CN100497302C - 二芳基脲衍生物和它们作为氯通道阻滞剂的用途 - Google Patents
二芳基脲衍生物和它们作为氯通道阻滞剂的用途 Download PDFInfo
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- CN100497302C CN100497302C CNB038209853A CN03820985A CN100497302C CN 100497302 C CN100497302 C CN 100497302C CN B038209853 A CNB038209853 A CN B038209853A CN 03820985 A CN03820985 A CN 03820985A CN 100497302 C CN100497302 C CN 100497302C
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- phenyl
- chloro
- urea
- tetrazolium
- trifluoromethyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明由通式(I)表示的新颖的二芳基脲衍生物,它们可用作氯通道阻滞剂。本发明的其它方面涉及这些化合物在治疗方法中的用途,例如用于治疗骨代谢疾病、对肥大细胞或嗜碱细胞活性的调节有应答的疾病,对血管生成抑制有应答的疾病或镰状细胞性贫血,还涉及包含本发明化合物的药物组合物。
Description
技术领域
本发明涉及新颖的二芳基脲衍生物,它们可用作氯通道阻滞剂。
另一方面,本发明涉及这些化合物在治疗方法中的用途,例如用于治疗骨代谢疾病、对肥大细胞或嗜碱细胞活性调节有应答的疾病、对血管生成抑制有应答的疾病或者镰状细胞性贫血,还涉及包含本发明化合物的药物组合物。
背景技术
氯通道发挥多种特定的细胞功能,例如对骨骼与平滑肌细胞的正常功能有贡献。氯通道可能见于每类细胞,从细菌到哺乳动物。它们的生理任务从细胞容量调节到膜电位的稳定化、跨上皮或跨细胞转运和细胞内细胞器的酸化都有广泛涉猎。
WO 97/45400、WO 98/47879、WO 00/20378和WO 00/24707(均为NeuroSearch A/S)描述了有氯通道阻滞剂活性的化合物,例如取代的苯基衍生物。
然而,仍然需要为治疗患有破骨细胞相关性骨疾病、例如骨质疏松的患者提供更有效、更有选择性和更少副作用的化合物。
也仍然需要为治疗患有对肥大细胞或嗜碱细胞活性调节有应答的疾病、对血管生成抑制有应答的疾病或者镰状细胞性贫血的患者提供更有效、更有选择性和更少副作用的化合物。
发明概述
本发明的目的是提供新颖的化合物,它们充当氯通道阻滞剂。
本发明的进一步目的是提供具有更好选择性的化合物。另一目的是提供具有更好效力的化合物。
进一步的目的是提供作用于细胞或组织特异性氯通道的化合物,例如破骨细胞的氯通道。本发明的另一目的是提供作用于细胞或组织特异性氯通道的化合物,例如肥大细胞或嗜碱细胞的氯通道。另一目的是提供作用于特定氯通道小组或亚型的化合物。
进一步的目的是提供具有更优药效学性质的化合物,例如动力学行为、生物利用度、溶解度和功效。
第一方面,本发明提供通式(I)化合物,
或其药学上可接受的盐,其中A、R1和D是如下所定义的。
第二方面,本发明提供药物组合物,包含治疗有效量的本发明化合物或其药学上可接受的盐以及至少一种药学上可接受的载体、赋形剂或稀释剂。
另一方面,本发明提供本发明化合物或其药学上可接受的盐在药物组合物制备中的用途,所述组合物用于治疗、预防或减轻哺乳动物、包括人类的疾病或障碍或病症,该疾病、障碍或病症对氯通道的阻滞有应答。
另一方面,本发明涉及治疗、预防或减轻活动物体、包括人类的疾病或障碍或病症的方法,该障碍、疾病或病症对氯通道的阻滞有应答,该方法包含给予有此需要的活动物体治疗有效量的本发明化合物或其药学上可接受的盐的步骤。
本发明的其他方面将因下列详细说明和实施例而为本领域技术人员所显而易见。
发明的详细公开
二芳基脲衍生物
在其第一方面,本发明提供通式(I)化合物,
或其药学上可接受的盐,其中
A代表一种环系,选自由环己烷基、苯基、吡啶基、噻吩基、噻唑基、萘基、吲哚基、吡唑基和氧代-吡咯烷基组成的组,该环系可选地被一个或多个取代基取代,所述取代基独立地选自由卤素、三氟甲基、硝基、烷基、烷氧基和苯基组成的组;
R1代表-H;并且
D代表
其中
R2、R3和R4之一选自由四唑基、-COORa、-B(OH)2、-PO(ORa)2、-CH2-PO(ORa)2和-CONH组成的组;其中Ra是氢或烷基;
或者R2和R3或R3和R4都代表氟;
R5、R6和其余R2、R3和R4之一或之二彼此独立地代表:
○ 氢、卤素、三氟甲基,
○ -CH=CH-COORb、-CH2-CH2-COORb,
○ -CO-NRb-CH2-COORc、-CO-NRbRc,
○ -CH=CH-CO-NRbRc、-CH2-CH2-CO-NRbRc,
○ 哌啶基羰基,
○ -NH-CO-Rd或-NH-CO-NH-Rd,
○ 其中Rd是苯基,可选地被一个或多个独立选自卤素或三氟甲基的取代基取代,或者
○ 苯基,可选地被-SO2-NRbRc、-CO-NRbRc、-CO-NRb-CH2-COORc或哌啶基羰基取代,
其中Rb和Rc独立地是氢或烷基;
或者R1代表-H;并且
D代表
其中R2’、R3’、R4’、R5’、R6’彼此独立地代表氢、卤素或三氟甲基;
或者R1与D一起构成-CHRe-CH2-CHRf-CH2-,其中Re代表-COOH,Rf代表氢或羟基。
在通式(I)化合物的一种实施方式中,R2、R3和R4之一代表四唑基,例如1H-四唑-5-基。在具体实施方式中,R2代表四唑基,例如1H-四唑-5-基。在另一具体实施方式中,R3代表四唑基,例如1H-四唑-5-基。在另一具体实施方式中,R4代表四唑基,例如1H-四唑-5-基。在通式(I)化合物的另一实施方式中,R2代表卤素,例如溴。在通式(I)化合物的另一实施方式中,R2和R3都代表卤素,例如溴。
在通式(I)化合物的另一实施方式中,A选自由1H-吲哚-2-基、环己基、萘基、吡啶-2-基、吡啶-3-基、吡啶-4-基、噻吩-2-基、噻唑-2-基、噻唑-3-基、2H-1λ4-噻唑-2-基、3,6-二氯-吡啶-4-基、2,6-二氯-吡啶-4-基、5-氯-吡啶-2-基、2-氯-吡啶-3-基、5-苯基-2H-吡唑-3-基和5-氧代-1-苯基-吡咯烷-3-基组成的组。
在通式(I)化合物的另一实施方式中,A选自由苯基、2-氯-苯基、2-氟-苯基、2-溴-苯基、2-甲氧基-苯基、2-三氟甲基-苯基、2,3-二氯-苯基、2,4,6-三氯-苯基、2,6-二氯-苯基、3-溴-苯基、3-氯-苯基、3-碘-苯基、3-甲氧基-苯基、3-硝基-苯基、3,4-二氯-苯基、3-氟-4-氯-苯基、3-硝基-4-氯-苯基、3-三氟甲基-4-氯-苯基、3-三氟甲基-4-氟-苯基、3,5-二氯-苯基、3,5-二氟-苯基、3-氟-5-三氟甲基-苯基、3,5-二甲基-苯基、3,5-二甲氧基-苯基、3,5-双-三氟甲基-苯基、4-氯-苯基、4-甲氧基-苯基、4-丁氧基-苯基和4-苯基-苯基组成的组。
在通式(I)化合物的另一实施方式中,该化合物是通式(II)化合物
或其药学上可接受的盐,其中
R3、R4、R5和R6彼此独立地代表:
○ 氢、卤素、三氟甲基,
○ -CH=CH-COORb、-CH2-CH2-COORb,
○ -CO-NRb-CH2-COORc、-CO-NRbRc,
○ -CH=CH-CO-NRbRc、-CH2-CH2-CO-NRbRc,
○ 哌啶基羰基,
○ -NH-CO-Rd或-NH-CO-NH-Rd,其中Rd是苯基,可选地被一个或多个独立选自卤素或三氟甲基的取代基取代,或者
○ 苯基,可选地被-SO2-NRbRc、-CO-NRbRc、-CO-NRb-CH2-COORc或哌啶基羰基取代,
其中Rb和Rc独立地是氢或烷基;
R12、R13、R14、R15和R16彼此独立地代表氢、卤素、三氟甲基、硝基、烷基或烷氧基。
在通式(II)化合物的一种实施方式中,R12代表氢。在另一实施方式中,R12代表卤素,例如氯、氟或溴。在另一实施方式中,R12代表烷氧基,例如甲氧基。在另一实施方式中,R12代表三氟甲基。
在通式(II)化合物的另一实施方式中,R13代表卤素,例如氯、氟、溴或碘。在另一实施方式中,R13代表三氟甲基。在另一实施方式中,R13代表烷氧基,例如甲氧基。在另一实施方式中,R13代表硝基。在另一实施方式中,R13代表烷基,例如甲基。在另一实施方式中,R13代表氢。
在通式(II)化合物的另一实施方式中,R14代表卤素,例如氯。在另一实施方式中,R14代表氢。在另一实施方式中,R14代表烷氧基,例如甲氧基或丁氧基。在另一实施方式中,R14代表苯基。
在通式(II)化合物的另一实施方式中,R15代表卤素,例如氟或氯。在另一实施方式中,R15代表三氟甲基。在另一实施方式中,R15代表氢。在另一实施方式中,R15代表三氟甲基。
在通式(II)化合物的另一实施方式中,R16代表氢。在通式(II)化合物的另一实施方式中,R16代表卤素,例如氯。
在通式(II)化合物的另一实施方式中,R12、R14和R16各自代表氢。在通式(II)化合物的另一实施方式中,R12、R15和R16各自代表氢。
在通式(II)化合物的另一实施方式中,R5代表卤素,例如氯,R2、R3、R4和R6各自代表氢。
在通式(II)化合物的另一实施方式中,R4和R6各自代表卤素,例如溴或氯,R2、R3和R5各自代表氢。在具体实施方式中,R4和R6各自代表溴。在另一具体实施方式中,R4和R6各自代表氯。
在通式(II)化合物的另一实施方式中,R4和R6各自代表卤素,例如溴或氯,R2、R3和R5各自代表氢;R12、R13、R14、R15和R16之二或之三彼此独立地代表卤素,例如氯或氟,其余R12、R13、R14、R15和R16之三或之二代表氢。在具体实施方式中,R12和R16独立地代表氯或氟,R13、R14和R15代表氢。在另一具体实施方式中,R13和R15独立地代表氯或氟,R12、R14和R16代表氢。在另一具体实施方式中,R13和R14独立地代表氯或氟,R12、R12和R15代表氢。在另一具体实施方式中,R12、R14和R16独立地代表氯或氟,R13和R15代表氢。
在通式(II)化合物的另一实施方式中,R4代表-CO-NRbRc,例如-CO-NHCH3、-CO-N(CH3)2或-CO-N(CH2CH3)2,R2、R3、R5和R6各自代表氢。
在通式(II)化合物的另一实施方式中,R4代表-CO-NRb-CH2-COORc,例如-CO-NH-CH2-COOH,R2、R3、R5和R6各自代表氢。
在通式(II)化合物的另一实施方式中,R4代表-CH=CH-COORb,例如-CH=CH-COOH,R2、R3、R5和R6各自代表氢。
在通式(II)化合物的另一实施方式中,R4代表-CH2-CH2-COORb,例如-CH2-CH2-COOH,R2、R3、R5和R6各自代表氢。
在通式(II)化合物的另一实施方式中,R4代表-CH2-CH2-CO-NRbRc,例如-CH2-CH2-CO-NHCH3,R2、R3、R5和R6各自代表氢。
在通式(II)化合物的另一实施方式中,R4代表-CH=CH-CO-NRbRc,例如-CH-CH-CO-N(CH3)2或-CH=CH-CO-NHCH3,R2、R3、R5和R6各自代表氢。
在通式(II)化合物的另一实施方式中,R4代表哌啶基羰基,例如1-哌啶基羰基,R2、R3、R5和R6各自代表氢。
在通式(II)化合物的另一实施方式中,R4代表苯基,被-SO2-NRbRc取代,例如-SO2N(CH3)2,R2、R3、R5和R6各自代表氢。在具体实施方式中,R4代表4-(N,N-二甲基-氨磺酰基)-苯基。
在通式(II)化合物的另一实施方式中,R4代表苯基,被-CO-NRbRc取代,例如-CO-N(CH3)2、-CO-NHCH3或-CO-NH2,R2、R3、R5和R6各自代表氢。在具体实施方式中,R4代表4-(N,N-二甲基-氨甲酰基)-苯基、4-(N-甲基-氨甲酰基)-苯基或4-氨甲酰基-苯基。
在通式(II)化合物的另一实施方式中,R4代表苯基,被-CO-NRb-CH2-COORc取代,例如-CONH-CH2-COOH或-CO-N(CH3)-CH2-COOH,R2、R3、R5和R6各自代表氢。
在通式(II)化合物的另一实施方式中,R4代表苯基,被哌啶基羰基取代,例如1-哌啶基羰基,R2、R3、R5和R6各自代表氢。
在通式(II)化合物的另一实施方式中,R4代表-NH-CO-Rd,例如-NH-CO-苯基,R2、R3、R5和R6各自代表氢。
在通式(II)化合物的另一实施方式中,R4代表-NH-CO-NH-Rd,例如-NH-CO-NH-(3,5-双-三氟甲基苯基),R2、R3、R5和R6各自代表氢。
在通式(II)化合物的另一实施方式中,该化合物是通式(III)化合物
或其药学上可接受的盐,其中
R9代表-CO-NRbRc、-CO-NRb-CH2-COORc或哌啶基羰基,其中Rb和Rc独立地是氢或烷基;
R12、R13、R14、R15和R16之二彼此独立地代表卤素、三氟甲基、硝基、烷基或烷氧基,其余R12、R13、R14、R15和R16之三代表氢。
在通式(III)化合物的一种实施方式中,R13和R15代表三氟甲基,R12、R14和R16各自代表氢。
在通式(III)化合物的第二种实施方式中,R13和R15代表卤素,例如氯或氟,R12、R14和R16各自代表氢。
在通式(III)化合物的另一实施方式中,R13和R14代表卤素,例如氯,或者三氟甲基,R12、R15和R16各自代表氢。在具体实施方式中,R13代表三氟甲基,R14代表氯。在另一具体实施方式中,R13代表氯,R14代表三氟甲基。
在通式(III)化合物的另一实施方式中,Rg代表-CO-NRbRc,例如-CO-NH2或-CO-N(CH3)2。
在通式(III)化合物的另一实施方式中,Rg代表-CO-NRb-CH2-COORc,例如-CO-NH2-CH2-COOH或-CO-NHCH3-CH2-COOH。
在通式(III)化合物的另一实施方式中,Rg代表哌啶基羰基,例如1-哌啶基羰基。
在通式(III)化合物的另一实施方式中,Rg代表-CO-NRbRc,例如-CO-N(CH3)2;R13和R15代表卤素,例如氯或氟;R12、R14和R16各自代表氢。
在通式(I)化合物的另一实施方式中,
A代表一种环系,选自由环己烷基、苯基、吡啶基、噻吩基、噻唑基和吡唑基组成的组,该环系可选地被一个或多个取代基取代,所述取代基独立地选自由卤素、三氟甲基、硝基、烷基、烷氧基和苯基组成的组;
R1代表-H;并且
D代表
其中
