CN1127250A - 2，3-桥连的1，4-二氢吡啶类化合物及其制法和其药用 - Google Patents
2，3-桥连的1，4-二氢吡啶类化合物及其制法和其药用 Download PDFInfo
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- CN1127250A CN1127250A CN95116650A CN95116650A CN1127250A CN 1127250 A CN1127250 A CN 1127250A CN 95116650 A CN95116650 A CN 95116650A CN 95116650 A CN95116650 A CN 95116650A CN 1127250 A CN1127250 A CN 1127250A
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Abstract
本发明涉及新的通式(I)的2，3-桥连的1，4-二氢吡啶类化合物，其中R、R1、R2、D和E如说明书中所定义，本发明还涉及这些化合物的制备方法，它们作为药物的用途，优选用于治疗中枢神经系统疾病。
Description
本发明涉及新的2，3-桥连的1，4-二氢吡啶类化合物及其制备方法和它们作为药物的用途，优选用于治疗中枢神经系统疾病。
由公开文献DE 2003148已知具有解痉作用和抗高血压作用的1，4，5，6，7，8-六氢-5-氧代喹啉类化合物和1，2，3，4，5，6，7，8，9，10-十氢-1，8-二氧代吖啶类化合物。
另外，还已知具有增加大脑循环作用的1-取代-1，4-二氢吡啶衍生物[参见DE2302866]。
本发明涉及新的通式(I)的2，3-桥连的1，4-二氢吡啶类化合物及其盐：其中：
R代表具有6至10个碳原子的芳基或吡啶基，它们各自以相同或不同的方式至多5次被氰基、卤素、三氟甲基或具有至多6个碳原子的直链或支链烷硫基任意取代，
R1代表氢或代表具有至多8个碳原子的直链或支链烷基，
R2代表具有至多6个碳原子的直链或支链烷基，或代表具有3至6个碳原子的环烷基，和
D和E一起代表式-CO-(CH2)3-、-CO-CH2-C(CH3)2-CH2-、-CO-O-CH2-或-CH2-O-CO-的二价基团。
令人惊奇地，本发明化合物对钾通道表现出特定的选择性的调节作用，因此它们适合用作药物，特别是用作治疗中枢神经系统疾病的药剂。
生理上可接受的盐一般为本发明化合物与无机酸或有机酸形成的盐。优选的盐是与无机酸形成的盐，所述无机酸为例如盐酸、氢溴酸、磷酸或硫酸，或与有机羧酸或磺酸形成的盐，例如乙酸、马来酸、富马酸、苹果酸、柠檬酸、酒石酸、乳酸或苯甲酸或甲磺酸、乙磺酸、苯磺酸、甲苯磺酸或萘二磺酸。
本发明化合物可以立体异构体形式存在，它们表现为镜像(对映体)或非镜像(非对映体)。本发明涉及对映体、外消旋体以及非对映体混合物。外消旋体如非对映体可按已知方法分离成单一的立体异构体组分。
优选的化合物是如下定义的通式(I)化合物及其盐，其中：
R代表苯基、萘基或吡啶基，它们各自以相同或不同的方式至多3次被氰基、氟、氯、溴、碘、三氟甲基或具有至多4个碳原子的直链或支链烷硫基任意取代，
R1代表氢或代表具有至多6个碳原子的直链或支链烷基，
R2代表具有至多4个碳原子的直链或支链烷基、环丙基、环戊基或环己基，和
D和E一起代表式-CO-(CH2)3-、-CO-CH2-C(CH3)2-CH2-、-CO-O-CH2-或-CH2-O-CO-基团。
特别优选的通式(I)化合物是如下定义的通式(I)化合物及其盐，其中：
R代表苯基或吡啶基，它们各自以相同或不同的方式至多2次被氰基、氟、氯、三氟甲基或甲硫基任意取代，
R1代表具有至多4个碳原子的直链或支链烷基，
R2代表甲基、乙基或环丙基，和
D和E一起代表式-CO-(CH2)3-、-CO-CH2-C(CH3)2-CH2-、-CO-O-CH2-或-CH2-O-CO-基团。
