CN1174986C - 作为血管升压素受体拮抗剂的三环苯并二氮杂�类 - Google Patents
作为血管升压素受体拮抗剂的三环苯并二氮杂�类 Download PDFInfo
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- CN1174986C CN1174986C CNB998164887A CN99816488A CN1174986C CN 1174986 C CN1174986 C CN 1174986C CN B998164887 A CNB998164887 A CN B998164887A CN 99816488 A CN99816488 A CN 99816488A CN 1174986 C CN1174986 C CN 1174986C
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- Prior art keywords
- phenyl
- benzodiazepine
- carbonyl
- tetrahydrochysene
- benzamide
- Prior art date
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Abstract
本发明涉及式(I)或(II)的三环苯并二氮杂䓬类:可用作治疗包括血管阻力增加和心功能不全病症的血管升压素受体拮抗剂。本发明还公开了包含本发明三环苯并二氮杂䓬的组合物和治疗例如高血压、充血性心力衰竭、心功能不全、冠状动脉血管痉挛、心脏缺血、肝硬化、肾血管痉挛、肾衰、脑水肿和缺血、中风、血栓形成或水潴留病症的方法。
Description
发明领域
本专利申请要求于1999年1月19日申请的临时专利申请序号60/116,358的优先权,该临时专利申请通过引用结合到本文中。
本发明涉及新的三环血管升压素受体拮抗剂。更具体地说,本发明的化合物阻断肽类激素血管升压素与其受体的结合,并因此可用来治疗涉及血管阻力增加和心功能不全的病症。
发明背景
血管升压素是一种主要由垂体后叶腺分泌的九肽激素。所述激素通过膜结合V-1和V-2受体亚型发挥其作用。血管升压素的功能包括收缩子宫、膀胱和平滑肌;刺激肝脏中的糖原分解;从垂体前叶释放促肾上腺皮质激素;诱导血小板聚集;和中枢神经系统调节行为反应和应激反应。V-1受体介导平滑肌的收缩以及血管升压素的肝糖原分解作用和中枢神经系统效应。V-2受体(估计可能只在肾中发现)通过刺激腺苷酸环化酶实现血管升压素的抗利尿作用。
看来血浆血管升压素水平的升高在充血性心力衰竭的发病机理方面起作用(P.A.Van Zwieten,Progr.Pharmacol.Clin.Pharmacol.1990,7.49)。根据治疗充血性心力衰竭的进展,九肽血管升压素V-2受体拮抗剂在患有充血性心力衰竭的神志清醒的狗中诱导了低重量摩尔渗透压浓度的促排水作用(low osmolality aquaresis)并减少外周阻力(H.Ogawa,J.Med.Chem.1996,39,3547)。在某些病理状态下,血浆血管升压素水平对于特定重量摩尔渗透压浓度可能为不合适地升高,由此导致肾脏水潴留和低钠血症。与水肿性病症(肝硬化、充血性心力衰竭、肾衰)相关的低钠血症可以伴有抗利尿激素不适当分泌综合征(SIADH)。用血管升压素V-2拮抗剂治疗SIADH-缺乏免疫力的大鼠已治愈其已有的低钠血症(G.Fujisawa,Kidney Int.1993,44(1),19)。部分由于血管升压素在血管系统的V-1受体上的收缩作用,因此血管升压素V-1拮抗剂降低血压可作为一种潜在治疗高血压的药物。因此,血管升压素受体拮抗剂可用作高血压、充血性心力衰竭/心功能不全、冠状动脉血管痉挛、心脏缺血、肝硬化、肾血管痉挛、肾衰、脑水肿和缺血、中风、血栓形成和水潴留病症中的治疗药物。
发明概述
本发明涉及由以下通式(I)和(II)代表的化合物及其药学上可接受的盐:
其中m为1-2的整数,使得式(II)化合物中的“HET”为由多个碳原子和一个杂原子组成稳定的五元或六元单环芳族环系,其中所述杂原子选自可以在任-杂原子或碳原子上连接的N、O或S,由此产生的环系是稳定的;例如为噻吩、呋喃、吡咯或吡啶;
A选自-C(O)-、SO2或CH2,最好是,A为-C(O)-;
Y选自CH2或作为烯烃部分的CH;
X选自CH2、作为烯烃部分的CH、NR3、S或O;
前提是:如果Y为CH2,则X为(CH2)2;
Z选自N或CH;
R1选自氢、烷基、烷氧基、卤、氨烷基或硝基;
Ar选自萘基,其中萘基任选地用1-3个独立地选自以下的取代基取代:C1-C8烷基、C1-C8烷氧基、氟化C1-C8烷基(最好是三氟甲基)、氟化C1-C8烷氧基(最好是三氟甲氧基)、卤、氰基、羟基、氨基、硝基、C1-C4烷基氨基(最好是-NH-C1-C4烷基)、C1-C4二烷基氨基(最好是-N-[C1-C4烷基]2,其中所述烷基可以相同或不同);或苯基,其中苯基任选地用1-3个独立地选自以下的取代基取代:C1-C8烷基、C1-C8烷氧基、氟化C1-C8烷基、氟化C1-C8烷氧基、C1-C8芳烷基(其中任选地所述烷基或芳基部分独立地被取代和所述烷基部分可以用至少1个氟取代和/或所述芳基部分可以独立地用1-2个选自卤、C1-C4烷基、C1-C8烷硫基或羟基的取代基取代)、C1-C8芳烷氧基(其中任选地所述烷氧基或芳基部分独立地被取代和所述烷氧基部分可以用至少1个氟取代和/或所述芳基部分可以独立地用1-2个选自卤、C1-C4烷基、C1-C8烷硫基或羟基的取代基取代)、卤、氰基、羟基、氨基、硝基、C1-C8烷基氨基、C1-C4二烷基氨基(其中所述烷基可以相同或不同)、C1-C8烷基磺酰基、C1-C8烷硫基、C1-C8烷基亚磺酰基、杂芳基、一个第二苯基(其中所述第二苯基任选地用1-2个独立地选自以下的取代基取代:C1-C4烷基、C1-C4烷氧基、氟化C1-C4烷基、氟化C1-C4烷氧基、卤、氰基、羟基、氨基、硝基、C1-C4烷基氨基、C1-C4二烷基氨基[其中所述烷基可以相同或不同]、C1-C4烷基磺酰基、C1-C4烷硫基或C1-C4烷基亚磺酰基);
R2选自氢、NR4COAr、NR4CO-杂芳基、NR4Ar、CH=CH-Ar、CF=CH-Ar、CH=CF-Ar、CCl=CH-Ar、CH=CCl-Ar、CH=CH-杂芳基、CF=CH-杂芳基、CH=CF-杂芳基、-CCl=CH-杂芳基、CH=CCl-杂芳基、OCH2-Ar、OCH2-杂芳基、SCH2-Ar或NR4CH2Ar;
R2优选为NR4COAr;最优选是,R2为NHCOAr;
R3选自氢、酰基、烷基、烷氧羰基、烷基磺酰基或芳基磺酰基;
R4选自氢或C1-C4烷基;R4优选为氢或甲基;最优选是,R4为氢;和
R5选自氢、C1-C4烷基、C1-C4烷氧基、氯、氟、羟基、二烷基氨基(其中所述烷基可以相同或不同)、三氟甲基或三氟甲氧基。
本发明的化合物是可用作促水排泄药和总的来讲可用来治疗心血管疾病的血管升压素受体拮抗剂。
在本发明的一个实施方案中是一种式(III)的化合物及其药学上可接受的盐:
其中
R1选自氢、C1-C4烷基、C1-C4烷氧基、卤、氨基C1-C4烷基或硝基;
R2为NHCOAr;
R3选自氢、酰基、烷基、烷氧羰基、烷基磺酰基或芳基磺酰基;和
R5选自氢、C1-C4烷基、C1-C4烷氧基、氯、氟、羟基、二烷基氨基、三氟甲基或三氟甲氧基;
所有其它可变基团如先前所限定。
在本发明的一个类型中是一种化合物其药学上可接受的盐,其中X选自CH2、作为烯烃部分的CH、S或O;
Z为CH;
Ar为苯基,其中苯基任选地用1-3个独立地选自以下的取代基取代:
C1-C8烷基、C1-C8烷氧基、氟化C1-C8烷基、氟化C1-C8烷氧基、C1-C8芳烷基(其中任选地所述烷基或芳基部分独立地被取代和所述烷基部分可以用至少1个氟取代和/或所述芳基部分可以独立地用1-2个选自卤、C1-C4烷基、C1-C8烷硫基或羟基的取代基取代)、C1-C8芳烷氧基(其中任选地所述烷氧基或芳基部分独立地被取代和所述烷氧基部分可以用至少1个氟取代和/或所述芳基部分可以独立地用1-2个选自卤、C1-C4烷基、C1-C8烷硫基或羟基的取代基取代)、卤、氰基、羟基、氨基、硝基、C1-C8烷基氨基、C1-C4二烷基氨基(其中所述烷基可以相同或不同)、C1-C8烷基磺酰基、C1-C8烷硫基、C1-C8烷基亚磺酰基、杂芳基、一个第二苯基(其中所述第二苯基任选地用1-2个独立地选自以下的取代基取代:C1-C4烷基、C1-C4烷氧基、氟化C1-C4烷基、氟化C1-C4烷氧基、卤、氰基、羟基、氨基、硝基、C1-C4烷基氨基、C1-C4二烷基氨基[其中所述烷基可以相同或不同]、C1-C4烷基磺酰基、C1-C4烷硫基或C1-C4烷基亚磺酰基;
而所有其它可变基团如先前所限定。
在本发明的一个实施方案中是一种式(IV)的化合物及其药学上可接受的盐:
其中
R6选自苯基(其中所述苯基任选地用1-2个独立地选自以下的取代基取代:C1-C4烷基、C1-C4烷氧基、氟化C1-C4烷基、氟化C1-C4烷氧基、卤、氰基、羟基、氨基、硝基、C1-C4烷基氨基、C1-C4二烷基氨基[其中所述烷基可以相同或不同]、C1-C4烷基磺酰基、C1-C4烷硫基或C1-C4烷基亚磺酰基);芳烷基(其中所述烷基或芳基部分任选地独立地被取代和所述烷基部分可以用至少1个氟[最好是1个]取代和/或所述芳基部分可以独立地用1-2个选自卤[最好是氟或氯]、C1-C4烷基[最好是C1-C2烷基]、C1-C8烷硫基[最好是C1-C4]或羟基的取代基取代)和芳烷氧基(其中所述烷氧基或芳基部分任选地独立地被取代和所述烷氧基部分可以用至少1个氟[最好是1个]取代和/或所述芳基部分可以独立地用1-2个选自卤[最好是氟或氯]、C1-C4烷基[最好是C1-C2烷基]、C1-C8烷硫基[最好是C1-C4]或羟基的取代基取代);和
R7独立地选自氢、氟、氯、羟基、C1-C8烷基(优选是C1-C4,更优选为C1-C2)、C1-C8烷氧基(优选是C1-C4,更优选为C1-C2)和它们的组合,其中R7可以为1-4个独立选定的基团;
所有其它可变基团如先前所限定。
以下化合物及其药学上可接受的盐是本发明的其它实施方案:
10-[4-[[(2-联苯基)羰基]氨基]苯甲酰基]-10,11-二氢-5H-哌啶并[2,1-c][1,4]苯并二氮杂;
10-[4-[[(2-联苯基)羰基]氨基]苯甲酰基]-10,11-二氢-5H-(四氢吡啶并)[2,1-c][1,4]苯并二氮杂;
