CN101400672A - 作为钾通道开放剂的吡唑基喹唑啉酮 - Google Patents
作为钾通道开放剂的吡唑基喹唑啉酮 Download PDFInfo
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- CN101400672A CN101400672A CNA2007800083093A CN200780008309A CN101400672A CN 101400672 A CN101400672 A CN 101400672A CN A2007800083093 A CNA2007800083093 A CN A2007800083093A CN 200780008309 A CN200780008309 A CN 200780008309A CN 101400672 A CN101400672 A CN 101400672A
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Abstract
本发明涉及新的吡唑基喹唑啉酮衍生物、包含它们的药物组合物和它们在治疗与钾通道相关的病症中的用途。
Description
发明领域
本发明涉及新的吡唑基喹唑啉酮衍生物、包含它们的药物组合物和它们在治疗钾通道相关的病症中的用途。因此,本发明的化合物可用于治疗各种病症。这些包括但不局限于:尿失禁,膀胱活动过度,高血压症,勃起功能紊乱,女性性功能障碍,痛经,肠易激综合症,呼吸道机能亢进,癫痫,中风,阿尔海默氏和帕金森疾病,心肌损伤和冠状动脉病,以及脱发和秃顶。
发明背景
离子通道通过调节贯穿细胞膜的离子迁移而在细胞代谢(hormeostasis)功能中起到基本作用。细胞活动可以受离子通道活性改变的影响。这导致膜电位差的改变。钾通道是互异且普遍存在的一组离子通道。它们主要调节细胞的膜静电位,并且减弱细胞的激发水平。功能性的K ATP通道是由四个内向整流钾通道亚单元(Kir6.2)和四个磺酰脲受体(SUR)亚单元组装的杂八聚体。有两个SUR基因,SUR1和SUR2。在胰腺和脑中发现了SUR1/Kir6.2通道。两个主要的拼接变体由SUR2基因SUR2A和SUR2B产生,其区别仅在于C-末端42氨基酸的不同。在心脏和骨组织中发现了SUR2A/Kir6.2,而在许多组织包括膀胱的平滑肌中发现了SUR2B/Kir6.2通道(Aguilar-Bryan,1998)。许多疾病或病症可以用钾通道开放剂治疗。这包括膀胱活动过度,尿失禁,男性勃起功能紊乱,女性性功能障碍,早产,良性前列腺增生(BPH),痛经,神经变性,中风,疼痛,冠状动脉病,心绞痛,局部缺血,进食障碍,肠易激综合症和脱发。
尿失禁(UI)是可以影响患者生活的综合质量的疾病。膀胱活动过度(OAB)是UI的最普通形式,在所有确诊的UI病例当中,报道的流行率是40至70%(Wein,2000)。OAB的特点在于尿频、尿急和尿失禁的症状。OAB的根本原因是膀胱过分敏感,其出乎意料地和无意地进行收缩。理想的药学试剂应该抑制不随意收缩,同时保持正常排泄收缩的完好性。ATP-敏感性钾通道开放剂(KCO)可以充当这种药剂。ATP-敏感性钾通道(KATP)是在膀胱平滑肌中表达的,并且在这些细胞中起到膜静电位的关键调节剂的作用。选择性地打开这些通道的化合物,可以使细胞超极化,并且降低细胞兴奋性,从而抑制膀胱的无意识收缩,同时保持正常泌尿线路完好。
本发明概述
本发明涉及式I的化合物:
其中:
R1选自氢,卤素,羧基,C1-4烷基,卤代C1-4烷基,-C(O)-C1-4烷基,-C(O)-(卤代C1-4烷基),-C(O)O-C1-4烷基,-S(O)0-2-C1-4烷基,CN和NO2;
R2选自氢,卤素,羧基,C1-4烷基,卤代C1-4烷基,-C(O)-C1-4烷基,-C(O)-(卤代C1-4烷基),-C(O)O-C1-4烷基,-S(O)0-2-C1-4烷基,CN和NO2;
R3选自氢,C1-4烷基和卤代C1-4烷基;
R4选自氢,羧基,C1-4烷基,卤代C1-4烷基,芳基,杂芳基,-C(O)-烷基,-C(O)-(卤代C1-4烷基)和-C(O)O-C1-4烷基;
其中芳基或杂芳基不论单独或作为取代基团的一部分,任选被一个或多个独立选自下列的取代基取代:卤素,C1-4烷基,C1-4烷氧基,卤代C1-4烷基,卤代C1-4烷氧基,氰基,硝基,-C(O)O-C1-4烷基和-S(O)0-2-C1-4烷基;
或其药学可接受的盐。
应理解,式(I)的化合物可以存在互变异构体。本领域技术人员可以认识到,当N(1)和C(2)形成双键时,则C(2)和N(3)形成单键。在其它互变异构形式中,当N(1)和C(2)形成单键时,则C(2)和N(3)形成双键。在这种后面的互变异构形式中,所标示的与N(3)键合的H原子将自然与N(1)键合。
本发明的例子是包含药学可接受载体和如上所述的任一种化合物的药物组合物。本发明的实例是药物组合物,其由如上所述的任一种化合物与药学可接受载体进行混合来制备。举例说明本发明是制备药物组合物的方法,其包含将如上所述任一种的化合物和药学可接受载体相混合。
作为本发明的例子,是治疗与离子通道相关的病症的方法,优选钾离子通道,更优选ATP敏感型钾离子通道,该方法包括给予需要其的患者治疗有效量的上述任一种化合物或药物组合物。
本发明的一个例子是治疗选自下列病症的方法:尿失禁,膀胱活动过度,高血压症,勃起功能紊乱,女性性功能障碍,痛经,肠易激综合症,呼吸道机能亢进,癫痫,中风,阿尔海默氏疾病,帕金森疾病,心肌损伤,冠状动脉病,脱发和秃顶,优选尿失禁,该方法包括给予需要其的患者有效量的上述任一种化合物或药物组合物。