本发明的通式(I)化合物表现出不可预见的有用的药理作用谱。
本发明化合物是对钙依赖性的钾通道(BK(Ca)通道)的大传导具有令人惊奇的选择性的通道调节剂，特别是中枢神经系统的钾通道调节剂，而且它们的特征在于没有显著的钙拮抗作用和钙激动作用。
根据本发明化合物的药理性质，它们可用于制备治疗中枢变性疾病的药物，例如痴呆(多发梗塞性痴呆(MID)，原发性变性痴呆(PDD)，早老性和老年性阿尔茨海默氏病、HIV痴呆和其它形式的痴呆)，帕金森病或肌萎缩性侧索硬化以及多发性硬化。
本发明的活性化合物还适合用于治疗与年龄有关的大脑功能失调、器质性脑病综合征(OBS)以及与年龄有关的记忆损伤(AAMI)。
本发明化合物适合用于预防和治疗以及处理大脑循环失调产生的后遗症如大脑局部缺血、中风和颅脑创伤，以及蛛网膜下出血产生的后遗症。
本发明化合物可用于治疗抑郁症和精神病如精神分裂症。另外它们也适合用于治疗神经内分泌失调和神经传质分泌失调以及与健康方面有关的失调如躁狂、醇中毒、药物滥用、成瘾或病理性饮食行为。使用的其它领域是治疗偏头痛、睡眠失调和神经病。另外，本发明化合物还适于用作止痛药。
本发明活性化合物还适合用于治疗免疫系统失调特别是T细胞增殖，并且适于对平滑肌系统特别是对子宫、膀胱和支气管道的平滑肌系统产生作用，因此可用于治疗有关疾病如哮喘、尿失禁，以及用于治疗心律失常、绞痛和糖尿病。
本发明的通式(I)化合物可按下述方法制备：
[A]当D/E≠-CH2-O-CO-时，使通式(II)的醛：
R-CHO (II)其中R包括上述定义范围，与通式(III)和(IV)化合物在惰性溶剂中若必要的话在碱和/或助剂存在下反应，
其中：R1、D和E具有上述定义，但R1不代表氢，将通式(II)化合物首先转化为通式(V)化合物：
其中R、R1、D和E具有上述定义，然后按常规方法使产物与式(VI)的烷基化剂反应，
R2-X (VI)其中：
R2具有上述定义，和
X代表卤素，优选碘，或者
[B]当D/E代表式-CH2-O-CO基团时，使式(VII)的2-氨基-2-丁烯-4-交酯
与通式(VIII)的亚苄基化合物在惰性溶剂中在乙酸存在下反应，
其中R和R1具有上述定义，得到通式(IX)化合物：
其中R和R1具有上述定义，然后用常规试剂进行烷基化反应，当其中的R1＝H时，用常规方法水解酯化合物。
用下列反应式通过实例说明本发明的方法：
用于此反应的合适溶剂为在反应条件下不发生变化的所有惰性有机溶剂，优选包括醇类如甲醇、乙醇、丙醇或异丙醇，或醚类如乙醚、二噁烷、四氢呋喃、乙二醇二甲醚或二甘醇二甲醚、乙腈、丙酮或酰胺类如六甲基磷酰三胺或二甲基甲酰胺，或卤代烃如二氯甲烷或四氯化碳，或烃如苯或甲苯。也可以使用上述溶剂的混合物。特别优选异丙醇、乙醇、四氢呋喃、甲醇、二噁烷、丙酮和二甲基甲酰胺。
合适的碱一般为碱金属氢化物、碳酸盐或醇盐如氢化钠、碳酸钾或叔丁醇钾，或环胺如哌啶或二甲基氨基吡啶，或C1-C4烷基胺如三乙胺。根据具体的反应步骤，优选哌啶、二甲基氨基吡啶、吡啶、氢化钠、叔丁醇钾和碳酸钾。
为实施本发明的方法，可使用任何所需比例的参与反应的物质。然而，一般使用摩尔量的反应物。
反应温度可在相当宽的范围内变化。一般地，反应可在+10℃至+150℃，优选+20℃至+100℃下，特别是在具体溶剂的沸点下进行。
反应可在常压下进行，但也可以在加压或减压(例如0.5至3bar)下进行。一般地反应在常压下进行。
同样用于烷基化反应的合适的溶剂为在反应条件下不发生变化的常用有机溶剂，优选包括醚类如乙醚、二噁烷、四氢呋喃或乙二醇二甲醚，烃如苯、甲苯、二甲苯、己烷、环己烷或石油馏分，或卤代烃如二氯甲烷、氯仿、四氯化碳、二氯乙烯、三氯乙烯或氯苯，或乙酸乙酯，或三乙胺、吡啶、二甲亚砜、二甲基甲酰胺、六甲基磷酰三胺、乙腈、丙酮或硝基甲烷。也可以使用上述溶剂的混合物。优选二甲基甲酰胺。
合适的碱一般为碱金属氢化物或醇盐如氢化钠或叔丁醇钾，或环胺如哌啶或二甲基氨基吡啶，或C1-C4烷基胺如三乙胺。优选氢化钠。