(RS)-2-苯基-N-[4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-(4-羟基苯基)-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-苯基-4-羟基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-(3-羟基苯基)-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-苯基-5-羟基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(4-甲基-噻吩基)-4-氟代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2,6-二甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2,3-二甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(4-甲基-苯基)-N-[4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(R)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[3-甲氧基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[2-甲氧基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2,3,4,5-四氟代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-氯代-5-三氟甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-氟代-3-氯代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(二氟甲硫基)-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-5-氧代-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[2-羟基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[3-羟基-4-(1,3,4,12a-四氢-6H[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(4-甲基-苯基)-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-甲基-N-[4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-甲基-N-[3-甲基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(4-甲基-苯基)-N-[3-甲基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[3-甲基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(4-甲基-苯基)-N-[3-氟代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8-甲氧基-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8-氟代-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8,9-二甲氧基-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(9-氯代-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8,9-二氟代-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8-甲基-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8-氯代-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[3-氯代-4-(8-氟代-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(10-甲基-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(10-甲氧基-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-3,5-二甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-碘代-3-甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-3,5-二氯代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-甲基-3-碘代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-氟苯基-N-[4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-苯基-N-[3-二甲氨基-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺。
本发明的另一实施方案是一种式(V)的中间体化合物:
本发明的再一实施方案是一种式(VI)的中间体化合物:
作为本发明例证的是一种包含一种药学上可接受的载体和任一上述化合物的药用组合物。说明本发明的是一种通过将任一上述化合物与一种药学上可接受的载体混合制备的药用组合物。本发明的一个实例是制备一种药用组合物的方法,所述方法包括将任一上述化合物与一种药学上可接受的载体混合。
本发明的一个实例是一种治疗需要治疗的受治疗者的充血性心力衰竭的方法,所述方法包括将一种治疗有效量的任一上述化合物或药用组合物给予所述受治疗者。
进一步例证本发明的是治疗充血性心力衰竭的方法,其中所述化合物的治疗有效量为约0.1至约300mg/kg/天。
本发明的另一实例是一种治疗治疗需要的受治疗者的选自以下的病症的方法:高血压、充血性心力衰竭、心功能不全、冠状动脉血管痉挛、心脏缺血、肝硬化、肾血管痉挛、肾衰、脑水肿和缺血、中风、血栓形成和水潴留,所述方法包括将一种治疗有效量的任一上述化合物或药用组合物给予所述受治疗者。给予治疗这些病症中的任一种的化合物的治疗有效量最好为约0.1至约300mg/kg/天。
本发明还包括应用任一上述化合物来制备治疗需要治疗的受治疗者的选自以下的病症的药物:高血压、充血性心力衰竭、心功能不全、冠状动脉血管痉挛、心脏缺血、肝硬化、肾血管痉挛、肾衰、脑水肿和缺血、中风、血栓形成和水潴留。
发明详述
本发明提供可用作血管升压素拮抗剂的三环苯并二氮杂化合物。更具体地说,式(I)和式(II)的化合物抑制血管升压素与V-1和V-2受体的结合,并因此可用于治疗具有血管阻力增加的病症。具有血管阻力增加的病症的实例包括但不限于充血性心力衰竭、水肿、水潴留状态等。更具体地说,本发明涉及所述式(I)和式(II)的化合物及其药学上可接受的盐;
其中A、X、Y、Z、R1、R2、R3和m如先前所限定。
本发明的三环苯并二氮杂化合物是血管升压素受体拮抗剂,在一个优选的实施方案中,所述化合物是口服有效的。如下文所述的药理学研究的结果证明,所述化合物显示出阻断血管升压素与重组V-1和V-2结合的能力,并在动物模型中降低精氨酸血管升压素升高的血压。
本发明的化合物还可以以药学上可接受的盐的形式存在。对于医学方面的应用,本发明化合物的盐是指无毒的“药学上可接受的盐”。然而,其它的盐可用于制备按照本发明的化合物或制备其药学上可接受的盐。代表性的有机酸或无机酸包括但不限于盐酸、氢溴酸、氢碘酸、高氯酸、硫酸、硝酸、磷酸、乙酸、丙酸、乙醇酸、乳酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、苯甲酸、苯乙醇酸、甲磺酸、羟基乙磺酸、苯磺酸、草酸、双羟萘酸、2-萘磺酸、对甲苯磺酸、环己烷氨基磺酸、水杨酸、糖精酸或三氟乙酸。
当按照本发明的化合物具有至少一个手性中心时,它们因此可以作为对映体存在。当所述化合物具有二个或更多个手性中心时,它们还可以作为非对映体存在。不用说所有这类异构体及其混合物包括在本发明的范围内。此外,某些结晶形式的化合物可以作为多晶型物存在,并因此确定为包括在本发明之内。另外,某些所述化合物可以与水(即水合物)或普通有机溶剂形成溶剂化物,并且这样的溶剂化物也确定为包括在本发明的范围内。
本文所用的术语“受治疗者”是指一直是治疗、观察或实验目的的动物、优选是哺乳动物、最优选是人。
本文所用的术语“治疗有效量”是指由研究人员、兽医、医学博士或其它医师测出的活性化合物或药物在组织系统、动物或人中引发生物学反应或药物反应的量,所述量包括缓解待治疗疾病或障碍的症状。
除非另有说明,本文所用的无论是单独使用还是作为取代基的一部分使用的烷基和烷氧基包括具有1-8个碳原子或该范围内的任何数目的直链和支链、环状(有或无碳侧链)基团。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、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基和2-甲基戊基。烷氧基为由先前所述的直链和支链烷基或环烷基形成的氧醚。环烷基和环烷氧基含有3-8个环上碳,而最好是5-7个环上碳。同样,链烯基和炔基包括具有1-8个碳原子或该范围内任何数目的直链和支链或环状烯和炔。
本文所用的术语“Ar”和“芳基”是同义语并且是指未取代的或取代的芳基例如苯基和萘基。当Ar或芳基被取代时,它可以具有1-3个独立地选自以下的取代基:
C1-C8烷基、C1-C8烷氧基、氟化C1-C8烷基(例如,三氟甲基)、氟化C1-C8烷氧基(例如,三氟甲氧基)、卤、氰基、羟基、氨基、硝基、C1-C4烷基氨基(即,-NH-C1-C4烷基)、C1-C4二烷基氨基(即,-N-[C1-C4烷基]2,其中所述烷基可以相同或不同)或苯基,其中苯基任选地用1-3个独立地选自以下的取代基取代:C1-C8烷基、C1-C8烷氧基、氟化C1-C8烷基、氟化C1-C8烷氧基、C1-C8芳烷基(其中任选地所述烷基或芳基部分独立地被取代和所述烷基部分可以用至少1个氟取代和/或所述芳基部分可以独立地用1-2个选自卤、C1-C8烷硫基或羟基的取代基取代)、C1-C8芳烷氧基(其中任选地所述烷氧基或芳基部分独立地被取代和所述烷氧基部分可以用至少1个氟取代和/或所述芳基部分可以独立地用1-2个选自卤、C1-C8烷硫基或羟基的取代基取代)、卤、氰基、羟基、氨基、硝基、C1-C8烷基氨基、C1-C4二烷基氨基(其中所述烷基可以相同或不同)、C1-C8烷基磺酰基、C1-C8烷硫基、C1-C8烷基亚磺酰基、杂芳基、一个第二苯基(其中所述第二苯基任选地用1-2个独立地选自以下的取代基取代:C1-C4烷基、C1-C4烷氧基、氟化C1-C4烷基、氟化C1-C4烷氧基、卤、氰基、羟基、氨基、硝基、C1-C4烷基氨基、C1-C4二烷基氨基[其中所述烷基可以相同或不同]、C1-C4烷基磺酰基、C1-C4烷硫基或C1-C4烷基亚磺酰基;