本发明的另一个例子是使用本文所描述的任一种化合物制备用于在需要其的患者中治疗下列疾病的药物中的用途:(a)尿失禁,(b)膀胱活动过度,(c)高血压症,(d)勃起功能紊乱,(e)女性性功能障碍,(f)痛经,(g)肠易激综合症,(h)呼吸道机能亢进,(i)癫痫,(j)中风,(k)阿尔海默氏疾病,(1)帕金森疾病,(m)心肌损伤,(n)冠状动脉病,(o)脱发或(p)秃顶。
本发明的详细说明
本发明涉及式(I)的化合物
(I)
其中R1、R2、R3和R4如本文所定义。本发明的化合物是钾通道开放剂。因此,所提供的化合物可用于治疗各种病症,包括但不限于:尿失禁,膀胱活动过度,高血压症,勃起功能紊乱,女性性功能障碍,痛经,肠易激综合症,呼吸道机能亢进,癫痫,中风,阿尔海默氏和帕金森疾病,心肌损伤,冠状动脉病,以及脱发和秃顶。优选,本发明的化合物可有效用于治疗尿失禁或膀胱活动过度。
本文使用的“卤素”是指氯、溴、氟和碘。优选,卤素是氯、溴或氟,更优选氯或氟。
本文使用的术语“烷基”,不论单独使用或作为取代基团的一部分,包括直链和支链烷基。例如,烷基包括甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,戊基等等。同样,术语“C1-4烷基”,不论单独使用或作为取代基团的一部分,包括含有4个碳原子的直链和支链烷基。例如,甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基和叔丁基。
除非另作说明,本文使用的“烷氧基”,不论单独使用或作为取代基团的一部分,表示上述直链或支链烷基的氧醚原子团。例如,甲氧基,乙氧基,正丙氧基,仲-丁氧基,叔丁氧基,正己氧基等等。同样,术语“C1-4烷氧基”,不论单独使用或作为取代基团的一部分,表示上述直链或支链C1-4烷基的氧醚原子团。例如,甲氧基,乙氧基,正丙氧基,仲-丁氧基,叔丁氧基,等等。
除非另作说明,本文使用的术语“卤素取代的C1-4烷基”是指被至少一个卤素原子取代的上述任何C1-4烷基,优选被至少一个氟原子取代。合适的例子包括但不局限于:-CF3,-CHF2,-CH2-CF3,-CF2-CF2-CF2-CF3,等等。同样,除非另作说明,本文使用的术语“卤素取代的C1-4烷氧基”是指被至少一个卤素原子取代的上述任何C1-4烷氧基,优选被至少一个氟原子取代。合适的例子包括但不局限于:-OCF3,-OCHF2,-OCH2-CF3,-OCF2-CF2-CF2-CF3,等等。
除非另作说明,本文使用的“芳基”是指未取代的碳环芳族基,例如苯基、萘基等等。优选,芳基是苯基或萘基,更优选苯基。
除非另作说明,当涉及环状结构时,本文使用的术语“部分不饱合的”是指环结构是稳定的,并且含有至少一个不饱和键(即至少一个双键)。合适例子包括但不局限于环己烯基,等等。
除非另作说明,本文使用的“杂芳基”表示含有至少一个选自O、N和S的杂原子的任一5或6元单环的芳香环结构,任选含有一个至三个独立选自O、N和S的额外杂原子;或含有至少一个选自O、N和S的杂原子的9或10元双环芳香环结构,任选含有一个至四个独立选自O、N和S的额外杂原子。杂芳基可以在环的任一杂原子或碳原子处连接,以得到稳定结构。
合适杂芳基的例子包括但不局限于:吡咯基,呋喃基,噻吩基,噁唑基,咪唑基,吡唑基(purazolyl),异噁唑基,异噻唑基,三唑基,噻二唑基,吡啶基,哒嗪基,嘧啶基,吡嗪基,吡喃基,呋咱基,吲嗪基,吲哚基,异二氢氮吲基,吲唑基,苯并呋喃基,苯并噻吩基,苯并咪唑基,苯并噻唑基,嘌呤基,喹嗪基,喹啉基,异喹啉基,异噻唑基,噌琳基,酞嗪基,喹唑啉基,喹喔啉基,萘啶基,喋啶基,等等。
本文使用的术语“杂环烷基”表示含有至少一个选自O、N和S的杂原子的任一5至7元单环的饱和或部分不饱合的环状结构,任选含有一个至三个独立选自O、N和S的额外杂原子;或含有至少一个选自O、N和S的杂原子的9或10元饱和、部分不饱合或部分芳香的双环系统,任选含有一个至四个独立选自O、N和S的额外杂原子。杂环烷基可以在环的任一杂原子或碳原子处连接,以得到稳定结构。
合适杂环烷基的例子包括但不局限于:吡咯啉基,吡咯烷基,二氧杂环戊烷基,咪唑啉基,咪唑烷基,吡唑啉基,吡唑烷基,哌啶基,二噁烷基,吗啉基,二硫杂环己烷基,硫吗啉基,哌嗪基,三噻烷基,二氢吲哚基,色烯基,3,4-亚甲基二氧基苯基,2,3-二氢苯并呋喃基,等等。
除非另作说明,本文使用的术语“杂环基”是指上述任一杂芳基或杂环基。优选,杂环基包含至少一个氮原子。更优选,杂环基包含一个至三个独立选自O、S和N的杂原子。还更优选,杂环基包含一个至两个独立选自O、S和N的杂原子。优选,杂环基包含一个N原子和进一步包含一个独立地选自O、S和N的额外杂原子。优选,杂环基是饱和的、芳香的或部分芳香的,更优选,杂环基是芳香的或苯并稠合的。
优选,杂环基选自4,5-二氢-噁唑基,哌啶基,咪唑基,嘧啶基,吡唑基,吡唑啉基,哒嗪基,二氢吲哚基,吲唑基,异氮吲基,吡咯并[3,4-c]吡啶基,苯并咪唑基,苯并异噻唑基,苯并异噁唑基,苯并噻唑基,苯并噁唑基,喹唑啉基,喹啉基和异喹啉基。
本文使用的符号“*”表示存在立构中心。
当具体基团是“取代的”(例如芳基、杂环烷基、杂芳基)时,该基团可以具有一个或多个取代基,优选一个至五个取代基,更优选一个至三个取代基,最优选一个至两个取代基,取代基独立地选自所列出的取代基。
对于取代基,术语“独立地”是指当可能是一个以上这种取代基时,这种取代基可以彼此相同或不同。
