CN1266434A - 1,2,4-三唑并[4,3b]吡啶并[3,2-d]哒嗪衍生物和含有它们的药用组合物 - Google Patents
1,2,4-三唑并[4,3b]吡啶并[3,2-d]哒嗪衍生物和含有它们的药用组合物 Download PDFInfo
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Abstract
式(Ⅰ)杂环化合物及其药学上可接受的盐,其中R1代表氢原子或-(CH2)m-Y基团,其中m是0—4的整数且Y代表烷基、卤代烷基、烷氧基、烷氧羰基、C3-C7环烷基、降冰片基或苯基链烯基、或芳基,所述芳基Y可任选一个或一个以上的卤原子取代;R2代表芳基该芳基可任选一个或一个以上的卤素原子或烷基、烷氧基、C3-C6环烷氧基、亚甲二氧基、硝基、二烷基氨基或三氟甲基基团取代;且R3代表氢或卤原子或烷基基团,以及它们的制备过程。这些化合物是磷酸二酯酶4抑制剂。
Description
本发明涉及新的对治疗有用的杂环化合物、及制备它们的方法和含有它们的药用组合物。
已知磷酸二酯酶4(PDE 4)抑制剂在治疗炎症和变态反应过程如哮喘、非甾体类抗炎药诱导的胃肠道损伤和特异性皮炎中是有用的。
现在我们已发现在上述结构中存在吡啶环以代替苯并环,得到抑制环磷酸二酯酶,尤其是4型环磷酸二酯酶并仅有极小催吐作用(对狗的诱导呕吐作用比环戊苯吡酮低10-100倍)的新化合物。
R1代表氢原子或-(CH2)m-Y基团,其中m是0-4的整数且Y代表烷基、卤代烷基(优选三氟甲基)、烷氧基、烷氧羰基、C3-C7环烷基、降冰片基(优选2-降冰片基)或苯基链烯基,或芳基(优选苯基或吡啶基)其芳基Y可任选被一个或一个以上的卤原子取代;
R2代表芳基(优选苯基、萘基或噻吩基)其芳基可任选一个或一个以上的卤原子或烷基、烷氧基、C3-C6环烷氧基、亚甲二氧基、硝基、二烷基氨基或三氟甲基取代;且
R3代表氢原子或卤原子(优选氯代)或烷基基团。
上述与本发明化合物中R1-R3基团相关的烷基、卤代烷基、链烯基、炔基基团和部分,如在烷氧基中,通常是“低级”烷基,即是含有多达6个(特别是多达4个)碳原子,烃链是直链或支链的烷基。烷基或部分的例子有CH3、C2H5、C3H7、i-C3H7、n-C4H9、i-C4H9、异戊基和新戊基。
当任一基团,如R1或R2具有手性中心时,式(I)化合物表现出旋光异构性而其异构体包括在本发明的范围内。
R1的实例优选为上述的烷基,环丙基、环丙基甲基、环丁基、环丁基甲基、环戊基和环戊基甲基。
R2的实例有苯基、3-氯苯基、4-氯苯基、3-氟苯基、4-氟苯基和3-硝基苯基。
R3的实例优选在8-或9-位有氢、烷基或氯代。
最优选的本发明化合物是:
6-(4-氟代苯基)-3-异丁基-1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪,3-环丙基甲基-6-(3-硝基苯基)-1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪、3-环丙基-6-苯基-1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪和3-环丁基甲基-6-(3-硝基苯基)-1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪。
根据本发明的另一个特征,式(I)杂环化合物可由式(II)的相应的肼衍生物:其中:
R2或R3与上述定义相同,通过与通式(III)的羧酸活性衍生物反应而制备:
HOOC-R1 (III)其中R1与上述定义相同。所述羧酸的活性衍生物可以是,例如,卤化物(优选氯化物)、酸酐或酸酐混合物。
该反应优选在在-10℃至+60℃的温度,在有机含氮碱,如三乙胺的存在下,在惰性有机溶剂如二氯甲烷、二噁烷或四氢呋喃中进行。在该反应中,一般首先形成相应的通式(IV)的酰肼:其中R1、R2和R3的定义同上。将该酰肼(IV)的有机溶剂如二噁烷、四氢呋喃、异丙醇或正丁醇的悬液加热,如在溶剂沸点下加热,得到相应的式(I)杂环化合物。
式(II)肼衍生物可按如下制备:
2)使式(VI)化合物与式(VII)的烷基carbazate(优选叔丁基carbazate)反应:
H2N-NH-COOR5 (VII)其中R5是烷基,得到烷氧基羰基肼衍生物(VIII):其中R2、R3和R5定义同上;和
3)用在无水溶剂如乙醇中的氯化氢处理式(VIII)化合物。
式(V)腙与卤化磷或磷酰卤的反应用过量试剂在80℃-120℃的温度下进行,然后除去过量试剂并倒入冷水中。以此方法得到式(VI)化合物。
式(VI)化合物与式(VII)烷基carbazate得到相应的烷氧羰基肼衍生物(VIII)的反应,优选在有机溶剂如四氢呋喃或二噁烷存在下,于60℃至反应介质沸点的温度下进行。
式(VIII)烷氧羰基肼衍生物可以,例如,于室温下,在氯化氢-乙醇饱和溶液中转变为式(II)肼衍生物。
式(V)腙衍生物是已知化合物,它可按文献描述的已知方法由相应的2-酰基烟酸制备。
测定对豚鼠心脏的环核苷酸磷酸二酯酶的抑制作用采用96孔微量滴定板以Verghese等(Molecular Pharmacology,47,1164-1171(1995))描述的方法进行。