R2代表-COORa,其中Ra是氢或烷基;
R3、R4、R5和R6彼此独立地代表:
○ 氢、卤素、三氟甲基,
○ -NH-CO-Rd或-NH-CO-NH-Rd,其中Rd是苯基,可选地被一个或多个独立选自卤素或三氟甲基的取代基取代,或者
○ 苯基,可选地被-SO2-NRbRc、-CO-NRbRc、-CO-NRb-CH2-COORc或哌啶基羰基取代,
其中Rb和Rc独立地是氢或烷基。
在D的一种实施方式中,R5代表卤素,例如氯、溴或碘,R3、R4和R6各自代表氢。
在D的第二种实施方式中,R4代表卤素,例如溴或氯,R3、R5和R6各自代表氢。
在D的另一实施方式中,R3、R4、R5和R6各自代表氢。
在D的另一实施方式中,R4和R6代表卤素,例如溴或氯,R3和R5代表氢。
在D的另一实施方式中,R2代表-COOH或-COOCH3。
在D的另一实施方式中,R4代表苯基,R3、R5和R6各自代表氢。
在D的另一实施方式中,R5代表苯基,R3、R4和R6各自代表氢。
在D的另一实施方式中,R2代表-COOH;R4和R6代表卤素,例如溴或氯;R3和R5代表氢。
在具体实施方式中,D代表2-羧基苯基、2-羧基-4-溴苯基、2-羧基-4-氯苯基、2-羧基-4-苯基苯基、2-羧基-4,6-二氯苯基、2-羧基-5-氯苯基、2-羧基-5-碘苯基、2-羧基-5-苯基苯基、2-羧基环己基、3-羧基吡啶-2-基、3-羧基-5-溴吡啶-2-基、2-甲氧基羰基-5-氯苯基或2-甲氧基羰基-4-溴苯基。
在通式(I)化合物的具体实施方式中,
A代表苯基,可选地被一个或多个取代基取代,所述取代基独立地选自由卤素和三氟甲基组成的组;
D代表
其中
R2代表-COOH;
R4和R6代表卤素,例如溴或氯;
R3和R5代表氢。
在通式(I)化合物的另一实施方式中,
A代表苯基,可选地被一个或多个取代基取代,所述取代基独立地选自由卤素和三氟甲基组成的组;
D代表
其中
R3代表-COORa,其中Ra是氢或烷基;
R2、R4、R5和R6彼此独立地代表
○氢、卤素或三氟甲基,或者
○-NH-CO-NH-Rd,其中Rd是苯基,可选地被一个或多个独立选自卤素或三氟甲基的取代基取代。
在具体实施方式中,D代表2,5-氯-3-羧基苯基、3-羧基-5-三氟甲基苯基、3-羧基-5-(3-溴-苯基脲基)-苯基或3-羧基-5-(3,5-二氯-苯基脲基)-苯基。
在通式(I)化合物的另一实施方式中,A代表
其中R12、R13、R14、R15和R16彼此独立地代表卤素、三氟甲基、硝基、烷基、烷氧基或苯基。
在具体实施方式中,R13和R15代表三氟甲基,R12、R14和R16各自代表氢。
在通式(I)化合物的另一实施方式中,
A代表一种环系,选自由环己烷基、苯基和吡啶基组成的组,该环系可选地被一个或多个取代基取代,所述取代基独立地选自由卤素、三氟甲基、硝基、烷基和烷氧基组成的组;
R1代表-H;并且
D代表
其中
R2代表-B(OH)2、-PO(ORa)2、-CH2-PO(ORa)2或-CONH,其中Ra是氢或烷基(氢、甲基、乙基);
R2、R3、R4、R5和R6彼此独立地代表氢、卤素、三氟甲基或苯基。
在D的一种实施方式中,R2代表-B(OH)2。在D的第二种实施方式中,R2代表-PO(ORa)2。在D的另一实施方式中,R2代表-CH2-PO(ORa)2。在D的另一实施方式中,R2代表-CONH。
在D的另一实施方式中,R3、R4、R5和R6各自代表氢。
在具体实施方式中,D代表2-二羟基硼基苯基、2-膦酰基苯基、2-膦酰基甲基苯基、2-膦酰基-4-溴苯基、2-膦酰基甲基-4-溴苯基、2-膦酰基甲基-4-氯苯基、2-二乙基膦酰基苯基、2-二甲基膦酰基甲基苯基、2-二甲基膦酰基甲基-4-氯苯基或2-二乙基膦酰基-4-溴苯基。
在通式(I)化合物的另一实施方式中,
A代表苯基,可选地被一个或多个取代基取代,所述取代基选自由卤素、三氟甲基、硝基、烷基和烷氧基组成的组;
R1代表-H;并且
D代表
其中
R2’、R3’、R4’、R5’和R6’彼此独立地代表氢、卤素或三氟甲基。
在具体实施方式中,D代表α-羧基-4-氟苄基或α-羧基-4-三氟甲基苄基。
在通式(I)化合物的另一实施方式中,
A代表一种环系,选自由环己烷基、苯基和吡啶基组成的组,该环系可选地被一个或多个取代基取代,所述取代基独立地选自由卤素、三氟甲基、硝基、烷基和烷氧基组成的组;
R1与D一起构成-CHRe-CH2-CHRf-CH2-,其中Re代表-COOH,Rf代表氢或羟基。
在一种实施方式中,Rf代表氢。在第二种实施方式中,Rf代表羟基。
在通式(I)化合物的另一实施方式中,
A代表一种环系,选自由环己烷基、苯基和吡啶基组成的组,该环系可选地被一个或多个取代基取代,所述取代基独立地选自由卤素、三氟甲基、硝基、烷基和烷氧基组成的组;
R1代表-H;并且
D代表
其中
R2和R3或者R3和R4都代表氟;
R5、R6和其余R2、R3和R4之一或之二彼此独立地代表氢、卤素或三氟甲基。
在D的一种实施方式中,R2和R3都代表氟。
在第二种实施方式中,R4、R5和R6各自代表氢。
在另一实施方式中,R4代表三氟甲基,并且R5和R6代表氢。
在具体实施方式中,D代表2,3-二氟苯基或2,3-二氟-4-三氟甲基苯基。
在通式(I)化合物的另一实施方式中,
A代表一种环系,选自由环己烷基、吡啶基和萘基组成的组,该环系可选地被一个或多个取代基取代,所述取代基独立地选自由卤素、三氟甲基、硝基、烷基和烷氧基组成的组;
R1代表-H;并且
D代表
其中
R2代表四唑基;
R3、R4、R5和R6彼此独立地代表
○ 氢、卤素、三氟甲基,或者
○ 苯基,被-SO2-NRbRc、-CO-NRbRc、-CO-NRb-CH2-COORc或哌啶基羰基取代,
其中Rb和Rc独立地是氢或烷基,例如甲基。
在具体实施方式中,A选自环己烷基、2,6-二氯-吡啶-4-基、吡啶-3-基和3-萘-1-基;D选自3-氯-6-(1H-四唑-5-基)苯基、4-溴-2-(1H-四唑-5-基)苯基和4′-(N,N-二甲基-1-羰基)-2-(1H-四唑-5-基)-联苯-4-基。
在具体实施方式中,本发明化合物为
N-(3,5-双-三氟甲基-苯基)-N′-[2-溴-4-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[2,6-二溴-3-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-(2-溴-5-(1H-四唑-5-基)-苯基]脲;
5-氯-2-[3-(1H-吲哚-2-基)-脲基]-苯甲酸;
5-溴-2-[3-(1H-吲哚-2-基)-脲基]-苯甲酸;
N-(3-氟-5-三氟甲基-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-磺酸-二甲基酰胺]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-磺酸-二甲基酰胺]脲;
N-(3,5-二氟-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-磺酸-二甲基酰胺]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3-溴-苯基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3-氯-苯基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(4-氟-3-三氟甲基-苯基)-N′-[2,4-二溴-6-(1H-四唑-5-基)-苯基]脲;
N-(3,4-二氯-苯基)-N′-[2,4-二溴-6-(1H-四唑-5-基)-苯基]脲;
N-(3-甲氧基-苯基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(2-甲氧基-苯基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(4-甲氧基-苯基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(2-三氟甲基-苯基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(3,5-二氯-苯基)-N′-[2,4-二溴-6-(1H-四唑-5-基)-苯基]脲;
N-(2-氯-苯基)-N′-[4′-(哌啶-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(3,5-二氯-苯基)-N′-[2,4-二氯-6-(1H-四唑-5-基)-苯基]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[2,4-二氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[2,4-二氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基)-N′-[2,4-二氯-5-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4-(N″-甲基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-(N″-甲基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-(羰基-氨基-乙酸)-2-(1H-四唑-5-基)-苯基]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-(丙烯酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4-(丙烯酸甲基酯)-2-(1H-四唑-5-基)苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(丙烯酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-(丙烯酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;
N-(2-氯-苯基)-N′-[4-(丙烯酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;
N-(4-氯-3-三氟-苯基)-N′-[4-(丙酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4-(丙酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(丙酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-(丙酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;
N-(2-氯-苯基)-N′-[4-(丙酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4-(N″-丙酰胺酸)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(N-丙酰胺酸)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-(N″-丙酰胺酸)-2-(1H-四唑-5-基)-苯基]脲;
N-(2-氯-苯基)-N′-[4-(N″-丙酰胺酸)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-{4-[(N″,N″-二甲基)-丙烯酰胺]-2-(1H-四唑-5-基)-苯基}脲;
N-(3,5-二氟-苯基)-N′-{4-[(N″,N″-二甲基)-丙烯酰胺]-2-(1H-四唑-5-基)-苯基}脲;
N-(2-氯-苯基)-N′-{4-[(N″,N″-二甲基)-丙烯酰胺]-2-(1H-四唑-5-基)-苯基}脲;
N-(3,5-二氯-苯基)-N′-{4-[(N″-甲基)-丙烯酰胺]-2-(1H-四唑-5-基)-苯基}脲;
N-(3,5-二氟-苯基)-N′-{4-[(N″-甲基)-丙烯酰胺]-2-(1H-四唑-5-基)-苯基}脲;
N-(2-氯-苯基-N′-[4-(哌啶-1-羰基)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4-(N″,N″-二乙基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(N″,N″-二乙基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-(N″,N″-二乙基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(2-氯-苯基)-N′-[4-(N″,N″-二乙基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-(哌啶-1-羰基)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4-(哌啶-1-羰基)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(哌啶-1-羰基)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-(哌啶-1-羰基)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4′-(羰基-(N″-甲基)氨基-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;
N-(3,5-二氯-苯基)-N′-[4-(N″,N″-二甲基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-(N″,N″-二甲基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(4-氯-3-三氟甲基)-N′-[4-(N″,N″二乙基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(2-氯-苯基)-N′-[4′-(羰基-氨基-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-(N″-甲基-丙基酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4-(N″-甲基-丙基酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(N″-甲基-丙基酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-(N″-甲基-丙基酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(2-氯-苯基)-N′-[4-(N″-甲基-丙基酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(2,6-二氯-苯基)-N′-[2,4-二氯-6-(1H-四唑-5-基)-苯基]脲;