为了提供更简明的说明书,本文给出的一些定量表达未用术语“大约”说明性质。应该理解,不论是否明确使用术语“大约”,本文给出的所有数量是指实际的给定值,并且它也是指基于本领域普通技术人员合理推断的这种给定值的近似值,包括由于对这种给定值的实验性和/或测量条件所造成的近似情况。
除非另作说明,本文使用的术语“离去基团”是指在取代或置换反应期间脱离的带电荷或不带电荷的原子或基团。合适例子包括但不局限于Br、Cl、I、甲磺酸酯、甲苯磺酸酯,等等。
除非另作说明,本文使用的术语“氮保护基”是指可以与氮原子连接、从而避免所述氮原子参与反应的基团,并且其可以在反应之后迅速地除去。合适的氮保护基包括但不局限于:式-C(O)O-R的氨基甲酸酯基团,其中R是例如甲基,乙基,叔丁基,苄基,苯乙基,CH2=CH-CH2-,等等;式-C(O)-R′的酰胺基团,其中R′是例如甲基,苯基,三氟甲基,等等;式-SO2-R”的N-磺酰基衍生物基团,其中R”是例如甲苯基,苯基,三氟甲基,2,2,5,7,8-五甲基色满-6-基-,2,3,6-三甲基-4-甲氧基苯,等等。其它合适的氮保护基可以在例如下列文献中得到:T.W.Greene & P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley & Sons,1991。
在贯穿本公开使用的标准命名中,首先描述的是指定侧链的末端部分,而后描述向连结点邻近的官能团。因此,例如“苯基-C1-4烷基-氨基-羰基-C1-4烷基-”取代基是指下式的基团:
在说明书中、特别是在反应路线和实施例中使用的缩写如下:
DCM = 二氯甲烷
DMAC = 二甲基乙酰胺
DMF = N,N-二甲基甲酰胺
DMSO = 二甲亚砜
Et = 乙基(即-CH2CH3)
EtI = 乙基碘
EtOAc = 乙酸乙酯
HPLC = 高压液相色谱
KO-t-Bu or = 叔丁醇钾
t-Bu-OK
Me = 甲基(即-CH3)
MeI = 甲基碘
MeOH = 甲醇
NaOAc = 乙酸钠
TEA或Et3N = 三乙胺
THF = 四氢呋喃
本文使用的术语“患者”是指所治疗、观察或实验的动物,优选哺乳动物,最优选人。
本文使用的术语“治疗有效量”是指活性化合物或药学试剂的数量,该数量可以在组织系统、动物或人中引起研究人员、兽医、医生或其它临床医师所探寻的生物学或医学响应,包括减轻所治疗疾病或病症的症状。
本文使用的术语“组合物”包括含有具体数量的具体组分的产品,以及直接或间接地由具体数量的具体组分的联用所得到的任何产品。
如果按照本发明的化合物具有至少一个手性中心,它们可以相应地存在对映体形式。如果化合物具有两个或多个手性中心,它们可以另外存在非对映体形式。应该理解,所有这种异构体和其混合物包括在本发明范围内。此外,化合物的一些结晶形态可以存在多晶型物形式,并且这种多晶型物包括在本发明中。此外,一些化合物可以与水(即水合物)或常见的有机溶剂形成溶剂化物,并且这种溶剂化物也包括在本发明范围内。
本发明包括在其范围内的本发明化合物的“前体药物”。通常,这种前体药物是化合物的功能性衍生物,其可在体内迅速地转变为所需要的化合物。因此,在本发明的治疗方法中,术语“给予”包括:用具体公开的化合物来治疗所描述的各种病症,或用没有具体公开、但可以在给予患者之后体内转变成具体化合物的化合物来治疗所描述的各种病症。选择和制备合适前体药物衍生物的常规方法描述在例如下列中:“Design of Prodrugs”,ed.H.Bundgaard,Elsevier,1985。
本发明包括在其范围内的本发明化合物的“药学可接受的盐”。对于药物用途,本发明化合物的盐涉及无毒的药学可接受的盐。然而,其它盐可有效用于制备按照本发明的化合物或其药学可接受的盐。化合物的合适药学可接受的盐包括酸加成盐,其可以是例如由化合物溶液与药学可接受酸的溶液混合形成的盐,酸例如盐酸、硫酸、富马酸、马来酸、琥珀酸、乙酸、苯甲酸、枸橼酸、酒石酸、碳酸或磷酸。此外,如果本发明的化合物携带酸性部分,其合适的药学可接受的盐可以包括碱金属盐,例如钠或钾盐;碱土金属盐,例如钙或镁盐;和与合适有机配位体形成的盐,例如季铵盐。因此,代表性的药学可接受的盐包括下列:
乙酸盐,苯磺酸盐,苯甲酸盐,碳酸氢盐,硫酸氢盐,酒石酸氢盐,硼酸盐,溴化物,乙二胺四乙酸钙,右旋樟脑磺酸盐,碳酸盐,氯化物,克拉维酸盐,柠檬酸盐,二盐酸盐,乙二胺四乙酸盐,乙二磺酸盐,丙酸酯十二烷基硫酸盐,乙磺酸盐,富马酸盐,葡庚糖酸盐,葡糖酸盐,谷氨酸盐,对α-羟乙酰氨基苯砷酸盐,己基间苯二酚盐,哈胺(hydrabamine),氢溴酸盐,盐酸盐,羟基萘酸盐,碘化物,硫代硫酸盐,乳酸盐,乳糖酸盐,月桂酸盐,苹果酸盐,马来酸盐,苦杏仁酸盐,甲磺酸盐,甲基溴,甲基硝酸盐,甲基硫酸盐,粘酸盐,萘磺酸盐,硝酸盐,N-葡甲胺铵盐,油酸盐,双羟萘酸盐(双羟萘酸盐),棕榈酸盐,泛酸盐,磷酸盐/磷酸氢盐,多聚半乳糖醛酸盐,水杨酸盐,硬脂酸盐,硫酸盐,碱式乙酸盐,琥珀酸盐,丹宁酸盐,酒石酸盐,茶氯酸盐,甲苯磺酸盐,三乙基碘和戊酸盐。
可以用于制备药学可接受盐的代表性的酸和碱包括下列:
酸,包括乙酸,2,2-二氯乙酸,酰化的氨基酸,己二酸,海藻酸,抗环血酸,L-门冬氨酸,苯磺酸,苯甲酸,4-乙酰胺基苯甲酸,(+)-樟脑酸,樟脑磺酸,(+)-(1S)-樟脑-10-磺酸,癸酸,己酸,辛酸,肉桂酸,枸橼酸,环拉酸,十二烷基硫酸,乙烷-1,2-二磺酸,乙磺酸,2-羟基-乙磺酸,甲酸,富马酸,粘酸,龙胆酸,葡庚糖酸,D-葡糖酸,D-葡萄糖醛酸,L-谷氨酸,α-氧代-戊二酸,羟基乙酸,马尿酸(hipuric acid),氢溴酸,盐酸,(+)-左旋乳酸,(±)-DL-乳酸,乳糖酸,马来酸,(-)-L-苹果酸,丙二酸,(±)-DL-扁桃酸,甲磺酸,萘-2-磺酸,萘-1,5-二磺酸,1-羟基-2-萘酸,烟碱酸,硝酸,油酸,乳清酸,草酸,棕榈酸,双羟萘酸酸,磷酸,L-焦谷氨酸,水杨酸,4-氨基-水杨酸,癸二酸(sebaicacid),硬脂酸,琥珀酸,硫酸,鞣酸,(+)-L-酒石酸,硫氰酸,对甲苯磺酸和十一碳烯酸;和