反应温度可在相当宽的范围内变化。一般地，反应可在-10℃至150℃，优选+20℃至+100℃下，特别是在室温下进行。
烷基化反应可在上述溶剂中在-5℃至+150℃温度，优选0℃至+100℃下进行。
反应可在常压下进行，但也可以在加压或减压(例如0.5至3bar)下进行。反应一般在常压下进行。
在每种情况下，对于每摩尔欲烷基化的化合物，一般使用的碱的量为1mol至3mol，优选1mol至2mol。
对映体纯形式可例如按下述方法制得，即按常规方法分离其中R1/R1′代表旋光酯基的通式(I)化合物的非对映体混合物，然后直接酯化，或首先制备手性羧酸然后通过酯化作用制备对映体纯的二氢吡啶类化合物。
非对映体一般可用分级结晶法、柱色谱法或Craig分配法分离。最佳方法应视具体情况而定，有时也可使用单个方法的组合。通过结晶法或Craig分配法或这两种方法的组合进行分离是特别适合的。
对映体纯化合物也可通过在手性相上对外消旋酯进行色谱分离得到。
通式(II)、(III)、(IV)、(V)、(VI)、(VII)和(VIII)化合物是已知的或可按常规方法制备。
本发明的新的通式(I)化合物表现出有用的、不可预见的作用谱，特别是基于它们对高传导性的钙依赖性钾通道的大传导所具有的选择性。从C6-BU1-神经胶质瘤细胞中流出的86铷流量
接Tas等人所述的方法(Neurosci.Lett.94，279-284，(1988))只做稍微改变进行试验。由试验数据计算用伊屋诺霉素引起的超过基本流量的流量增加值并且定为100％。在试验物质存在下的刺激以此值为基准计算。试验数据实施例14-(2，3-二氯苯基)-1，2-二甲基-5-氧代-1，4，5，7，8-六氢喹啉-3-羧酸异丙酯施用1μM试验物质时为38％剩余流量。实施例81，4，5，7-四氢-4-(4-氯苯基)-1，2-二甲基-7-氧代-呋喃并(furo)[3，4b]吡啶-3-羧酸甲酯施用1μM试验物质时为53％剩余流量。实施例111，4，5，7-四氢-4-(2，3-二氟苯基)-1，2-二甲基-5-氧代-呋喃并(furo)[3，4b]吡啶-3-羧酸甲酯施用1μM试验物质时为73％剩余流量。
本发明还涉及药物制剂，它除了含有惰性无毒适合药用的助剂和赋形剂外还包括一种或多种通式(I)化合物，或者它由一种或多种式(I)活性化合物组成，本发明也涉及这些制剂的制备方法。
式(I)活性化合物在这些制剂中存在的浓度应为占总混合物重量的0.1至99.5％(重量)，优选0.5至95％(重量)。
除了式(I)活性化合物之外，药物制剂还可含有其它药物活性化合物。
上述药物制剂可按常规方式用已知方法制备，例如使用助剂或一种或多种赋形剂。
一般地，为达到所希望的结果，在每24小时内最好施用活性化合物或式(I)化合物的总量为大约0.01至大约100mg/kg，优选总量为大约1mg/kg至50mg/kg体重，若必要的话，可采用几次分剂量形式给药。
然而，若必要的话，偏离上述剂量可能是有利的，特别应根据下述情况进行改变：受治疗者的状况和体重、个体对药物的反应、疾病的性质和严重程度、制剂和给药的特性以及给药的时间和间隔。流动相混合物：a：二氯甲烷/AcOEt 10＋1b：二氯甲烷/MeOH 10＋1c：PE/AcOEt 7＋3起始化合物实施例I1，4，5，7-四氢-4-(4-氯苯基)-2-甲基-5-氧代-呋喃并[3，4b]吡啶-3-甲酸甲酯
将3g(21.3mmol)4-氯苯甲醛、4.0g(21.3mmol)4-乙酸基乙酰乙酸甲酯(按DE 84 34436 78制备)和2.5g(21.3mmol)3-氨基丁烯酸甲酯溶于40ml异丙醇中，并将溶液加热回流12小时，然后加入10ml稀盐酸水溶液，并再将混合物加热回流30分钟。将混合物在甲苯和水之间分配。将有机相干燥(MgSO4)并浓缩得到白色固体，用50g硅胶(AcOEt：PE1＋1)过滤纯化，随后经AcOEt/PE重结晶，得到2.6g(8.13mmol，理论值的38％)标题化合物。实施例II4-(2，3-二氯苯基)-2-甲基-5-氧代-1，4，5，7，8-六氢喹啉-3-甲酸异丙酯