自该实验得到的结果见表1。
化合物* | PDE4IC50(μM) |
A67123147556061109112113 | 1020.330.20.70.20.120.040.70.2 |
(*)结构见表2。
化合物A是包括在EP-A-85840中的化合物3-异丁基-6-苯基-1,2,4-三唑并[3,4-a]2,3-二氮杂萘。
如表1所见,式(I)化合物是环磷酸二酯酶抑制剂,尤其是4型环AMP磷酸二酯酶抑制剂。这些化合物还可阻断某些炎症细胞因子前体,如TNFα的生成。因此,它们可用于治疗变态反应性、炎症性和免疫学上的疾病,及其中阻断炎症细胞因子前体或选择性抑制PDE4是有益的那些疾病或病症。
所述疾病包括哮喘、类风湿性关节炎、骨关节炎、骨质疏松症、骨形成失调、肾小球性肾炎、多发性硬化、格雷夫斯氏眼病、重症肌无力、胰岛素依赖性糖尿病、移植排斥反应、胃肠道失调如溃疡性结肠炎或克罗恩氏病、脓毒性休克、成人呼吸窘迫综合征、及皮肤病如特异性皮炎、接触性皮炎、急性皮肌炎和牛皮癣。
它们还用于改善脑血管功能以及治疗其它与中枢神经系统相关的疾病如痴呆、阿尔海默氏病、抑郁症和用作酰胺吡咯烷酮类药物。
本发明化合物当与其它药物如甾体类和免疫抑制剂,例如环胞菌素A、雷帕酶素或T-细胞受体阻断剂联合用药时也是有效的。在此情况下服用本化合物可减少其它药物的剂量,因此防止出现与甾体类和免疫抑制剂相关的不良副作用。
对于病原(etiological agents)如抗炎药(甾体类或非甾体类抗炎药)、紧张、氨、乙醇及浓酸诱发的腐蚀和致溃疡作用,本发明化合物还在预防和/或治疗给药后显示出阻断作用。它们可单独或与抗酸剂和/或抗分泌剂联合使用以预防和/或治疗胃肠道病症如药物诱发的溃疡、消化性溃疡、幽门螺杆菌(H.Pylori)-相关的溃疡、食管炎和胃-食管反流病。
它们还可用于治疗其中如缺氧条件下或自由基过量形成导致细胞或组织损伤的病理状态。此类有益作用的实例是在冠脉阻塞后保护心肌组织,或当本发明化合物加入用于贮存移植器官或体液如血液或精子的保存溶液时延长细胞或组织的存活期。它们还有利于组织修复及伤口愈合。
本发明还提供式(I)杂环化合物以治疗的形式用于人类或动物体的治疗方法,特别是用作PDE 4抑制剂或阻断炎症细胞因子前体如TNFα生成的方法。
此外本发明提供由至少一种作为活性成分的式(I)杂环化合物、和药学上可接受的载体或稀释剂组成的药用组合物。
优选的组合物是适于口服、吸入、直肠内、透皮、鼻腔内、局部或胃肠外给药的形式。
与一种或数种活性化合物混合以形成本发明组合物的药学上可接受的载体或稀释剂本身是为人们所熟知的,且使用的实际的赋形剂还取决于拟用的该组合物的用药方法。
本发明组合物优选采用口服给药。经口给药的组合物可采用片剂、胶囊、锭剂或泡腾颗粒剂或液体制剂如酏剂、糖浆剂或悬液,所有剂型中均含有一种或一种以上的本发明化合物。可以采用本领域所熟知的方法制备这些制剂,如将式(I)杂环化合物与药学上可接受的载体或稀释剂混合。
可以用于制备该组合物的稀释剂包括与活性成分相容的那些液体和固体稀释剂、需要时还包括着色剂或矫味剂。片剂或胶囊可方便地含有1-100mg并优选5-50mg的活性成分。这些化合物也可掺入以本领域已知合适的天然或合成的聚合物胞衣的丸剂中,以产生持续释放特性或与聚合物混合形成片剂以产生相同的特性。
适于口服的液体组合物可以溶液、悬液或气雾剂的形式使用。溶液可以是水或水-醇溶液与,如,蔗糖或山梨糖醇一起形成糖浆。悬液可由不溶或微囊形式的本发明活性化合物与水或其它可接受的溶剂以及悬浮剂或矫味剂共同组成。
吸入给药的组合物可以是装在适当吸入器中的溶液、悬液或微粒化粉末形式。
可制备供胃肠外注射用的组合物,其可以或不经过冷冻干燥并可溶于水或适当的胃肠外注射液体中。
在人体治疗中,这些杂环化合物的剂量取决于期望的效果和疗程;成人剂量一般为每天1mg-100mg。一般由医师决定剂量,并考虑接受治疗的患者的年龄和体重。
下列实施例进一步说明本发明。实施例1
a)将2-苯甲酰烟酸的叔丁氧羰基腙(45g;13.2mol)与磷酰氯(500ml)的混合物回流沸腾1小时,然后减压除去过量的磷酰氯,残留物以冰-水处理并以二氯甲烷抽提两次。有机溶液以4%的碳酸钠水溶液、盐水洗涤,并在干燥(Na2SO4)后真空除去溶剂。所得固体由乙醚-石油醚1∶1混合物收集得到5-氯-8-苯基吡啶并[2,3-d]哒嗪的红色固体(25.4g;产率80%)。
b)向上述化合物(18.2;0.075mols)的无水四氢呋喃(180ml)悬液中,加入叔丁基carbazate(10.0g;0.075mols)并使此混合物回流沸腾1小时。冷却后过滤收集结晶的固体得到5-叔丁氧基羰基肼基-8-苯基吡啶并[2,3-d]哒嗪(28.5g)。将该化合物溶于乙醇(150ml),加入氯化氢饱和的乙醇溶液(100ml)并将所得混合物在室温下搅拌15小时。过滤收集形成的固体并以乙醚洗涤给出5-肼基-8-苯基吡啶并[2,3-d]哒嗪二盐酸盐(21.6g;产率92%)。