本文所用的术语“HET”或“杂芳基”代表一个由多个碳原子和来自1-3个选自N、O或S的杂原子组成的稳定的未取代的或取代的五元或六元单环芳族环系或九元或十元苯并稠合的杂芳族环系。所述杂芳基可以在任一杂原子或碳原子上连接,导致一种稳定结构的产生。杂芳基的实例包括但不限于吡啶基、吡嗪基、哒嗪基、嘧啶基、噻吩基、呋喃基、咪唑基、异噁唑基、噁唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异噁唑基、苯并噁唑基、苯并吡唑基、吲哚基、苯并噻唑基、苯并噻二唑基、苯并三唑基或喹啉基。优选的杂芳基包括吡啶基、噻吩基、呋喃基和喹啉基。当所述杂芳基被取代时,则所述杂芳基可以具有1-3个取代基,所述取代基独立地选自C1-C8烷基、卤、芳基、杂芳基、烷氧基、烷基氨基、二烷基氨基、芳氨基、硝基、羟基。
术语“芳烷基”是指用一个芳基取代的烷基(例如,苄基、苯乙基)。同样,术语“芳烷氧基”是指用一个芳基取代的烷氧基(例如,苄氧基)。术语氨烷基是指用一个氨基取代的烷基(即,-烷基-NH2)。术语“烷基氨基”是指用一个烷基取代的氨基(即,-NH-烷基)。术语“二烷基氨基”是指用烷基双取代的氨基(其中所述烷基可以相同或不同)(即,-N-[烷基]2)。术语“烷硫基”是指烷基硫醚基(即,-S-烷基)。
本文所用的术语“酰基”是指通过去除羟基而衍生自有机酸、具有2-6个碳原子(支链或直链)的有机基团。
术语“卤”应包括碘、溴、氯和氟。
每当术语“烷基”或“芳基”或它们词头词尾的任一个以取代基(例如芳烷基、二烷基氨基)名义出现时,它都应被解释为包括“烷基”和“芳基”上述的那些限制。碳原子的命名数目(例如C1-C8)应独立地指一个烷基或环烷基部分中的碳原子数目或独立地指一个其中烷基作为其词头词尾出现的更大取代基的烷基部分。
一个分子中特定位置上的任何取代基或可变基团的定义将与它在该分中其它位置的定义无关。不用说,在本发明化合物上的取代基和取代模式可以由本领域一般技术人员选定,以提供化学上稳定的并可以通过本领域已知技术以及本文陈述的那些方法容易合成的化合物。
在本发明的一个实施方案中是一种式(IV)的化合物及其药学上可接受的盐:
其中
R6选自苯基(其中所述苯基任选地用1-2个独立地选自以下的取代基取代:C1-C4烷基、C1-C4烷氧基、氟化C1-C4烷基、氟化C1-C4烷氧基、卤、氰基、羟基、氨基、硝基、C1-C4烷基氨基、C1-C4二烷基氨基[其中所述烷基可以相同或不同]、C1-C4烷基磺酰基、C1-C4烷硫基或C1-C4烷基亚磺酰基);芳烷基(其中所述烷基或芳基部分任选地独立地被取代和所述烷基部分可以用至少1个氟[最好是1个]取代和/或所述芳基部分可以独立地用1-2个选自卤[最好是氟或氯]、C1-C4烷基[最好是C1-C2烷基]、C1-C8烷硫基[最好是C1-C4]或羟基的取代基取代)和芳烷氧基(其中所述烷氧基或芳基部分任选地独立地被取代和所述烷氧基部分可以用至少1个氟[最好是1个]取代和/或所述芳基部分可以独立地用1-2个选自卤[最好是氟或氯]、C1-C4烷基[最好是C1-C2烷基]、C1-C8烷硫基[最好是C1-C4]或羟基的取代基取代);和
R7独立地选自氢、氟、氯、羟基、C1-C8烷基(优选是C1-C4,更优选为C1-C2)、C1-C8烷氧基(优选是C1-C4,更优选为C1-C2)和它们的组合,其中R7可以为1-4个独立选定的基团。
本文所用的术语“组合物”是指包括一种包含规定剂量的规定成分的制品以及直接或间接地从所述规定剂量的所述规定成分的组合产生的任何制品。
按照本文描述的方法,可以测定所述化合物治疗血管阻力增加的疾病的效用。本发明因此提供一种治疗需要治疗的受治疗者血管阻力性疾病的方法,所述方法包括给予治疗血管阻力性疾病有效量的本文限定的化合物中的任一种。通过常规给药途径中的任一种,可以将一种化合物给予需要治疗的受治疗者,所述常规给药途径包括但不限于经口、鼻、舌下、眼、经皮、直肠、阴道和胃肠外(即皮下、肌内、皮内、静脉内等)途径。
本发明还提供包含一种或更多种本发明化合物与一种药学上可接的载体的药用组合物。
为了制备本发明的药用组合物,将作为有效成分的一种或更多种式(I)或(II)的化合物或其盐,按照常规药物混合技术直接与一种药用载体混合,根据所需给药制剂的形式(例如口服或胃肠外例如肌内),所述载体可以为各种各样的形式。合适的药学上可接的载体是本领域众所周知的。这些药学上可接受的载体中的某些载体的描述可以在
The Handbook of Pharmaceutical Excipients(由the American PharmaceuticalAssociation and the Pharmaceutical Society of Great Britain出版)中找到。
配制药用组合物的许多方法已经在许多出版物中描述,例如Pharmaceutical Dosage Forms:Tablets.第二版,经修正和扩充的 (Revised and Expanded),第1-3卷,由Lieberman等编辑;
Pharmaceutical Dosage Forms:Parenteral Medications,第1-2卷,由Avis等编辑;和Pharmaceutical Dosage Forms:Disperse Systems,第1-2卷,由Lieberman等编辑;由Marcel Dekker,Inc.出版。
在制备用于口服、局部和胃肠外给药的液体剂型的本发明药用组合物中,可以使用任一种常规药用介质或赋形剂。因此,对于液体剂型例如悬浮剂(即胶体、乳剂和分散体)和溶液,合适的载体和添加剂包括但不限于药学上可接受的润湿剂、分散剂、絮凝剂、增稠剂、pH控制剂(即缓冲剂)、渗透剂、着色剂、调味剂、芳香剂、防腐剂(即为了防止微生物生长等),并可以使用一种液体溶媒。对于每种液体剂型并不需要所有上述所列的组分。
在固体口服制剂例如粉剂、粒剂、胶囊、caplets、gelcaps、丸剂和片剂(每种包括速释制剂、定时释放制剂和缓释制剂)中,合适的载体和添加剂包括但不限于稀释剂、制粒剂、润滑剂、粘合剂、助流剂、崩解剂等。片剂和胶囊由于易于给药,代表最好的口服剂量单位剂型,在所述情况下,显然使用固体药用载体。必要时,通过标准技术,可以为片剂包上糖衣、明胶衣、薄膜包衣或肠溶包衣。
本文所述药用组合物每剂量单位例如片剂、胶囊、粉剂、注射液、茶匙等将含有传递如上所述有效剂量所必需的有效成分的量。本文所述药用组合物每单位剂量单位例如片剂、胶囊、粉剂、注射液、栓剂、茶匙等将含有约为0.03mg/kg-100mg/kg(最好约为0.1-30mg/kg)的剂量,并可以给予约为0.1-300mg/kg/天(优选约为1-50mg/kg/天,更优选约为0.03-10mg/kg/天)的剂量。最好是,根据采用如本文限定的所述化合物中任一种的、在本发明中描述的治疗血管阻力性疾病的方法,所述剂型将含有包含约0.01mg和100mg之间、更优选约为5-50mg的所述化合物的一种药学上可接受的载体,并可以构成适合于所选定的给药模式的任一剂型。然而,所述剂量可以根据所述患者的需要、待治疗病症的严重程度和将使用的化合物而变化。可以应用每天给药或定期给药(post-periodic dosing)的用法。
为了通过口服、鼻内、舌下、眼内、经皮、胃肠外、直肠、阴道、吸入法或吹入法给药,这些组合物最好为来自例如片剂、丸剂、胶囊、粉剂、粒剂、锭剂、无菌胃肠外溶液或悬浮液、计量气雾剂或液体喷雾剂、滴剂、安瓿、自动注射装置或栓剂的单位剂型。或者,所述组合物可以以适合于每周一次或每月一次给药的形式存在;可以采用例如所述活性化合物的不溶性盐诸如癸酸盐,以提供用于肌内注射的缓释型制剂。
为了制备固体药用组合物例如片剂,将所述主要有效成分与一种药用载体例如常规制片剂的成分诸如稀释剂、粘合剂、胶粘剂、崩解剂、润滑剂、抗粘附剂和助流剂混合。合适的稀释剂包括但不限于淀粉(即可以被水解的玉米淀粉、小麦淀粉或马铃薯淀粉)、乳糖(粒状的、喷雾干燥的或无水的)、蔗糖、基于蔗糖的稀释剂(糖粉,蔗糖加上约7%-10%(重量)转化糖,蔗糖加上约3%(重量)改性糊精;蔗糖加上转化糖,约4%(重量)转化糖,约0.1-0.2%(重量)玉米淀粉和硬脂酸镁)、葡萄糖、肌醇、甘露醇、山梨醇、微晶纤维素(即可得自FMC Corp.的AVICELTM微晶纤维素)、磷酸氢钙(dicalcium phosphate)、硫酸钙二水合物、乳酸钙三水合物等。合适的粘合剂和胶粘剂包括但不限于合金欢胶、瓜耳胶、西黄蓍胶、蔗糖、明胶、葡萄糖、淀粉和纤维素制品(即甲基纤维素、羧甲基纤维素钠、乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素等)、水溶性或水可分散性粘合剂(即藻酸及其盐、硅酸铝镁、羟乙基纤维素[即可得自Hoechst Celanese的TYLOSETM]、聚乙二醇、多糖酸(polysaccharide acids)、膨润土、聚乙烯吡咯烷酮、聚甲基丙烯酸酯和预胶凝化淀粉)等。合适的崩解剂包括但不限于淀粉(玉米、马铃薯等)、淀粉羟基乙酸钠、预胶凝化淀粉、粘土(硅酸铝镁)、纤维素(例如交联羧甲基纤维素钠和微晶纤维素)、藻酸盐、预胶凝化淀粉(即玉米淀粉等)、树胶(即琼脂、瓜耳胶、刺槐豆胶、梧桐胶、果胶和西黄蓍胶)、交联聚乙烯吡咯烷酮等。合适的润滑剂和抗粘附剂包括但不限于硬脂酸盐(硬脂酸镁、钙和钠)、硬脂酸、滑石粉蜡、stearowet、硼酸、氯化钠、DL-亮氨酸、carbowax 4000、carbowax 6000、油酸钠、苯甲酸钠、乙酸钠、十二烷基硫酸钠、十二烷基硫酸镁等。合适的助流剂包括但不限于滑石粉、玉米淀粉、二氧化硅(即可得自Cabot的CAB-O-SILTM二氧化硅、可得自W.R.Grace/Davison的SYLOIDTM二氧化硅和可得自Degussa的AEROSILTM二氧化硅)等。可以将甜味剂和调味剂加到可咀嚼的固体剂型中以改善所述口服剂型的可口性。另外,可以将着色剂和包衣加入或应用于所述固体剂型,以便容易鉴别所述药物或为了美感目的。将这些载体与所述药用活性剂一起配制,提供准确合适剂量的具有一定治疗释放型(therapeuticrelease profile)的药用活性剂。
