CN1345725A - 治疗慢性阻塞性肺部疾病的二氮杂䓬并吲哚 - Google Patents
治疗慢性阻塞性肺部疾病的二氮杂䓬并吲哚 Download PDFInfo
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- CN1345725A CN1345725A CN01120850A CN01120850A CN1345725A CN 1345725 A CN1345725 A CN 1345725A CN 01120850 A CN01120850 A CN 01120850A CN 01120850 A CN01120850 A CN 01120850A CN 1345725 A CN1345725 A CN 1345725A
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- amino
- diaza
- phenyl
- tetrahydrochysene
- indol
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Abstract
本发明涉及式(I)的二氮杂䓬并吲哚在治疗慢性阻塞性肺部疾病中的用途:其中A是芳基或含氮杂芳基,B是羟基或氨基。
Description
本发明涉及二氮杂并吲哚治疗慢性阻塞性肺部疾病(下文称COPD)的用途。
COPD是一种以气流障碍为特征的慢性、缓慢进行性疾病(与气道炎症和主要的中性白细胞含量有关)。大多肺功能损害是永久性的(虽然透过支气管扩张剂治疗可产生某些可能性)。这种疾病还被称为COPD,然而在过去还单独或联合使用过多种临床术语。这些术语包括肺气肿、慢性支气管炎、慢性气流限制、慢性气道阻塞、不可逆性阻塞性气道疾病、慢性阻塞性气道疾病和慢性阻塞性肺部疾病。
COPD的临床表现以严重程度而不同,从非病残的单纯性慢性支气管炎到慢性呼吸衰竭的严重病残状态。COPD患者的主要临床特征为慢性支气管炎和/或肺气肿(与气道严重和/或主要的中性白细胞含量有关)。
虽然COPD目前不是十分流行,但可以确定在发达国家,尤其是美国,COPD是第四大导致死亡的原因。另外,预期在未来、在发达的西方国家和其它国家,COPD问题都将呈增长趋势。预期在未来十年内,在东亚国家该问题将增长3倍,因为这些国家中男性的吸烟比率较高。
因此,仍需要COPD的有效治疗方法。
在过去的数年中,第二代选择性磷酸二酯酶4抑制剂(PDE4抑制剂)被认为是COPD的可能有效的治疗方法。特别参见Doherty,当代化学生物学观点(Current Opinion in Chemical Biology)1999,3:466-473;Mohammed等,抗炎和免疫调节研究药物(Anti-inflammatory& Immunomodulatory Investigational Drugs)1999 1(1):21-28;Schmidt等,临床和实验变态反应(Clinical and ExperimentalAllergy),29,增刊2,99-109。
Cilomilast(Ariflo),一种口服的活性PDE4抑制剂,被认为可用于COPD的治疗。特别参见:Nieman等,Am J Respir Crit Care Med1998,157:A413;Underwood等,欧洲呼吸杂志(Eur Respir J)1998,12:86s;Compton等,Am J Respir Crit Care Med 1999,159:A522。还参见Compton在欧洲呼吸协会会议(European Respiratory SocietyMeeting,Madrid,October 12,1999)上的口头发言,以及Torphy和Underwood在第四次世界炎症会议(4th World Congress onInflammation,Paris,June 27-30,1999)的口头发言。该化合物目前正处于COPD的III期临床试验中。
但是,用于治疗COPD的cilomilast存在某些缺点。据报告,当cilomilast以20mg的单次剂量给药时,产生相关的副作用,例如恶心和呕吐。参见Murdoch等,Am J Respir Crit Care Med 1998,157:A409。在如此低的剂量就表现出的副作用将使cilomilast的应用受到限制,排除了每次单次剂量的形式,给患者带来了不便。