c)向5-肼基-8-苯基吡啶并[2,3-d]哒嗪二盐酸盐(1.24g;0.004mols)的二氯甲烷(30ml)悬液中,加入三乙胺(1.9ml;0.013mols),然后于室温下搅拌15分钟并缓慢加入新戊酰氯(0.5ml;0.0044mols)。室温下搅拌2小时后加水(30ml),过滤收集形成的黄色固体并以乙醚洗涤给出中间体酰肼。将该化合物悬浮于正丁醇(30ml)中,沸腾回流1 5小时并在冷却时,过滤收集结晶的白色固体并以乙醚洗涤。所得固体以快速硅胶柱层析纯化且以二氯甲烷-乙醇-氢氧化铵200∶8∶1为洗脱液。得到3-叔丁基-6-苯基-1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪(0.83g;产率69%),m.p.188.1(微分扫描测热法测定,Perkin-ElmerDSC-7)(见表2中的化合物8)。
表2中的式(I)杂环化合物按照此实施例公开的步骤制备,但采用适当的起始物。
表2
化合物 | R1 | R2 | R3 | m.p.℃ |
12345678910111213141516171 819202122232425262728 | HCH3C2H5C3H7i-C3H7n-C4H9i-C4H9t-C4H9n-C5H11新戊基叔-戊基环丙基环丁基环戊基环己基环丙基-CH2环丁基-CH2环戊基-CH2环己基-CH22-降冰片基-CH2C6H5C6H5-CH2C6H5-CH2CH2C6H5-CH=CHCF3H3CO-CH22-CLC6H44-吡啶基 | C6H5″″″″″″″″″″″″″″″″″″″″″″″″″″″ | H″″″″″″″″″″″″″″″″″″″″″″″″″″″ | 215.8215.9194.1168.1176.8162.9179.7188.1137.4216.3153244.3218202.4196.3195183193212.8217304.1192176278192.5159206333.4 |
2930313233343536373839404142434445464748495051525354555657 | CH3n-C4H9i-C4H9t-C4H9新戊基环丙基环己基环丙基-CH2环丁基-CH2环戊基-CH22-降冰片基-CH2C6H5-CH=CHC2H5OOC-CH2i-C4H9新戊基环丙基环丙基-CH2环丁基-CH2环戊基-CH2i-C4H9t-C4H9新戊基环丙基环丙基-CH2i-C4H9环丙基i-C4H9t-C4H9新戊基 | 4-FC6H4″″″″″″″″″″″″3-FC6H4″″″″″2-FC6H4″″″″4-ClC6H4″3-ClC6H4″″ | ″″″″″″″″″″″″″″″″″″″″″″″″″″″″″ | 276111135195216245177160132162161272185147190222174139145202212235262224133208113160177 |
58596061626364656667686970717273747576777879808182838485 | 叔-戊基环丙基环丙基-CH2环丁基-CH2环戊基-CH2i-C4H9新戊基环丙基i-C4H9新戊基环丙基环丙基-CH2环戊基-CH22-降冰片基-CH2i-C4H9t-C4H9新戊基环丙基环丙基-CH2i-C4H9新戊基i-C4H9环丙基i-C4H9新戊基环丙基i-C4H9新戊基 | ″″″″″2-ClC6H4″″4-BrC6H4″″″″″3-BrC6H4″″″″3,4-二氯C6H3″3-CH3C6H4″2-CH3C6H4″″3,4-二CH3C6H3″ | ″″″″″″″″″″″″″″″″″″″″″″″″″″″″ | 150189136156147182216198135204208140187174152160177186143143215119206147191200165184 |
112113114115116117118119120121122123124125126127128129130 | 环丙基-CH2环丁基-CH2环戊基-CH2环丙基i-C4H9环丙基i-C4H9环丙基i-C4H9环丙基i-C4H9新戊基环丙基环戊基-CH22-降冰片基-CH2i-C4H9环丙基环丙基-CH2环戊基-CH2 | ″″″3-(CH3)2NC6H42-萘基″2-噻吩基″3-噻吩基″C6H5″″″″″″″″ | ″″″″″″″″″″8-H3C″″″″9-Cl″″″ | 164150183213140212196214166183170221185163193174149175175 |
下列实施例说明依据本发明的药用组合物。实施例2
3000支各装有40mg的3-叔丁基-6-苯基-1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪(活性化合物)的吸入瓶按如下配制:活性化合物 120g去水山梨糖醇三油酸酯 4g抛射剂 适量 60L步骤
以灌装机将这些组分制备的微晶悬液按每瓶20ml的体积导入吸入瓶。吸入瓶装有适当的阀门使每次触发时释放0.2ml的悬液(0.4mg活性化合物)。实施例3
15000粒各含20mg的3-叔丁基-6-苯基-1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪(活性化合物)胶囊按下列组方制备:活性化合物 300g羧甲基淀粉钠 330g滑石 195g氢化蓖麻油 165g玉米淀粉 495g步骤
上述组分以60目筛过筛后,以适当的混合器混合后装入15000粒明胶胶囊。
Claims (12)