碱,包括氨,L-精氨酸,苯明青霉素(benethamine),本乍生,氢氧化钙,胆碱,丹醇,二乙醇胺,二乙胺,2-(二乙基氨基)-乙醇,乙醇胺,乙二胺,N-甲基-葡糖胺,哈胺(hydrabamine),1H-咪唑,L-赖氨酸,氢氧化镁,4-(2-羟乙基)-吗啉,哌嗪,氢氧化钾,1-(2-羟乙基)-吡咯烷,仲胺,氢氧化钠,三乙醇胺,氨基丁三醇和氢氧化锌。
在本发明的一个实施方案中,R1选自氢,卤素,C1-4烷基,卤代C1-4烷基,CN和NO2。在本发明的另一个实施方案中,R1选自氢,卤素,卤代C1-4烷基和氰基。在本发明的另一个实施方案中,R1选自氢,溴,氯和氰基。在本发明的另一个实施方案中,R1选自溴和氯。
在本发明的一个实施方案中,R2选自氢,卤素,C1-4烷基,卤代C1-4烷基,CN和NO2。在本发明的另一个实施方案中,R2选自氢,卤素和卤代C1-4烷基。在本发明的另一个实施方案中,R2选自氢和卤代C1-4烷基。在本发明的另一个实施方案中,R2选自氢和三氟甲基。
在本发明的一个实施方案中,R3选自氢,C1-4烷基和卤代C1-4烷基。在本发明的另一个实施方案中,R3是C1-4烷基。在本发明的另一个实施方案中,R3是甲基。
在本发明的一个实施方案中,R4选自氢,羧基,C1-4烷基,卤代C1-4烷基,苯基和-C(O)O-C1-4烷基。在本发明的另一个实施方案中,R4是氢,C1-4烷基和C(O)O-C1-4烷基。在本发明的另一个实施方案中,R3是氢和C(O)O-Et。
本发明的其它实施方案,包括,其中对于一个或多个本文所定义的变量(即R1、R2、R3和n),所选择的取代基被独立地加以选择的那些实施方案,以使这些取代基是任何个别的取代基或选自本文所定义的一览表的取代基任何亚组。
本发明的代表性的化合物列于下面表1中。
表1:式(I)的化合物
ID | R1 | R2 | R3 | R4 |
1 | Cl | H | Me | H |
2 | Br | H | Me | H |
3 | H | CF3 | Me | H |
4 | Cl | H | Me | C(O)-O-Et |
合成
可以按照反应路线1列出的方法制备式(I)的化合物。
反应路线1
相应地,合适取代的式(II)化合物(其是已知的化合物或由已知方法制备的),在碱例如TEA、DIPEA等等的存在下,在有机溶剂例如DCM、THF等等中,优选在大约0℃和室温范围内的温度下,更优选在0℃温度下,与合适取代的(III)(已知的化合物)反应,得到相应的式(IX)的化合物。
在有机溶剂例如乙醇、甲醇、THF等等中,在大约从50℃和大约80℃范围内的温度下,用碱例如氢氧化氨、氢化钠等等处理式(IX)的化合物,得到相应的式(X)的化合物。
在有机溶剂例如醚、THF、二噁烷等等中,在大约从50℃和80℃范围内的温度下,用重氮源R4CHN2(已知的化合物或由已知方法制备的化合物)例如TMS重氮甲烷、重氮乙酸乙酯等等处理式(X)的化合物,得到相应的式(I)的化合物。
在制备本发明化合物的任何方法中,必须和/或希望保护任何有关分子上的敏感或反应基团。这可以利用常规保护基来实现,例如在ProtectiveGroupsinOrganicChemistry,ed.J.F.W.McOmie,PlenumPress,1973;和T.W.Greene & P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley & Sons,1991中的描述那些保护基。可以使用本领域已知的方法、在适当的随后步骤中除去保护基。
本领域技术人员可以认识到,如果本发明的反应步骤可以在各种溶剂或溶剂体系中进行,所述反应步骤也可以在合适溶剂或溶剂体系的混合物中进行。
本发明进一步包括药物组合物,其含有一或多种式(I)的化合物与药学可接受的载体。含有一或多种本文描述的本发明化合物作为活性组分的药物组合物,可以如下制备:按照常规药学混合技术,将一或多种化合物与药学载体进行紧密地混合。根据所需要的给药途径(例如口服,肠胃外),载体可以采用多种形式。因此,对于液体口服制剂,例如悬浮液、酏剂和溶液,合适载体和添加剂包括水,二醇类,油类,醇,调味剂,防腐剂,稳定剂,着色剂等等;对于固体口服制剂,例如粉末、胶囊和片剂,合适载体和添加剂包括淀粉,糖,稀释剂,成粒剂,润滑剂,结合剂,崩解剂等等。固体口服制剂也可以是用物质例如糖进行包衣,或是肠溶性涂层,以便调整吸收的主要位点。对于肠胃外给药,载体通常由无菌水组成,并且可以加入其它组分,以便提高溶解度或保存时间。可注射的悬浮液或溶液也可以使用含水载体连同合适的添加剂来制备。