本发明涉及一类已知作为PED4抑制剂的二氮杂并吲哚化合物用于治疗COPD的用途。这些化合物不具有副作用,尤其是对心脏或消化系统不具有副作用(参见Burnouf等,医药化学杂志(Journal ofMedicinal Chemistry)(2000),43:4850-4867),并且在更低剂量时比cilomilast更有效。
本发明涉及式(I)的[1,4]二氮杂并[6,7,1-hi]吲哚或其可药用盐用于制备治疗慢性阻塞性肺部疾病或COPD的药物的应用,其中-A是芳基或含氮杂芳基,所述基团各自可任选地被一至三个独立地选自下列的基团取代:卤素、低级烷基、低级卤代烷基、低级烷氧基、环烷氧基、氨基和低级烷基羰基氨基或烷氧羰基氨基;-B是羟基或氨基,其本身可任选被取代。
本发明还提供治疗COPD的方法,包括给需此治疗的人施用有效量的式I的二氮杂并吲哚。
这些化合物作为PDE4抑制剂的用途和它们的制备方法公开于WO97/36905,该文献内容引入本文中,以供参考。在本发明中,这些二氮杂并吲哚被用作活性成分。
在下面的说明书中参照附图,更详细地公开了本发明,其中:附图1显示了在Wistar大鼠中,作为施用的(3R)N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢-[1,4]二氮杂并[6,7,1-hi]吲哚-3-基)-烟酰胺的量的函数的气道(airway)中的中性白细胞数量和对LPS诱发的肺部中性白细胞增多症的百分抑制。附图2显示了在Wistar大鼠中,作为施用的cilomilast(顺-4-氰基-4-[3-(环戊氧基)-4-甲氧基苯基]环己烷羧酸)的量的函数的气道中的中性白细胞数量和对LPS诱发的肺部中性白细胞增多症的百分抑制。
本发明尤其涉及下式(I)的[1,4]二氮杂并[6,7,1-hi]吲哚类化合物、其外消旋体或异构体形式,尤其是由二氮杂并吲哚-4-酮环的碳3决定的构型的那些,及其可药用衍生物用于治疗COPD的用途,其中-A是芳基或含氮杂芳基,所述基团各自可任选地被一至三个独立地选自下列的基团取代:卤素、低级烷基、低级卤代烷基、低级烷氧基、环烷氧基、氨基和低级烷羰基氨基或烷氧羰基氨基;-B是:1)-OR1,R1是H或R4,2)-NR2R3,R2是-C(NH)NH2并且R3是-H,3)-NR2R3,R2是R4并且R3是-H,4)-NR2R3,R2和R3各自独立地是-H或低级烷基,或5)-NR2R3,R2和R3与和它们相连的氮原子一起形成饱和的5至7元杂环,该杂环可包含不与氮原子直接相连的第二个杂原子:氧、硫或氮;-R4是:1)-CH2-CO2H,2)-CO-(CH2)p-CO2H,3)-CO-A,其中A定义如上,4)-CO-CH=CH-CO2H,5)-CO-(CH2)n-CH3,n是等于或大于0且小于或等于18的整数,6)-CO-(CH2-O-CH2)p-CH2-O-CH3,7)-CO-(CH2-O-CH2)p-CO2H,8)-(CH2)P-NR5R6,R5和R6独立地是-H或低级烷基,或9)-(CH2)p-NR5R6,R5和R6与和它们相连的氮原子一起形成饱和的5至7元杂环,该杂环可包含不与氮原子直接相连的第二个杂原子:氧、硫或氮;-p是等于2、3或4的整数。
其中B是OR1或NR2R3,而R1、R2和R3表示氢的一组式(I)化合物是优选的。
有利地优选的另一组产物(I)包括那些化合物,其中A是被1-3个独立选自下列的基团取代的芳基:卤素、氨基、低级烷氧羰基氨基或烷氧基;以及一组产物(I),其中A是含1-2个氮原子的单环杂芳基或含1-4个氮原子的双环杂芳基。
更具体地说,特别令人感兴趣的用于COPD的一组化合物包括式I化合物,其中B是NH2,A是被1-3个独立地选自卤素和氨基的基团取代的芳基或含1-2个氮原子的杂芳基。
在上下文中:
-芳基是指苯基或萘基;
-含氮杂环是指含至少一个氮原子的不饱和单环或多环,优选含1-4个氮原子的5或6元单杂环,或是指含1-4个氮原子的不饱和稠合杂环,所述环的正电性氮原子任选被甲基化或乙基化;
-卤素是指氟、氯、溴或碘;
-对于含烷基的基团,低级是指直链或支链的并且含1-4个碳原子的烷基,或者表示环丙基甲基;
-环烷基是指环丙基、环丁基、环戊基或环己基;
-卤代烷基是指一、二或三卤代烷基。
用于本发明的化合物包括式I化合物的溶剂化物、水合物、可药用盐和其多晶型物(不同的晶格描述词),它们是其可药用衍生物。