N-(2,4,6-三氯-苯基)-N′-[2,4-二氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4-苯甲酰胺-2-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-苯甲酰胺-2-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4-苯甲酰胺-2-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-苯甲酰胺-2-(1H-四唑-5-基)-苯基)脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-(N″,N″-二甲基丙烯酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4-(N″,N″-二甲基丙烯酰胺)-2-(1H-四唑-5-基)苯基]脲;
N-(3-氯-4-氟-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-磺酸-二甲基酰胺]脲;
N-(4-氟-3-三氟甲基-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-磺酸-二甲基酰胺]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-羧酸二甲基酰胺]脲;
N-(3,5-二氯-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-羧酸二甲基酰胺]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[4′-(哌啶-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(3,5-二氯-苯基)-N′-[4′-(哌啶-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4′-(哌啶-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(3,5-二氟-苯基)-N′-[4′-(哌啶-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[4′-甲酰胺-2-(1H-四唑-5-基)-4-联苯]脲;
N-(3,5-二氯-苯基)-N′-[4′-甲酰胺-2-(1H-四唑-5-基)-4-联苯]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4′-甲酰胺-2-(1H-四唑-5-基)-4-联苯]脲;
N-(3,5-二氟-苯基)-N′-[4′-甲酰胺-2-(1H-四唑-5-基)-4-联苯]脲;
N-(3,5-二氯-苯基)-N′-[4′-(羰基-氨基-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;
N-(3,5-二氟-苯基)-N′-[4′-(羰基-氨基-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;
N-(4-氯-3-三氟甲基-苯基)-N-{4′-[羰基-(N′-甲基)-氨基-乙酸]-2-(1H-四唑-5-基)-4-联苯}脲;
N-(3,5-二氯-苯基)-N′-{4′-[羰基-(N″-甲基)-氨基-乙酸]-2-(1H-四唑-5-基)-4-联苯}脲;
N-(3,5-双-三氟甲基-苯基)-N′-{4′-[羰基-(N″-甲基)-氨基-乙酸]-2-(1H-四唑-5-基)-4-联苯}脲;
N-(3,5-二氟-苯基)-N′-[4′-(羰基-氨基-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4′-(N″-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[4′-(N″-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;
4-氯-2-(3-环己基-脲基)-苯甲酸;
5-溴-2-[3-(3,5-双-三氟甲基-苯基)-脲基]-苯甲酸;
2-[3-(3,5-双-三氟甲基-苯基)-脲基]-环己烷羧酸;
5-溴-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(3-溴-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(3,5-二氯-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(2,6-二氨-吡啶-4-基)-脲基]-苯甲酸;
N-(3,5-双-三氟甲基-苯基)-N′-(苯基-2-二羟基甲硼烷)脲;
N-(4-氯-3-氟-苯基)-N′-(苯基-2-二羟基甲硼烷)脲;
N-(3,5-二氯-苯基)-N′-(苯基-2-二羟基甲硼烷)脲;
N-环己基-N′-(苯基-2-二羟基甲硼烷)脲;
5-氯-2-[3-(吡啶-3-基)-脲基]-苯甲酸;
5-溴-2-[3-(吡啶-3-基)-脲基]-苯甲酸;
3,5-二氯-2-[3-(3,5-二氯-苯基)-脲基]-苯甲酸;
3,5-二氯-2-[3-(3-氯-4-氟-苯基)-脲基]-苯甲酸;
3,5-二氯-2-[3-(3,5-双-三氟甲基-苯基)-脲基]-苯甲酸;
3,5-二氯-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-苯甲酸;
3,5-二氯-2-[3-(4-氟-3-三氟甲基-苯基)-脲基]-苯甲酸;
3,5-二氯-2-[3-(3-氟-5-三氟甲基-苯基)-脲基]-苯甲酸;
3,5-二氯-2-[3-(3,5-二氟-苯基)-脲基]-苯甲酸;
2-[3-(噻吩基-2-基)-脲基]-苯甲酸;
2-[3-(吡啶-4-基)-脲基]-苯甲酸;
4-氯-2-[3-(吡啶-4-基)-脲基]-苯甲酸;
5-溴-2-[3-(吡啶-4-基)-脲基]-苯甲酸;
2-[3-(吡啶-3-基)-脲基]-烟酸;
2-[(3-(3-氯-苯基)-脲基]-环己烷羧酸;
2-[(3-(3-溴-苯基)-脲基]-环己烷羧酸;
2-[3-(3,5-二氯-苯基)-脲基]-环己烷羧酸;
2-(3-环己基-脲基)-环己烷羧酸;
2-[3-(2,6-二氨-吡啶-4-基)-脲基]-环己烷羧酸;
4-氯-2-[3-(2,6-二氯-吡啶-4-基)-脲基]-苯甲酸;
5-溴-2-[3-(3-氯-苯基)-脲基]-苯甲酸;
2-[3-(3,5-双-三氟甲基-苯基)-脲基]-烟酸;
5-溴-2-(3-环己基-脲基)-苯甲酸;
2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-环己烷羧酸;
2-[3-(3-氯-苯基)-脲基]-环己烷羧酸;
2-[3-(3-溴-苯基)-脲基]-环己烷羧酸;
2-[3-(2,6-二氯-苯基)-脲基]-环己烷羧酸;
2-[3-(2,6-二氯-吡啶-4-基)-脲基]-环己烷羧酸;
4-氯-2-[3-(噻唑-2-基)-脲基]-苯甲酸甲基酯;
5-溴-2-[3-(吡啶-2-基)-脲基]-苯甲酸甲基酯;
4-氯-2-[3-(5-氯-吡啶-2-基)-脲基]苯甲酸;
5-溴-2-(3-噻唑-2-基-脲基)-苯甲酸甲基酯;
2-[3-(5-溴-吡啶-3-基)-脲基]-4-氯-苯甲酸;
5-溴-2-[3-(吡啶-2-基)-脲基]-苯甲酸;
3-溴-2-[3-(2H-1λ4-噻唑-2-基)-脲基]-苯甲酸;
3-[3-(4-氯-3-三氟甲基-苯基)-脲基]-联苯-4-羧酸酰胺;
4-[3-(3,5-二氯-苯基)-脲基]-联苯-3-羧酸;
4-[3-(3,5-双-三氟甲基-苯基)脲基]-联苯-3-羧酸;
4-[3-(3,5-二氟-苯基)-脲基]-联苯-3-羧酸;
4-[3-(2-氯-苯基)-脲基]-联苯-3-羧酸;
4-氯-2-[3-(5-苯基-2H-吡唑-3-基)-脲基]-苯甲酸;
2-[3-(2-氯-吡啶-3-基)-脲基]-烟酸;
4-氯-2-[3-(2-氯-吡啶-3-基)-脲基]-苯甲酸;
2-[3-(4-氯-苯基)-脲基]-5-碘-苯甲酸;
5-氯-2-[3-(5-氧代-1-苯基-吡咯烷-3-基)-脲基]-苯甲酸;
5-溴-2-(3-苯基-脲基)-苯甲酸;
5-溴-2-[3-(2-氟-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(2-氯-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(3,5-二甲基-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(3,5-二氟-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(3,5-二甲氧基-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(2,6-二氯-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(2-溴-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(4-氯-3-硝基-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(4-丁氧基-苯基)-脲基]-苯甲酸;
5-氯-2-[3-(2-氯-苯基)-脲基]-苯甲酸;
5-氯-2-[3-(3,5-二甲基-苯基)-脲基]-苯甲酸;
2-[3-(4-联苯)-脲基]-5-溴-苯甲酸;
5-氯-2-[3-(3-碘-苯基)-脲基]-苯甲酸;
5-氯-2-(3-苯基-脲基)-苯甲酸;
5-氨-2-[3-(2-氟-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-烟酸;
5-溴-2-[3-(3,5-双-三氟甲基-苯基)-脲基]-烟酸;
5-氯-2-[3-(3,5-二氟-苯基)-脲基]-苯甲酸;
5-氯-2-[3-(3,5-二甲氧基-苯基)-脲基]-苯甲酸;
5-氯-2-[3-(3,4-二氯-苯基)-脲基]-苯甲酸;
2-[3-(4-丁氧基-苯基)-脲基]-5-氯-苯甲酸;
5-溴-2-[3-(3,5-二氯-苯基)-脲基]-烟酸;
3,5-双-[3-(3,5-二氟-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(3,5-二氟-苯基)-脲基]-烟酸;
5-溴-2-[3-(2,4,6-三氯-苯基)-脲基]-烟酸;
5-氯-2-[3-(2,6-二氯-苯基)-脲基]-苯甲酸;
2,5-二氯-3-[3-(3-溴-苯基)-脲基]-苯甲酸;
2,5-二氯-3-[3-(3,5-二氯-苯基)-脲基]-苯甲酸;
3,5-双-[3-(3-溴-苯基)-脲基]-苯甲酸;
3,5-双-[3-(3,5-二氯-苯基)-脲基]-苯甲酸;
3-[3-(3-溴-苯基)-脲基]-5-三氟-苯甲酸;
3-[3-(3,5-二氯-苯基)-脲基]-5-三氟-苯甲酸;
3,5-双-[3-(3,5-双-三氟甲基苯基)-脲基]-苯甲酸;
2-[3-(吡啶-3-基)-脲基]-苯基-二羟基甲硼烷;
2-[3-(2,6-二氯-吡啶-4-基)-脲基]-苯基-二羟基甲硼烷(boronic acid);
2-[3-(3-溴-苯基)-脲基]-苯基-二羟基-硼烷;
{2-[3-(3,5-双-三氟甲基-苯基)-脲基]苯基}-膦酸二乙基酯;
{2-[3-(3,5-双-三氟甲基-苯基)-脲基]苯基}-膦酸;
{2-[3-(4-氯-3-三氟甲基-苯基)-脲基]苯基}-膦酸二乙基酯;
{2-[3-(4-氯-3-三氟甲基-苯基)-脲基]苯基}-膦酸;
{2-[3-(3-氯-苯基)-脲基]-苯基}-膦酸二乙基酯;
{2-[3-(3-氯-苯基)-脲基]苯基}-膦酸;
{2-[3-(3-溴-苯基)-脲基]苯基}-膦酸二乙基酯;
{2-[3-(3-溴-苯基)-脲基]苯基}-膦酸;
{2-[3-(3,5-二氯-苯基)-脲基]苯基}-膦酸二乙基酯;
{2-[3-(3,5-二氯-苯基)-脲基]苯基}-膦酸;
{5-溴-2-[3-(3,5-双-三氟甲基-苯基)-脲基]苯基}-膦酸二乙基酯;
{5-溴-2-[3-(3,5-双-三氟甲基-苯基)-脲基]苯基}-膦酸;
{5-溴-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]苯基}-膦酸二乙基酯;
{5-溴-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]苯基}-膦酸;
{5-溴-2-[3-(3-氯-苯基)-脲基]苯基}-膦酸二乙基酯;
{5-溴-2-[3-(3-氯-苯基)-脲基]苯基}-膦酸;
{5-溴-2-[3-(3-溴-苯基)-脲基]苯基}-膦酸二乙基酯;
{5-溴-2-[3-(3-溴-苯基)-脲基]苯基}-膦酸;
{5-溴-2-[3-(3,5-二氯-苯基)-脲基]苯基}-膦酸二乙基酯;
{5-溴-2-[3-(3,5-二氯-苯基)-脲基]苯基}-膦酸;
{5-溴-2-[3-(2,6-二氯-吡啶-4-基)-脲基]苯基}-膦酸二乙基酯;
{5-溴-2-[3-(2,6-二氯-吡啶-4-基)-脲基]苯基}-膦酸;
2-{[3-(4-氯-3-三氟甲基-苯基)-脲基]-苄基}-膦酸二甲基酯;
2-{[3-(4-氯-3-三氟甲基-苯基)-脲基]-苄基}-膦酸;
2-{[3-(3,5-二氯-苯基)-脲基]-苄基}-膦酸二甲基酯;
2-{[3-(3,5-二氯-苯基)-脲基]-苄基}-膦酸;
2-[(3-苯基-脲基)-苄基]-膦酸二甲基酯;
2-[(3-苯基-脲基)-苄基]-膦酸;