将3.50g(20mmol)2，3-二氯苯甲醛、2.24g(20mmol)二氢间苯二酚和2.86g(20mmol)3-氨基丁烯酸异丙酯溶于100ml异丙醇中，并将溶液回流搅拌5小时。产物沉淀，加入50ml水，并将混合物冷却至室温。抽吸滤出产物，接着依次用异丙醇、乙醇和乙醚洗涤。产量：5.8g(理论值的74％)。实施例III2-叠氮基-γ-丁内酯
将1.56g(10mmol)2-溴-γ-丁内酯溶于2ml二甲基甲酰胺中，并在0℃下加入612mg(12.5mmol)叠氮化锂。将混合物在室温下搅拌2小时，加入水，用二氯甲烷萃取混合物三次。将合并的有机相用水洗涤三次，用硫酸钠干燥并浓缩，得到1.10g(理论值的86.6％)标题化合物。MS：127实施例IV2-氨基-丁烯-4-交酯
将1.02g(0.8mmol)实施例III化合物与2ml乙醇的混合物在20℃下滴加到50g钠的5ml乙醇溶液中。然后将混合物在室温下搅拌30分钟并在减压下浓缩。沉淀出的固体在搅拌下用乙醇萃取，将残余物溶于热的乙酸乙酯中。将溶液过滤并浓缩，得到350mg(理论值的44％)无色固体。MS：99实施例V1，4，5，7-四氢-4-(2，3-二氯苯基)-2-甲基-7-氧代-呋喃并[3，4-b]吡啶-3-甲酸异丙酯
将9.0g(30mmol)2-乙酰基-3-(2，3-二氯苯基)丙烯酸异丙酯和3.0g(30mmol)实施例IV化合物溶于60ml异丙醇中，加入1.7ml(30mmol)AcOH。将混合物保持回流20小时，然后浓缩，残余物用100g硅胶60(乙酸乙酯/石油醚10∶1，然后5∶1)进行色谱纯化。所得物质用乙醚重结晶，得到4.08g(理论值的36％)标题化合物。MS：381，Rf＝0.61(石油醚/AcOEt＝7＋3)。制备实施例实施例14-(2，3-二氯苯基)-1，2-二甲基-5-氧代-1，4，5，7，8-六氢喹啉-3-甲酸异丙酯
将1.5g(3.8mmol)4-(2，3-二氯苯基-2-甲基-5-氧代-1，4，5，7，8-六氢喹啉-3-甲酸异丙酯溶于20ml二甲基甲酰胺中，并在0℃下加入138mg(4.6mmol)NaH。将混合物在室温下搅拌15分钟，在0℃下加入1.08g(7.6mmol)甲基碘，将混合物再在室温下搅拌30分钟。加入水，并用AcOEt萃取混合物3次。将有机相用水洗涤5次、干燥并浓缩。残余物经异丙醇/石油醚重结晶。得到1.20g(理论值的77％)标题化合物，MS：407，Rf＝0.52(a)。
按类似实施例1的方法制备表1中列出的化合物。
表1
| 实施例编号 | X，Y | R1 | 产率(理论值的％) | 熔点(℃)/Rf/MS |
| 2 | 3-H，4-Cl | CH3 | 72 | 0.42(CH2Cl2/AcOEt10＋1)345 |
| 3 | 2-Cl，3-Cl | -CH3 | 74 | 0.33(CH2Cl2/AcOEt10＋1)379 |
按类似实施例1的方法，用在二甲基甲酰胺中的1.04g(7.14mol)甲基碘甲基化1.5g(3.55mol)4-(2，3-二氯苯基)-2-甲基-5-氧代-1，4，5，6，7，8-六氢喹啉-3-甲酸异丙酯得到0.98g(理论值的63％)标题化合物。产率：理论值的60％Rf＝0.59(CH2Cl2/AcOEt＝10＋1)，MS：435。
按类似实施例4的方法制备表2中列出的化合物。
表2
| 实施例编号 | X，Y | R1 | 产率(理论值的％) | 熔点(℃)/Rf |
| 5 | 3-H，4-Cl | CH3 | 76 | 0.9(CH2Cl2/MeOH 10＋1) |
| 6 | 2-Cl，3-Cl | CH3 | 77 | 0.85(CH2Cl2/MeOH 10＋1) |
