CN1148188C - 镇痛剂 - Google Patents
镇痛剂 Download PDFInfo
- Publication number
- CN1148188C CN1148188C CNB998123684A CN99812368A CN1148188C CN 1148188 C CN1148188 C CN 1148188C CN B998123684 A CNB998123684 A CN B998123684A CN 99812368 A CN99812368 A CN 99812368A CN 1148188 C CN1148188 C CN 1148188C
- Authority
- CN
- China
- Prior art keywords
- ethyl
- methyl
- piperidin
- phenyl
- isoquinolin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明提供一种用于头痛、偏头痛等各种疾病以及外伤、物理性压迫引起的疼痛的新型镇痛剂。本发明的镇痛剂的有效成分为下面通式表示的苯衍生物(I)或其药理学允许的盐。式中,R1为下面通式表示的基团或下面通式表示的基团。R2、R3、R4、R5表示取代基,环A表示苯环或噻吩环。
Description
技术领域
本发明涉及新型的镇痛剂。
先有技术
头痛、偏头痛等的各种疾病以及外伤、物理性压迫等引发的各种疼痛,通常要持续一定时间,虽然症状有所不同,但大多难以忍耐。所以与原因性疾病等的治疗不同,缓解疼痛将会极大地提高患者的生活质量。
目前使用的治疗疼痛的镇痛剂主要是解热镇痛消炎剂和麻药。
解热镇痛消炎剂可以使用具体如阿司匹林、布洛芬、吲哚美辛、吡罗昔康、甲芬那酸等,麻药例如盐酸吗啡、硫酸吗啡等。
但是由于上述解热镇痛消炎剂对前列腺素的生合成产生抑制作用,通常会造成消化道的损害,副作用较大。另外阿司匹林等会引发哮喘的恶化。
另外对于麻药来说,由于存在药物依赖性的问题,有必要慎重给药,另外存在引起便秘等副作用。
所以在目前还没有对头痛、偏头疼等各种疾病以及伴随外伤和物理性压迫等引发的疼痛具有治疗、改善作用,且安全性优良的镇痛剂的现状下,强烈期待开发出新型的镇痛药物。
发明的公开
为改善这种现状,本发明者对新型镇痛剂的开发进行了多年的探索研究。
结果意外发现,本发明的苯衍生物(I)具有与麻药相同获更优良的镇痛作用,且具有高度安全性,由此达到了研究的目的,完成了本发明。
本发明的目的是提供一种对以往临床中没有有用性高的药物治疗的头痛、偏头痛等各种疾病以及伴随外伤、物理性压迫引起的疼痛具有治疗、改善作用的新型药物,这种药物具有临床有效性高、安全性优良等特点。
另外,本发明提供将药理学有效剂量的苯衍生物(I)或其药理学允许的盐给予人用于预防、治疗、改善疼痛的方法,以及将苯衍生物(I)或其药理学允许的盐用于镇痛剂的制造的用途。
本发明的有效成分是下式表示的苯衍生物(I)或其药理学允许的盐。
式中,R1为下式表示的基团
(式中,R4表示从低级酰基氨基烷基、酰氨基低级烷基、N-低级烷基酰氨基烷基、N,N-二低级烷基酰氨基烷基和N-羟基低级烷基酰氨基烷基中选择的基团,n表示0或1-3的整数,键
表示单键或双键。)
或下式表示的基团
(式中,环A表示苯环或噻吩环、R5表示低级烷基或羟基低级烷基。);
R2、R3可以相同也可以不同,表示从氢原子、卤素原子、低级烷基、低级烷氧基、氰基、羟基低级烷基、羟基低级烷氧基、N-低级烷基酰氨基和低级烷基磺酰基氨基烷基中选择的基团。
作为上述低级烷基,具体例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基等碳原子数1-6的直链或支链烷基。
作为卤素原子,具体例如氟原子、氯原子、溴原子等,优选氟原子或氯原子。
作为低级烷氧基为上述低级烷基与氧原子结合的基团,具体例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、戊氧基、己氧基等。
本发明的苯衍生物(I)存在光学异构体、几何异构体、水和物或多晶形,本发明也包括这些物质。
另外本发明中药理学允许的盐,只要是与苯衍生物(I)形成的加成盐即可,没有特别的限定,通常例如盐酸盐、硫酸盐、硝酸盐、磷酸盐等无机盐;草酸盐、马来酸盐、富马酸盐等有机酸盐;甲磺酸盐、苯磺酸盐、甲苯磺酸盐等磺酸盐。
作为苯衍生物(I)优选如下式(II)或(III)表示的化合物或其药理学允许的盐。
式中,R6与上述R4,R7、R8、R10、R11与上述R2、R3含义相同,R9与R5含义相同,环A与上述含义相同,另外键
表示单键或双键。
作为本发明的苯衍生物(I),具体例如下面的化合物,但本发明并不局限于此。
(1)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基氨基甲基〕吲哚