为了制备本发明的药物组合物,按照常规药学混合技术,将所选择的作为活性组分的一或多种本发明化合物与药学载体密切地混合,根据所希望给予制剂的形式,例如口服或肠胃外例如肌注,载体可以采用多种形式。在制备口服剂型组合物过程中,可以使用任何常见的药学介质。因此,对于液体口服制剂,例如悬浮液、酏剂和溶液,合适载体和添加剂包括水,二醇类,油类,醇,调味剂,防腐剂,着色剂等等;对于固体口服制剂,例如粉末、胶丸、锭剂、胶囊和片剂,合适载体和添加剂包括淀粉,糖,稀释剂,成粒剂,润滑剂,结合剂,崩解剂等等。由于容易给药的性质,片剂和胶囊代表最有利的口服剂量单位形式,在这样的情况下,可以显而易见地使用固体药学载体。如果需要的话,可以利用标准技术将片剂包糖衣或进行肠溶包衣。对于肠胃外给药,载体通常包括无菌水,但也可以包括其它组分,例如,为了例如帮助溶解或保存的目的。也可以制备可注射的悬浮液,在这样的情况下,可以使用合适的液体载体、悬浮剂等等。每个剂量单位中,例如片剂、胶囊、粉末、针剂、一茶匙容量等等,本文的药物组合物含有活性组分的量,必须可以递送如上所述的有效剂量。每个单位剂量单元中,例如片剂、胶囊、粉末、针剂、栓剂、一茶匙容量等等中,本文的药物组合物将含有从大约50-100毫克,并且可以以大约0.5-5.0毫克/千克/天的剂量给予,优选大约1.0-3.0毫克/千克/天。然而,根据患者的要求、所治疗病症的严重程度和所使用的化合物,可以改变剂量。可以使用每日给药或周期后给药的用法。
优选这些组合物是单元剂型,例如片剂,丸剂,胶囊,粉末,粒剂,无菌的肠胃外溶液或悬浮液,计量气溶胶或液体喷雾剂,滴液,安瓿剂,自动注射装置或栓剂;用于口服、肠胃外、鼻内、舌下或直肠给药,或用于吸入或喷射给药。或者,可以提供适合每周一次或每月一次给药形式的组合物;例如,活性化合物的不溶性盐,例如癸酸盐,可以适合于提供肌肉注射的长效(depot)制剂。为了制备固体组合物,例如片剂,将主要的活性组分与下列混合:药学载体,例如常规片剂组分例如玉米淀粉、乳糖、蔗糖、山梨糖醇、滑石粉、硬脂酸、硬脂酸镁、磷酸氢钙或树胶,及其它药学稀释剂,例如水,形成含有本发明化合物或其药学可接受盐的均匀混合物的固体预制剂组合物。当涉及这些均匀形式的预制剂组合物时,其是指活性组分均匀地分散在组合物中,以使组合物可以容易地细分为平均有效的剂型,例如片剂、丸剂和胶囊。然后将这种固体预制剂组合物细分为如上所述类型的单元剂型,含有0.1至大约500毫克本发明的活性组分。可以将新组合物的片剂或丸剂涂层或者另外复合,提供具有延长作用的优点的剂型。例如,片剂或丸剂可以包括内部剂量和外部剂量组份,后者是在前者外面的包膜形式。利用肠溶层可以分离两个组分,肠溶层用来阻止在胃中的崩解,并且容许内部组份完好通过到十二指肠中,或延迟释放。对于这种肠溶层或涂层,可以使用各种材料,这种材料包括许多聚合物酸,例如片胶、鲸蜡醇和醋酸纤维素。
可以口服或通过注射给药引入本发明新组合物的液体形式包括水溶液、适当加香的糖浆剂、水或油悬浮液和用食用油例如棉子油、芝麻油、椰子油或花生油加香的乳液、以及酏剂和类似的药学载体。水悬浮液的合适的分散或悬浮剂包括合成与天然树胶,例如黄芪胶,阿拉伯胶,藻朊酸盐,右旋糖酐,羧甲基纤维素钠,甲基纤维素,聚乙烯-吡咯烷酮或凝胶。
在本发明中描述的治疗与离子通道例如钾离子通道相关病症的方法,也可以使用药物组合物进行,药物组合物包含本文所定义的任何化合物和药学可接受的载体。药物组合物可以含有大约0.01毫克和1000毫克之间的化合物,优选大约1至500毫克,更优选10至100毫克,并且可以构成任何适于所选择的给药方式的形式。载体包括必须的和惰性的药学赋形剂,包括但不限于:结合剂,悬浮剂,润滑剂,香味素,甜味剂,防腐剂,颜料和涂层。适合口服的组合物包括固体形式,例如丸剂,片剂,锭剂,胶囊(每个包括立即释放、延时释放和持续释放制剂),粒剂和粉末,和液体形式,例如溶液,糖浆剂,酏剂,乳液和悬浮液。用于肠胃外给药的形式包括无菌溶液、乳液和悬浮液。
优选,可以以单一日剂量形式给予本发明的化合物,或可以以每天两次、三次或四次的分开剂量形式来给予总的日剂量。此外,通过局部使用合适鼻内载体,以鼻内形式给予本发明化合物,或通过本领域普通技术人员熟知的那些透皮皮肤贴剂形式给予本发明化合物。对于用透皮递送系统的形式给予,剂量给药在给药方案期间当然是连续的,而不是间歇性的。
例如,对于口服形式的片剂或胶囊,活性药物组份可以与口服的、无毒的药学可接受的惰性载体例如乙醇、丙三醇、水等等混合。此外;当需要或必要时,合适的结合剂、润滑剂、崩解剂和着色剂还可以结合进混合物中。合适结合剂包括但不限于:淀粉,凝胶,天然糖例如葡糖或β-乳糖,玉米甜味剂,天然和合成树胶例如阿拉伯胶,黄芪胶或油酸钠,硬脂酸钠,硬脂酸镁,苯甲酸钠,乙酸钠,氯化钠等等。崩解剂包括但不限于:淀粉,甲基纤维素,琼脂,膨润土,黄原胶等等。
在适当调味的悬浮或分散剂中的液体形式,例如合成和天然树胶例如黄芪胶、阿拉伯胶、甲基-纤维素等等。对于肠胃外给药,需要无菌的悬浮液和溶液。当需要静脉内给予时,使用通常含有合适防腐剂的等渗制剂。
本发明的化合物还可以以脂质体递送系统的形式给予,例如小单层脂质体、大单层脂质体和多层小囊。脂质体可以由各种磷脂例如胆固醇、硬脂胺或磷脂酰胆碱形成。
本发明的化合物也可以利用作为独立载体的、与化合物分子偶合的单克隆抗体来递送。本发明的化合物也可以与作为可靶向药物载体的可溶性聚合物结合。这种聚合物可以包括聚乙烯吡咯烷酮,吡喃共聚物,聚羟基丙基甲基丙烯酰基酰胺酚,聚羟乙基天冬酰胺酚,或被棕榈酰残基取代的聚氧化乙烯聚赖氨酸。此外,本发明的化合物可以与可生物降解的聚合物结合,用于实现药物的控制释放,例如聚乳酸,聚环氧聚酰胺纤维己内酯,聚羟基丁酸,聚原酸酯,聚乙缩醛,聚二氢吡喃,聚氰基丙烯酸酯和水凝胶的交联或两性嵌段共聚物。
无论何时需要治疗离子通道例如钾离子通道相关病症,可以在任何先前的组合物中、并按照本领域确定的给药方案给予本发明的化合物。