具有碱性部分的式(I)化合物的可药用盐是指式(I)化合物的酸加成盐,它们可由无毒的无机酸或有机酸形成,例如由氢溴酸、盐酸、硫酸、磷酸、硝酸、乙酸、琥珀酸、酒石酸、柠檬酸、马来酸、羟基马来酸、苯甲酸、富马酸、甲磺酸和羟乙磺酸等形成。本发明也包括衍生物(I)的各种季铵盐。此外,具有酸性部分的式(I)化合物的可药用是指可由无毒的无机碱或有机碱形成的常用盐,例如碱金属和碱土金属的氢氧化物(钠、钾、镁和钙盐)、胺(二苄基亚乙基二胺、三甲胺、哌啶、吡咯烷和苄胺等)或季铵氢氧化物,例如四甲基氢氧化铵(还可参见,Berge S.M.等,“药用盐”,1997,J.Pharm.Sci.66:1-19,本文中引述该文献作为参考)。
本发明还包括式(I)化合物的前药的用途,例如本领域普通技术人员所想到的(参见Bundgaard等,Acta Pharm.Suec.,1987;24:233-246)。
根据Cahn-Ingold-Prelog规则,其中在相对于二氮杂环“3-酮”羰基的α位的非对称碳原子具有(R)绝对构型的式(I)的二氮杂并吲哚通常是优选的。
更具体地是,下列化合物优选用于制备治疗COPD的药物:
-(3R)-异喹啉-3-羧酸(9-羟基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-(3R)-4-叔丁氧羰基氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]苯甲酰胺;
-(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-3,5-二氯苯甲酰胺;
-(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-5-氯-2-甲氧基苯甲酰胺;
-(3R)-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-异烟酰胺;
-(3R)-3-叔丁氧羰基氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]异烟酰胺;
-(3R)-异喹啉-3-羧酸(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-(3R)-喹啉-3-羧酸(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-(3R)-4,7-二甲基吡唑并[5,1-c][1,2,4]三嗪-3-羧酸(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-(3R)-4-氨基-3,5-二氯-N-(9-二甲氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基)苯甲酰胺;
-(3R)-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基)-2-苯并呋喃甲酰胺;
-(3R)-4,7-二甲基吡唑并[5,1-c][1,2,4]三嗪-3-羧酸[4-氧代-1-苯基-9-(吡咯烷-1-基)-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-吡啶-2-羧酸(3R)-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-吡嗪-2-羧酸(3R)-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]苯甲酰胺;和
-(3R)-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]烟酰胺。
最优选的化合物是:
-(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-3,5-二氯苯甲酰胺;
-(3R)-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-异烟酰胺;
-(3R)-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-烟酰胺;和
-(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]苯甲酰胺。
尤其优选的式(I)化合物是:
-(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]苯甲酰胺;和
-(3R)-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-烟酰胺(化合物1)。
这些化合物相应于WO97/36905的实施例11和3的化合物。
用于本发明的化合物可按照WO97/36905中公开的方法制备;本领域技术人员可参考该文献制备本发明化合物。