(2)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-丙酰基氨基甲基〕吲哚
(3)1-〔1-(4-甲氧基苯乙基)哌啶-4-基〕-6-〔N-乙酰基氨基甲基〕吲哚
(4)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基氨基甲基〕吲哚
(5)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基酰氨基甲基〕吲哚
(6)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-羟乙基酰氨基甲基〕吲哚
(7)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N,N-二甲基酰氨基甲基〕吲哚
(8)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-酰氨基甲基吲哚
(9)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-甲基酰氨基甲基〕吲哚
(10)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-甲基酰氨基甲基〕吲哚
(11)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-乙基酰氨基甲基〕吲哚
(12)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-羟乙基酰氨基甲基〕吲哚
(13)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-酰氨基甲基吲哚
(14)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基氨基甲基〕二氢吲哚
(15)1-(4-乙基哌嗪-1-基)-3-(4-甲氧基苯基)异喹啉
(16)1-(4-乙基哌嗪-1-基)-3-(4-羟基乙氧基苯基)异喹啉
(17)1-(4-乙基哌嗪-1-基)-3-〔4-(1-羟丙基)苯基〕异喹啉
(18)1-(4-乙基哌嗪-1-基)-3-〔4-(N-丙基酰氨基)苯基〕异喹啉
(19)1-(4-乙基哌嗪-1-基)-3-〔3-氟-4-(3-羟基-3-甲基丁基)苯基〕异喹啉
(20)1-(4-乙基哌嗪-1-基)-3-(3-甲氧基-4-羟丙基苯基)异喹啉
(21)1-(4-乙基哌嗪-1-基)-3-(3-氰基-4-羟基乙氧基苯基)异喹啉
(22)1-(4-乙基哌嗪-1-基)-3-(3-羟基丙基苯基)异喹啉
(23)1-(4-乙基哌嗪-1-基)-3-(3-氯-4-丙基磺酰基氨基甲基苯基)异喹啉
(24)4-(4-乙基哌嗪-1-基)-6-〔4-(2-羟基丙氧基)苯基〕噻吩并〔3,2-c〕吡啶
(25)4-(4-乙基哌嗪-1-基)-6-〔4-(2-羟基-2-甲基丙氧基)苯基〕噻吩并〔3,2-c〕吡啶
(26)4-(4-乙基哌嗪-1-基)-6-〔4-(1-羟基乙基)苯基〕噻吩并〔3,2-c〕吡啶
(27)4-(4-羟基乙基哌嗪-1-基)-6-〔4-(2-羟基-2-甲基丙氧基)苯基〕噻吩并〔3,2-c〕吡啶
这些化合物具体例的结构式如下所示。
另外本发明的苯衍生物(I)为公知化合物,可以按照国际公开公报WO98/43956号或WO99/18077号记载的方法合成。
下面按照乙酸writhing法通过药理试验例具体说明本发明苯衍生物(I)的镇痛效果。
药理试验例
(1)供试动物
使用4-7周龄的雄性ddY小鼠。将小鼠预备饲养1周以上后用于试验。饲养期间可随意摄取固体饲料和灭菌自来水,试验开始前一天晚上开始禁食,可随意饮水。
(2)试验设计
试验者无法识别被检药物,随机给药。每组10只。
(3)试验方法
3-1)被检药物
使用下面化合物作为本发明苯衍生物(I)的代表例。
另外使用盐酸吗啡、特开平5-170,743号公报(EP-512,755号公报)公开的WAY-100,635以及US-5,134,149号公报公开的MDL-100,907作为对照品。
(1)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基氨基甲基〕吲哚
(2)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-丙酰基氨基甲基〕吲哚
(3)1-〔1-(4-甲氧基苯乙基)哌啶-4-基〕-6-〔N-乙酰基氨基甲基〕吲哚
(4)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基氨基甲基〕吲哚
(5)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基酰氨基甲基〕吲哚