一般而言,将这些载体与所述药用活性剂混合,制成一种含有本发明所述药用活性剂或其一种药学上可接受的盐的均相混合物的固体预制剂(preformulation)组合物。总的来讲,通过三种常用方法的其中一种制备所述预制剂:(a)湿制粒法,(b)干制粒法和(c)干式混合。当将这些预制剂组合物称为均相时,是指所述有效成分在整个所述组合物中均匀分散,使得可以容易地将所述组合物再分为同等有效的剂型例如片剂、丸剂和胶囊剂。然后将这种固体预制剂组合物再分为上述类型的单位剂型中,所述单位剂型含约0.1mg-约500mg的本发明的有效成分。含有所述新型组合物的片剂或丸剂也可以被配制成多层片剂或丸剂,提供一种缓释制品或提供二重释放(dual relealed)制品。例如,二重释放片剂或丸剂可以包含一种内给药成分或一种外给药成分,后者为前者的包膜形式。这两种成分可以由一层肠溶衣分隔开,所述肠溶衣层在胃中起抵抗分解的作用,使所述内成分完整通过十二指肠或被延迟释放。这样的肠溶衣层或包衣可以使用各种各样的材料,这样的材料包括许多聚合物材料例如虫胶、醋酸纤维素(即醋酸邻苯二甲酸纤维素、cellulose acetate trimetllitate)、聚乙酸乙烯酯邻苯二甲酸酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸琥珀酸酯、甲基丙烯酸酯和乙基丙烯酸酯共聚物、甲基丙烯酸酯和甲基丙烯酸甲酯共聚物等。采用在溶液中微溶和不溶性物质(它们对于湿制粒法而言起粘合剂的作用)或低熔点固体的熔融形式(在湿制粒法中它们可以掺入有效成分),通过薄膜包衣或湿制粒法,也可以制备缓释片剂。这些材料包括天然和合成的聚合蜡、氢化油、脂肪酸和醇类(即蜂蜡、巴西棕榈蜡、鲸蜡醇、十六烷基硬脂酰醇等)、脂肪酸酯金属皂和可以用于制粒、包衣、俘获或者限制有效成分溶解度以达到延长或缓慢释放制品的其它可接受的材料。
用于口服给药或通过注射给药的液体形式(其中可以掺入本发明的新型组合物)包括但不限于水溶液、合适调味的糖浆、水性或油性悬浮液和用食用油例如棉籽油、芝麻油、椰子油或花生油调味的乳剂以及酏剂和相似的药用溶媒。适合于水性悬浮液的悬浮剂包括合成的和天然的树胶例如合金欢胶、琼脂、藻酸酯或盐(即藻酸丙二酯、藻酸钠等)、瓜耳胶、梧桐胶、刺槐豆胶、果胶、西黄蓍胶和黄原胶、纤维素制品例如羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素和羟丙基甲基纤维素及其组合、合成的聚合物例如聚乙烯吡咯烷酮、carbomer(即羧基聚亚甲基(carboxypolymethylene))、和聚乙二醇;粘土例如膨润土、水辉石、硅镁土或海泡石;和其它药学上可接受的悬浮剂例如卵磷脂、明胶等。合适的表面活性剂包括但不限于多库酯钠(sodium docusate)、十二烷基硫酸钠、聚山梨醇、辛苯聚醇-9(octoxynol-9)、壬苯聚醇-10(nonoxynol-10)、聚山梨醇20、聚山梨醇40、聚山梨醇60、聚山梨醇80、polyoxamer 188、polyoxamer 235及其组合。合适的抗絮凝剂或分散剂包括药用级卵磷脂。合适的絮凝剂包括但不限于简单的中性电解质(即氯化钠、氯化钾等)、高度带电不溶性聚合物和聚电解质类、水溶性二价或三价离子(即钙盐、明矾或硫酸盐、柠檬酸盐和磷酸盐)(它们可以在制剂中共同用作pH缓冲剂和絮凝剂)。合适的防腐剂包括但不限于对羟基苯甲酸酯类(即甲酯、乙酯、丙酯和丁酯)、山梨酸、乙基汞硫代水杨酸钠、季铵盐、苄醇、苯甲酸、氯己定、葡萄糖酸盐、苯基乙醇等。有许多可以在液体药物剂型中使用的液体溶媒,然而,用于特定剂型中的液体溶媒必须与悬浮剂相容。例如,非极性液体溶媒例如脂肪酸酯和油液体溶媒最好与悬浮剂例如低HLB(亲水-亲油平衡)表面活性剂、stearalkonium hectorite、水不溶性树脂、水不溶性成膜聚合物等一起使用。相反,极性液体例如水、醇类、多元醇和甘醇最好是与悬浮剂例如较高HLB表面活性剂、粘土硅酸盐、树胶、水溶性纤维素制品、水溶性聚合物等一起使用。对于胃肠外给药,最好是无菌悬浮液和溶液。可用于胃肠外给药的液体剂型包括无菌溶液、乳剂和悬浮液。当需要静脉内给药时,使用一般含有合适防腐剂的等渗制剂。
此外,可以以鼻内形式通过局部应用合适的鼻内载体或通过透皮贴剂,给予本发明的化合物,其组合物是本领域一般技术人员熟知的。为了以经皮传递系统形式给药,给予的治疗剂量当然在整个给药方案中是连续的而不是间断的。
还可以以脂质体传递系统形式给予本发明的化合物,例如小单层囊泡、大单层囊泡、多层囊泡等。脂质体可以由各种磷脂例如胆固醇、硬脂酰胺、磷脂酰胆碱等制备。
还可以利用单克隆抗体作为偶合所述化合物分子的单一载体传递本发明的化合物。本发明的化合物还可以与作为可定向药物载体的可溶性聚合物偶合。这类聚合物可以包括但不限于聚乙烯吡咯烷酮、吡喃共聚物、聚羟基丙基甲基丙烯酰胺酚(ployhydroxypropylmethacrylamidephenol)、聚羟基-乙基天冬酰胺酚(ployhydroxy-ethylaspartamidephenol)或用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一类可用于达到控制释放药物的生物可降解聚合物偶合,例如与以下的均聚物和共聚物(它们是指含有两个或更多个化学上可区分的重复单元的聚合物)偶合:丙交酯(它包括乳酸d-、l-和内消旋丙交酯)、乙交酯(包括乙醇酸)、ε-己内酯、对二噁酮(p-dioxanone)(1,4-二噁烷-2-酮)、亚丙基碳酸酯(1,3-二噁烷-2-酮)、亚丙基碳酸酯的烷基衍生物、δ-戊内酯、β-丁内酯、γ-丁内酯、ε-癸内酯、羟丁酸酯、羟戊酸酯、1,4-dioxepan-2-one(包括它的二聚体1,5,8,12-四氧杂环十四烷-7,14-二酮)、1,5-dioxepan-2-one、6,6-二甲基-1,4-二噁烷-2-酮、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰丙烯酸酯和水凝胶的交联或两亲嵌段共聚物及它们的混合的。
当按照本发明的化合物的制备方法产生立体异构体的混合物时,这些异构体可以通过常规技术例如制备性色谱法分离。所述化合物可以制备成外消旋形式或各个对映体可以或者通过对映有择合成或者通过折分进行制备。所述化合物可以例如通过标准技术(例如通过盐的形成形成非对映体对)解析为其各种组分的对映体。所述化合物还可以通过非对映体酯或酰胺的形成,然后通过色谱分离和手性助剂的去除进行解析。或者,可以采用手性HPLC柱,使所述化合物解析。
在任何制备本发明化合物的方法中,可能必需和/或最好是保护任一目的分子上的敏感基或反应基。这可以借助于常规保护基来达到,例如在
Protective Groups in Organic Chemistry,J.F.W.McOmie编辑,Plenum Press,1973;和T.W.Greene和P.G.M.Wuts,
Protective Groups in Organic Synthesis,John Wiley & Sons,1991中描述的那些保护基。采用本领域已知的方法,在随后方便的步骤中所述保护基可以被去除。
每当受治疗者需要治疗血管阻力性疾病时,总是可以以任何前述组合物和按照本领域已建立的给药方案给予本发明的化合物。
本发明药用组合物的日剂量可以在每个成人约0.01-30,000mg/天的大范围内变化,然而该剂量范围最好为每个成人约0.01-1,000mg/天。对于口服给药,最好以含有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和500mg的有效成分的片剂剂型,并根据症状调节剂量,将所述组合物提供给待治疗的受治疗者。通常所提供的药物的有效剂量的剂量水平为约0.01mg/kg体重/天-约300mg/kg体重/天。所述范围最好为约0.03-约100mg/kg体重/天,最优选为约0.03-约10mg/kg体重/天。可以以1-4次/天的方案给予所述化合物。
需给予的最适剂量可以容易地由本领域的技术人员确定,并将随所用的特定化合物、给药方式、制剂强度和病症的发展而变化。另外,与特定待治疗的受治疗者相关的因素,包括受治者的年龄、体重、饮食和给药时间,导致需要将所述剂量调节到一种适当的治疗水平。
本说明书、尤其是所述方案和实施例中所用的缩写如下:
Bn或Bzl = 苄基
Boc = 叔-丁氧羰基
BOP-Cl = 双(2-氧代-3-噁唑烷基)-次膦酰氯
CBZ = 苄氧羰基
CP = 化合物
DCM = 二氯甲烷
DIC = 二异丙基碳二亚胺
DIEA = 二异丙基乙胺
DMAP = 4-二甲氨基吡啶
DMF = N,N-二甲基甲酰胺
DMSO = 二甲亚砜
EDC = 乙基二甲氨基丙基碳二亚胺
Et2O = 二乙酯
EtOAc = 乙酸乙酯
EtOH = 乙醇
HBTU = 六氟磷酸2-(1H-苯并三唑-1-基)-1,1,3,3-
四甲基尿鎓
HOBT = 羟基苯并三唑
HPLC = 高效液相层析
i-Pr = 异丙基
LAH = 氢化铝锂
Me = 甲基
MeOH = 甲醇
MPK = 每公斤毫克
NMM = N-甲基吗啉
NT = 没有测试
Ph = 苯基
PPT = 沉淀
RT或rt = 室温
TEA = 三乙胺
THF = 四氢呋喃
TFA = 三氟乙酸
Z = 苄氧羰基
本发明化合物的命名方法采用普通接受的命名法则。当注明时,字母“R”或“S”代表绝对构型(Cahn-Ingold-Prelog法则)。例如,结构名称总的来讲是按照以下系统衍生的:
因此,代表化合物4的名称为:
(S)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺。
本发明特别优选的化合物包括示于表1中的那些化合物。
表1
实施例# X Y R5 构型
1 CH2 CH2 H RS
2 CH CH H RS
3 S CH2 H RS
4 O CH2 3-Cl R
其中X和Y为亚甲基的本发明化合物可以如方案AA中所示的方法制备。使靛红酸酐和2-哌啶酸在DMF中于高温下进行缩合,得到中间体酰胺AA3。酰胺AA3用氢化铝锂在回流THF中还原,然后与酰基氯AA5偶合,得到4-硝基苯甲酰胺AA6。硝基可以用锌还原成相应的胺,然后与酰基氯AA8偶合,得到终产物AA9。对于其中X为O或S而Y为亚甲基的化合物,可以如所公开的方法(U.Larsson和R.Carison,Acta Chimica Scandinavica 1994,48,517-525)制备对应于AA1的环氨基酸中间体。对于其中X为CH而Y为CH(烯烃)的化合物,可以如所公开的方法(F.Rutjes,Tetrahedron Lett.1997,38,677-680)制备对应于AA1的环氨基酸中间体。
表II
实施例# X R1 R5 R4 R7 构型
5 O H 3-Cl 4′-OH-Ph H S
6 O H 3-Cl Ph 4-OH S
7 O H 3-Cl 3′-OH-Ph H S
8 O H 3-Cl Ph 5-OH S
9 O H 3-Cl 4-Me-2-thi 4-F RS
10 O H 3-Cl Me 6-Me RS
11 O H 3-Cl Me 3-Me RS
12 O H H 4′-Me-Ph H RS
13 O H 3-Cl Ph H R
14 O H 3-OMe Ph H RS
15 O H 2-OMe Ph H RS
16 O H 3-Cl F 3,4,5-F3 RS
17 O H 3-Cl Cl 5-F RS
18 O H 3-Cl F 3-Cl RS
19 O H 3-Cl SCHF2 H RS