产品的日剂量可以在每个成人每天0.01至1,000毫克的宽范围内改变。对于口服,优选以片剂形式提供组合物,片剂含有0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100、150、200、250、500和1000毫克活性组分,用于给予所治疗的患者,进行症状调节。通常以每天大约0.01毫克/千克至大约300毫克/千克体重的剂量水平提供有效量药物。优选,该范围是每天大约0.5至大约5.0毫克/千克体重,最优选,每天大约1.0至大约3.0毫克/千克体重。化合物可以基于每天1至4次的方案来给予。
本领域技术人员可以迅速地确定所给予的最佳剂量,并且随所使用的具体化合物、给予形式、制剂浓度、给予方式和疾病的发展而变化。此外,与所治疗的具体患者有关的因素,包括患者年龄、重量、饮食和给予时间,也会产生调节剂量的需要。
列出下列实施例来帮助理解本发明,无论如何不应该将其视为对后面的权利要求的限制。
在下述实施例中,一些列出的合成产物是以残余物的形式分离出来的。本领域普通技术人员将会理解,术语“残余物”不限制所分离产物的物理状态,并且可以包括例如固体、油、泡沫、胶质、糖浆剂等等。
实施例1
5-氯-2-(2-甲基-丙烯酰基氨基)-苯甲酰胺
在DCM中,在0℃,将文献已知的化合物2-氨基-5-氯-苯甲酰胺(2.5mmol)用TEA(3.0mmol)处理,而后用甲基丙烯酰基氯(2.5mmol)处理。将反应慢慢地升温到室温,另外保持2小时。然后在DCM和水之间分配反应混合物。用饱和Na2CO3、盐水洗涤有机层,用无水Na2SO4干燥,过滤,浓缩,利用硅胶柱色谱纯化,提供标题化合物白色固体。
1H NMR:(CDCl3)δ 8.70(d,J=7.5Hz,1H),7.52(s,1H),7.44(d,J=7.5Hz,1H),6.60(br,s,2H),6.05(br,s,1H),6.00(s,1H),5.51(s,1H),2.05(s,3H)。MS(m/z):MH+239。
实施例2
5-溴-2-(2-甲基-丙烯酰基氨基)-苯甲酰胺
按照实施例1描述的方法,使用2-氨基-5-氯-苯甲酰胺作为起始原料,得到标题化合物白色固体。
1H NMR:(CDCl3)δ 8.65(d,J=7.5Hz,1H),7.65(s,1H),7.60(d,J=7.5Hz,1H),6.40(br,s,2H),6.00(s,1H),5.91(br,s,1H),5.55(s,1H),2.10(s,3H)。MS(m/z):MH+284。
实施例3
2-(2-甲基-丙烯酰基氨基)-4-三氟甲基-苯甲酰胺
按照实施例1描述的方法,使用2-氨基-4-三氟甲基-苯甲酰胺作为起始原料,得到标题化合物白色固体。
1H NMR:(CDCl3)δ 9.05(s,1H),7.65(d,J=8.0Hz,1H),7.30(d,J=7.5Hz,1H),6.50(br,s,1H),6.00(s,1H),5.91(br,s,1H),5.55(s,1H),2.10(s,3H)。MS(m/z):MH+273。
实施例4
6-氯-2-异丙烯基-3H-喹唑啉-4-酮
在80℃,将5-氯-2-(2-甲基-丙烯酰基氨基)-苯甲酰胺(1.5mmol)在EtOH(10毫升)中用氢氧化氨(~3.0mmoL)处理4小时。然后冷却反应,除去溶剂。然后在DCM和水之间分配反应混合物。用饱和NH4Cl、盐水洗涤有机层,用无水Na2SO4干燥,过滤,浓缩,利用硅胶柱色谱纯化,提供标题化合物白色固体。
1H NMR:(CDCl3)δ 8.45(s,1H),8.20(d,J=8.5Hz,1H),7.75(br,s,1H),7.30(d,J=8.5Hz,1H),5.85(s,1H),5.55(s,1H),2.05(s,3H)。MS(m/z):MH+221。
实施例5
6-溴-2-异丙烯基-3H-喹唑啉-4-酮
按照实施例4描述的方法,使用5-溴-2-(2-甲基-丙烯酰基氨基)-苯甲酰胺作为起始原料,得到标题化合物白色固体。
1H NMR:(CDCl3)δ 10.50(br,s,1H),8.40(s,1H),7.85(d,J=7.5Hz,1H),7.62(d,J=7.5Hz,1H),6.05(s,1H),5.71(s,1H),2.25(s,3H)。MS(m/z):MH+266。
实施例6
2-异丙烯基-7-三氟甲基-3H-喹唑啉-4-酮
按照实施例4描述的方法,使用2-(2-甲基-丙烯酰基氨基)-4-三氟甲基-苯甲酰胺作为起始原料,得到标题化合物白色固体。
1H NMR:(CDCl3)δ 7.56(d,J=8.0Hz,1H),7.25(d,J=7.5Hz,1H),6.70(br,s,1H),6.10(s,1H),5.71(s,1H),2.25(s,3H)。MS(m/z):MH+255。
实施例7
6-氯-2-(3-甲基-3,4-二氢-2H-吡唑-3-基)-3H-喹唑啉-4-酮
在50℃,将6-氯-2-异丙烯基-3H-喹唑啉-4-酮(1mmol)在THF(5毫升)中用TMSCHN2(1.0N,3.0mmol)处理4小时。除去溶剂,利用硅胶柱色谱纯化残余物,得到标题化合物白色固体。
1H NMR:(CDCl3)δ 10.61(br,s,1H),8.21(s,1H),7.65(d,J=6.5Hz,1H),7.60(d,J=7.5Hz,1H),6.81(br,s,1H),3.15(abq,J=12.5Hz,2H),1.70(s,3H)。MS(m/z):MH+263。
实施例8
6-溴-2-(3-甲基-3,4-二氢-2H-吡唑-3-基)-3H-喹唑啉-4-酮
按照实施例7描述的方法,使用6-溴-2-异丙烯基-3H-喹唑啉-4-酮和TMSCHN2作为起始原料,得到标题化合物白色固体。
