,体表、经皮、皮下、肌内或静脉内的给药形式,直肠给药形式和植入给药形式。对于体表施用,可以使用霜剂、凝胶剂、膏剂或洗剂形式的本发明组合物。
举例而言,本发明的化合物的片剂形式的单位给药形式可以包括以下组分:
本发明的化合物:50.0mg
甘露醇:223.75mg
交联羟甲纤维素钠6.0mg
玉米淀粉15.0mg
羟丙基-甲基纤维素2.25mg
硬脂酸镁3.0mg
通过口服途径,每天给药的活性成分的剂量可以为0.01-100mg/kg,以一次或多次服用,优选地为0.02-50mg/kg。
在此可以有特殊情况,其中更高或更少的剂量也是适合的;这些剂量不超出本发明的范围。根据一般实践,适合于每个患者的剂量由医生根据用药方式、所述患者的体重和反应进行确定。
根据本发明的其他方面,其还涉及治疗上述病理的方法,其包括向患者给药有效剂量的本发明的化合物或水合物或溶剂化物。
Claims (14)
1.符合下式的化合物:
其中
-Z表示N(R3)XR4,N(R3)COOR5或OCON(R3)R5;
-X表示基团-CO-,-SO2-,-CON(R6)-或-CSN(R6)-;
-R1和R2各自独立表示氢原子或(C1-C7)烷基或R1和R2与跟它们连接的氮原子一起组成饱和或不饱和的3-8个链节的杂环基团,其可以包括一个或多个选自氧、硫、或氮原子的其他杂原子,所述基团是未被取代的或被一个或多个(C1-C4)烷基基团取代;
-R3表示氢原子或(C1-C4)烷基;
-R4表示:
未被取代的或被CF3取代的(C3-C10)烷基;
非芳族(C3-C12)碳环基团,其是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:(C1-C4)烷基,羟基,(C1-C4)烷氧基,(C1-C4)烷硫基,氰基;
含氧、硫或氮的3-8个原子的杂环基团,其是饱和或不饱和的,未被取代的或被一个或多个相同或不同的选自以下的取代基取代:卤原子、(C1-C4)烷基、羟基、三氟甲基、(C1-C4)烷氧基、三氟甲氧基、三氟甲硫基、(C1-C4)烷硫基、氰基、硝基或氧基;
吲哚基,其是未被取代的或被卤原子或被(C1-C4)烷基、三氟甲基、羟基、(C1-C4)烷氧基、三氟甲氧基、三氟甲硫基、(C1-C4)烷硫基、氰基、硝基取代;
四氢萘基;萘基;
苯并苯硫基或苯并呋喃基;
苯基,其是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基、苯基、S(O)nAlk、OS(O)nAlk或NR7R8基团;
苯并二氧基;
苯氧基亚甲基,1-苯氧基亚乙基,所述苯基是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基、苯基、S(O)nAlk、OS(O)nAlk或NR7R8基团;所述亚甲基或亚乙基是未被取代的或被(C1-C4)烷基或被(C3-C7)环烷基取代一次或多次;
苯基环丙基,该苯基是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基、苯基、S(O)nAlk、OS(O)nAlk或NR7R8基团;
(C1-C2)亚烷基,其被一个或两个相同或不同的选自以下的取代基取代:
(i)未被取代的或被(C1-C4)烷基取代一次或多次的非芳族C3-C12碳环基;
(ii)未被取代的或被一个或多个相同或不同的选自以下的取代基取代的苯基:卤原子、(C1-C4)烷基、羟基、三氟甲基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲氧基、三氟甲硫基、(C1-C4)链烷酰基、氰基、硝基、苯基、S(O)nAlk,OS(O)nAlk或NR7R8基团;
(iii)含氧、含硫或含氮的3-8个原子的杂环基团,其是饱和或不饱和的,未被取代或被一个或多个相同或不同的选自以下的基团取代的:卤原子、(C1-C4)烷基、羟基、三氟甲基、(C1-C4)烷氧基、三氟甲氧基、三氟甲硫基、(C1-C4)烷硫基、氰基、硝基;
而且,当X表示基团-CON(R6)-或-CSN(R6)-,R4可以表示(C1-C6)链烷酰基或苯甲酰基或苯甲基羰基,所述基团的苯基是未被取代的或被相同或不同的选自以下的取代基取代:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、硝基、(C1-C4)链烷酰基、苯基、S(O)nAlk,OS(O)nAlk或NR7R8基团;