20 O H H Ph H RS
21 O H(5-氧代) 3-Cl Ph H RS
22 O H 2-OH Ph H RS
23 O H 3-OH Ph H RS
24 O H 3-Cl Me H RS
25 O H 3-Cl 4′-Me-Ph H RS
26 O H H Me H RS
27 O H 3-Me Me H RS
28 O H 3-Me 4′-Me-Ph H RS
29 O H 3-Me Ph H RS
30 O H 3-F 4′-Me-Ph H RS
表III
实施例# X R1 R5 R6 R7 构型
3 S H H Ph H RS
31 S 8-OMe H Ph H RS
32 S 8-F H Ph H RS
33 S 8,9-(OMe)2 H Ph H RS
34 S 9-Cl H Ph H RS
35 S 8,9-(F)2 H Ph H RS
36 S 8-Me H Ph H RS
37 S 8-Cl H Ph H RS
38 S 8-F 3-Cl Ph H RS
39 S 10-Me H Ph H RS
40 S 10-OMe H Ph H RS
41 S H 3-Cl H 3,5-Me RS
42 S H 3-Cl I 3-Me RS
43 S H 3-Cl H 3,5-Cl2 RS
44 S H 3-Cl Me 3-1 RS
45 S H H 2′-FPh H RS
46 S H 3-NMe2 Ph H S
47 S H 3-Cl Ph H S
可以采用邻氨基苯甲酸衍生物,即2-氨基-3-噻吩-羧酸或2-氨基-3-吡啶-羧酸如同式(I)化合物一样制备式(II)的化合物及其区域异构体(regioisomer)。通过标准方法(与碳酰二咪唑缩合),可以使邻氨基苯甲酸衍生物转化成相应的靛红酸酐衍生物,然后如方案AA中所示使用。
方案AA
其中X为O而Y为亚甲基的本发明化合物可以如方案AB中所示的方法制备。氮丙啶AB1通过氯甲酸苄酯作用而得到保护,得到AB2,然后与2-氯乙醇反应,得到丝氨酸衍生物AB3,化合物AB3通过氢解法去保护,然后在三乙胺存在下环化,得到吗啉AB5。AB5用2-硝基苯甲酰氯酰化,然后通过铁介导的还原性环化作用,得到苯并二氮杂二酮AB7。该双-内酰胺用氢化铝锂还原,解析为它的二甲苯酰酒石酸盐,然后用2-氯-4-硝基苯甲酰氯酰化,得到AB9。用锌粉还原AB9,然后通过用2-联苯基碳酰氯酰化,得到噁嗪4。
方案AB
其中X为S而Y为亚甲基的本发明化合物可以如方案AC中所示的方法制备。将氨基乙硫醇和3-溴丙酮酸缩合并环化,产生AC1。该亚胺通过氰基硼氢化钠还原,得到噻嗪AC2。用2-硝基苯甲酰氯酰化AC2,然后通过铁介导的还原作用,得到双-内酰胺AC4。中间体AC4可以继续如方案AB中的方法进行,得到最终的噻嗪靶化合物。
方案AC
所用试剂购自Aldrich Chemical Company。在Bruker AC-360分光计上于360MHz下记录高场1H NMR谱,并以赫兹(Herz)给出偶合常数。熔点在Mel-Temp II熔点测定器上测定并且未校正。微量分析在Robertson Microlit Laboratories,Inc.,Madison,New Jersey进行,并以每种元素的重量/总分子量的百分比(重量)表示。在所获得的产物为盐的那些情况下,通过本领域技术人员已知的方法,例如通过阳离子交换纯化获得游离碱。氢原子的核磁共振(NMR)波谱在指示溶剂中用四甲基硅烷(TMS)作为内标在Bruker AM-360(360MHz)分光计上进行测定。数值以由TMS向低场移动的百万分之几表示。采用电喷雾电离技术,所述质谱(MS)在Micromass/Hewlett Packard Series 1050质谱仪(MH+)上进行测定。除非另有说明,所述实施例中所用的材料均得自容易得到的市售供应商或通过本领域任一技术人员已知的标准化学合成方法进行合成。除非另有说明,在实施例之间变化的取代基是氢。
实施例1
10-[4-[[(2-联苯基)羰基]氨基]苯甲酰基]
-10,11-二氢-5H-哌啶并[2,1-c][1,4]
苯并二氮杂·HCl(1)
将靛红酸酐(1.1g,0.0068mol)和2-哌啶酸(1.0g,0.0078mol)在二甲基甲酰胺(5mL)中的混合物于150℃加热18小时,冷却至室温后,倾至冰水(10mL)中。过滤白色沉淀,用冰冷水洗涤,然后于真空下干燥,得到AA3(1.0g)。AA3的THF(10mL)溶液在室温下用氢化铝锂(134mL,1.0M的THF溶液,0.013mol)处理,于回流下加热4小时,然后冷却至室温。将该混合物用水(5mL)和氢氧化钠(5mL)缓慢猝灭,然后所述产物用EtOAc(50mL)萃取。有相层用饱和碳酸氢钠(20mL)洗涤,干燥(硫酸钠)并蒸发,得到固体AA4(0.53g)。AA4、DCM(15mL)和TEA(0.34g,0.0034mol)的溶液于室温下用AA5(0.54g,0.0029mol)处理并搅拌18小时。反应物用DCM(50mL)稀释,用饱和碳酸氢钠(15mL)洗涤,干燥(硫酸钠)并蒸发,得到玻璃状物质AA6(0.83g)。AA6、MeOH(29mL)和氯化铵(0.75g)的混合物用锌粉(5.2g,0.08mol)处理,然后于回流下加热2小时。让反应物冷却至室温,通过celite过滤,并将滤液浓缩。残余物用10%乙酸(1mL)处理,用饱和碳酸氢钠中和,产物用EtOAc(50mL)萃取。有机层用水(15mL)洗涤,干燥(硫酸钠)并蒸发,得到白色固体AA7(0.59g)。AA7、DCM(9mL)和TEA(0.24g,0.0024mol)的溶液于室温下用AA8(0.44g,0.002mol)处理并搅拌18小时。反应物用DCM(50mL)稀释,用饱和碳酸氢钠(20mL)洗涤,干燥(硫酸钠)并蒸发至黄色固体。将所述固体通过反相HPLC(0.01%TFA/MeCN,C18柱)纯化,得到白色固体。所述固体用HCl(1.0
N,1.0mL)处理并蒸发,得到褐色粉末AA9:mp191-193℃。1H NMR(DMSO-d6)1.2(m,2H),1.6(m,5H),2.3(t,J=4,1H),2.4(m,1H),2.7(t,J=4,1H),2.9(d,J=4,1H),3.4(d,J=6,1H),3.8(d,J=6,1H),4.8(d,J=6,1H),6.4(d,J=3,1H),6.7-7.0(m,7H),7.1-7.4(m,8H),7.8(d,J=3,1H);MS m/e 502.3(MH+)。
实施例2
10-[4-[[(2-联苯基)羰基]氨基]苯甲酰基]
-10,11-二氢-5H-(四氢吡啶并)[2,1-c][1,4]
苯并二氮杂(2)
1H NMR(CDCl3)1.1(m,1H),2.9(m,1H),2.3(m,1H),2.7(m,1H),2.9(m,2H),3.1(m,1H),3.9(m,1H),4.7(m,1H),5.6(br s,2H),6.7(m,1H),7.1(m,4H),7.2-7.6(m,12H),10.31(s,1H);MS m/e 500.3(MH+)。
实施例3
(RS)-2-苯基-N-[4-(1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺(3)
1H NMR(DMSO-d6)2.5(m,5H),2.9(m,1H),3.2(m,2H),3.8(d,J=6,1H),4.1(d,J=6,1H),4.7(m,1H),6.7(m,1H),7.0-7.2(m,4H),7.3-7.6(m,11H);MS m/e 520.5(MH+)。
实施例4
(S)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(4)
AB1(49g,0.48mol)、DCM(1.0L)和Et3N(48.6g,1eq)的溶液于0℃下用氯甲酸苄酯(96g,1eq)的DCM(100mL)溶液滴加1小时进行处理。去除冰浴,将混合物搅拌20小时。混合物用水(200mL)、20%柠檬酸(150mL)和盐水(100mL)洗涤。将有机层干燥(Na2SO4),蒸发,然后在高真空下干燥,得到琥珀色油状物AB2(87.4g,77%)。AB2(87.4g)、DCM(1.5L)和2-氯乙醇(225mL,10eq)的溶液于室温下用BF3·Et2O(14mL)处理,搅拌48小时,然后用水(1L)稀释。分离各层,将有机层干燥(Na2SO4),蒸发,然后在高真空下干燥,得到琥珀色油状物AB3(114g,99%)。AB3(114g,0.36mol)、MeOH(2L)、HCl(1N,360mL)和10%Pd-C(10g)的混合物于50psig/rt下在Parr仪器中氢化7小时。将混合物通过celite过滤,将滤液蒸发并干燥,得到白色晶体AB4(79.2g,99%)。AB4(79.2g)、MeOH(8L)和Et3N(73g,2eq)的混合物在回流下加热7小时,冷却至室温,并蒸发至干。将该残余物溶于DCM(1.2L)中,有机层用盐水(2×300mL)洗涤,干燥(Na2SO4),蒸发并在高真空下干燥,得到深琥珀色油状物AB5(29g,56%)。AB5(29g,0.20mol)、DCM(3L)和Et3N(26.3g,1.3eq)的溶液于0℃用2-硝基苯甲酰氯(454g,1.1eq)的DCM(500ml)溶液滴加1小时进行处理。去除冰浴,将混合物搅拌18小时。用水(250mL)稀释该混合物,分离各层。将有机层干燥(Na2SO4),蒸发并经硅胶快速色谱纯化(EtOAc),得到固体AB6(53g,90%)。AB6(50g,0.17mol)、AcOH(1L)和铁(60g,5eq)的混合物在回流下加热20小时,冷却至室温,过滤并用AcOH洗涤。将滤液蒸发,冷却的棕色残余物用冰冷的水(150mL)处理。将该黑色固体过滤并干燥,得到褐色固体AB7(24.6g,62%)。AB7(20g,0.087mol)和THF(600mL)的溶液于0℃下用LAH(1N的THF溶液,Fluka,270mL,3.1eq)滴加1小时进行处理,然后去除冰浴。将混合物搅拌18小时,冷却至0℃,顺序地用水(24mL)、NaOH(1N,36mL)和THF(500mL)处理。将该混合物过滤,将滤液干燥(Na2SO4)并蒸发,得到琥珀色油状物。将所述油状物经快速色谱(1∶1己烷/EtOAc)纯化,得到浅黄色晶体外消旋三环二胺产物(10.9g,61%)。边搅拌边向二胺产物(6.2g,0.030mol)的MeOH(40mL)溶液中加入D-二对甲苯酰-酒石酸(5.8g,1eq)。一旦溶解发生,就加入Et2O(80mL)以得到一种混浊溶液,然后滴加MeOH直到恢复澄清为止。将溶液加盖并让其静置3天以得到晶体。将晶体过滤,用冷Et2O洗涤并干燥,得到3.4g解析的盐(58%)。让该物质在EtOAc和NaOH(1N)之间分配,充分混合,然后分离各层。将有机层用水和盐水洗涤,干燥(Na2SO4)并蒸发,得到白色固体AB8(1.52g,52%;采用Pirkle位移试剂NMR没有检测到相反的对映体)。