2-[3-(4-氯-苯基)-脲基]-苄基}-膦酸二甲基酯;
2-[3-(4-氯-苯基)-脲基]-苄基}-膦酸;
2-{[3-(3,4-二氯-苯基)-脲基]-苄基}-膦酸二甲基酯;
2-{[3-(3,4-二氯-苯基)-脲基]-苄基}-膦酸;
{5-氯-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-苄基}-膦酸二甲基酯;
{5-氯-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-苄基}-膦酸;
{5-氯-2-[3-(3,5-二氯-苯基)-脲基]-苄基}-膦酸二甲基酯;
{5-氯-2-[3-(3,5-二氯-苯基)-脲基]-苄基}-膦酸;
[5-氯-2-(3-苯基-脲基)-苄基]-膦酸二甲基酯;
[5-氯-2-(3-苯基-脲基)-苄基]-膦酸;
{5-氯-2-[3-(3,4-二氯-苯基)-脲基]-苄基}-膦酸二甲基酯;
{5-氯-2-[3-(4-氯-苯基)-脲基]-苄基}-膦酸;
{5-氯-2-[3-(3,4-二氯-苯基)-脲基]-苄基}-膦酸二甲基酯;
{5-氯-2-[3-(3,4-二氯-苯基)-脲基]-苄基}-膦酸;
{2-[3-(2,6-二氯-吡啶-4-基)-脲基]-苯基}-膦酸二乙基酯;
{2-[3-(2-三氟甲基-苯基)-脲基]-苯基}-膦酸二乙基酯;
{2-[3-(2-三氟甲基-苯基)-脲基]-苯基}-膦酸;
3-[3-(3,5-二氯-苯基)-脲基]-联苯-4-羧酸酰胺;
3-[3-(2,3-二氯-苯基)-脲基]-联苯-4-羧酸酰胺;
3-[3-(3,5-双-三氟甲基-苯基)-脲基]-联苯-4-羧酸酰胺;
{2-[3-(2,6-二氯-吡啶-4-基)-脲基]-苯基}-膦酸;
[3-(3,5-双-三氟甲基-苯基)-脲基]-(4-氟-苯基)-乙酸;
[3-(3,5-双-三氟甲基-苯基)-脲基]-(5-三氟甲基-苯基)-乙酸;
[3-(4-氯-3-氟-苯基)-脲基]-(4-氟-苯基)-乙酸;
[3-(3,5-二氯-苯基)-脲基]-(4-氟-苯基)-乙酸;
[3-(3-氯-苯基)-脲基]-(4-氟-苯基)-乙酸;
1-(3,5-双-三氟甲基-苯基氨甲酰基)-吡咯啉-2-羧酸;
1-(3,5-双-三氟甲基-苯基氨甲酰基)-4-羟基-吡咯啉-2-羧酸;
1-(4-氯-3-三氟甲基-苯基氨甲酰基)-吡咯烷-2-羧酸;
1-(3-氯-苯基氨甲酰基)-吡咯烷-2-羧酸;
1-(3-溴-苯基氨甲酰基)-吡咯烷-2-羧酸;
1-(3,5-二氯-苯基氨甲酰基)-吡咯烷-2-羧酸;
1-(环己基-氨甲酰基)-吡咯烷-2-羧酸;
1-(2,6-二氯-吡啶-4-基氨甲酰基)-吡咯烷-2-羧酸;
1-(4-氯-3-三氟甲基-苯基氨甲酰基)-4-羟基-吡咯烷-2-羧酸;
1-(3-氯-苯基氨甲酰基)-4-羟基-吡咯烷-2-羧酸;
1-(3-溴-苯基氨甲酰基)-4-羟基-吡咯烷-2-羧酸;
1-(吡啶-3-基氨甲酰基)-吡咯烷-2-羧酸;
N-环己基-N′-(2,3-二氟-4-三氟甲基-苯基)脲;
N-环己基-N′-(2,3-二氟-苯基)脲;
N-(2,3-二氟-4-三氟甲基-苯基)-N′-(吡啶-3-基)脲;
N-(吡啶-3-基)-N′-(2,3-二氟-苯基)脲;
N-(4-氯-3-三氟甲基-苯基)-N′-(2,3-二氟-4-三氟甲基-苯基)脲;
N-(2,6-二氯-吡啶-4-基)-N′-(2,3-二氟-4-三氟甲基-苯基)脲;
N-(2,3-二氟-4-三氟甲基-苯基)-N′-(吡啶-4-基)脲;
N-(2,3-二氟-苯基)-N′-(吡啶-4-基)脲;
N-(环己基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(2,6-二氯-吡啶-4-基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
N-环己基-N′-[4′-(N″,N″-二甲基-1-羰基)-2-(1H-四唑-5-基)-联苯-4-基]脲;
N-(2,6-二氯-吡啶-4-基)-N′-[4′-(N″,N″-二甲基-1-羰基)-2-(1H-四唑-5-基)-联苯-4-基]脲;
N-环己基-N′-[4-溴-2-(1H-四唑-5-基)-苯基]脲;
N-(2,6-二氯-吡啶-4-基)-N′-[4-溴-2-(1H-四唑-5-基)-苯基]脲;
N-[5-氯-2-(1H-四唑-5-基)-苯基]-N′-(吡啶-3-基)脲;
N-[4-溴-2-(1H-四唑-5-基)-苯基]-N′-(吡啶-3-基)脲;
N-(萘-1-基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-[2,4-二溴-6-(1H-四唑-5-基)-苯基]-N′-(2,6-二氯-吡啶-4-基)脲;
或其药学上可接受的盐。
两种或多种本文所述实施方式的任意组合被视为在本发明的范围内。
取代基的定义
在本发明的上下文中,卤素代表氟、氯、溴或碘。
烷基表示一至六个碳原子的直链或支链,包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基和己基;甲基、乙基、丙基和异丙基是优选的基团。
烷氧基是-烷基,其中烷基是如上所定义的。
氨基是NH2或NH-烷基或N-(烷基)2,其中烷基是如上所定义的。
立体异构体
本发明化合物可以存在(+)和(-)形式以及外消旋形式。这些异构体的外消旋物和单个异构体本身都在本发明的范围内。
外消旋形式可以借助已知方法和技术拆分为旋光对映体。一种分离非对映盐的方式是利用旋光活性酸,通过碱处理释放出旋光活性胺化合物。另一种拆分外消旋物为旋光对映体的方法是基于在旋光活性基质上进行色谱分离。本发明的外消旋化合物因而可以被拆分为它们的旋光对映体,例如d-或1-(酒石酸盐、扁桃酸盐或樟脑磺酸盐)的分步结晶。
本发明化合物也可以这样加以拆分,使本发明化合物与旋光活性活化羧酸反应,例如从(+)或(-)苯基丙氨酸、(+)或(-)苯基甘氨酸、(+)或(-)樟脑酸,生成非对映酰胺,或者使本发明化合物与旋光活性氯甲酸酯反应,生成非对映氨基甲酸酯,等等。
其他拆分旋光异构体的方法是本领域已知的。这类方法包括JaquesJ,Collet A,& Wilen S在″Enantiomers,Racemates,and Resolutions″,John Wiley and Sons,New York(1981)中所述那些。
旋光活性化合物也可以从旋光活性原料制备。
药学上可接受的盐
本发明化合物可以被提供成任意适合于给药的形式。适合的形式包括本发明化合物的药学上(即生理学上)可接受的盐和前药或前体药物形式。
药学上可接受的加成盐的实例非限制性地包括无毒的无机与有机酸加成盐,例如从盐酸衍生的盐酸盐、从氢溴酸衍生的氢溴酸盐、从硝酸衍生的硝酸盐、从高氯酸衍生的高氯酸盐、从磷酸衍生的磷酸盐、从硫酸衍生的硫酸盐、从甲酸衍生的甲酸盐、从乙酸衍生的乙酸盐、从乌头酸衍生的乌头酸盐、从抗坏血酸衍生的抗坏血酸盐、从苯磺酸衍生的苯磺酸盐、从苯甲酸衍生的苯甲酸盐、从肉桂酸衍生的肉桂酸盐、从柠檬酸衍生的柠檬酸盐、从扑酸衍生的扑酸盐、从庚酸衍生的庚酸盐、从富马酸衍生的富马酸盐、从谷氨酸衍生的谷氨酸盐、从乙醇酸衍生的乙醇酸盐、从乳酸衍生的乳酸盐、从马来酸衍生的马来酸盐、从丙二酸衍生的丙二酸盐、从扁桃酸衍生的扁桃酸盐、从甲磺酸衍生的甲磺酸盐、从萘-2-磺酸衍生的萘-2-磺酸盐、从邻苯二甲酸衍生的邻苯二甲酸盐、从水杨酸衍生的水杨酸盐、从山梨酸衍生的山梨酸盐、从硬脂酸衍生的硬脂酸盐、从琥珀酸衍生的琥珀酸盐、从酒石酸衍生的酒石酸盐、从对-甲苯磺酸衍生的甲苯-对-磺酸盐等。可以借助本领域熟知的和已描述过的工艺生成这类盐。
其他酸、例如草酸,可能不被视为药学上可接受的,也可以用于盐的制备,这些盐在获得本发明化合物及其药学上可接受的酸加成盐时可用作中间体。
本发明化合物的药学上可接受的阳离子盐的实例非限制性地包括含有阴离子基团的本发明化合物的钠、钾、钙、镁、锌、铝、锂、胆碱、赖氨酸和铵的盐等。可以借助本领域熟知的和已描述过的工艺生成这类阳离子盐。
在本发明的上下文中,含N化合物的″鎓盐″也被视为药学上可接受的盐(氮杂-鎓盐)。优选的氮杂-鎓盐包括烷基-鎓盐,特别是甲基-和乙基-鎓盐;环烷基-鎓盐,特别是环丙基-鎓盐;和环烷基烷基-鎓盐,特别是环丙基-甲基-鎓盐。
制备方法
本发明化合物可以借助常规化学合成方法加以制备,例如实施例所述那些。本申请所述方法的原料是已知的或者可以容易借助常规方法从商业上可得到的化学品制备。
也可以利用常规方法将一种本发明化合物转化为另一种本发明化合物。
本文所述反应的终产物可以借助常规技术加以分离,例如萃取、结晶、蒸馏、色谱等。
药物组合物
另一方面,本发明提供新颖的药物组合物,包含治疗有效量的本发明化合物。
尽管用于治疗的本发明化合物可以以化合物生品的形式给药,不过优选将活性成分(可选为生理学上可接受的盐的形式)与一种或多种辅助剂、赋形剂、载体、缓冲剂、稀释剂和/或其他惯用药物助剂一起制成药物组合物。
在优选的实施方式中,本发明提供药物组合物,包含本发明化合物或其药学上可接受的盐或衍生物以及一种或多种药学上可接受的载体,和可选的其他治疗性和/或预防性成分,这些都是本领域已知和已使用过的。载体在与制剂其他成分相容和对其接受者无害的意义上必须是″可接受的″。在另一实施方式中,本发明提供药物组合物,包含一种以上本发明化合物/前体药物,例如两种不同的本发明化合物/前体药物。
本发明药物组合物可以是适合于口服、直肠、支气管、鼻、肺、局部(包括口腔和舌下)、透皮、阴道或肠胃外(包括皮肤、皮下、肌内、腹膜内、静脉内、动脉内、脑内、眼内注射或输注)给药的那些,或者适合于吸入或吹入给药的那些,包括粉剂和液体气溶胶,或者借助持续释放系统给药。持续释放系统的适合实例包括含有本发明化合物的固体疏水性聚合物的半透性基质,该基质可以是成形品的形式,例如膜或微囊。
本发明化合物与常规助剂、载体或稀释剂因而可以被制成药物组合物及其单元剂量的形式。这类形式包括固体,特别是药片、填充胶囊、粉末和颗粒形式,和液体,特别是水性或非水性溶液、悬液、乳液、酏剂和填充有它们的胶囊,全部为口服使用;直肠给药用栓剂;和肠胃外用无菌可注射溶液。这类药物组合物及其单元剂型可以包含常规比例的常规成分,以及或者没有其他活性化合物或成分,这类单元剂型可以含有任意适合的有效量的活性成分,与所采用的每日剂量范围是相称的。
本发明化合物可以在广泛的口服和肠胃外剂型中给药。对本领域技术人员而言将显而易见的是,下列剂型可以包含本发明化合物或者本发明化合物的药学上可接受的盐作为活性组分。
就从本发明化合物制备药物组合物而言,药学上可接受的载体可以是固体或液体。固体形式制备物包括粉剂、片剂、丸剂、胶囊剂、扁囊剂、栓剂和可分散颗粒剂。固体载体可以是一种或多种物质,它也可以充当稀释剂、矫味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或包封材料。
在粉剂中,载体是微细粉碎的固体,它是与微细粉碎的活性组分的混合物。
在片剂中,将活性组分与具有必要粘合能力的载体按适合比例混合,再压制成所需形状和大小。
粉剂和片剂优选地含有百分之五或十至约七十的活性化合物。适合的载体是碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。术语″制备物″打算包括活性化合物与作为载体的包封材料的制剂,得到一种胶囊,其中活性组分以及或者没有载体被一种载体包围,因而与之缔合。类似地,包括扁囊剂和锭剂。片剂、粉剂、胶囊剂、丸剂、扁囊剂和锭剂可以用作适合于口服给药的固体剂型。
就制备栓剂而言,首先熔化低熔点蜡,例如脂肪酸甘油酯混合物或可可脂,再随着搅拌将活性组分均匀分散其中。然后将熔化了的均匀混合物倒入适宜大小的模具中,冷却,从而固化。
适合于阴道给药的药物组合物可以是阴道栓、棉塞、霜剂、凝胶、糊剂、泡沫或喷雾剂,除了活性成分以外酌情含有本领域已知的载体。
液体制备物包括溶液、悬液和乳液,例如水或水-丙二醇溶液。例如,肠胃外注射液体制备物可以被配制成在含水聚乙二醇溶液中的溶液。
根据本发明的化合物因而可以被配制成肠胃外给药(例如注射,例如大丸剂注射或连续输注),可以是在安瓿、预填充注射器、小体积输注器或多剂量容器中的单元剂量形式,其中加入有防腐剂。组合物可以采取在油性或水性载体中的悬液、溶液或乳液形式,可以含有配制剂,例如悬浮剂、稳定剂和/或分散剂。作为替代选择,活性成分可以是粉末的形式,通过无菌固体的除菌分离或者溶液的冷冻干燥而得,在使用前用适合的载体再生,例如无菌无热原的水。
适合于口服使用的水溶液可以这样制备,将活性组分溶于水,根据需要加入适合的着色剂、矫味剂、稳定剂和增稠剂。
适合于口服使用的水悬液可以这样制备,将微细粉碎的活性组分分散在水中,其中含有粘性材料,例如天然或合成树胶、树脂、甲基纤维素、羧甲基纤维素钠或者其他熟知的悬浮剂。
还包括固体形式的制备物,用于在使用前不久转化为口服给药用液体形式制备物。这类液体形式包括溶液、悬液和乳液。除了活性组分以外,这类制备物还可以包含着色剂、矫味剂、稳定剂、缓冲剂、人工与天然甜味剂、分散剂、增稠剂、增溶剂等。
就表皮局部给药而言,本发明化合物可以被配制成软膏剂、霜剂或洗剂,或者透皮贴剂。软膏剂和霜剂例如可以用水性或油性基质配制,其中加入适合的增稠剂和/或胶凝剂。洗剂可以用水性或油性基质配制,一般也将含有一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂或着色剂。
适合于口内局部给药的组合物包括锭剂,在经过矫味的基质中包含活性成分,基质通常为蔗糖和阿拉伯胶或黄蓍胶;软锭剂,在惰性基质中包含活性成分,基质例如明胶和甘油或者蔗糖和阿拉伯胶;和漱口剂,在适合的液体载体中包含活性成分。
借助常规装置将溶液或悬液直接施用于鼻腔,例如用滴管、吸移管或喷雾器。组合物可以被提供成单一或多重剂量形式。
对呼吸道给药也可以借助气溶胶来实现,其中活性成分被提供在加压包装中,其中含有适合的推进剂,例如氯氟碳化合物(CFC),例如二氯二氟甲烷、三氯氟代甲烷或二氯四氟乙烷;二氧化碳;或者其他适合的气体。气溶胶也可以适宜含有表面活性剂,例如卵磷脂。药物的剂量可以通过计量阀加以控制。
作为替代选择,活性成分可以被提供成干燥粉末的形式,例如化合物在适合粉末基质中的粉末混合物,基质例如乳糖、淀粉、淀粉衍生物(例如羟丙基甲基纤维素)和聚乙烯吡咯烷酮(PVP)。适宜地,粉末载体将在鼻腔中形成凝胶。粉末组合物可以是单元剂量形式,例如在明胶胶囊或药筒中或者在发泡包装中,从中粉末可以借助吸入器给药。
在对呼吸道给药的组合物中,包括鼻内组合物,化合物一般将具有较小的粒径,例如5微米或以下的数量级。这样一种粒径可以借助本领域已知的手段来获得,例如微粉化。
在需要时,可以采用经过调整的组合物,以产生活性成分的持续释放。