1H NMR:(CDCl3)δ 8.01(s,1H),7.75(d,J=7.5Hz,1H),7.62(d,J=7.5Hz,1H),6.91(br,s,1H),3.55(abq,J=12.5Hz,1H),2.60(abq,J=12.5Hz,1H),1.55(s,3H)。MS(m/z):MH+308。
实施例9
2-(3-甲基-3,4-二氢-2H-吡唑-3-基)-7-三氟甲基-3H-喹唑啉-4-酮
按照实施例7描述的方法,使用2-异丙烯基-7-三氟甲基-3H-喹唑啉-4-酮和TMSCHN2作为起始原料,得到标题化合物白色固体。
1H NMR:(CDCl3)δ 10.70(br,s,1H),8.35(d,J=8.0Hz,1H),7.95(s,1H),7.65(d,J=7.5Hz,1H),3.25(abq,J=10.5Hz,1H),1.75(s,3H)。MS(m/z):MH+297。
实施例10
5-(6-氯-4-氧代-3,4-二氢-喹唑啉-2-基)-5-甲基-4,5-二氢-1H-吡唑-3-羧酸
乙酯
按照实施例7描述的方法,使用6-氯-2-异丙烯基-3H-喹唑啉-4-酮和重氮乙酸乙酯作为起始原料,得到标题化合物白色固体。
1H NMR:(CDCl3)δ 8.25(s,1H),7.75(d,J=7.0Hz,1H),7.55(d,J=7.5Hz,1H),7.00(s,1H),4.35(q,J=9.5Hz,2H),3.60(abq,J=10.5Hz,1H),3.25(abq,J=10.5Hz,1H),1.75(s,3H),1.40(q,J=9.5Hz,3H)。MS(m/z):MH+335。
实施例11:钾通道试验
从ATCC处获得TE671人类成神经管细胞瘤细胞,并在Dulbecco′s改进的、补充有10%胎儿牛血清、100U/ml青霉素和100U/ml链霉素的Eagle′s介质(DMEM)中培育。
试验之前的当天,将细胞以50K/孔涂覆在黑色96孔平皿中。试验当天,除去生长培养基,然后将100μl FLIPR缓冲液(20mM HEPES,120mM NaCl,2mM KCl,2mM CaCl2,1mM MgCl2,5mM葡糖)和溶于FLIPR缓冲液中的100μl膜电位试验颜料(Molecular Devices)加入到每个孔中。将细胞在室温下培养15至30分钟。
在室温下,在荧光成像板读数器(FLIPR,Molecular Devices)上评估试验化合物对于KATP通道的效果。基线时间之后,加入50μl试验化合物的5X储备溶液(在FLIPR缓冲液中制备),检测荧光变化3分钟。读数之后,加入KATP通道阻断剂优降糖,至5μM的最后浓度,以检查试验化合物作为KATP通道开放剂的专一性。以荧光强度降低的方式,观察KATP通道开放引起的过极化。
按照如上所述方法试验本发明的代表性化合物,结果列于下面表2中。以百分数的方式测定试验化合物活性。在30μM时,如果化合物产生大于或等于10%的响应,称为活性化合物。在30μM时,如果化合物产生小于10%的响应,称为非活性的化合物。
表2
ID No | 响应 |
1 | 活性 |
2 | 活性 |
3 | 活性 |
4 | 活性 |
实施例12
作为口服组合物的具体实施方案,将100毫克实施例7中制备的化合物与足够的细碎乳糖进行配制,提供580至590毫克的总数量,填充规格O的硬凝胶胶囊。
尽管上述说明书公开了本发明的原理,同时为举例说明的目的而提供了实施例,但可以理解,本发明的实践包括所有通常的改变、适应和/或改良,这些都在下列权利要求和其等效内容的范围之内。
Claims (10)
2.权利要求1的化合物,其中
R1选自氢、溴、氯和氰基;
R2选自氢和三氟甲基;
R3是甲基;和
R4是氢和C(O)-O-Et。
3.药物组合物,其包含药学可接受的载体和权利要求1的化合物。
4.制备药物组合物的方法,包括将权利要求1的化合物和药学可接受的载体进行混合。
5.治疗离子通道相关病症的方法,包括给予需要其的患者治疗有效量的权利要求1的化合物。
6.权利要求5的方法,其中离子通道是钾离子通道。
7.权利要求5的方法,其中离子通道是ATP敏感的钾离子通道。
8.权利要求5的方法,其中与离子通道相关的病症选自:尿失禁,膀胱活动过度,高血压症,勃起功能紊乱,女性性功能障碍,痛经,肠易激综合症,呼吸道机能亢进,癫痫,中风,阿尔海默氏疾病,帕金森疾病,心肌损伤,冠状动脉病,脱发和秃顶。
9.权利要求5的方法,其中与离子通道相关的病症选自尿失禁和膀胱活动过度。
10.治疗选自下列病症的方法:尿失禁,膀胱活动过度,高血压症,勃起功能紊乱,女性性功能障碍,痛经,肠易激综合症,呼吸道机能亢进,癫痫,中风,阿尔海默氏疾病,帕金森疾病,心肌损伤,冠状动脉病,脱发和秃顶,该方法包括给予需要其的患者治疗有效量的权利要求2的组合物。
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EP2114916A2 (en) * | 2007-02-02 | 2009-11-11 | NeuroSearch A/S | Pyridinyl-pyrazole derivatives and their use as potassium channel modulators |
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US4766211A (en) * | 1985-09-06 | 1988-08-23 | Ciba-Geigy Corporation | Chromogenic quinazolines |