本发明的产物以组合物形式给药,所述给药根据所治疗的适应症的性质和严重程度适当进行。对于人的每日剂量通常为2mg-1g产物,该剂量可一次或分次服用。将组合物制备成与期望给药的途径相顺应的形式,例如片剂、包衣片、胶囊、漱口剂、气雾剂、吸入粉末、栓剂、凝胶剂或悬浮液。这些组合物可采用本领域技术人员熟悉的方法制备,它们含有0.5-60%(重量)的活性成分(式I化合物)和40-99.5%(重量)与活性成分及目的组合物的物理形式相适应和相容的药物赋形剂或载体。
对于急性COPD适应症的治疗,剂量通常为每天约20mg-约500mg。优选剂量为每天约50mg-约300mg(对于约70kg的成人而言)。
所述组合物优选每日服用两次。所述组合物更优选每日服用一次。
当考虑到慢性疾病,例如COPD的治疗时,给药频度对于患者舒适性而言是重要的,因为这些患者将接受长期规律的治疗。
cilomilast在人中的清除半衰期约为8小时(Torphy等,Pulmonary Pharmacology & Therapeutics(1999)12,131-135)。由于已知相对较短的半衰期,每日一次给药cilomilast用于治疗COPD似乎不可能实现:在20mg剂量时表现出的副作用排除了高剂量单次给药;因此可能优选每日给药两次。
测定了化合物1在人中的半衰期:给健康自愿者单次口服化合物1,剂量为1-25mg。出人意料地是,所有剂量下的平均末端半衰期都相近并且相当地长,为13.9-17.1小时(平均15.4小时)。该半衰期表明了化合物1可每日给药一次。
下面以举例方式描述片剂组合物及其制备:
组成 | 量 |
式(I)化合物 | 1-75mg |
乳糖 | 124-74mg |
微晶纤维素 | 16-60mg |
聚乙烯吡咯烷酮 | 6mg |
羧甲基淀粉钠 | 8mg |
硬脂酸镁 | 1mg |
将乳糖、微晶纤维素和羧甲基淀粉钠与活性物质混合。用适当浓度的聚乙烯吡咯烷酮水或醇溶液润湿并制粒。干燥并调至颗粒的粒径分布。与硬脂酸镁均匀混合。再压制成每片200mg的片剂。
固体形式制剂包括粉末、片剂、分散颗粒、胶囊、扁囊剂和栓剂。固体载体可以是一种或多种物质,它们可作为稀释剂、芳香剂、增溶剂、润滑剂、悬浮剂、粘合剂或片剂崩解剂;也可以是包囊材料。粉末中,载体是固体细粉,它与活性成分细粉混合。片剂中,活性成分以适宜比例与具有所需粘合性质的载体混合并压制成所需的形状和尺寸。对于栓剂的制备,首先熔融低熔点蜡,例如脂肪酸甘油酯与椰子油的混合物,然后通过,例如搅拌,使活性成分分散于其中。而后将熔融的均匀混合物倾入方便大小的模具中,使其冷却并固化。粉末、片剂、扁囊剂或囊化形式的胶囊优选含有5%-约70%的活性成分。适宜的载体是碳酸镁、硬脂酸镁、滑石、乳糖、蔗糖、果胶、糊剂、淀粉、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡和椰子油等。
片剂、粉末、扁囊剂和胶囊可用作适于口服的固体形式。药物也可以喷雾剂形式(装在安有适合阀门的压力容器或安有计量阀门的非压力容器中)传递。
液体形式制剂包括溶液、悬浮液和乳液。
作为适于非胃肠给药的液体制剂实例,可例举活性化合物的无菌的水溶液或水-丙二醇溶液。液体制剂也可配制成聚乙二醇水溶液的溶液。
口服水溶液可如下制备:在水中溶解活性成分并按需加入适宜的着色剂、芳香剂、稳定剂和增稠剂。口服使用的水悬浮液可如下制备:将活性成分细粉与粘性物质,例如天然合成的胶、树脂、甲基纤维素、羧甲基纤维素钠,和药剂领域已知的其它悬浮剂一起分散到水中。
药物制剂优选是单位剂量形式。以单位剂量形式,制剂可分为含适宜量药物的单位剂型。单位剂型可以是包装制剂,包含独立数量包装制剂,例如包装片剂、胶囊和小瓶或安瓿中的粉末。单位剂型也可以是胶囊、扁囊剂或片剂本身,或者它可以是适宜数量的其包装形式。
下列实施例对本发明进行非限制性说明。
用于评价本发明化合物治疗COPD有用性的模型是中性白细胞增多症模型。通过使大鼠或小鼠与脂多糖(LPS)气雾剂接触诱发中性白细胞增多症。实施例1:用LPS气雾剂诱发C57b1/6小鼠的中性白细胞增多症1.1实验方案给药化合物1
在动物清醒时,通过口服途径对动物施用化合物1。与LPS接触
给药1小时后,将小鼠放入有机玻璃盒中(一盒至多25只小鼠),以100μg/ml的量给予LPS气雾剂(Escherichia coli,serotype055:B5)1小时。对照小鼠不给予LPS气雾剂。麻醉和气管切开术
与LPS接触后24小时,以15ml/kg的速率腹膜内注射0.6%戊巴比妥钠麻醉动物。施行气管切开术并插入气管插管。支气管肺泡的洗涤