-R5表示未被取代的或被相同或不同的选自以下的取代基取代一次或多次的苯基:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、氰基、硝基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、S(O)nAlk,OS(O)nAlk或NR7R8基团;
-R6表示氢原子或(C1-C4)烷基;
-或R4和R6与跟它们连接的氮原子一起构成3-8个原子的杂环基团,其不包含或包含选自氧、硫或氮原子的第二杂原子,其是未被取代的或被选自以下基团取代一次或多次:(C1-C4)烷基;(C1-C4)链烷酰基;NR7R8或CONR7R8基团;苯基,其是未被取代的或被选自以下的基团取代一次或多次:卤原子、(C1-C4)烷基、(C1-C4)烷氧基或三氟甲基、(C1-C4)烷硫基、三氟甲氧基、三氟甲硫基、S(O)nAlk、OS(O)nAlk或NR7R8基团;
-R7和R8各自相互独立表示氢原子、(C1-C4)烷基,或者R7和R8与跟它们连接的氮原子一起构成4-8个原子的饱和杂环基团,其可以包含选自氮、氧、或硫原子的其他杂原子;
-Ar1和Ar2各自相互独立表示苯基,其是未被取代的或被以下取代:卤原子、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、三氟甲基、三氟甲氧基、三氟甲硫基、氰基、硝基或S(O)nAlk、OS(O)nAlk或NR7R8基团;
-n表示0,1或2;
-Alk表示(C1-C7)烷基;
其呈碱或加成盐形式,以及水合物或溶剂化物形式。
2.权利要求1的下式的化合物:
其中:
-X表示-CO-,-SO2-或-CON(R6)-;
-R1和R2为如对(I)所定义;
-R3表示氢原子或(C1-C4)烷基;
-R4表示:
(C3-C10)烷基;
非芳族(C3-C12)碳环基团,其是未被取代的或被(C1-C4)烷基取代一次或多次;
含氮、氧、或硫的饱和或不饱和的4-8个原子的杂环基团,其是未被取代的或被一个或多个相同或不同的选自以下的取代基取代:卤原子、(C1-C4)烷基、羟基、三氟甲基、(C1-C4)烷氧基、三氟甲氧基、(C1-C4)烷硫基、氰基、硝基;
吲哚基,其是未被取代的或在氮原子上被卤原子、(C1-C4)烷基、(C1-C4)烷氧基取代;
苯基,其是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、(C1-C4)烷氧基、(C1-C4)烷硫基、三氟甲硫基、氰基、(C1-C4)链烷酰基、苯基或者S(O)nAlk或OS(O)nAlk基团;
苯甲基,其是未被取代的或被相同或不同的选自以下的取代基取代一次或多次:卤原子、(C1-C4)烷基、三氟甲基、三氟甲氧基、三氟甲硫基、(C1-C4)烷氧基、氰基、苯基,或者S(O)nAlk或OS(O)nAlk基团;
-R6表示氢原子或(C1-C4)烷基;
-或R4和R6与跟它们连接的氮原子一起构成4-8个原子的杂环基团,其包含或不包含选自氧、硫或氮原子的第二杂原子,其是未被取代的或被选自以下的取代一次或多次:(C1-C4)烷基;(C1-C4)链烷酰基;NR7R8或CONR7R8基团;苯基,其是未被取代的或被选自以下的基团取代一次或多次:卤原子、(C1-C4)烷基、(C1-C4)烷氧基或三氟甲基;
-R7和R8各自相互独立表示氢原子、(C1-C4)烷基,或者R7和R8与跟它们连接的氮原子一起构成杂环基团,其选自哌啶基、吡咯烷基、哌嗪基、N-甲基哌嗪基、吖庚因基或吗啉基;
-Ar1和Ar2各自相互独立表示苯基,其是未被取代的或被以下取代:卤原子、(C1-C6)烷基、(C1-C6)烷氧基、三氟甲基、三氟甲硫基、三氟甲氧基或者S(O)nAlk或OS(O)nAlk基团;
-n表示0,1或2;
-Alk表示(C1-C4)烷基;
其呈碱或加成盐形式,以及水合物或溶剂化物形式。
3.权利要求1的下式的化合物:
其中
-R1和R2各自相互独立表示氢原子或(C1-C7)烷基,或者R1和R2与跟它们连接的氮原子一起构成选自以下的基团:azéridinyle、吖丁啶基、吡咯烷基、哌啶基、吖庚因基、哌嗪基、N-甲基哌嗪基、吗啉基、咪唑基、吡唑基、四唑基、三唑基;
-R3表示氢原子或甲基;