化合物AB8(2.0g,0.0099mol)、DCM(20mL)和Et3N(1.8mL,1.3eq)的溶液于0℃下用2-氯代-4-硝基苯甲酰氯(2.4g,1.1eq)的DCM(10mL)溶液处理,温至室温,并搅拌1.5小时。反应物用DCM稀释,用水洗涤,干燥(Na2SO4),蒸发,并经硅胶快速色谱(0.1%NH4OH/1%MeOH/DCM)纯化,得到白色泡沫状物AB9(3.8g,99%)。该泡沫状物和MeOH(100mL)的溶液用NH4Cl(2.6g,5eq)和锌粉(22.7g,35eq)处理,在回流下加热2小时,然后冷却至室温。将混合物通过celite过滤,将滤液蒸发成固体。让固体在EtOAc和水之间分配,然后将水相用EtOAc萃取一次。合并的有机相用盐水洗涤,干燥(Na2SO4),并蒸发,得到白色固体AB10(3.6g,99%)。将2-联苯基羧酸(2.2g,0.011mol)、DCM(15mL)、DMF(0.1mL)和草酰氯(1.0mL,1eq)的溶液搅拌2.5小时,然后加入到AB10(3.6)、DCM(20mL)和Et3N(1.8mL)的溶液中。将该混合物搅拌3小时,用DCM(100mL)稀释,然后用10%NaHCO3、水和盐水洗涤。将有机层干燥(Na2SO4),蒸发,并经硅胶快速色谱(0.1%NH4OH/1% MeOH/DCM)纯化,得到白色固体(约2g)。将固体溶于MeOH(25mL)中,用HCl/Et2O(1N,15mL)处理,然后蒸发溶剂,得到白色固体4(1.0HCl·1.3H2O·0.25Et2O)(2.5g):mp>210℃(分解);MSm/e 538和540(MH+);□D 23+215.5°(c 0.278,MeOH)。C32H28ClN3O3·1.0HCl·1.3H2O·0.25Et2O(616.46)的分析计算值:C,64.30;H,5.58;N,6.82;Cl,11.50。实测值:C,64.40;H,5.44;N,6.70;Cl,11.90。
实施例5
(S)-2-(4-羟苯基)-N-[3-氯代-4-(1,3,4,12a-
四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·TFA(5)
白色粉末:1H NMR(CD3OD)2.61(s,1H),3.1(m,1H),3.3(m,3H),3.8(dt,J=6Hz,2H),4.1(m,2H),4.4(d,J=9Hz,1H),4.9(m,4H),6.7(d,J=4Hz,1H),6.82(s,2H),7.0-7.7(m,12H);MS m/e 554和556(MH+)。
实施例6
(S)-2-苯基-4-羟基-N-[3-氯代-4-(1,3,4,12a-
四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·TFA(6)
白色粉末:1H NMR(CD3OD)2.59(s,1H),3.1(m,1H),3.3(m,3H),3.8(dt,J=6Hz,2H),4.1(m,2H),4.4(d,J=9Hz,1H),4.9(m,4H),6.8(m,2H),7.0-7.7(m,13H);MS m/e 554和556(MH+)。
实施例7
(S)-2-(3-羟苯基)-N-[3-氯代-4-(1,3,4,12a-
四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·TFA(7)
白色粉末:1H NMR(CD3OD)2.60(s,1H),3.1(m,1H),3.3(m,3H),3.8(dt,J=6Hz,2H),4.1(m,2H),4.3(d,J=9Hz,1H),5.0(m,4H),6.7(d,J=4Hz,1H),6.9(d,J=4Hz,1H),7.1-7.7(m,13H);MS m/e 554和556(MH+)。
实施例8
(S)-2-苯基-5-羟基-N-[3-氯代-4-(1,3,4,12a-
四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·TFA(8)
白色粉末:1H NMR(CD3OD)2.59(s,1H),3.1(m,1H),3.3(m,3H),3.8(dt,J=6Hz,2H),4.1(m,2H),4.4(d,J=9Hz,1H),5.0(m,4H),6.9.1(s,2H),7.0(d,J=4Hz,1H),7.12(s,1H),7.2-7.7(m,11H);MS m/e 554和556(MH+)。
实施例9
(RS)-2-(4-甲基-噻吩基)-4-氟代-N-[3-氯代-4-
(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-
苯并二氮杂-11(12H)-基-羰基)苯基]
苯甲酰胺·TFA(9)
白色粉末:1H NMR(CD3OD)2.14(s,3H),2.59(s,1H),3.1(m,1H),3.3(m,3H),3.8(dt,J=6Hz,2H),4.1(m,2H),4.4(d,J=9Hz,1H),4.9(m,3H),6.9(d,J=4Hz,2H),7.0-7.7(m,9H),7.62(s,1H);MS m/e 576和578(MH+)。
实施例10
(RS)-2,6-二甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·TFA(10)
白色粉末:1H NMR(CD3OD)1.4(m,1H),2.30(s,6H),3.2-4.1(m,7H),4.2(d,J=9Hz,2H),4.5(m,1H),4.9(m,2H),6.9(d,J=4Hz,2H),7.0-7.7(m,7H),7.83(s,1H);MS m/e 490和492(MH+)。
实施例11
(RS)-2,3-二甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·TFA(11)
白色粉末:1H NMR(CD3OD)2.28(s,3H),2.31(s,3H),3.1(m,1H),3.3-4.1(m,8H),4.4(d,J=9Hz,1H),5.0(m,2H),7.0-7.5(m,8H),7.5(d,J=4Hz,1H),7.6(d,J=4Hz,1H),7.82(s,1H);MS m/e 490和492(MH+)。
实施例12
(RS)-2-(4-甲基-苯基)-N-[4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·TFA(12)
白色粉末:1H NMR(CD3OD)2.30(s,6H),3.0(m,1H),3.5(m,4H),3.8(m,2H),4.1(m,2H),4.5(d,J=9Hz,1H),5.1(m,2H),6.9(d,J=4Hz,1H),7.2-7.7(m,16H);MS m/e 518(MH+)。
实施例13
(R)-2苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(13)
白色粉末:MS m/e 538和540(MH+)。
实施例14
(RS)-2苯基-N-[3-甲氧基-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(14)
白色粉末:MS m/e 534.6(MH+)。
实施例15
(RS)-2苯基-N-[2-甲氧基-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(15)
褐色粉末:MS m/e 534.6(MH+)。
实施例16
(RS)-2,3,4,5-四氟代-N-[3-氯代-4-(1,3,4,12a-
四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·TFA(16)
黄色粉末:MS m/e 535和537(MH+)。
实施例17
(RS)-2-氯代-5-三氟甲基-N-[3-氯代-4-(1,3,4,12a-
四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·TFA(17)
白色粉末:MS m/e 565和567(MH+)。
实施例18
(RS)-2-氟代-3-氯代-N-[3-氯代-4-(1,3,4,12a-
四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·TFA(18)
白色粉末:MS m/e 514和516(MH+)。
实施例19
(RS)-2-(二氟甲硫基)-N-[3-氯代-4-(1,3,4,12a-
四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·TFA(19)
白色粉末:MS m/e 544和546(MH+)。
实施例20
(RS)-2-苯基-N-[4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·TFA(20)
白色粉末:MS m/e 504.6(MH+)。
实施例21
(RS)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-5-氧代-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·TFA(21)
白色粉末:MS m/e 552和554(MH+)。
实施例22
(RS)-2苯基-N-[2-羟基-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(22)
褐色粉末:MS m/e 520.6(MH+);mp 188-195℃(分解)。
实施例23
(RS)-2苯基-N-[3-羟基-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(23)
褐色粉末:MS m/e 520.6(MH+);mp 185-188℃(分解)。
实施例24
(RS)-2-甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·TFA(24)
白色粉末:MS m/e 476和478(MH+)。
实施例25
(RS)-2-(4-甲基-苯基)-N-[3-氯代-4-(1,3,4,12a-
四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·TFA(25)
白色薄片:MS m/e 552和554(MH+)。
实施例26
(RS)-2-甲基-N-[4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·TFA(26)
白色粉末:MS m/e 442.5(MH+)。
实施例27
(RS)-2-甲基-N-[3-甲基-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a ][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·TFA(27)