为回收气道腔中存在的细胞,用1ml的注射器,用0.3ml体积的PBS溶液(37℃)连续洗涤6次。将如此回收的洗涤液贮存于4℃冰箱中。支气管肺泡洗涤液的细胞组成测定
用库尔特粒度仪计数支气管肺泡洗涤液中含有的细胞。先通过离心(Cytospin)使样品沉着在显微镜载波片上,然后用MayGrunwald-Gismsa染料对样品进行染色。根据形态学标准,在显微镜(×100)下区分计数细胞数量。评价标准
主要的评价标准是中性白细胞的数量/毫升支气管肺泡洗涤液。以105(E+05)细胞/毫升表示。结果表达
:治疗(或参考)组中细胞浓度的算术平均。
如果合适,用“δ(Delta)方法”或“Fieller方法”i,ii和iii(Armitage&al,1997;Feuerstein & al,1997;Hubert & al,1988)计算百分抑制率的90%置信区间。1.2结果
这些实验的结果表明式I化合物,尤其是化合物1强烈地抑制LPS诱发的小鼠肺部的中性白细胞增多症。实施例2:用LPS气雾剂诱发Wistar大鼠的中性白细胞增多症2.1实验方案给药治疗物质
在动物清醒时,通过口服途径对动物施用化合物1或cilomilast。与LPS接触
给药1小时后,将小鼠放入有机玻璃盒中,以200μg/ml的量给予LPS气雾剂(Escherichia coli,serotype 055:B5)1小时。对照小鼠不给予LPS气雾剂。在附图1和2中对照组被称为“假(sham)”。麻醉和气管切开术
与LPS接触后2小时,以1ml/kg的速率腹膜内注射6%戊巴比妥钠麻醉动物。施行气管切开术并插入气管插管。支气管肺泡的洗涤
为回收气道腔中存在的细胞,用5ml的注射器,用5ml体积的0.9% M NaCl+EDTA溶液(37℃)连续洗涤3次。将如此回收的洗涤液贮存于4℃冰箱中。支气管肺泡洗涤液的细胞组成测定
参见实施例1。评价标准
参见实施例1。结果表达
参见实施例12.2结果
如附图1所示,化合物1强烈地并显著地抑制LPS诱发的Wistar大鼠肺部的中性白细胞增多症,在10mg/kg剂量下的百分抑制率为74%。
将这些实验结果与在相同模型中用cilomilast(Ariflo)获得的结果(附图2)进行比较,表明在相同剂量下,化合物1(在30mg/kg剂量下的百分抑制率为80%)比cilomilast更有效。尤其是在10mg/kg的剂量下,化合物1的有效性比相同剂量的cilomilast高两倍。换句话说,10mg/kg化合物1的活性(百分抑制率为74%)与30mg/kgcilomilast的相同(百分抑制率为74%)。实施例3:COPD患者全血中LPS诱发的TNFα产生的体外抑制
该研究的目的是比较三种选择性PDE4抑制剂(化合物1、咯利普兰(rolipram)(4-[3-(环戊氧基)-4-甲氧基-苯基]-2-吡咯烷酮)和cilomilast)在降低COPD患者的全血中脂多糖(LPS)诱发的TNFα释放的活性。该研究包括按照ATS规则iv诊断的13名COPD患者,测定LPS对TNFα产生的的浓度-效应(n=6)及化合物、咯利普兰和cilomilast的IC50值(n=7)。3.1实验方案
在肝素试管中收集血液(15ml/患者)并分配到96孔微滴板(250μl/孔)中。
在37℃培养30分钟后,在不同的孔中,加入25μl浓度增高的试验或载体化合物。在37℃下使微滴板保温30分钟,然后以50μg/ml的量加入25μl LPS(E.coli)(刺激的孔)或25μl无菌盐水(未刺激的孔)。使微滴板在37℃保温22-24小时。
将125μl上清血浆轻轻地转移到无菌96孔微滴板中并贮存于-80℃直至进行TNFα分析。然后通过ELISA分析测定TNFα的产生。3.2结果
与LPS保温过夜后,在50μg/ml LPS下,全血TNFα水平以浓度依赖方式从检测不到的基线水平增至8.1±2.0ng/ml的均值水平。与化合物1的预培养对TNFα释放产生了剂量依赖性抑制作用,其IC50值为1.3±0.7μM。咯利普兰的IC50值为2.8±0.9μM,cilomilast的IC50值大于10μM。这些数据表明式I化合物体外抑制LPS诱发的COPD患者中TNFα产生的作用优于咯利普兰和cilomilast,可用于该疾病中的抗炎治疗。
文献
i. ARMITAGE P.& COLTON T.(1998).Fieller’s Theorem.生物统计学百科全书(Encyclopedia of Biostatistics),Volume 2,pp.1515-1516.Wiley,New York.