-R4表示:
(C5-C10)烷基;
(C5-C7)环烷基,其是未被取代的或被甲基取代一次或多次;
含氧、硫、氮的4-8个原子的饱和杂环基团,其是未被取代的或被甲基取代一次或多次;
苯基,其被独立选自以下的基团取代一次或多次:卤原子、三氟甲基、三氟甲氧基、三氟甲硫基、(C1-C4)烷氧基、(C1-C4)烷硫基、SO2Alk或OSO2Alk;
-Ar1和Ar2各自相互独立表示苯基,其被一个或两个独立选自以下的取代基取代:卤原子、甲氧基、甲硫基、三氟甲硫基、三氟甲氧基、SO2Alk、OSO2Alk;其呈碱或加成盐形式,以及呈水合物或溶剂化物形式。
4.权利要求1的下式的化合物:
其中:
-R1和R2各自相互独立表示(C1-C7)烷基,或者R1和R2与跟它们连接的氮原子一起构成选自以下的基团:azéridinyle、吖丁啶基、吡咯烷基、哌啶基、吖庚因基、哌嗪基、N-甲基哌嗪基、吗啉基、咪唑基、吡唑基、四唑基、三唑基;
-R3表示氢原子或甲基;
-R4表示:
(C5-C10)烷基;
(C5-C7)环烷基,其是未被取代的或被甲基取代一次或多次;
含氧、硫、氮的4-8个原子的饱和杂环基团,其是未被取代的或被甲基取代一次或多次;
苯基,其被独立选自以下的基团取代一次或多次:卤原子、三氟甲基、三氟甲氧基、三氟甲硫基、(C1-C4)烷氧基、(C1-C4)烷硫基、SO2Alk或OSO2Alk;
-R6表示氢原子或甲基;
-Ar1和Ar2各自相互独立表示苯基,其被一个或两个独立选自以下的取代基取代:卤原子和甲氧基、甲硫基、三氟甲硫基、三氟甲氧基、SO2Alk、OSO2Alk;
其呈碱或加成盐形式,以及呈水合物或溶剂化物形式。
5.权利要求3的式(IA)的化合物,其中:
-Z表示NHCOR4;
-R1和R2各自相互独立表示(C1-C7)烷基,或者R1和R2与跟它们连接的氮原子一起构成选自以下的基团:azéridinyle、吖丁啶基,吡咯烷基、哌啶基、吖庚因基、哌嗪基,N-甲基哌嗪基、吗啉基、咪唑基、吡唑基、四唑基、三唑基;
-R4表示2-丙基戊基,1-丙基丁基,5-甲基壬基,4-甲基庚基,4-甲基-2,6-二甲基庚基,环戊基,四甲基环戊基,环己基,四氢呋喃基,吡咯烷基,1,1,4,4-四甲基环戊基,2,2,5,5-四甲基呋喃基,2,2,5,5-四甲基吡咯烷基,苯基,其是未被代的或被卤原子、三氟甲基、三氟甲氧基、三氟甲硫基或被SO2Alk或OSO2Alk取代;
-和/或Ar1和Ar2各自相互独立表示苯基,其被独立地选自以下的取代基取代:氯、溴原子或甲氧基、甲硫基;
其呈碱或加成盐形式,以及水合物或溶剂化物形式。
6.权利要求4的式(IC)的化合物,其中:
-Z表示基团-NHCONHR4;
-R1和R2彼此独立地表示(C1-C7)烷基或者R1和R2与跟它们连接的氮原子一起构成选自以下的基团:azéridinyle,吖丁啶基,吡咯烷基、哌啶基、吖庚因基、哌嗪基,N-甲基哌嗪基、吗啉基、咪唑基、吡唑基、四唑基、三唑基;
-R4表示环己基、未被取代的或被以下基团取代的苯基:卤原子、甲氧基、三氟甲基、三氟甲氧基或三氟甲硫基;
-Ar1和Ar2各自相互独立表示苯基,其是未被取代的或被独立选自以下的取代基取代一次或多次:氯原子、溴原子、甲氧基或甲硫基;其呈碱或加成盐形式,以及水合物或溶剂化物形式。
7.式(I)的化合物的制备方法,在该式中Z表示基团N(R3)XR4或N(R3)COOR5,特征在于处理下式的化合物:
其中,取代基R1-R3和Ar1,Ar2为如对(I)所定义:
-当希望制备式(IA)的化合物时,在该式中X表示基团-CO-,使用式R4CO2H(III)的酸,在该式中R4为如对(I)所定义,或者使用所述酸的活性衍生物;或者
-当希望制备式(IB)的化合物时,在该式中X表示-SO2-基团,使用式R4SO2Hal(IV)的磺酰基卤化物,在该式中R4是如在(I)所定义,Hal表示卤原子,优选地是氯;或者
-为了制式(IC)的化合物,在该式中X表示基团-CONH-,使用式R4-N=C=O(VII)的异氰酸酯,在该式中R4为如对(I)所定义;或者
-为了制备式(ID)的化合物,在该式中X表示基团-CSNH-,使用式R4-N=C=S(VII bis)的异硫氰酸酯,其中R4为如上面对(I)所定义;或者
-当希望制备式(IE)的化合物时,在该式中Z表示基团N(R3)COOR5,使用式HalCOOR5的芳氧基羰基卤化物,其中R5如在式(I)所定义。