白色粉末:MS m/e 456.5(MH+)。
实施例28
(RS)-2-(4-甲基-苯基)-N-[3-甲基-4-(1,3,4,12a-
四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·TFA(28)
乳白色粉末:MS m/e 532.6(MH+)。
实施例29
(RS)-2-苯基-N-[3-甲基-4-(1,3,4,12a-四氢-6H-
[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·TFA(29)
白色粉末:MS m/e 518.6(MH+)。
实施例30
(RS)-2-(4-甲基-苯基)-N-[3-氟代-4-(1,3,4,12a-
四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·TFA(30)
乳白色薄片:MS m/e 536.6(MH+)。
AC4的合成
在一只1L圆底烧瓶中装上2-氨基乙硫醇盐酸盐(5.24g,0.046mol)、碳酸氢钠(9.70g,2.5equiv.)、4.0g 3A分子筛(在微波炉中活化)和200ml干燥甲醇。为了监测pH,加入指示剂一溴甲酚红紫50mg,反应混合物通过氮气吹洗并保持在氮气氛围中。通过注射器泵,以使反应混合物的pH保持在6以上(反应混合物为暗橄榄色)的这种速度下,加入溴丙酮酸乙酯(10g,0.051mol)。加入过程约需要3小时。使反应再保持30分钟,然后按一份儿加入氰基硼氢化钠(5.8g,2equiv.)。
通过小心加入6.0M HCl,使反应酸化至pH4并在该pH下保持3小时。反应混合物的颜色为黄色,pH用Panpeha试纸进行监测。然后加入过量的盐酸至得到pH1-2,气体逸出停止后,将反应混合物通过Celite过滤,并真空蒸发。将残余物溶于200ml水中,用二乙醚萃取一次,弃去醚溶液。水溶液通过加入6N氢氧化钠水溶液而制成碱性(pH8-9),然后每次用50ml二乙醚萃取,共萃取5次。混合的有机萃取物经硫酸镁干燥并过滤。该溶液用气态HCl饱和,导致通过过滤分离的氨基酸酯盐酸盐沉淀。白色晶体在真空炉中干燥,得到7.9g(0.037mol)的AC2(光谱数据符合文献(U.Larsson和R.Carison,ActaChem.Scand.48(1994),517-525)。在一个100ml烧瓶中,将AC2(8.66g,0.041mol)溶于含有5ml水的50ml二噁烷中。一次性加入碳酸氢钠(12.0g,0.14mol)后,滴加6.82g(0.036mol)2-硝基苯甲酰氯,加入过程约需要45分钟。于室温下将体系保持4小时,用200ml盐水稀释,并用乙醚萃取(每次50ml,4次)。混合的有机部分经无水硫酸镁干燥并蒸发,得到12.0g(0.037mol)粘稠黄色油状物(AC3),所述油状物不需进一步纯化就可使用。向具有回流冷凝器的200ml烧瓶中装入AC3(12.0g,0.037mol)和10g铁填充剂。将反应物回流4小时后,轻轻倒入500ml冷水中。搅拌20分钟后,沉淀出白色固体。将其过滤,用大量冷水洗涤,在真空炉中干燥,得到白色固体AC4(7.0g,0.028mol)。1H NMR(DMSO-d6)2.65(dd,J=14.4和5.8Hz,1H),2.74-2.91(m,2H),3.16(dt,J=12.6和4.7Hz,1H),3.33-3.41(m,1H),4.19(dd,J=9.9和5.8Hz,1H),4.58(dd,J 14.1和4.3Hz,1H),7.11(d,J 8.0Hz,1H),7.25(t,J=7.7Hz,1H),7.54(t,J 7.2Hz,1H),7.80(t,J=8.0Hz,1H);MS m/e 249(MH+)。
实施例31
(RS)-2-苯基-N-[4-(8-甲氧基-1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(31)
白色粉末:MS m/e 550.7(MH+)。
实施例32
(RS)-2-苯基-N-[4-(8-氟代-1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(32)
白色薄片:MS m/e 538.6(MH+);mp 177-180℃。
实施例33
(RS)-2-苯基-N-[4-(8,9-二甲氧基-1,3,4,12a-四氢-
6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(33)
白色粉末:MS m/e 550.7(MH+)。
实施例34
(RS)-2-苯基-N-[4-(9-氯代-1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(34)
白色薄片:MS m/e 554和556(MH+)。
实施例35
(RS)-2-苯基-N-[4-(8,9-二氟代-1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(35)
白色粉末:MS m/e 556.6(MH+);mp 194-199℃。
实施例36
(RS)-2-苯基-N-[4-(8-甲基-1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(36)
白色薄片:MS m/e 534.7(MH+);mp 191-196℃。
实施例37
(RS)-2-苯基-N-[4-(8-氯代-1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(37)
白色薄片:MS m/e 554和556(MH+)。
实施例38
(RS)-2-苯基-N-[3-氯代-4-(8-氟代-1,3,4,12a-
四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-
11(12H)-基-羰基)苯基]苯甲酰胺·HCl(38)
白色薄片:MS m/e 572和574(MH+)。
实施例39
(RS)-2-苯基-N-[4-(10-甲基-1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(39)
白色粉末:MS m/e 534.7(MH+)。
实施例40
(RS)-2-苯基-N-[4-(10-甲氧基-1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(40)
白色粉末:MS m/e 550.7(MH+)。
实施例41
(RS)-3,5-二甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(41)
白色粉末:MS m/e 506和508(MH+)。
实施例42
(RS)-2-碘代-3-甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(42)
黄色粉末:MS m/e 618和620(MH+)。
实施例43
(RS)-3,5-二氯代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(43)
白色粉末:MS m/e 547和549(MH+)。
实施例44
(RS)-2甲基-3-碘代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(44)
褐色粉末:MS m/e 618和620(MH+)。
实施例45
(RS)-2-氟苯基-N-[4-(1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(45)
白色粉末:MS m/e 538.6(MH+)。
实施例46
(S)-2-苯基-N-[3-二甲氨基-4-(1,3,4,12a-四氢-
6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(46)
白色粉末:MS m/e 563.7(MH+)。
实施例47
(S)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-
[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-
羰基)苯基]苯甲酰胺·HCl(47)
白色粉末:mp192-197℃ MS m/e 554和556(MH+);□D 23+173.4°(c0.154,MeOH);mp192-197℃。C32H28ClN3O2S·1.0 HCl·1.0 H2O(608.58)的分析计算值:C,63.15;H,5.13;N,6.90;Cl,11.65。实测值:C,63.29;H,4.99;N,6.78;Cl,11.40。
实施例48
10-[4-[[(2-联苯基)羰基]氨基]苯甲酰基]
-10,11-二氢-1,2-亚甲基吡咯烷并[2,1-c][1,4]
苯并二氮杂·TFA(48)
白色粉末:MS m/e 500.3(MH+)。
实施例49
作为口服组合物的一个具体实施方案,将100mg实施例1的化合物9与足够精细的乳糖一起配制,得到的总量为580-590mg,装入一个规格○的硬明胶胶囊中。
实施例50
体外重组血管升压素受体结合测定。
评价化合物自身从HEK-293细胞中的人V-1或V-2受体置换3H-精氨酸血管升压素的能力。测定缓冲液是含有5μg/ml抑蛋白酶肽、亮抑蛋白酶肽、胃蛋白酶抑制剂、50μg/ml杆菌肽和1mM Pefabloc的50mM Tris-Cl、5mM MgCl2、0.1%BSA(pH7.5)。3H-血管升压素是3H-精氨酸-8-血管升压素(68.5Ci/mmol,测定中的终浓度为0.65-0.75nM)。向96孔圆底聚丙烯板的各孔中加入缓冲液、试验化合物、膜(含有克隆的人V-1或V-2受体)和3H-2-管升压素。让反应板于室温下静置1小时。样品通过Unifilter GF/C板(在0.3聚乙烯亚胺中预浸泡过)过滤。将板用含0.05%吐温20的冷生理盐水洗涤5次。干燥后,将滤板底密封并将0.025ml Microscint-20加入到每个滤板中。将所述板顶部密封,并对所述板计数。通过在那些孔中加入1.25μM精氨酸-8-血管升压素测定非特异性的结合。
实施例51
大鼠中血管升压素诱发的高血压的逆转。
在血管升压素诱发的高血压的麻醉模型中,筛选抗高血压活性的化合物。体重350-450g的雄性Long Evans正常血压的大鼠用戊巴比妥(35mg/kg,腹膜内)麻醉,并通过用腹膜内输注10mg/kg/小时在整个程序期间保持麻醉。以30ng/kg/分钟静脉内输注精氨酸血管升压素,诱发稳定高血压状态(平均动脉血压约增加50mmHg)。以上升剂量方式给予目的化合物并记录平均动脉血压的最大降低数。根据对每只动物的剂量-反应关系的线性部份确定ED50。