(6)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-羟乙基酰氨基甲基〕吲哚
(7)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N,N-二甲基酰氨基甲基〕吲哚.草酸盐
(8)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-酰氨基甲基吲哚
(9)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-甲基酰氨基甲基〕吲哚
(10)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-甲基酰氨基甲基〕吲哚
(11)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-乙基酰氨基甲基〕吲哚
(12)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-羟乙基酰氨基甲基〕吲哚
(13)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-酰氨基甲基吲哚
(14)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基氨基甲基〕二氢吲哚
(15)1-(4-乙基哌嗪-1-基)-3-(4-甲氧基苯基)异喹啉
(16)1-(4-乙基哌嗪-1-基)-3-(4-羟基乙氧基苯基)异喹啉
(17)1-(4-乙基哌嗪-1-基)-3-〔4-(1-羟丙基)苯基〕异喹啉
(18)1-(4-乙基哌嗪-1-基)-3-〔4-(N-丙基酰氨基)苯基〕异喹啉.盐酸盐
(19)1-(4-乙基哌嗪-1-基)-3-〔3-氟-4-(3-羟基-3-甲基丁基)苯基〕异喹啉.盐酸盐
(20)1-(4-乙基哌嗪-1-基)-3-(3-甲氧基-4-羟丙基苯基)异喹啉.盐酸盐
(21)1-(4-乙基哌嗪-1-基)-3-(3-氰基-4-羟基乙氧基苯基)异喹啉.盐酸盐
(22)1-(4-乙基哌嗪-1-基)-3-(3-羟基丙基苯基)异喹啉.盐酸盐
(23)1-(4-乙基哌嗪-1-基)-3-(3-氯-4-丙基磺酰基氨基甲基苯基)异喹啉.盐酸盐
(24)4-(4-乙基哌嗪-1-基)-6-〔4-(2-羟基丙氧基)苯基〕噻吩并〔3,2-c〕吡啶.盐酸盐
(25)4-(4-乙基哌嗪-1-基)-6-〔4-(2-羟基-2-甲基丙氧基)苯基〕噻吩并〔3,2-c〕吡啶.盐酸盐
(26)4-(4-乙基哌嗪-1-基)-6-〔4-(1-羟基乙基)苯基〕噻吩并〔3,2-c〕吡啶.草酸盐
(27)4-(4-羟基乙基哌嗪-1-基)-6-〔4-(2-羟基-2-甲基丙氧基)苯基〕噻吩并〔3,2-c〕吡啶.盐酸盐
3-2)被检药物的调制
将被检化合物在试验当天溶解在溶剂(5%糖溶液)中,然后用溶剂稀释。对不能溶解的被检药物,加入溶剂用超声波处理使药物分散,然后加入1N盐酸溶解。
3-3)试验程序
测定试验开始前一日晚开始禁食的小鼠的体重,然后分别转移至饲养箱中驯化30分钟以上。将被检药物在小鼠颈部背侧方皮下给药(1ml/100gBW),然后15分钟后腹腔注射0.6%乙酸(1ml/100g BW),10分钟后开始观察,计数小鼠10分钟内腹部的细微蠕动次数(writhing运动)。
3-4)数据解析
求出每组平均的writhing次数及标准误差。分散分析writhing运动的统计学差异,通过Dunnett型多重比较检定(两侧检定,显著水平:5%),求出统计学的最小有效量。
(4)结果
下表所示为本发明化合物和对照品的镇痛作用(最小有效量)。
另外,根据国际申请号JP98/01481号或特愿平10-281752号说明书记载的方法进行测定,记录5-羟色胺(5HT)受体的结合作用(RBA;invitro)和肌肉松弛作用(in vivo)。(表中n.t.表示未进行试验)。
化合物 镇痛作用 RBA 肌肉松弛作用
(mg/kg) (Ki,nM) (mg/kg)
(sc) 5HT1A 5HT2 (po) (ip)
盐酸吗啡 1 n.t. n.t. 无效(引起紧张)
WAY-100,635 3 0.4 >200 n.t. >10
MDL-100,907 3 >200 0.4 1 0.3
(1) 0.3 0.51 1.38 1 0.3
(2) 3 1.0 2.6 3 0.3
(3) 10 0.27 >20 n.t. n.t.
(4) 3 1.58 0.75 10 n.t.
(5) 3 1.05 2.86 10 n.t.
(6) >10 1.73 3.55 10 n.t.
(7) >10 0.8 21.9 n.t. n.t.
(8) >3 0.06 3.29 3 n.t.
(9) 1 1.82 1.26 3 0.3
(10) 3 4.02 1.23 <1 3
(11) 3 1.78 1.64 10 n.t.