9.式(I)的化合物的制备方法,在该式中Z表示基团N(R3)XR4,该方法的特征在于:
a)处理下式的化合物:
其中取代基Ar1,Ar2和R3为如对(I)所定义:
-使用式R4CO2H(III)的酸,在该式中R4为如对(I)所定义,或使用所述酸的活性衍生物;或者
-使用式R4SO2Hal(IV)的磺酰卤,在该式中R4为如对(I)所定义,和Hal表示卤原子,优选地是氯;或者
-使用式R4-N=C=O(VII)的异氰酸酯,在该式中R4为如对(I)所定义;或者
-使用式R4-N=C=S(VII bis)的异硫氰酸酯,在该式中R4为如上面对(I)所定义;
b)使用脱烷剂如BBr3或氢溴酸处理如此获得的下式的化合物:
c)使用式HNR1R2的胺处理如此获得的下式的化合物:
12.药物,特征在于它包含权利要求1-6的任一项的式(I)的化合物,或这种化合物与药物可接受酸的加成盐,或式(I)的化合物的水合物或溶剂化物。
13.药物组合物,特征在于它包含权利要求1-6任一项的式(I)的化合物,或这种化合物的药物可接受盐,水合物或溶剂化物,以及至少一种药物可接受的赋形剂。
14.权利要求1-6任一项的式(I)的化合物用于制备药物的用途,所述药物用来治疗和预防食欲病症、代谢病症、胃肠病症、发炎症状、免疫系统疾病、精神病症、酒精依赖和烟碱依赖疾病。
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FR2838438A1 (fr) * | 2002-04-11 | 2003-10-17 | Sanofi Synthelabo | Derives de diphenylpyridine,leur preparation, les compositions pharmaceutiques en contenant |
FR2838439B1 (fr) * | 2002-04-11 | 2005-05-20 | Sanofi Synthelabo | Derives de terphenyle, leur preparation, les compositions pharmaceutqiues en contenant |
FR2856684B1 (fr) * | 2003-06-26 | 2008-04-11 | Sanofi Synthelabo | Derives de diphenylpyridine, leur preparation et leur application en therapeutique |
FR2864958B1 (fr) * | 2004-01-12 | 2006-02-24 | Sanofi Synthelabo | Derive de n-[(1,5-diphenyl-1h-pyrazol-3-yl)methyl] sulfonamide, leur preparation et leur application en therapeutique. |
FR2876691B1 (fr) * | 2004-10-18 | 2006-12-29 | Sanofi Aventis Sa | Derives de pyridine, leur preparation, leur application en therapeutique |
-
2006
- 2006-04-14 FR FR0603382A patent/FR2899899A1/fr not_active Withdrawn
-
2007
- 2007-04-10 DO DO2007000067A patent/DOP2007000067A/es unknown
- 2007-04-11 TW TW096112757A patent/TW200813037A/zh unknown
- 2007-04-12 JP JP2009504782A patent/JP2009533400A/ja not_active Withdrawn
- 2007-04-12 PE PE2007000452A patent/PE20071224A1/es not_active Application Discontinuation
- 2007-04-12 CN CNA2007800131701A patent/CN101421240A/zh active Pending