1、式(I)化合物和其药学上可接受的盐其中:
R1代表氢原子或-(CH2)m-Y基团,其中m是0-4的整数且Y代表烷基、卤代烷基、烷氧基、烷氧碳基、C3-C7环烷基、降冰片基或苯基链烯基,或芳基其中芳基Y可任选被一个或一个以上的卤原子取代;
R2代表芳基,所述芳基可任选一个或一个以上的卤原子或烷基、烷氧基、C3-C6环烷氧基、亚甲二氧基、硝基、二烷基氨基或三氟甲基取代;且
R3代表氢原子或卤原子或烷基基团。
2、根据权利要求1的化合物,其中烷基、卤代烷基和烷氧基含有多达6个碳原子,烷氧羰基基团含有多达7个碳原子且苯基链烯基含有多达12个碳原子。
3、根据权利要求1或2的化合物,其中R1代表-(CH2)m-Y其中m是0或1且Y代表C1-C6烷基或C3-C7环烷基。
4、根据前述权利要求任何一项的化合物,其中R2代表苯基、萘基或噻吩基,所述基团R2可任选被一个或一个以上的卤原子、甲基、甲氧基、环戊氧基、硝基或二甲氨基取代。
5、根据权利要求4的化合物,其中的R2代表苯基、3-氯代苯基、4-氯代苯基、3-氟代苯基、4-氟代苯基或3-硝基苯基。
6、根据前述权利要求任何一项的化合物,其中R3代表氢原子、C1-C6烷基或氯原子在1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪碳架的8-或9-位。
7、根据权利要求1的化合物,所述化合物为6-(4-氟代苯基)-3-异丁基-1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪,3-环丙基甲基-6-(3-硝基苯基)-1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪,3-环丙基-6-苯基-1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪和3-环丁基甲基-6-(3-硝基苯基)-1,2,4-三唑并[4,3-b]吡啶并[3,2-d]哒嗪。
9、由根据权利要求1-7中任何一项的化合物或其药学上可接受的盐与药学上可接受的稀释剂或载体混合而成的组合物。
10、根据权利要求1-7中任何一项的化合物或其药学上可接受的盐或根据权利要求9的组合物用于治疗人或动物体的方法中。
11、根据权利要求1-7中任何一项的化合物或其药学上可接受的盐或根据权利要求9的组合物在制备用于治疗疾病的药物中的用途,所述疾病已知的治疗方法是抑制磷酸二酯酶4,所述疾病包括变态反应及其疾病状态、炎症、溃疡和免疫学上的疾病。
12、治疗已知是通过抑制磷酸二酯酶4治疗的疾病的方法,该方法包括给予需要接受这种治疗的人或动物以有效治疗量的根据权利要求1-7中任何一项的化合物或其药学上可接受的盐或根据权利要求9的组合物。
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Families Citing this family (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2792938B1 (fr) * | 1999-04-28 | 2001-07-06 | Warner Lambert Co | NOUVELLES 1-AMINO TRIAZOLO [4,3-a] QUINAZOLINE-5-ONES INHIBITRICES DE PHOSPHODIESTERASES IV |
JP5038568B2 (ja) | 1999-08-21 | 2012-10-03 | ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング | 協力剤の組合せ物 |
WO2002080974A1 (fr) * | 2001-04-04 | 2002-10-17 | Sankyo Company, Limited | Utilisation medicale d'inhibiteur de production de cytokine |
US20040242597A1 (en) * | 2001-09-19 | 2004-12-02 | Thomas Klein | Combination |
FR2832711B1 (fr) * | 2001-11-26 | 2004-01-30 | Warner Lambert Co | Derives de triazolo [4,3-a] pyrido [2,3-d] pyrimidin-5-ones, compositions les contenant, procede de preparation et utilisation |
JP4700965B2 (ja) * | 2002-11-06 | 2011-06-15 | あすか製薬株式会社 | ピラゾロナフチリジン誘導体 |
ES2211344B1 (es) | 2002-12-26 | 2005-10-01 | Almirall Prodesfarma, S.A. | Nuevos derivados de piridazin-3(2h)-ona. |
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 |