药物制备物优选地是单元剂型。在这类剂型中,制备物被细分为含有适量活性组分的单元剂量。单元剂型可以是带包装的制备物,包装含有离散量的制备物,例如包装在小瓶或安瓿中的片剂、胶囊剂和粉剂。单元剂型也可以是胶囊剂、片剂、扁囊剂或锭剂本身,或者可以是适当数量任意这些的带包装形式。
口服给药用片剂或胶囊剂和静脉内给药与连续输注用液体是优选的组合物。
关于制剂和给药技术的进一步细节,可以参见最新版的Remington′s Pharmaceutical Sciences(Maack Publishing Co.,Easton,PA)。
治疗学上的有效剂量表示活性成分改善症状或病症的量。治疗功效和毒性、例如ED50和LD50,可以借助标准药理学工艺在细胞培养物或实验动物中加以测定。治疗效果与毒性效果之间的剂量比是治疗指数,可以表示为LD50/ED50之比。治疗指数大的药物组合物是优选的。
给药剂量当然必须谨慎地根据受治疗个体的年龄、体重与状况以及给药途径、剂型、制度和所需结果加以调整,精确的剂量当然应当取决于执业人员。
实际剂量依赖于所治疗疾病的属性和严重性,由医师来决定,可以根据本发明特定环境来调整剂量,以产生所需治疗效果。不过,目前所关注的是适合于治疗性处置的药物组合物含有约0.1至约500mg活性成分每单剂,优选约1至约100mg,最优选约1至约10mg。
活性成分可以每天分一剂或多剂给药。在某些情形中,在低达0.1μg/kg i.v.和1μg/kg p.o.的剂量下可以获得令人满意的结果。剂量范围的上限目前被视为约10mg/kg i.v.和100mg/kg p.o.。优选的范围是约0.1μg/kg至约10mg/kg/天i.v.和约1μg/kg至约100mg/kg/天p.o.。
生物学活性
本发明化合物可用作氯通道的阻滞剂,例如破骨细胞的氯通道。在另一实施方式中,本发明化合物可用作肥大细胞和嗜碱细胞的氯通道的阻滞剂。就测量化合物的活性而言,可以使用各种体外和体内方法,例如本领域已知的各种破骨细胞抑制测定法。
治疗方法
有氯通道阻滞剂活性的化合物可能可用于治疗大量疾病、障碍和病症,包括骨代谢疾病。进而,有氯通道阻滞剂活性的化合物可能可用于治疗对肥大细胞或嗜碱细胞活性调节有应答的疾病、对血管生成抑制有应答的疾病或者镰状细胞性贫血。
因而在另一方面,本发明化合物被视为可用于治疗、预防或减轻对氯通道阻滞有应答的疾病、障碍或病症。
在具体实施方式中,该疾病或障碍或病症是骨代谢疾病,例如破骨细胞相关性骨疾病。在另一实施方式中,该疾病或障碍或病症是破骨细胞相关性骨疾病,例如骨质疏松、经绝后骨质疏松、继发性骨质疏松、溶骨性乳腺癌的骨转移、溶骨性癌侵袭和骨的佩吉特氏病。
在另一具体实施方式中,该疾病或障碍或病症对肥大细胞或嗜碱细胞活性的调节有应答。在另一实施方式中,该疾病或障碍或病症对肥大细胞或嗜碱细胞产生或分泌组胺、中性蛋白酶或类胰蛋白酶(例如类胰凝乳蛋白酶和羧基肽酶)、白三烯(例如LTC4和LTB4)、前列腺素(例如PGD2)、TXA2、PAF或细胞因子(例如IL-4和TNF-α)的调节有应答。在另一实施方式中,对肥大细胞或嗜碱细胞活性调节有应答的障碍或疾病是对肥大细胞或嗜碱细胞产生或分泌组胺调节的障碍或疾病。在另一实施方式中,对肥大细胞或嗜碱细胞活性调节有应签的障碍或疾病是变应性支气管肺曲霉病(ABPA)、变应性鼻炎、变应性皮肤疾病、变应性皮肤反应、药物诱发的变应性皮肤反应、过敏、哮喘、动脉粥样硬化、特应性皮炎(AD)、支气管哮喘、癌症、慢性阻塞性肺疾病(COPD)、克罗恩氏病、接触性皮炎、扩张型心肌病、致命性哮喘、移植排斥、过敏性肺炎、缺血性心脏病、肺纤维变性、类风湿性关节炎、全身性硬化、荨麻疹或眼色素层视网膜炎。在具体实施方式中,对肥大细胞或嗜碱细胞活性调节有应答的障碍或疾病是变应性支气管肺曲霉病(ABPA)、变应性鼻炎、变应性皮肤疾病、变应性皮肤反应、药物诱发的变应性皮肤反应、哮喘、支气管哮喘、致命性哮喘或慢性阻塞性肺疾病(COPD)。在另一具体实施方式中,该障碍或疾病是哮喘、支气管哮喘、致命性哮喘或慢性阻塞性肺疾病(COPD)。在另一具体实施方式中,该障碍或疾病是COPD。在另一具体实施方式中,该障碍或疾病是哮喘。
在另一具体实施方式中,该疾病或障碍或病症对血管生成的抑制有应答。在具体实施方式中,对血管生成抑制有应答的疾病、障碍或病症选自:
●牵涉肿瘤细胞增殖的疾病、障碍或病症,例如癌症、前列腺癌、肺癌、乳腺癌、膀胱癌、肾癌、结肠癌、胃癌、胰腺癌、卵巢癌、黑素瘤、肝细胞瘤、肉瘤和淋巴瘤;
●眼血管生成相关性疾病、障碍或病症,例如渗出性黄斑变性、年龄-相关性黄斑变性(AMD)、视网膜病、糖尿病性视网膜病、增生性糖尿病性视网膜病、糖尿病性黄斑水肿(DME)、缺血性视网膜病(例如视网膜静脉或动脉阻塞)、早产儿视网膜病、新生血管性青光眼和角膜新生血管化;和
●类风湿性关节炎和牛皮癣。
在具体实施方式中,所要治疗的疾病、障碍或病症是肿瘤前期疾病状态。在另一实施方式中,治疗是抗转移性治疗。在另一实施方式中,所要预防的疾病、障碍或病症是转移性癌症。在另一实施方式中,所要预防或减轻的疾病、障碍或病症是DME。
在本发明的上下文中,″年龄-相关性黄斑变性″(AMD)包括干性AMD(非渗出性AMD)和湿性AMD(渗出性AMD)。
在另一实施方式中,对氯通道阻滞有应答的疾病、障碍或病症是镰状细胞性贫血、继发于缺血或肿瘤的脑水肿、腹泻、高血压、利尿性高血压、青光眼或溃疡。
目前所关注的是适合的剂量范围是0.1至1000毫克每天、10-500毫克每天、尤其30-100毫克每天,这通常依赖于精确的给药方式、给药的剂型、给药所针对的适应症、所牵涉的受治疗者和所牵涉受治疗者的体重,进而有主治医师或兽医的偏好和经验。在与本领域已知的化合物联合给药治疗疾病时,可以减少剂量。
本发明化合物可以与一种或多种其他药物联合使用。
本发明化合物可以与其他骨代谢控制性化合物联合用于治疗骨代谢疾病。这类已知的骨代谢控制性化合物包括双膦酸盐,例如依替膦酸盐、帕米膦酸盐或氯膦酸盐,可选地与钙联用;雌激素受体活性化合物,例如雌激素(即雌二醇和乙基雌二醇)、降钙素、1,25-二羟基维生素D及其代谢产物、氟化物、生长激素、甲状旁腺激素、三碘甲状腺素、胶原降解酶(例如蛋白酶抑制剂)或者癌症治疗剂。
进而,本发明化合物可以与一种或多种其他药物联合用于治疗、预防或减轻对血管生成抑制有应答的疾病,例如可用于抗转移性治疗的化合物。这类其他药物包括细胞毒性化合物、抗有丝分裂化合物和抗代谢产物。
细胞毒性化合物(包括细胞毒性烷基化剂)的实例包括卡莫司汀(BCNU)、福莫司汀、替莫唑胺(temodal)、异环磷酰胺和环磷酰胺。
抗有丝分裂化合物的实例包括paclitaxel(紫杉醇)和多西他赛。
抗代谢产物的实例包括甲氨蝶呤。
此外,本发明化合物可以与其他治疗或疗法联合使用或者给药。其他治疗或疗法的实例包括放射疗法和手术。
疾病和障碍的治疗可以是慢性或长期治疗以及疾病与障碍突发危象的治疗。
实施例
参照下列实施例进一步阐述发明,它们不打算以任何方式限制所要求保护的发明的范围。
实施例1
(2-氨基-苯基)-膦酸二乙基酯
向亚磷酸二乙基酯(1.5g,11mmol)的液氨(大约100ml)溶液加入叔丁醇钾(1.23g,11mmol),将反应混合物搅拌10分钟,然后加入2-碘苯胺。对反应混合物照射(Hg灯)一小时。使氨蒸发,加入氯化铵和一些氨,蒸发除去氨。向残余物加入水,用二氯甲烷萃取。标题化合物经过柱色谱纯化。产量1.7g(黄色的油)。
实施例2
(2-氨基-5-溴-苯基)-膦酸二乙基酯
在搅拌下,历经20分钟向(2-氨基-苯基)-膦酸二乙基酯(0.23g,1mmol)的冰乙酸(2ml)溶液加入溴(0.16g,1mmol,1eq.)的冰乙酸(2ml)溶液。反应完成后,将反应混合物倒入饱和碳酸氢钠水溶液中。将标题化合物用二氯甲烷萃取,经过柱色谱纯化。产量0.23g。
实施例3
[(二甲氧基-磷酰基)-羟基-(2-硝基-苯基)-甲基]-膦酸二甲基酯
在氩气氛下,将亚磷酸三甲基酯(5.7g,45.7mmol)冷却至-10℃,加入冰乙酸(1.44ml),在保持温度低于0℃的同时,滴加2-硝基苯甲酰氯,将反应混合物加热至室温,搅拌一小时。在100mmHg压力下,将反应混合物加热至40℃达一小时,冷却至室温。加入乙酸乙酯,溶液用5%碳酸氢钠(aq.)洗涤,将有机相干燥,蒸发,标题化合物经过柱色谱纯化。
类似地制备下列化合物:
[(二甲氧基-磷酰基)-羟基-(3-氯-6-硝基-苯基)-甲基]-膦酸二甲基酯。
实施例4
5-氨基-呋喃-2-羧酸
向5-硝基-2-糠酸甲基酯(14.3g,84mmol)的乙酸乙酯(110ml)溶液加入披钯碳(0.75g,5%),将溶液在40℃和氢气氛下搅拌4小时,将反应混合物通过C盐过滤,蒸发分离标题化合物,直接用于下一反应。
实施例5
4-氨基-1-羟基-环己-2,4-二烯羧酸甲基酯
将5-氨基-呋喃-2-羧酸(实施例4粗产物)溶于苯(0.5L),加入丙烯腈(200ml),将反应混合物在回流下加热,搅拌16小时,蒸发,向残余物加入甲苯,蒸发。使标题化合物从乙酸乙酯中结晶,无需进一步纯化即可用于下一反应。
实施例6
4-氨基-3-氰基-苯甲酸甲基酯
将4-氨基-1-羟基-环己-2,4-二烯羧酸甲基酯(实施例5粗产物)溶于甲苯(600ml),加入三氟化硼乙醚合物(20ml,40%乙醚溶液),向反应混合物加入四氢呋喃(100ml),在85℃下搅拌30分钟。将反应混合物冷却至室温,倒入冰/水中,将混合物用氢氧化钠(1M)中和,用饱和碳酸氢钠碱化。分离各层,水相用二氯甲烷萃取。将有机相干燥,蒸发。借助柱色谱从残余物中分离标题化合物。产量3.2g。
施例7
4-氨基-3-氰基-苯甲酸
向4-氨基-3-氰基-苯甲酸甲基酯(3.2g,10mmol)的四氢呋喃/水(110ml,1:1)溶液加入氢氧化锂水合物(2.3g,30mmol),将反应混合物在室温下搅拌20小时,加入盐酸(1M)至pH=3。从混合物中蒸馏出四氢呋喃,从溶液中沉淀出标题化合物。
实施例8
4-氨基-3-氰基-N-甲基-苯甲酰胺
向4-氨基-3-氰基-苯甲酸(0.97g,6mmol)、苯并三唑-1-基氧基三-(吡咯烷子基)-鏻六氟磷酸盐(3.3g,6.3mmol)和二异丙基乙胺(6ml,12mmol)的无水二甲基甲酰胺(25ml)溶液加入二甲胺(6ml,2M四氢呋喃溶液),将反应混合物在室温下搅拌过夜。蒸发除去一些二甲基甲酰胺,将粗产物溶于乙酸乙酯(25ml),用硫酸氢钾(0.5M(25ml) x 2)、氢氧化钠(1M(25ml) x 2)、水(10ml)和盐水(25ml)洗涤。将有机层干燥,蒸发,借助柱色谱分离标题化合物。产量0.39g。
类似地制备下列化合物:
4-氨基-3-氰基-N,N-二甲基-苯甲酰胺;
(4-氨基-3-氰基-苯甲酰氨基)-乙酸乙基酯;
2-氨基-5-(哌啶-1-羰基)-苄腈;
4-氨基-3-氰基-N,N-二乙基-苯甲酰胺;
[(4-氨基-3-氰基-苯甲酰基)-甲基-氨基]-乙酸。
实施例9
(2-氨基-苄基)-膦酸二甲基酯
向[(二甲氧基-磷酰基)-羟基-(2-硝基-苯基)-甲基]-膦酸二甲基酯(4.7g,17.7mmol)的99%乙醇(40ml)溶液加入氯化锡(II)二水合物(14.4g,64mmol,5eq.),将反应混合物在70℃下加热20分钟,倒入冰(250ml)中,用氢氧化钠(1M)调节pH至7,加入乙酸乙酯,使乳液通过硅藻土过滤两次,将有机层用盐水洗涤,干燥,蒸发,分离标题化合物,为油。产量2g。
类似地制备下列化合物:
(2-氨基-5-氯-苄基)-膦酸二甲基酯。
实施例10
2-氨基-苯二羟基甲硼烷
向2-硝基-苯二羟基甲硼烷(2.32g,14mmol)的乙醇(130ml,99%)溶液加入披钯碳(0.232g,10%),在氢气氛(3巴)下搅拌过夜,过滤。蒸发滤液,使标题化合物从甲醇和水中结晶。产量0.52g。
实施例11
4-甲基-苯基-二羟基甲硼烷
将4-溴-甲苯(50g,0.29mol)的无水乙醚(500ml)溶液冷却至-20℃,在保持温度在-20℃以下的同时,加入丁基锂(127ml,2.5M己烷溶液,0.31mol),15分钟后将溶液加热至15℃,在该温度下搅拌一小时,然后冷却至-55℃,在保持温度在-47℃以下的同时,加入硼酸三丁酯(110ml,94g,0.41mol,1.4eq.),将反应混合物加热至室温,搅拌过夜。加入盐酸(450ml,1M)。分离各相,水相用乙醚萃取,合并有机相,用氢氧化钠(aq.)萃取(300ml+100ml x 2(2M)),向水相加入浓盐酸(约100ml),沉淀出标题化合物,过滤分离。产量32.6g。
实施例12
4-(二羟基硼基)苯甲酸
将4-甲基-苯基-二羟基甲硼烷(32.6g,0.24mol)溶于含有氢氧化钠(19.2g,0.48mol,2eq.)的水(900ml),加入高锰酸钾(79.6g,0.5mol,2.1eq.),将反应混合物在室温下搅拌72小时,过滤,沉淀用水(50ml)洗涤三次,向滤液加入浓盐酸(约55ml),沉淀出标题化合物。产量34.5g。
实施例13
4-(二羟基硼基)-(N,N-二甲基苯甲酰胺)
向亚硫酰氯(300ml)加入4-(二羟基硼基)苯甲酸(34.4g,0.21mol),将反应混合物在回流下加热过夜,蒸发至干,向残余物加入二甲胺(167ml,40%水溶液),将反应混合物在回流下加热20分钟,趁热过滤,将滤液冷却至室温,加入浓盐酸,沉淀出标题化合物。产量25.1g。
类似地制备下列化合物:
4-(二羟基硼基)-苯甲酰胺;
[4-(二羟基硼基)-苯甲酰氨基]-乙酸;
[4-(二羟基硼基)-苯甲酰基-(N-甲基)-氨基]-乙酸。
实施例14
4′-氨基-3′-氰基-联苯-4-羧酸二甲基酰胺
将4-(二羟基硼基)-(N,N-二甲基苯甲酰胺)(1.2g,6.2mmol)、2-氨基-5-溴苄腈(1.1g,5.6mmol,0.9eq)、碳酸钾(2.3g,16.9mmol,3.3eq.)、二甲氧基乙二醇(20ml)和水(10ml)混合,向混合物通入氮,加入双(三苯膦)氯化钯(II)(0.05g),将反应混合物在回流下加热40分钟,冷却至室温,加入水(50ml),用乙酸乙酯(50ml)萃取,将有机相用水(30ml)洗涤,干燥,蒸发,得到标题化合物,为油。产量1.17g。
实施例15
3-(4-氨基-3-氰基-苯基)-丙烯酸甲基酯
向2-氨基-5-溴-苄腈(0.59g,3mmol)、丙烯酸甲酯(0.52g,6mmol)与三-邻-甲苯膦(0.49mg,0.16mmol)的无水N,N-二甲基甲酰胺(5ml)溶液加入三乙胺(0.44ml),向混合物通入氩和乙酸钯(II)(4.5mg,0.02mmol),在120℃下搅拌2.5小时。然后终止反应,将反应混合物冷却至室温,加入盐酸(15ml,1M),将标题化合物用乙醚萃取(25ml x4),将有机相干燥,蒸发。
类似地制备下列化合物:
3-(氨基-3-氰基-苯基)-丙烯酰基N,N-二甲基酰胺。