- 2007-04-12 AR ARP070101551A patent/AR060800A1/es unknown
- 2007-04-12 BR BRPI0710741-2A patent/BRPI0710741A2/pt not_active IP Right Cessation
- 2007-04-12 KR KR1020087024954A patent/KR20080108540A/ko not_active Application Discontinuation
- 2007-04-12 EP EP07731288A patent/EP2010492A2/fr not_active Withdrawn
- 2007-04-12 WO PCT/FR2007/000620 patent/WO2007119001A2/fr active Application Filing
- 2007-04-12 MX MX2008013208A patent/MX2008013208A/es not_active Application Discontinuation
- 2007-04-12 AU AU2007239344A patent/AU2007239344A1/en not_active Abandoned
- 2007-04-12 RU RU2008144952/04A patent/RU2008144952A/ru not_active Application Discontinuation
- 2007-04-12 CA CA002645961A patent/CA2645961A1/fr not_active Abandoned
- 2007-04-13 UY UY30285A patent/UY30285A1/es unknown
-
2008
- 2008-10-06 IL IL194573A patent/IL194573A0/en unknown
- 2008-10-10 US US12/249,140 patent/US20090203699A1/en not_active Abandoned
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103003242A (zh) * | 2010-07-20 | 2013-03-27 | 科学与工业研究委员会 | 吡啶-2-基硫基酸酯及其制备方法 |
CN103003242B (zh) * | 2010-07-20 | 2015-04-22 | 科学与工业研究委员会 | 吡啶-2-基硫基酸酯及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
UY30285A1 (es) | 2007-11-30 |
DOP2007000067A (es) | 2007-10-31 |
WO2007119001A2 (fr) | 2007-10-25 |
FR2899899A1 (fr) | 2007-10-19 |
TW200813037A (en) | 2008-03-16 |
PE20071224A1 (es) | 2008-01-23 |
RU2008144952A (ru) | 2010-05-20 |
IL194573A0 (en) | 2009-09-22 |
BRPI0710741A2 (pt) | 2011-06-07 |
EP2010492A2 (fr) | 2009-01-07 |
US20090203699A1 (en) | 2009-08-13 |
AR060800A1 (es) | 2008-07-16 |
JP2009533400A (ja) | 2009-09-17 |
MX2008013208A (es) | 2008-10-27 |
KR20080108540A (ko) | 2008-12-15 |
AU2007239344A1 (en) | 2007-10-25 |
WO2007119001A3 (fr) | 2007-12-13 |
CA2645961A1 (fr) | 2007-10-25 |
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