RU2246496C1 (ru) * | 2003-09-12 | 2005-02-20 | Тец Виктор Вениаминович | Вещество с противовирусной и антибактериальной активностью на основе производных 2,8-дитиоксо-1h-пирано[2,3-d, 6,5-d`] дипиримидина и их 10-аза-аналогов |
ES2251866B1 (es) | 2004-06-18 | 2007-06-16 | Laboratorios Almirall S.A. | Nuevos derivados de piridazin-3(2h)-ona. |
PT1898903E (pt) * | 2005-06-10 | 2013-06-28 | Merck Sharp & Dohme | Inibidores da atividade de akt |
JP2009506069A (ja) | 2005-08-26 | 2009-02-12 | ブレインセルス,インコーポレイティド | ムスカリン性受容体調節による神経発生 |
EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
CN101268073B (zh) | 2005-09-15 | 2011-10-19 | Aska制药株式会社 | 杂环化合物、制备方法及其用途 |
AU2006304787A1 (en) | 2005-10-21 | 2007-04-26 | Braincells, Inc. | Modulation of neurogenesis by PDE inhibition |
CA2625210A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
EP2377531A2 (en) | 2006-05-09 | 2011-10-19 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
EP2026813A2 (en) | 2006-05-09 | 2009-02-25 | Braincells, Inc. | 5 ht receptor mediated neurogenesis |
WO2008021781A1 (en) | 2006-08-07 | 2008-02-21 | Incyte Corporation | Triazolotriazines as kinase inhibitors |
US7998971B2 (en) | 2006-09-08 | 2011-08-16 | Braincells Inc. | Combinations containing a 4-acylaminopyridine derivative |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
ES2689444T3 (es) | 2006-11-22 | 2018-11-14 | Incyte Holdings Corporation | Imidazotriazinas e imidazopirimidinas como inhibidores de la quinasa |
WO2009089027A1 (en) * | 2008-01-09 | 2009-07-16 | Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Service, National Institutes Of Health | Phosphodiesterase inhibitors |
SI2300455T1 (sl) | 2008-05-21 | 2017-12-29 | Incyte Holdings Corporation | Soli 2-fluoro-n-metil-4-(7-(kinolin-6-il-metil)-imidazo(1,2-b)1,2,4) triazin-2-il)benzamid in postopki v zvezi z njihovo pripravo |
EP2196465A1 (en) | 2008-12-15 | 2010-06-16 | Almirall, S.A. | (3-oxo)pyridazin-4-ylurea derivatives as PDE4 inhibitors |
US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
EP2226323A1 (en) | 2009-02-27 | 2010-09-08 | Almirall, S.A. | New tetrahydropyrazolo[3,4-c]isoquinolin-5-amine derivatives |
SG182297A1 (en) | 2009-12-31 | 2012-08-30 | Ct Nac Investigaciones Oncologicas Cnio | Tricyclic compounds for use as kinase inhibitors |