JP2007523873A (ja) * | 2003-07-15 | 2007-08-23 | スミスクライン・ビーチャム・コーポレイション | 新規化合物 |
EP1667982B1 (en) * | 2003-09-23 | 2013-07-31 | Merck Sharp & Dohme Corp. | Isoquinolinone potassium channel inhibitors |
WO2005030217A1 (en) * | 2003-09-23 | 2005-04-07 | Merck & Co., Inc. | Quinazoline potassium channel inhibitors |
MX2007010991A (es) * | 2005-03-14 | 2007-11-07 | Neurosearch As | Agentes que modulan el canal de potasio y su uso medico. |
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- 2007-02-16 CN CNA2007800083093A patent/CN101400672A/zh active Pending
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- 2007-02-16 WO PCT/US2007/062287 patent/WO2007098386A1/en active Application Filing
- 2007-02-16 AU AU2007217099A patent/AU2007217099A1/en not_active Abandoned
- 2007-02-16 US US11/675,724 patent/US8053441B2/en not_active Expired - Fee Related
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Cited By (8)
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CN107056715A (zh) * | 2017-04-07 | 2017-08-18 | 江南大学 | 一种增强TRPV4‑KCa2.3复合体耦联度的化合物及其在抗高血压中的应用 |
WO2018184274A1 (zh) * | 2017-04-07 | 2018-10-11 | 江南大学 | 一种增强TRPV4-KCa2.3复合体耦联度的化合物及其在抗高血压中的应用 |
US10336712B2 (en) | 2017-04-07 | 2019-07-02 | Jiangnan University | Compound for enhancing the coupling degree of complex TRPV4-KCa2.3 and anti-hypertension applications thereof |
CN107056715B (zh) * | 2017-04-07 | 2019-07-30 | 江南大学 | 一种增强TRPV4-KCa2.3复合体耦联度的化合物及其在抗高血压中的应用 |
RU2718913C1 (ru) * | 2017-04-07 | 2020-04-15 | Цзяннань Юниверсити | Способ получения соединения для укрепления степени сцепленности комплексного вещества trpv4-kca2.3 |
RU2718913C9 (ru) * | 2017-04-07 | 2020-10-01 | Цзяннань Юниверсити | Способ получения соединения для укрепления степени сцепленности комплексного вещества trpv4-kca2.3 |
CN112390782A (zh) * | 2020-11-09 | 2021-02-23 | 江南大学 | 一种特异性增强TRPV4-KCa2.3复合体的空间耦联度的化合物及其用途 |
CN112390782B (zh) * | 2020-11-09 | 2021-12-03 | 江南大学 | 一种特异性增强TRPV4-KCa2.3复合体的空间耦联度的化合物及其用途 |
Also Published As
Publication number | Publication date |
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US8053441B2 (en) | 2011-11-08 |
US20070197566A1 (en) | 2007-08-23 |
CA2642832A1 (en) | 2007-08-30 |
JP2009527493A (ja) | 2009-07-30 |
EP1989197A1 (en) | 2008-11-12 |
WO2007098386A1 (en) | 2007-08-30 |
AU2007217099A1 (en) | 2007-08-30 |
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