(12) 10 13.46 1.49 >10 n.t.
(13) 3 0.59 2.81 3 1
(14) 0.3 6.43 0.43 0.3 0.3
(15) 3 59.9 11.1 n.t. n.t.
(16) 1 31.5 4.2 3 1
(17) 1 6.9 1.6 10 1
(18) 1 14.6 1.1 3 >10
(19) 1 31.2 0.7 3 <10
(20) 3 7.9 10.9 10 n.t.
(21) 1 13.4 4.5 n.t. 10
(22) 3 54.5 17.4 n.t. n.t.
(23) 3 0.9 0.7 >30 n.t.
(24) 1 27.9 0.9 3 1
(25) 10 54.9 1.4 1 0.3
(26) 1 15.0 16.9 <3 n.t.
(27) 1 1530 0.35 n.t. n.t.
本发明化合物的给药剂型可以为散剂、微粒剂、颗粒剂、片剂、包衣片剂、胶囊剂等口服制剂;软膏、贴付剂等外用制剂;以及栓剂和注射用制剂等。在制剂化时,可以使用常用的制剂载体按通用方法制造。
在制备口服制剂时,可以将苯衍生物(I)和赋型剂,或根据需要再加入抗氧化剂、粘合剂、崩解剂、润滑剂、着色剂、矫味剂等,按常法制得散剂、微粒剂、颗粒剂、片剂、包衣片剂、胶囊剂等。
作为赋型剂,例如乳糖、玉米淀粉、白糖、葡萄糖、甘露糖醇、山梨糖醇、微晶纤维素、二氧化硅等;作为粘合剂,例如聚乙烯醇、聚乙烯醚、甲基纤维素、乙基纤维素、阿拉伯胶、黄耆胶、明胶、紫胶、羟丙基甲基纤维素、羟丙基纤维素、聚乙烯吡咯烷酮、聚丙烯醇-聚氧乙烯-嵌段聚合物、葡甲胺等;作为崩解剂,例如淀粉、琼脂、明胶粉、微晶纤维素、碳酸钙、碳酸氢钠、枸橼酸钙、右旋糖苷、果胶、羧甲基纤维素钙等;作为润滑剂例如滑石、聚乙烯醇、硅胶、硬化植物油等;作为矫味剂例如古柯粉、薄荷脑、芳香散、薄荷油、桂脑、桂皮末等。这些片剂和颗粒剂也可以根据需要包糖衣或包衣。
在制造注射用制剂时,可以在苯衍生物(I)中加入pH调整剂、溶解剂、等张化剂等,也可以根据需要加入溶解辅助剂、稳定化剂、抗氧化剂等,按常法制得。
制造外用制剂的方法没有特别的限定,可以根据常法制备。作为制剂化使用的基质原料,可以使用药品、医药外用品、化妆品等通常使用的各种原料。
作为所使用基质原料的具体例,如动植物油、矿物油、酯油、蜡、高级醇类、脂肪酸类、硅油、表面活性剂类、醇类、多价醇类、水溶性高分子类、粘土矿物质类、精制水等,也可以根据需要添加pH调整剂、抗氧化剂、螯合剂、防腐剂、着色剂、香料等。本发明使用的外用制剂的基质原料没有特别的限定。另外也可以根据需要与血流促进剂、杀菌剂、消炎剂、细胞赋活剂、维生素类、氨基酸类、保湿剂、角质溶解剂等成分配合使用。上述基质原料的添加量可以根据通常使用外用制剂时设定的浓度来添加。
本发明的苯衍生物(I)的临床给药量,根据给药对象、症状、疾病程度、年龄、并发症等不同没有特别的限定,另外给药途径也不相同。通常成人1日给药量为0.01mg-2000mg,优选0.1mg-1500mg,更优选1mg-1000mg,可以口服、静脉内注射、肌肉注射、直肠给药或皮下给药。
根据以上所述,可以明确得知本发明的苯衍生物(I)具有与盐酸吗啡相同或更优良的镇痛作用。另外由于本发明衍生物(I)同时具有很高的安全性,所以期待本发明在临床上具有更大的用途。
Claims (6)
1.选自以下的化合物或其可药用盐用于制备镇痛剂的用途:
(1)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基氨基甲基〕吲哚;
(2)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-丙酰基氨基甲基〕吲哚;
(4)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基氨基甲基〕吲哚;
(5)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基酰氨基甲基〕吲哚;
(9)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-甲基酰氨基甲基〕吲哚;
(10)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-甲基酰氨基甲基〕吲哚;
(11)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-乙基酰氨基甲基〕吲哚;
(13)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-酰氨基甲基吲哚;
(14)1-〔1-(4-氟苯乙基)哌啶-4-基〕-6-〔N-乙酰基氨基甲基〕二氢吲哚;
(15)1-(4-乙基哌嗪-1-基)-3-(4-甲氧基苯基)异喹啉;
(16)1-(4-乙基哌嗪-1-基)-3-(4-羟基乙氧基苯基)异喹啉;
(17)1-(4-乙基哌嗪-1-基)-3-〔4-(1-羟丙基)苯基〕异喹啉;
(18)1-(4-乙基哌嗪-1-基)-3-〔4-(N-丙基酰氨基)苯基〕异喹啉;