BR112012019302B1 (pt) | 2010-02-03 | 2022-06-21 | Incyte Holdings Corporation | Imidazo[1,2-b] [1,2,4]triazinas como inibidores de c-met, composição que as compreende e métodos in vitro de inibir a atividade de c-met cinase, de inibir a via de sinalização da hgf/c-met cinase em uma célula e de inibir a atividade proliferativa de uma célula |
EP2380890A1 (en) | 2010-04-23 | 2011-10-26 | Almirall, S.A. | New 7,8-dihydro-1,6-naphthyridin-5(6h)-one-derivatives as PDE4 inhibitors |
EP2394998A1 (en) | 2010-05-31 | 2011-12-14 | Almirall, S.A. | 3-(5-Amino-6-oxo-1,6-dihydropyridazin-3-yl)-biphenyl derivatives as PDE4 inhibitors |
WO2012098387A1 (en) | 2011-01-18 | 2012-07-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | 6, 7-ring-fused triazolo [4, 3 - b] pyridazine derivatives as pim inhibitors |
WO2013004984A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncologicas (Cnio) | Tricyclic compounds for use as kinase inhibitors |
WO2013005057A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncológicas (Cnio) | New compounds |
WO2013005041A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncológicas (Cnio) | Tricyclic heterocyclic compounds as kinase inhibitors |
EP2804603A1 (en) | 2012-01-10 | 2014-11-26 | President and Fellows of Harvard College | Beta-cell replication promoting compounds and methods of their use |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3122670A1 (de) | 1981-06-06 | 1982-12-23 | Dr. Karl Thomae Gmbh, 7950 Biberach | "neue 1,4,9,10-tetrahydro-pyrazolo(4,3-e) pyrido(3,2-b)(1,4)diazepin-10-one, verfahren zu ihrer herstellung und ihre verwendung zur herstellung von pharmazeutischen wirkstoffen" |
FI81350C (fi) * | 1982-01-18 | 1990-10-10 | Lepetit Spa | Analogfoerfarande foer framstaellning av nya, farmakologiskt aktiva 6-substituerade s-triatsolo/3,4-a/ ftalazinderivat. |
JP3120857B2 (ja) * | 1990-02-19 | 2000-12-25 | 中外製薬株式会社 | 新規な縮合複素環化合物とこれを用いた抗喘息剤 |
HUT66969A (en) * | 1991-10-09 | 1995-01-30 | Syntex Inc | Benzo- and pyrido-pyridazinone- and pyridazin-thion derivatives, pharmaceutical compositions containing the same and process for the production of thereof |
GB9514465D0 (en) | 1995-07-14 | 1995-09-13 | Glaxo Lab Sa | Chemical compounds |
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