ii. FEUERSTEIN T.J.,ROSSNER R.& SCHUMACHER M.(1997).如何以对照平均值的百分数表示效应平均值(How to Express an EffectMean as Percentage of a Control Mean.)药理学和毒理学方法杂志(Journal of Pharmacology and Toxicology Methods)37,pp.187-190.
iii. HUBERT J.J.,BOHIDARD N.R.& PEACE K.E.(1988)。药物开发的生物药物统计学,评价药理活性部分(BiopharmaceuticalStatistics for Drug Development,Assessment of PharmacologicalActivity section),pp.83-148.Karl peace,New York.
iv. Am.J.Respir.Crit.Care Med.1995;152:S77-S120.
Claims (12)
1.下式(I)的二氮杂并吲哚类化合物、其外消旋体或异构体形式,尤其是由二氮杂并吲哚-4-酮环的碳3决定的构型的那些,及其可药用衍生物在制备治疗慢性阻塞性肺部疾病药物中的应用,其中-A是芳基或含氮杂芳基,所述基团各自可任选地被一至三个独立地选自下列的基团取代:卤素、低级烷基、低级卤代烷基、低级烷氧基、环烷氧基、氨基和低级烷羰基氨基或烷氧羰基氨基;-B是:1)-OR1,R1是H或R4,2)-NR2R3,R2是-C(NH)NH2并且R3是-H,3)-NR2R3,R2是R4并且R3是-H,4)-NR2R3,R2和R3各自独立地是-H或低级烷基,或5)-NR2R3,R2和R3与和它们相连的氮原子一起形成饱和的5至7元杂环,该杂环可包含不与氮原子直接相连的第二个杂原子:氧、硫或氮;-R4是:1)-CH2-CO2H,2)-CO-(CH2)p-CO2H,3)-CO-A,其中A定义如上,4)-CO-CH=CH-CO2H,5)-CO-(CH2)n-CH3,n是等于或大于0且小于或等于18的整数,6)-CO-(CH2-O-CH2)p-CH2-O-CH3,7)-CO-(CH2-O-CH2)p-CO2H,8)-(CH2)p-NR5R6,R5和R6独立地是-H或低级烷基,或9)-(CH2)p-NR5R6,R5和R6与和它们相连的氮原子一起形成饱和的5至7元杂环,该杂环可包含不与氮原子直接相连的第二个杂原子:氧、硫或氮;-p是等于2、3或4的整数。
2.根据权利要求1的应用,其特征在于考虑在相对于二氮杂环羰基的α位的非对称碳原子,根据Cahn-Ingold-Prelog规则,式(I)的二氮杂并吲哚类化合物具有(R)绝对构型。
3.根据权利要求1或2的应用,其特征在于在式(I)的二氮杂并吲哚中,B是OR1或NR2R3,其中R1、R2和R3是氢。
4.根据权利要求1、2或3的应用,其特征在于在式(I)的二氮杂并吲哚中,A是被1-3个独立选自下列的基团取代的芳基:卤素、氨基、低级烷氧羰基氨基或烷氧基。
5.根据权利要求1、2或3的应用,其特征在于在式(I)的二氮杂并吲哚中,A是含1-2个氮原子的单环含氮杂芳基或含1-4个氮原子的双环含氮杂芳基。
6.根据权利要求5的应用,其特征在于杂芳基被氨基、低级烷基、低级烷氧羰基氨基或烷基羰基氨基取代。
7.根据权利要求4的应用,其特征在于在式(I)的二氮杂并吲哚中,B是NH2,A是被1-3个独立地选自卤素和氨基的取代基取代的芳基。
8.根据权利要求5的应用,其特征在于在式(I)的二氮杂并吲哚中,B是NH2,A是含1-2个氮原子的单环杂芳基。
9.根据权利要求1、2或3的应用,其特征在于式(I)的二氮杂并吲哚是下列化合物:
-(3R)-异喹啉-3-羧酸(9-羟基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-(3R)-4-叔丁氧羰基氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]苯甲酰胺;
-(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]3,5-二氯苯甲酰胺;
-(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-5-氯-2-甲氧基苯甲酰胺;
-(3R)-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-异烟酰胺;
-(3R)-3-叔丁氧羰基氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]异烟酰胺;
-(3R)-异喹啉-3-羧酸(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-(3R)-喹啉-3-羧酸(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-(3R)-4,7-二甲基吡唑并[5,1-c][1,2,4]三嗪-3-羧酸(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-(3R)-4-氨基-3,5-二氯-N-(9-二甲氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基)苯甲酰胺;
-(3R)-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基)-2-苯并呋喃甲酰胺;
-(3R)-4,7-二甲基吡唑并[5,1-c][1,2,4]三嗪-3-羧酸[4-氧代-1-苯基-9-(吡咯烷-1-基)-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-吡啶-2-羧酸(3R)-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-吡嗪-2-羧酸(3R)-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]酰胺;
-(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]苯甲酰胺;和
-(3R)-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]烟酰胺。
10.根据权利要求9的应用,其特征在于式(I)的二氮杂并吲哚是下列化合物:
-(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-3,5-二氯苯甲酰胺;
-(3R)-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-异烟酰胺;
-(3R)-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-烟酰胺;和
-(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]苯甲酰胺。
11.(3R)-4-氨基-N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]苯甲酰胺在制备治疗慢性阻塞性肺部疾病药物中的应用。
12.(3R)N-(9-氨基-4-氧代-1-苯基-3,4,6,7-四氢[1,4]二氮杂并[6,7,1-hi]吲哚-3-基]-烟酰胺在制备治疗慢性阻塞性肺部疾病药物中的应用。
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AU (1) | AU5181301A (zh) |
BR (1) | BR0102289A (zh) |
CA (1) | CA2347337A1 (zh) |
CZ (1) | CZ20011999A3 (zh) |
EA (1) | EA200100515A3 (zh) |
HU (1) | HUP0102388A3 (zh) |
IL (1) | IL143636A0 (zh) |
MX (1) | MXPA01005726A (zh) |
NO (1) | NO20012831L (zh) |
NZ (1) | NZ512222A (zh) |
PL (1) | PL347922A1 (zh) |
SK (1) | SK7832001A3 (zh) |
ZA (1) | ZA200104616B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108578413A (zh) * | 2012-05-22 | 2018-09-28 | Paion英国有限公司 | 包含短效苯二氮杂*类化合物的组合物 |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050085430A1 (en) * | 2003-07-31 | 2005-04-21 | Robinson Cynthia B. | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a PDE-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease |
US20090274676A1 (en) * | 2003-07-31 | 2009-11-05 | Robinson Cynthia B | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a pde-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease |
US20050026883A1 (en) * | 2003-07-31 | 2005-02-03 | Robinson Cynthia B. | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a PDE-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease |
US20050187278A1 (en) * | 2003-08-28 | 2005-08-25 | Pharmacia Corporation | Treatment or prevention of vascular disorders with Cox-2 inhibitors in combination with cyclic AMP-specific phosphodiesterase inhibitors |
ES2378374T3 (es) | 2003-11-20 | 2012-04-11 | Astellas Pharma Inc. | Inhibidores de la PDE 4 para el tratamiento de la cistitis intersticial |
DE102004002557A1 (de) * | 2004-01-17 | 2005-08-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von substituierten Pyrimido(5,4-d)pyrimidinen zur Behandlung von Atemwegserkrankungen |
WO2008007071A1 (en) | 2006-07-10 | 2008-01-17 | Cenes Limited | Short-acting benzodiazepine salts and their polymorphic forms |
US8426673B2 (en) | 2008-01-11 | 2013-04-23 | Astellas Pharma, Inc. | Pathological animal model for pelvic pain syndrome |
EP2450039A1 (en) | 2010-11-08 | 2012-05-09 | PAION UK Ltd. | Dosing regimen for sedation with CNS 7056 (Remimazolam) |
AR094963A1 (es) | 2013-03-04 | 2015-09-09 | Ono Pharmaceutical Co | Reacción de oxidación excelente en el índice de conversión |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2652352A1 (fr) | 1989-09-28 | 1991-03-29 | Jouveinal Sa | Benzodiazepines, leur procede et intermediaires de preparation et leurs applications en therapeutique. |