实施例16
3-(4-氨基-3-氰基-苯基)-丙酸甲基酯
将3-(4-氨基-3-氰基-苯基)-丙烯酸甲基酯(10g,49mmol)与披钯碳(2g,10%)的四氢呋喃(200ml)溶液在氢气氛下剧烈搅拌20分钟,使反应混合物通过C盐过滤,过滤分离标题化合物。产量10g。
类似地制备下列化合物:
3-(4-氨基-3-氰基-苯基)-丙酸N,N-二甲基酰胺。
实施例17
4′-氨基-3′-(1H-四唑-5-基)-联苯-4-羧酸二甲基酰胺
向4′-氨基-3′-氰基-联苯-4-羧酸二甲基酰胺(1.15g,4.3mmol)的甲苯(25ml)溶液加入叠氮化钠(0.42g,6.5mmol,1.5eq.)和三乙基氯化铵(0.9g,6.5mmol,1.5eq.),将反应混合物在60℃下搅拌48小时。从底层中倾析顶部相,向残余物加入水(25ml)、96%乙醇(25ml)和浓盐酸(约1ml),沉淀出标题化合物。产量0.79g。
类似地制备下列化合物:
4′-氨基-3-(1H-四唑-5-基)-联苯-4-二甲基-磺酰胺;
2-溴-4-(1H-四唑-5-基)-苯胺;
2,6-二溴-4-(1H-四唑-5-基)-苯胺;
2-溴-5-(1H-四唑-5-基)-苯胺;
3-氯-6-(1H-四唑-5-基)-苯胺;
4-溴-2-(1H-四唑-5-基)-苯胺;
2,4-二溴-6-(1H-四唑-5-基)苯胺;
[4′-氨基-3′-(1H-四唑-5-基)-联苯-4-基]-羰基-哌啶-1-基;
2,4-二氯-6-(四唑-5-基)-苯胺;
4-氨基-N-甲基-3-(1H-四唑-5-基)-苯甲酰胺;
[4-氨基-3-(1H-四唑-5-基)-苯甲酰氨基]-乙酸;
3-[4-氨基-3-(1H-四唑-5-基)-苯基]-丙烯酸甲基酯;
3-[4-氨基-3-(1H-四唑-5-基)-苯基]-丙酸甲基酯;
N-[4-氨基-3-(1H-四唑-5-基)-苯基]-丙酰胺酸;
3-[4-氨基-3-(1H-四唑-5-基)-苯基]-N,N-二甲基-丙烯酰胺;
3-[4-氨基-3-(1H-四唑-5-基)-苯基]-N-甲基-丙烯酰胺;
4-氨基-N,N-二乙基-3-(1H-四唑-5-基)-苯甲酰胺;
4-氨基-3-(1H-四唑-5-基)-苯甲酰基-哌啶-1-基;
4′-氨基-3′-(1H-四唑-5-基)-联苯-4-羧酸酰胺;
4-氨基-N,N-二甲基-3-(1H-四唑-5-基)-苯甲酰胺;
[4-氨基-N-甲基-3-(1H-四唑-5-基)-苯甲酰氨基]-乙酸;
3-[4-氨基-3-(1H-四唑-5-基)-苯基]-N-甲基-丙酰胺;
N-[4-氨基-3-(1H-四唑-5-基)-苯基]-苯甲酰胺。
实施例18
N-(3,5-双-三氟甲基-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-羧酸二甲基酰胺]脲
向2′-氨基-3′-(1H-四唑-5-基)-联苯-4-羧酸二甲基酰胺(1g,3.2mmol)的甲苯(25ml)溶液加入3,5-双-(三氟甲基)-苯基异氰酸酯(0.88g,3.3mmol,大约1eq.)和三乙胺(0.36g,3.6mmol,1.2eq.),将反应混合物搅拌过夜,分离烧瓶底部的油。将该油溶于2-丙醇(20ml),向溶液加入盐酸(1M)直至pH=2-3,沉淀出标题化合物。产量0.86g。M.p.222-224℃。
类似地制备下列化合物:
N-(3-氯-4-氟-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-磺酸-二甲基酰胺]脲;M.p.240-243℃;
N-(4-氟-3-三氟甲基-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-磺酸-二甲基酰胺]脲;M.p.254-258℃;
N-(3-氟-5-三氟甲基-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-磺酸-二甲基酰胺]脲;M.p.255-256℃;
N-(4-氯-3-三氟甲基-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-磺酸-二甲基酰胺]脲;M.p.203-205℃;
N-(3,5-二氟-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-磺酸-二甲基酰胺]脲;M.p.254-255℃;
N-(3,5-二氯-苯基)-N′-[2-(1H-四唑-5-基)-联苯-4-基-4′-羧酸二甲基酰胺]脲;M.p.201-204℃;
N-(3,5-双-三氟甲基-苯基)-N′-[2-溴-4-(1H-四唑-5-基)-苯基]脲;M.p.229-233℃;
N-(3,5-双-三氟甲基-苯基)-N′-[2,6-二溴-3-(1H-四唑-5-基)-苯基]脲;M.p.220-222℃;
4-氯-2-(3-环己基-脲基)-苯甲酸;M.p.
N-环己基-N′-(2,3-二氟-4-三氟甲基-苯基)脲;
[3-(3,5-双-三氟甲基-苯基)-脲基]-(4-氟-苯基)-乙酸;
1-(3,5-双-三氟甲基-苯基氨甲酰基)-吡咯啉-2-羧酸;
1-(3,5-双-三氟甲基-苯基氨甲酰基)-4-羟基-吡咯啉-2-羧酸;
N-环己基-N′-(2,3-二氟-苯基)脲;
N-(3,5-双-三氟甲基-苯基)-N′-[2-溴-5-(1H-四唑-5-基)-苯基]脲;
N-(环己基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
5-溴-2-[3-(3,5-双-三氟甲基-苯基)-脲基]-苯甲酸;
2-[3-(3,5-双-三氟甲基-苯基)-脲基]-环己烷羧酸;
[3-(3,5-双-三氟甲基-苯基)-脲基]-(5-三氟甲基-苯基)-乙酸;
5-溴-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(3-溴-苯基)-脲基]-苯甲酸;
N-(4-氯-3-三氟甲基-苯基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
[3-(4-氯-3-氟-苯基)-脲基]-(4-氟-苯基)-乙酸;
N-(3-溴-苯基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(3-氯-苯基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
[3-(3,5-二氯-苯基)-脲基]-(4-氟-苯基)-乙酸;
5-溴-2-[3-(3,5-二氯-苯基)-脲基]-苯甲酸;
5-溴-2-[3-(2,6-二氯-吡啶-4-基)-脲基]-苯甲酸;
N-(3,5-双-三氟甲基-苯基)-N′-(苯基-2-二羟基甲硼烷)脲;
N-(4-氯-3-氟-苯基)-N′-(苯基-2-二羟基甲硼烷)脲;
N-(3,5-二氯-苯基)-N′-(苯基-2-二羟基甲硼烷)脲;
N-环己基-N′-(苯基-2-二羟基甲硼烷)脲;
N-(2,6-二氯-吡啶-4-基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;M.p.201-203℃;
N-环己基-N′-[4′-(N″,N″-二甲基-1-羰基)-2-(1H-四唑-5-基)-联苯-4-基]脲;M.p.156-158℃;
N-(2,6-二氯-吡啶-4-基)-N′-[4′-(N″,N″-二甲基-1-羰基)-2-(1H-四唑-5-基)-联苯-4-基]脲;M.p.163.8-164.5℃;
N-环己基-N′-[4-溴-2-(1H-四唑-5-基)-苯基]脲;M.p.233-239℃;
N-(2,6-二氯-吡啶-4-基)-N′-[4-溴-2-(1H-四唑-5-基)-苯基]脲;M.p.231-233℃;
5-氯-2-[3-(吡啶-3-基)-脲基]-苯甲酸;M.p.>240℃;
5-溴-2-[3-(吡啶-3-基)-脲基-]-苯甲酸;M.p.>240℃;
3,5-二氯-2-[3-(3,5-二氯-苯基)-脲基]-苯甲酸;M.p.259-261℃;
3,5-二氯-2-[3-(3-氯-4-氟-苯基)-脲基]-苯甲酸;M.p.174.5-175.9℃;
3,5-二氯-2-[3-(3,5-双-三氟甲基-苯基)-脲基]-苯甲酸;M.p.199-200℃;
3,5-二氯-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-苯甲酸;M.p.190.3-191.1℃;
3,5-二氯-2-[3-(4-氟-3-三氟甲基-苯基)-脲基]-苯甲酸;M.p.180-181℃;
3,5-二氯-2-[3-(3-氟-5-三氟甲基-苯基)-脲基]-苯甲酸;M.p.168-169℃;
3,5-二氯-2-[3-(3,5-二氟-苯基)-脲基]-苯甲酸;M.p.245-249℃;
N-(4-氟-3-三氟甲基-苯基)-N′-[2,4-二溴-6-(1H-四唑-5-基)-苯基]脲;M.p.195-196℃;
N-(3,4-二氯-苯基)-N′-[2,4-二溴-6-(1H-四唑-5-基)-苯基]脲;M.p.201-203℃;
2-[3-(噻吩-2-基)-脲基]-苯甲酸;
2-[3-(吡啶-4-基)-脲基]-苯甲酸;M.p.>230℃;
4-氯-2-[3-(吡啶-4-基)-脲基]-苯甲酸;M.p.>270℃;
5-溴-2-[3-(吡啶-4-基)-脲基]-苯甲酸;
2-[3-(吡啶-3-基)-脲基]-烟酸;M.p.>220℃;
1-(4-氯-3-三氟甲基-苯基氨甲酰基)-吡咯烷-2-羧酸;M.p.159-161℃;
1-(3-氯-苯基氨甲酰基)-吡咯烷-2-羧酸;M.p.157-158℃;
1-(3-溴-苯基氨甲酰基)-吡咯烷-2-羧酸;M.p.176-177℃;
1-(3,5-二氯-苯基氨甲酰基)-吡咯烷-2-羧酸;M.p.180-181℃;
1-(环己基-氨甲酰基)-吡咯烷-2-羧酸;M.p.172-174℃;
1-(2,6-二氯-吡啶-4-基氨甲酰基)-吡咯烷-2-羧酸;M.p.177-178℃;
2-[(3-(3-氯-苯基)-脲基]-环己烷羧酸;M.p.194-195℃;
2-[(3-(3-溴-苯基)-脲基]-环己烷羧酸;M.p.199-200℃;
2-[3-(3,5-二氯-苯基)-脲基]-环己烷羧酸;M.p.141-142℃;
2-(3-环己基-脲基)-环己烷羧酸;M.p.190-191℃;
2-[3-(2,6-二氯-吡啶-4-基)-脲基]-环己烷羧酸;M.p.199-200℃;
4-氯-2-[3-(2,6-二氯-吡啶-4-基)-脲基]-苯甲酸;M.p.200-201℃;
5-溴-2-[3-(3-氯-苯基)-脲基]-苯甲酸;M.p.194-195℃;
2-[3-(3,5-双-三氟甲基-苯基)-脲基]-烟酸;
N-(2,3-二氟-4-三氟甲基-苯基)-N′-(吡啶-3-基)脲;M.p.232-235℃;
N-[5-氯-2-(1H-四唑-5-基)-苯基]-N′-(吡啶-3-基)脲;M.p.214-220℃;
N-(吡啶-3-基)-N′-(2,3-二氟-苯基)脲;M.p.211-215℃;
N-(4-氯-3-三氟甲基-苯基)-N′-(2,3-二氟-4-三氟甲基-苯基)脲;M.p.194-195℃;
N-(2,6-二氯-吡啶-4-基)-N′-(2,3-二氟-4-三氟甲基-苯基)脲;M.p.210-211℃;
N-[4-溴-2-(1H-四唑-5-基)-苯基]-N′-(吡啶-3-基)脲;M.p.193-194℃;
2-[3-(吡啶-3-基)-脲基]-苯基-二羟基甲硼烷;M.p.220-227℃;
5-溴-2-(3-环己基-脲基)-苯甲酸;M.p.178-179℃;
[3-(3-氯-苯基)-脲基]-(4-氟-苯基)-乙酸;M.p.153-187℃;
N-(2,3-二氟-4-三氟甲基-苯基)-N′-(吡啶-4-基)脲;M.p.205-206℃;
N-(2,3-二氟-苯基)-N′-(吡啶-4-基)脲;M.p.201-215℃;
2-[3-(2,6-二氯-吡啶-4-基)-脲基]-苯基-二羟基甲硼烷;M.p.232-233℃;
2-[3-(3-溴-苯基)-脲基]-苯基-二羟基-硼烷;M.p.226-227℃;
2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-环己烷羧酸;M.p.213-214℃;
2-[3-(3-氯-苯基)-脲基]-环己烷羧酸;M.p.173-178℃;
2-[3-(3-溴-苯基)-脲基]-环己烷羧酸;M.p.175-223℃;
2-[3-(2,6-二氯-苯基)-脲基]-环己烷羧酸;M.p.182-241℃;
1-(4-氯-3-三氟甲基-苯基氨甲酰基)-4-羟基-吡咯烷-2-羧酸;M.p.67-80℃;
1-(3-氯-苯基氨甲酰基)-4-羟基-吡咯烷-2-羧酸;M.p.156-157℃;
1-(3-溴-苯基氨甲酰基)-4-羟基-吡咯烷-2-羧酸;
1-(吡啶-3-基氨甲酰基)-吡咯烷-2-羧酸;M.p.185-186℃;
2-[3-(2,6-二氯-吡啶-4-基)-脲基]-环己烷羧酸;M.p.168-197℃;
4-氯-2-[3-(噻唑-2-基)-脲基]-苯甲酸甲基酯;
5-溴-2-[3-(吡啶-2-基)-脲基]-苯甲酸甲基酯;
4-氯-2-[3-(5-氯-吡啶-2-基)-脲基]苯甲酸;
5-溴-2-(3-噻唑-2-基-脲基)-苯甲酸甲基酯;
2-[3-(5-溴-吡啶-3-基)-脲基]-4-氯-苯甲酸;M.p.>220℃;
5-溴-2-[3-(吡啶-2-基)-脲基]-苯甲酸;
{2-[3-(3,5-双-三氟甲基-苯基)-脲基]苯基}-膦酸二乙基酯;
{2-[3-(3,5-双-三氟甲基-苯基)-脲基]苯基}-膦酸;
N-(3-甲氧基-苯基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(2-甲氧基-苯基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(4-甲氧基-苯基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(萘-1-基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(2-三氟甲基-苯基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[4′-(N″,N″-二甲基-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-[2,4-二溴-6-(1H-四唑-5-基)-苯基]-N′-(2,6-二氯-吡啶-4-基)脲;M.p.202-203℃;
N-(3,5-二氯-苯基)-N′-[2,4-二溴-6-(1H-四唑-5-基)-苯基]脲;M.p.221-223℃;