(19)1-(4-乙基哌嗪-1-基)-3-〔3-氟-4-(3-羟基-3-甲基丁基)苯基〕异喹啉;
(20)1-(4-乙基哌嗪-1-基)-3-(3-甲氧基-4-羟丙基苯基)异喹啉;
(21)1-(4-乙基哌嗪-1-基)-3-(3-氰基-4-羟基乙氧基苯基)异喹啉;
(22)1-(4-乙基哌嗪-1-基)-3-(3-羟基丙基苯基)异喹啉;
(23)1-(4-乙基哌嗪-1-基)-3-(3-氯-4-丙基磺酰基氨基甲基苯基)异喹啉;
(24)4-(4-乙基哌嗪-1-基)-6-〔4-(2-羟基丙氧基)苯基〕噻吩并〔3,2-c〕吡啶;
(26)4-(4-乙基哌嗪-1-基)-6-〔4-(1-羟基乙基)苯基〕噻吩并〔3,2-c〕吡啶;和
(27)4-(4-羟基乙基哌嗪-1-基)-6-〔4-(2-羟基-2-甲基丙氧基)苯基〕噻吩并〔3,2-c〕吡啶。
2.权利要求1的用途,其中所述化合物是(10)1-〔1-(2-氟苯乙基)哌啶-4-基〕-6-〔N-甲基酰氨基甲基〕吲哚。
3.权利要求1或2的用途,其中镇痛剂用于预防、治疗或改善头痛。
4.权利要求1或2的用途,其中镇痛剂基于5HT1A受体结合作用。
5.权利要求1或2的用途,其中镇痛剂基于5HT2受体结合作用。
6.权利要求1或2的用途,其中镇痛剂基于5HT1A受体结合作用和5HT2受体结合作用。
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WO2003059351A1 (en) * | 2001-12-21 | 2003-07-24 | Eisai Co., Ltd. | Hydroxylated indole derivatives and uses thereof |
EP1438956A1 (en) * | 2003-01-16 | 2004-07-21 | Newron Pharmaceuticals S.p.A. | Alpha-aminoamide derivatives useful as antimigraine agents |
EP2332527A3 (en) | 2004-10-20 | 2011-11-16 | Resverlogix Corp. | Flavanoids and Isoflavanoids for the prevention and treatment of cardiovascular diseases |
AU2006275514B2 (en) | 2005-07-29 | 2012-04-05 | Resverlogix Corp. | Pharmaceutical compositions for the prevention and treatment of complex diseases and their delivery by insertable medical devices |
PT2118074E (pt) | 2007-02-01 | 2014-03-20 | Resverlogix Corp | Compostos para a prevenção e tratamento de doenças cardiovasculares |
CA2711103C (en) | 2008-06-26 | 2016-08-09 | Resverlogix Corp. | Methods of preparing quinazolinone derivatives |
CA2747417C (en) | 2009-01-08 | 2017-01-03 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular disease |
CA3146333A1 (en) | 2009-03-18 | 2010-09-23 | Resverlogix Corp. | Phenyl-quinazolin-4(3h)-one and phenyl-pyrido[2,3-d]pyrimidin-4(3h)-one derivatives and compositions thereof useful as anti-inflammatory agents |
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JP5992049B2 (ja) | 2011-11-01 | 2016-09-14 | レスバーロジックス コーポレイション | 置換されたキナゾリノンのための経口速放性製剤 |
US9073878B2 (en) | 2012-11-21 | 2015-07-07 | Zenith Epigenetics Corp. | Cyclic amines as bromodomain inhibitors |
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CA2345406A1 (en) | 2000-04-27 |
WO2000023075A1 (fr) | 2000-04-27 |
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