FR2725719B1 (fr) | 1994-10-14 | 1996-12-06 | Jouveinal Inst Rech | Diazepino-indoles inhibiteurs de phosphodiesterases iv |
FR2746800B1 (fr) * | 1996-03-29 | 1998-06-05 | Jouveinal Inst Rech | Diazepino-indoles inhibiteurs de phosphodiesterases 4 |
FR2762841B1 (fr) | 1997-04-30 | 1999-07-02 | Jouveinal Inst Rech | Diazepino-indolones inhibitrices de phosphodiesterases iv |
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2000
- 2000-06-09 EP EP00401646A patent/EP1161949A1/en not_active Withdrawn
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2001
- 2001-05-11 CA CA002347337A patent/CA2347337A1/en not_active Abandoned
- 2001-06-05 CZ CZ20011999A patent/CZ20011999A3/cs unknown
- 2001-06-06 PL PL01347922A patent/PL347922A1/xx not_active Application Discontinuation
- 2001-06-06 EA EA200100515A patent/EA200100515A3/ru unknown
- 2001-06-06 ZA ZA200104616A patent/ZA200104616B/xx unknown
- 2001-06-07 IL IL14363601A patent/IL143636A0/xx unknown
- 2001-06-07 SK SK783-2001A patent/SK7832001A3/sk unknown
- 2001-06-07 US US09/876,719 patent/US6544983B2/en not_active Expired - Fee Related
- 2001-06-07 AU AU51813/01A patent/AU5181301A/en not_active Abandoned
- 2001-06-07 NZ NZ512222A patent/NZ512222A/xx unknown
- 2001-06-07 AR ARP010102725A patent/AR030291A1/es not_active Application Discontinuation
- 2001-06-07 BR BR0102289-0A patent/BR0102289A/pt not_active IP Right Cessation
- 2001-06-07 MX MXPA01005726A patent/MXPA01005726A/es unknown
- 2001-06-08 KR KR1020010031887A patent/KR20010111457A/ko not_active Application Discontinuation
- 2001-06-08 NO NO20012831A patent/NO20012831L/no not_active Application Discontinuation
- 2001-06-08 HU HU0102388A patent/HUP0102388A3/hu unknown
- 2001-06-08 CN CN01120850A patent/CN1345725A/zh active Pending
- 2001-06-08 JP JP2001174372A patent/JP2002138090A/ja active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108578413A (zh) * | 2012-05-22 | 2018-09-28 | Paion英国有限公司 | 包含短效苯二氮杂*类化合物的组合物 |
Also Published As
Publication number | Publication date |
---|---|
MXPA01005726A (es) | 2003-08-20 |
JP2002138090A (ja) | 2002-05-14 |
PL347922A1 (en) | 2001-12-17 |
HUP0102388A3 (en) | 2004-11-29 |
US6544983B2 (en) | 2003-04-08 |
KR20010111457A (ko) | 2001-12-19 |
CA2347337A1 (en) | 2001-12-09 |
EA200100515A2 (ru) | 2001-12-24 |
BR0102289A (pt) | 2002-03-12 |
EA200100515A3 (ru) | 2002-06-27 |
NO20012831L (no) | 2001-12-10 |
EP1161949A1 (en) | 2001-12-12 |
IL143636A0 (en) | 2002-04-21 |
AR030291A1 (es) | 2003-08-20 |
HU0102388D0 (en) | 2001-08-28 |
NO20012831D0 (no) | 2001-06-08 |
HUP0102388A2 (hu) | 2002-04-29 |
NZ512222A (en) | 2002-10-25 |
SK7832001A3 (en) | 2002-05-09 |
AU5181301A (en) | 2001-12-13 |
CZ20011999A3 (cs) | 2002-04-17 |
US20020010175A1 (en) | 2002-01-24 |
ZA200104616B (en) | 2002-10-30 |
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