3-溴-2-[3-(2H-1λ4-噻唑-2-基)-脲基]-苯甲酸;M.p.>250℃;
{2-[3-(4-氯-3-三氟甲基-苯基)-脲基]苯基}-膦酸二乙基酯;M.p.90-197℃;
{2-[3-(3-氯-苯基)-脲基]-苯基}-膦酸二乙基酯;M.p.油;
{2-[3-(3-溴-苯基)-脲基]苯基}-膦酸二乙基酯;M.p.油;
{2-[3-(3,5-二氯-苯基)-脲基]苯基}-膦酸二乙基酯;M.p.156-158℃;
{5-溴-2-[3-(3,5-双-三氟甲基-苯基)-脲基]苯基}-膦酸二乙基酯;M.p.152-158℃;
{5-溴-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]苯基}-膦酸二乙基酯;M.p.油;
{5-溴-2-[3-(3-氯-苯基)-脲基]苯基}-膦酸二乙基酯;M.p.160-207℃;
{5-溴-2-[3-(3-溴-苯基)-脲基]苯基}-膦酸二乙基酯;M.p.145-250℃;
{5-溴-2-[3-(3,5-二氯-苯基)-脲基]苯基}-膦酸二乙基酯;M.p.139-144℃;
{5-溴-2-[3-(2,6-二氯-吡啶-4-基)-脲基]苯基}-膦酸二乙基酯;
2-{[3-(4-氯-3-三氟甲基-苯基)-脲基]-苄基}-膦酸二甲基酯;M.p.205-206℃;
2-{[3-(3,5-二氯-苯基)-脲基]-苄基}-膦酸二甲基酯;M.p.195-196℃;
2-[(3-苯基-脲基)-苄基]-膦酸二甲基酯;
2-[3-(4-氯-苯基)-脲基]-苄基}-膦酸二甲基酯;M.p.200-202℃;
2-{[3-(3,4-二氯-苯基)-脲基]-苄基}-膦酸二甲基酯;M.p.197-198℃;
{5-氯-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-苄基}-膦酸二甲基酯;M.p.210-211℃;
{5-氯-2-[3-(3,5-二氯-苯基)-脲基]-苄基}-膦酸二甲基酯;M.p.201-205℃;
[5-氯-2-(3-苯基-脲基)-苄基]-膦酸二甲基酯;M.p.193-197℃;
{5-氯-2-[3-(3,4-二氯-苯基)-脲基]-苄基}-膦酸二甲基酯;
{5-氯-2-[3-(3,4-二氯-苯基)-脲基]-苄基}-膦酸二甲基酯;M.p.208-212℃;
2,5-二氯-3-[3-(3-溴-苯基)-脲基]-苯甲酸;M.p.254-255℃;
2,5-二氯-3-[3-(3,5-二氯-苯基)-脲基]-苯甲酸;M.p.256-257℃;
{2-[3-(2,6-二氯-吡啶-4-基)-脲基]-苯基}-膦酸二乙基酯;M.p.166-167℃;
{2-[3-(2-三氟甲基-苯基)-脲基]-苯基}-膦酸二乙基酯;M.p.油;
5-氯-2-[3-(1H-吲哚-2-基)-脲基]-苯甲酸;M.p.>200℃;
5-溴-2-[3-(1H-吲哚-2-基)-脲基]-苯甲酸;M.p.>230℃;
3-[3-(3-溴-苯基)-脲基]-5-三氟-苯甲酸;M.p.230-231℃;
3-[3-(3,5-二氯-苯基)-脲基]-5-三氟-苯甲酸;M.p.218-233℃;
3-[3-(4-氯-3-三氟甲基-苯基)-脲基]-联苯-4-羧酸酰胺;M.p.210-211℃;
3-[3-(3,5-二氯-苯基)-脲基]-联苯-4-羧酸酰胺;
3-[3-(2,3-二氯-苯基)-脲基]-联苯-4-羧酸酰胺;
3-[3-(3,5-双-三氟甲基-苯基)-脲基]-联苯-4-羧酸酰胺;
4-[3-(3,5-二氯-苯基)-脲基]-联苯-3-羧酸;
4-[3-(3,5-双-三氟甲基-苯基)-脲基]-联苯-3-羧酸;
4-[3-(3,5-二氟-苯基)-脲基]-联苯-3-羧酸;
4-[3-(2-氯-苯基)-脲基]-联苯-3-羧酸;
N-(4-氯-3-三氟甲基-苯基)-N′-[4′-(哌啶-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(3,5-二氯-苯基)-N′-[4′-(哌啶-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4′-(哌啶-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(3,5-二氟-苯基)-N′-[4′-(哌啶-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
N-(2-氯-苯基)-N′-[4′-(哌啶-1-羰基)-3-(1H-四唑-5-基)-联苯-4-基]脲;
4-氯-2-[3-(5-苯基-2H-吡唑-3-基)-脲基]-苯甲酸;M.p.>270℃;
2-[3-(2-氯-吡啶-3-基)-脲基]-烟酸;M.p.>260℃;
4-氯-2-[3-(2-氯-吡啶-3-基)-脲基]-苯甲酸;M.p.>215℃;
2-[3-(4-氯-苯基)-脲基]-5-碘-苯甲酸;M.p.>200℃;
5-氯-2-[3-(5-氧代-1-苯基-吡咯烷-3-基)-脲基]-苯甲酸;M.p.>240℃;
5-溴-2-(3-苯基-脲基)-苯甲酸;M.p.>200℃;
5-溴-2-[3-(2-氟-苯基)-脲基]-苯甲酸;M.p.>200℃;
5-溴-2-[3-(2-氯-苯基)-脲基]-苯甲酸;M.p.>220℃;
5-溴-2-[3-(3,5-二甲基-苯基)-脲基]-苯甲酸;M.p.>210℃;
5-溴-2-[3-(3,5-二氟-苯基)-脲基]-苯甲酸;M.p.214-215℃;
5-溴-2-[3-(3,5-二甲氧基-苯基)-脲基]-苯甲酸;M.p.194-195℃;
N-(3,5-二氯-苯基)-N′-[2,4-二氯-6-(1H-四唑-5-基)-苯基]脲;
N-(4-氯-3-三氟甲基-苯基)-N′-[2,4-二氯-6-(1H-四唑-5-基)-苯基]脲;M.p.205-207℃;
N-(3,5-二氟-苯基)-N′-[2,4-二氯-6-(1H-四唑-5-基)-苯基]脲;M.p.212-214℃;
5-溴-2-[3-(2,6-二氯-苯基)-脲基]-苯甲酸;M.p.>225℃;
5-溴-2-[3-(2-溴-苯基)-脲基]-苯甲酸;M.p.>225℃;
5-溴-2-[3-(4-氯-3-硝基-苯基)-脲基]-苯甲酸;M.p.>230℃;
5-溴-2-[3-(4-丁氧基-苯基)-脲基]-苯甲酸;M.p.>195℃;
5-氯-2-[3-(2-氯-苯基)-脲基]-苯甲酸;M.p.>210℃;
5-氯-2-[3-(3,5-二甲基-苯基)-脲基]-苯甲酸;M.p.>200℃;
2-[3-(4-联苯)-脲基]-5-溴-苯甲酸;M.p.>200℃;
5-氯-2-[3-(3-碘-苯基)-脲基]-苯甲酸;M.p.>210℃;
5-氯-2-(3-苯基-脲基)-苯甲酸;M.p.>195℃;
5-氯-2-[3-(2-氟-苯基)-脲基]-苯甲酸;M.p.>195℃;
N-(3,5-双-三氟甲基)-N′-[2,4-二氯-5-(1H-四唑-5-基)-苯基]脲;M.p.>200-203℃;
5-溴-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-烟酸;M.p.>300℃;
N-(3,5-二氯-苯基)-N′-[4-(N″-甲基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;M.p.276-277℃;
N-(3,5-二氟-苯基)-N′-[4-(N″-甲基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;M.p.277-278℃;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-(羰基-氨基-乙酸)-2-(1H-四唑-5-基)-苯基]脲;M.p.187-191℃;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-(丙烯酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;M.p.244-248℃;
N-(3,5-二氯-苯基)-N′-[4-(丙烯酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;M.p.237-245℃;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(丙烯酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-(丙烯酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;M.p.257-258℃;
N-(2-氯-苯基)-N′-[4-(丙烯酸甲基酯)-2-(1H-四唑-5-基-苯基]脲;M.p.184-185℃;
N-(4-氯-3-三氟-苯基)-N′-[4-(丙酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;M.p.168-169℃;
N-(3,5-二氯-苯基)-N′-[4-(丙酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;M.p.169-177℃;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(丙酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;M.p.194-195℃;
N-(3,5-二氟-苯基)-N′-[4-(丙酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;M.p.173-177℃;
N-(2-氯-苯基)-N′-[4-(丙酸甲基酯)-2-(1H-四唑-5-基)-苯基]脲;M.p.228-229℃;
5-溴-2-[3-(3,5-双-三氟甲基-苯基)-脲基]-烟酸;M.p.>300℃;
N-(3,5-二氯-苯基)-N′-[4-(N″-丙酰胺酸)-2-(1H-四唑-5-基)-苯基]脲;M.p.223-225℃;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(N″-丙酰胺酸)-2-(1H-四唑-5-基)-苯基]脲;M.p.172-175℃;
N-(3,5-二氟-苯基)-N′-[4-(N″-丙酰胺酸)-2-(1H-四唑-5-基)-苯基]脲;M.p.170-173℃;
N-(2-氯-苯基)-N′-[4-(N″-丙酰胺酸)-2-(1H-四唑-5-基)-苯基]脲;M.p.158-160℃;
N-(3,5-双-三氟甲基-苯基)-N′-{4-[(N″,N″-二甲基)-丙烯酰胺]-2-(1H-四唑-5-基)-苯基}脲;
N-(3,5-二氟-苯基)-N′-{4-[(N″,N″-二甲基)-丙烯酰胺]-2-(1H-四唑-5-基)-苯基}脲;
N-(2-氯-苯基)-N′-4-[(N″,N″-二甲基)-丙烯酰胺]-2-(1H-四唑-5-基)-苯基}脲;
N-(3,5-二氯-苯基)-N′-{4-[(N″-甲基)-丙烯酰胺]-2-(1H-四唑-5-基)-苯基}脲;
N-(3,5-二氟-苯基)-N′-{4-[(N″-甲基)-丙烯酰胺]-2-(1H-四唑-5-基)-苯基}脲;
N-(2-氯-苯基)-N′-[4-(哌啶-1-羰基)-2-(H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4-(N″,N″-二乙基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(N″,N″-二乙基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-(N″,N″-二乙基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(2-氯-苯基)-N′-[4-(N″,N″-二乙基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;M.p.174-177℃;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-(哌啶-1-羰基)-2-(1H-四唑-5-基)-苯基]脲;M.p.210-212℃;
N-(3,5-二氯-苯基)-N′-[4-(哌啶-1-羰基)-2-(1H-四唑-5-基)-苯基]脲;M.p.192-196℃;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(哌啶-1-羰基)-2-(1H-四唑-5-基)-苯基]脲;M.p.189-190℃;
N-(3,5-二氟-苯基)-N′-[4-(哌啶-1-羰基)-2-(1H-四唑-5-基)-苯基]脲;M.p.183-185℃;
N-(3,5-二氯-苯基)-N′-[4′-(羰基-(N″-甲基)氨基-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;M.p.286-287℃;
N-(4-氯-3-三氟甲基-苯基)-N′-[4′-甲酰胺-2-(1H-四唑-5-基)-4-联苯]脲;M.p.245-247℃;
N-(3,5-二氯-苯基)-N′-[4′-甲酰胺-2-(1H-四唑-5-基)-4-联苯]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4′-甲酰胺-2-(1H-四唑-4-联苯]脲;M.p.190-244℃;
N-(3,5-二氟-苯基)-N′-[4′-甲酰胺-2-(1H-四唑-5-基)-4-联苯]脲;
N-(3,5-二氯-苯基)-N′-[4-(N″,N″-二甲基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;M.p.184-244℃;
N-(3,5-二氟-苯基)-N′-[4-(N″,N″-二甲基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;M.p.183-198℃;
N-(4-氯-3-三氟甲基)-N′-[4-(N″,N″-二乙基-甲酰胺)-2-(1H-四唑-5-基)-苯基]脲;M.p.191-240℃;
N-(3,5-二氯-苯基)-N′-[4′-(羰基-氨基-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;M.p.265-266℃;