可以对该模型稍加改进以评价目的化合物的生物利用度。不以上升剂量方式对动物静脉内给药,而是将单一剂量直接给予到每个动物的十二指肠。然后持续60分钟监测抗高血压效应并计算出逆转的最大百分比。
表IV
体外结果
化合物 V2 Bdg V1 Bdg V2 cAMP
IC60(nM) (%1nh,0.1uM) IC50(uM)
1 9 31% 0.21
2 14 29% 0.46
3 10 42% 0.71
4 2 (0.082uM) 0.011
5 9 29% NT
6 3 49% NT
7 11 1% NT
8 27 32% NT
9 11 18% NT
10 9 15% NT
11 8 11% NT
12 6 (0.030uM) NT
13 32 (2.8uM) NT
14 9 36% NT
15 13 69% NT
16 25 20% NT
17 (63%/0.1uM) 13% NT
18 18 15% NT
19 27 24% NT
20 8 69% NT
21 (59%/0.1uM) 2% NT
22 6 67% NT
23 10 33% NT
24 16 34% NT
25 12 60% NT
26 (65%/0.1uM) 58% NT
27 13 7% NT
28 10 14% NT
29 6 3% NT
30 14 74% NT
31 43 27%/10uM NT
32 20 44%/10uM NT
33 (19%/0.1uM) 6%/10uM NT
34 (41%/0.1uM) 1%/10uM NT
35 38 15%/10uM NT
36 18 76% NT
37 22 75% NT
38 18 9% NT
39 (37%/0.1uM) (0.77uM) NT
40 (12%/0.1uM) (4.3uM) NT
41 (38%/0.1uM) 5% NT
42 (62%/0.1uM) 0% NT
43 (47%/0.1uM) 11% NT
44 (43%/0.1uM) 2% NT
45 (69%/0.1uM) 15% NT
46 47 8% NT
47 11 (0.85uM) NT
NT=没有测试。
表V
体内血压降低结果
化合物# I.D.剂量(mg/kg) 血压降低(%)
1 10 67%
3 10 100%
4 10 100%
虽然先前的说明书叙述了本发明的原理、提供用于说明实施例,但是不用说本发明的实施包括属于以下权利要求书范围内进行的所有通常的变化、改进和/或修改及其等同实施方案。
Claims (7)
2.权利要求1的化合物及其药学上可接受的盐为式(IV)的化合物及其药学上可接受的盐:
其中
X选自CH2、S或O;
R1为氢或卤素;
R5选自氢、C1-C4烷基、C1-C4烷氧基、氯或氟;
R6为可以被1-2个选自C1-C6烷基或羟基的取代基取代的苯基、可以被C1-C6烷基取代的噻吩基或者卤素;
和
R7独立地选自氢、氟、氯、羟基、C1-C6烷基和它们的组合,其中R7代表1-4个独立选定的基团。
3.权利要求1的化合物及其药学上可接受的盐,选自以下的化合物及其药学上可接受的盐:
10-[4-[[(2-联苯基)羰基]氨基]苯甲酰基]-10,11-二氢-5H-哌啶并[2,1-c][1,4]苯并二氮杂;
10-[4-[[(2-联苯基)羰基]氨基]苯甲酰基]-10,11-二氢-5H-(四氢吡啶并)[2,1-c][1,4]苯并二氮杂;
(RS)-2-苯基-N-[4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-(4-羟基苯基)-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-苯基-4-羟基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-1 1(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-(3-羟基苯基)-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-苯基-5-羟基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(4-甲基-2-噻吩基)-4-氟代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2,6-二甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2,3-二甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(4-甲基-苯基)-N-[4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(R)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[3-甲氧基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[2-甲氧基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2,3,4,5-四氟代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-氯代-5-三氟甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-氟代-3-氯代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(二氟甲硫基)-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[2-羟基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[3-羟基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(4-甲基-苯基)-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-甲基-N-[4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-甲基-N-[3-甲基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(4-甲基-苯基)-N-[3-甲基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[3-甲基-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(4-甲基-苯基)-N-[3-氟代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8-甲氧基-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8-氟代-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8,9-二甲氧基-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(9-氯代-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8,9-二氟代-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8-甲基-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(8-氯代-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[3-氯代-4-(8-氟代-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(10-甲基-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-苯基-N-[4-(10-甲氧基-1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-3,5-二甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-碘代-3-甲基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-3,5-二氯代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-甲基-3-碘代-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(RS)-2-(2-氟苯基)-N-[4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-苯基-N-[3-二甲氨基-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺;
(S)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噻嗪并[4,3-a][1,4]-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺。
4.(RS)-2-苯基-N-[3-氯代-4-(1,3,4,12a-四氢-6H-[1,4]噁嗪并[4,3-a][1,4]-5-氧代-苯并二氮杂-11(12H)-基-羰基)苯基]苯甲酰胺及其药学上可接受的盐。
5.一种药用组合物,所述药用组合物包含一种药学上可接受的载体和权利要求1-4中任一项的化合物。
6.权利要求5的药用组合物,其中所述药用组合物适合于提供0.1-300mg/kg/天的剂量。
7.权利要求1-4中任一项的化合物或权利要求5或6的组合物在制备用于治疗选自以下的病症的药物中的用途:高血压、充血性心力衰竭、心功能不全、冠状动脉血管痉挛、心脏缺血、肝硬化、肾血管痉挛、肾衰竭、脑水肿和缺血、中风、血栓形成或水潴留。
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US11635899P | 1999-01-19 | 1999-01-19 | |
US60/116358 | 1999-01-19 | ||
US60/116,358 | 1999-01-19 | ||
US46865099A | 1999-12-21 | 1999-12-21 | |
US09/468,650 | 1999-12-21 | ||
US09/468650 | 1999-12-21 |
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