N-(3,5-二氟-苯基)-N′-[4′-(羰基-氨基-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;M.p.235-242℃;
N-(2-氯-苯基)-N′-[4′-(羰基-氨基-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;M.p.253-254℃;
N-(4-氯-3-三氟甲基-苯基)-N′-{4′-[羰基-(N″-甲基)-氨基-乙酸]-2-(1H-四唑-5-基)-4-联苯}脲;M.p.249-250℃;
N-(3,5-二氯-苯基)-N′-{4′-[羰基-(N″-甲基)-氨基-乙酸]-2-(1H-四唑-5-基)-4-联苯}脲;M.p.251-286℃;
N-(3,5-双-三氟甲基-苯基)-N′-{4′-[羰基-(N″-甲基)-氨基-乙酸]-2-(1H-四唑-5-基)-4-联苯}脲;M.p.190-191℃;
N-(3,5-二氟-苯基)-N′-[4′-(羰基-氨基-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;M.p.分解;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-(N″-甲基-丙基酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氯-苯基)-N′-[4-(N″-甲基-丙基酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-双-三氟甲基-苯基)-N′-[4-(N″-甲基-丙基酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(3,5-二氟-苯基)-N′-[4-(N″-甲基-丙基酰胺)-2-(1H-四唑-5-基)-苯基]脲;
N-(2-氯-苯基)-N′-[4-(N″-甲基-丙基酰胺)-2-(1H-四唑-5-基)-苯基]脲;
5-氯-2-[3-(3,5-二氟-苯基)-脲基]-苯甲酸;
5-氯-2-[3-(3,5-二甲氧基-苯基)-脲基]-苯甲酸;
5-氯-2-[(3,4-二氯-苯基)-脲基]-苯甲酸;
2-[3-(4-丁氧基-苯基)-脲基]-5-氯-苯甲酸;
5-溴-2-[3-(3,5-二氯-苯基)-脲基]-烟酸;M.p>300℃;
5-溴-2-[3-(3,5-二氟-苯基)-脲基]-烟酸;M.p>300℃;
N-(2,6-二氯-苯基)-N′-[2,4-二氯-6-(1H-四唑-5-基)-苯基]脲;M.p.214-215℃;
N-(2,4,6-三氯-苯基)-N′-[2,4-二氯-6-(1H-四唑-5-基)-苯基]脲;M.p.207-209℃;
5-溴-2-[3-(2,4,6-三氯-苯基)-脲基]-烟酸;M.p.>300℃;
N-(3,5-二氯-苯基)-N′-[4-苯甲酰胺-2-氯-6-(1H-四唑-5-基)-苯基]脲;M.p.238-239℃;
N-(3,5-二氟-苯基)-N′-[4-苯甲酰胺-2-氯-6-(1H-四唑-5-基)-苯基]脲;M.p.254-256℃;
N-(3,5-双-三氟甲基-苯基)-N′-[4-苯甲酰胺-2-氯-6-(1H-四唑-5-基)-苯基]脲;M.p.250-253℃;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-苯甲酰胺-2-(1H-四唑-5-基)-苯基)脲;M.p.248-250℃;
5-氯-2-[3-(2,6-二氯-苯基)-脲基]-苯甲酸;M.p.>300℃;
N-(3,5-双-三氟甲基-苯基)-N′-[4′-(N″-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;M.p.244-245℃;
N-(4-氯-3-三氟甲基-苯基)-N′-[4-(N″,N″-二甲基丙烯酰胺)-2-(1H-四唑-5-基)-苯基]脲;M.p.169-171℃;
N-(3,5-二氯-苯基)-N′-[4-(N″,N″-二甲基丙烯酰胺)-2-(1H-四唑-5-基)-苯基]脲;M.p.190-193℃;
N-(4-氯-3-三氟甲基-苯基)-N′-[4′-(N″-乙酸)-2-(1H-四唑-5-基)-4-联苯]脲;M.p.275-296℃。
实施例19
3,5-双-[3-(3-溴-苯基)-脲基]-苯甲酸
在氩气氛下,向3,5-二氨基苯甲酸(152mg,1mmol)的无水乙腈(5ml)溶液加入3-溴苯基异氰酸酯(396mg,2mmol,2eq.)。将反应混合物在60℃下搅拌16小时。从溶液中沉淀出标题化合物,过滤分离。产量377mg。M.p.>300℃。
类似地制备下列化合物:
3,5-双-[3-(3,5-二氯-苯基)-脲基]-苯甲酸;M.p.>300℃;
3,5-双-[3-(3,5-二氟-苯基)-脲基]-苯甲酸;M.p.>300℃;
3,5-双-[3-(3,5-双-三氟甲基苯基)-脲基]-苯甲酸;M.p.>300℃。
实施例20
{2-[3-(4-氯-3-三氟甲基-苯基)-脲基]苯基}-膦酸
将{2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-脲基]-苯基}-膦酸二乙基酯(400mg,0.8mmol)溶于无水二氯甲烷(3ml)。在氩气氛下加入三甲基甲硅烷基溴(2ml,15mmol,19eq.),将反应混合物在回流下加热过夜,然后蒸发至干,向残余物加入水(10ml)和乙酸乙酯(10ml),分离有机层,干燥,蒸发。使标题化合物从二氯甲烷中结晶。产量340mg。M.p.153-157℃。
类似地制备下列化合物:
{2-[3-(3-氯-苯基)-脲基]苯基}-膦酸;M.p.147-149℃;
{2-[3-(3-溴-苯基)-脲基]苯基}-膦酸;M.p.145-151℃;
{2-[3-(3,5-二氯-苯基)-脲基]苯基}-膦酸;M.p.167-170℃;
{5-溴-2-[3-(3,5-双-三氟甲基-苯基)-脲基]苯基}-膦酸;M.p.150-153℃;
{5-溴-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]苯基}-膦酸;M.p.267-273℃;
{5-溴-2-[3-(3-氯-苯基)-脲基]苯基}-膦酸;M.p.160-207℃;
{5-溴-2-[3-(3-溴-苯基)-脲基]苯基}-膦酸;M.p.204-210℃;
{5-溴-2-[3-(3,5-二氯-苯基)-脲基]苯基}-膦酸;M.p.212-288℃;
{5-溴-2-[3-(2,6-二氯-吡啶-4-基)-脲基]苯基}-膦酸;
2-{[3-(4-氯-3-三氟甲基-苯基)-脲基]-苄基}-膦酸;M.p.185-197℃;
2-{[3-(3,5-二氯-苯基)-脲基]-苄基}-膦酸;M.p.192-193℃;
2-[(3-苯基-脲基)-苄基]-膦酸;M.p.166-168℃;
2-[3-(4-氯-苯基)-脲基]-苄基}-膦酸;M.p.184-191℃;
2-{[3-(3,4-二氯-苯基)-脲基]-苄基}-膦酸;M.p.177-178℃;
{5-氯-2-[3-(4-氯-3-三氟甲基-苯基)-脲基]-苄基}-膦酸;M.p.177-180℃;
{5-氯-2-[3-(3,5-二氯-苯基)-脲基]-苄基}-膦酸;Mp.18]-182℃;
[5-氯-2-(3-苯基-脲基)-苄基]-膦酸;M.p.174-182℃;
{5-氯-2-[3-(4-氯-苯基)-脲基]-苄基}-膦酸;M.p.189-190℃;
{5-氯-2-[3-(3,4-二氯-苯基)-脲基]-苄基}-膦酸;M.p.191-192℃;
{2-[3-(2,6-二氯-吡啶-4-基)-脲基]-苯基}-膦酸;M.p.185-189℃;
{2-[3-(2-三氟甲基-苯基)-脲基]-苯基}-膦酸;M.p.155-162C。
Claims (10)
1、由通式(I)代表的化合物
或其药学上可接受的盐,其中
A代表一种环系,选自由吡啶基、噻吩基、噻唑基、吲哚基、吡唑基和氧代-吡咯烷基组成的组,该环系任选地被一个或多个取代基取代,所述取代基独立地选自由卤素、三氟甲基、硝基、C1-6烷基、C1-6烷氧基和苯基组成的组;及
R1代表-H;并且
D代表
其中
R2、R3和R4之一为四唑基;并且
R5、R6和其余R2、R3和R4之一或之二彼此独立地代表:
○氢、卤素、三氟甲基,
○-CH=CH-COORb、-CH2-CH2-COORb,
○-CO-NRb-CH2-COORc、-CO-NRbRc,
○-CH=CH-CO-NRbRc、-CH2-CH2-CO-NRbRc,
○哌啶基羰基,
○-NH-CO-Rd或-NH-CO-NH-Rd,
○其中Rd是苯基,任选地被一个或多个独立选自卤素或三氟甲基的取代基取代,或者
○苯基,任选地被-SO2-NRbRc、-CO-NRbRc、-CO-NRb-CH2-COORc或哌啶基羰基取代,
其中Rb和Rc独立地是氢或C1-6烷基。
3、权利要求1的化合物,其为
N-(2,6-二氯-吡啶-4-基)-N′-[3-氯-6-(1H-四唑-5-基)-苯基]脲;
N-(2,6-二氯-吡啶-4-基)-N′-[4′-(N″,N″-二甲基-1-羰基)-2-(1H-四唑-5-基)-联苯-4-基]脲;
N-(2,6-二氯-吡啶-4-基)-N′-[4-溴-2-(1H-四唑-5-基)-苯基]脲;
N-[5-氯-2-(1H-四唑-5-基)-苯基]-N′-(吡啶-3-基)脲;
N-[4-溴-2-(1H-四唑-5-基)-苯基]-N′-(吡啶-3-基)脲;
N-[2,4-二溴-6-(1H-四唑-5-基)-苯基]-N′-(2,6-二氯-吡啶-4-基)脲;
或其药学上可接受的盐。
4、药物组合物,包含治疗有效量的根据权利要求1-3任意一项的化合物或其药学上可接受的盐以及至少一种药学上可接受的载体、赋形剂或稀释剂。
5、根据权利要求1-3任意一项的化合物或其药学上可接受的盐用于制备药物组合物的用途,该组合物用于治疗、预防或减轻哺乳动物的疾病或障碍或病症,该疾病、障碍或病症对氯通道的阻滞有应答。
6、根据权利要求5的用途,其中该对氯通道阻滞有应答的疾病、障碍或病症是骨代谢疾病或破骨细胞相关性骨疾病。
7、根据权利要求5的用途,其中该对氯通道阻滞有应答的疾病、障碍或病症是骨质疏松、经绝后骨质疏松、继发性骨质疏松、溶骨性乳腺癌的骨转移、溶骨性癌侵袭、骨的佩吉特氏病。
8、根据权利要求5的用途,其中该对氯通道阻滞有应答的疾病、障碍或病症是对肥大细胞或嗜碱细胞活性或者血管生成抑制有应答的疾病、障碍或病症。
9、根据权利要求5的用途,其中该对氯通道阻滞有应答的疾病、障碍或病症是变应性支气管肺曲霉病、变应性鼻炎、变应性皮肤疾病、变应性皮肤反应、药物诱发的变应性皮肤反应、过敏、哮喘、动脉粥样硬化、特应性皮炎、支气管哮喘、癌症、慢性阻塞性肺疾病、克罗恩氏病、接触性皮炎、扩张型心肌病、致命性哮喘、移植排斥、过敏性肺炎、缺血性心脏病、肺纤维变性、类风湿性关节炎、全身性硬化、荨麻疹、眼色素层视网膜炎、癌症、转移癌、前列腺癌、肺癌、乳腺癌、膀胱癌、肾癌、结肠癌、胃癌、胰腺癌、卵巢癌、黑素瘤、肝细胞瘤、肉瘤、淋巴瘤、渗出性黄斑变性、年龄-相关性黄斑变性、视网膜病、糖尿病性视网膜病、增生性糖尿病性视网膜病、缺血性视网膜病、早产儿视网膜病、新生血管性青光眼、角膜新生血管化、类风湿性关节炎、牛皮癣、镰状细胞性贫血、继发于缺血或肿瘤的脑水肿、腹泻、高血压、利尿性高血压、青光眼或溃疡。
10、根据权利要求5的用途,其中所述的哺乳动物是人类。
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CN112076185A (zh) * | 2020-08-17 | 2020-12-15 | 西安交通大学 | 一类卤代二芳基脲类化合物及其在制备抗过敏药物中的应用 |
JP2023541153A (ja) * | 2020-09-14 | 2023-09-28 | ジェンザイム・コーポレーション | 鎌状赤血球症を処置するための、ビスホスホグリセリン酸ムターゼのモジュレーターとしてのカルボン酸含有化合物 |
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- 2003-09-04 AT AT03793605T patent/ATE435199T1/de not_active IP Right Cessation
- 2003-09-04 MX MXPA05002493A patent/MXPA05002493A/es active IP Right Grant
- 2003-09-04 EP EP03793605A patent/EP1537075B1/en not_active Expired - Lifetime
- 2003-09-04 US US10/526,208 patent/US20060160856A1/en not_active Abandoned
- 2003-09-04 WO PCT/DK2003/000575 patent/WO2004022529A2/en active Application Filing
- 2003-09-04 NZ NZ538513A patent/NZ538513A/en unknown
- 2003-09-04 JP JP2004533214A patent/JP2005538152A/ja active Pending
- 2003-09-04 DE DE60328202T patent/DE60328202D1/de not_active Expired - Lifetime
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US20060160856A1 (en) | 2006-07-20 |
JP2005538152A (ja) | 2005-12-15 |
WO2004022529A2 (en) | 2004-03-18 |
CA2495284A1 (en) | 2004-03-18 |
WO2004022529A3 (en) | 2004-05-13 |
CN1678573A (zh) | 2005-10-05 |
DE60328202D1 (de) | 2009-08-13 |
EP1537075B1 (en) | 2009-07-01 |
ATE435199T1 (de) | 2009-07-15 |
AU2003258490A1 (en) | 2004-03-29 |
NZ538513A (en) | 2007-02-23 |
MXPA05002493A (es) | 2005-05-27 |
EP1537075A2 (en) | 2005-06-08 |
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