按类似实施例1的方法，用在二甲基甲酰胺中的1.47g(10.4mol)甲基碘甲基化2.0g(5.24mol)1，4，5，7-四氢-4-(4-氯苯基)-2-甲基-5-氧代-呋喃并[3，4-b]吡啶-3-甲酸甲酯得到1.07g标题化合物。产率：理论值的29％Rf＝0.40(CH2Cl2/AcOEt10＋1)，MS：395。
按类似实施例7的方法制备表3中列出的化合物：
表3
| 实施例编号 | X，Y | R1 | R2 | 产率(理论值的％) | 熔点(℃)/Rf |
| 8 | 4-Cl，3-H | CH3 | CH3 | 54 | 167-70 |
| 9 | 2-Cl，3-Cl | (CH3)2HC- | C2H5 | 9 | 154-55 |
| 10 | 2-Cl，3-Cl | CH3 | CH3 | 69 | 0.72/b |
| 11 | 2-F，3-F | CH3 | CH3 | 65 | 0.29/a |
| 12 | 4-F | CH3 | CH3 | 35 | 0.28/a |
| 13 | 2-F，6-Cl | CH3 | CH3 | 34 | 0.37/a |
使1.5g(3.92mmol)1，4，5，7-四氢-4-(2，3-二氯苯基)-2-甲基-7-氧代-呋喃并[3，4-b]吡啶-3-甲酸异丙酯与141mg(4.70mmol)NaH和1.11g(7.84mmol)甲基碘反应得到0.97g(理论值的63％)的标题化合物。MS：395Rf＝0.61(PE/AcOEt＝7＋3)
按类似实施例14的方法制备表4中列出的化合物。
表4
| 实施例编号 | R1 | R2 | 产率(理论值的％) | Rf |
| 15 | -CH(CH3)2 | 2-Cl，3-Cl | 63 | 0.61/c |
| 16 | -CH(CH3)2 | 4-Cl | 47 | 0.65/c |
| 17 | -CH3 | 2-Cl，3-Cl | 62 | 0.47/c |
Claims (8)
1.通式(I)的2，3-桥连的1，4-二氢吡啶类化合物及其盐：其中：
R代表具有6至10个碳原子的芳基或吡啶基，它们各自以相同或不同的方式至多5次被氰基、卤素、三氟甲基或具有至多6个碳原子的直链或支链烷硫基任意取代，
R1代表氢或代表具有至多8个碳原子的直链或支链烷基，
R2代表具有至多6个碳原子的直链或支链烷基，或代表具有3至6个碳原子的环烷基，和
D和E一起代表式-CO-(CH2)3-、-CO-CH2-C(CH3)2-CH2-、-CO-O-CH2-或-CH2-O-CO-的二价基团。
2.根据权利要求1的通式(I)化合物及其盐，其中：
R代表苯基、萘基或吡啶基，它们各自以相同或不同的方式至多3次被氰基、氟、氯、溴、碘、三氟甲基或具有至多4个碳原子的直链或支链烷硫基任意取代，
R1代表氢或代表具有至多6个碳原子的直链或支链烷基，
R2代表具有至多4个碳原子的直链或支链烷基、环丙基、环戊基或环己基，和
D和E一起代表式-CO-(CH2)3-、-CO-CH2-C(CH3)2-CH2-、-CO-O-CH2-或-CH2-O-CO-基团。
3.根据权利要求1的通式(I)化合物及其盐，其中：
R代表苯基或吡啶基，它们各自以相同或不同的方式至多2次被氰基、氟、氯、三氟甲基或甲硫基任意取代，
R1代表具有至多4个碳原子的直链或支链烷基，
R2代表甲基、乙基或环丙基，和
D和E一起代表式-CO-(CH2)3-、-CO-CH2-C(CH3)2-CH2-、-CO-O-CH2-或-CH2-O-CO-基团。
4.权利要求1的通式(I)化合物的制备方法，其特征在于：
[A]当D/E≠-CH2-O-CO-时，使通式(II)的醛：
R-CHO (II)其中R包括在上述定义范围内，与通式(III)和(IV)化合物在惰性溶剂中若必要的话在碱和/或助剂存在下反应；
其中：R1、D和E具有上述定义，但R1不代表氢，将通式(II)化合物首先转化为通式(V)化合物：其中R、R1、D和E具有上述定义，然后按常规方法使产物与式(VI)的烷基化剂反应
R2-X (VI)其中：
R2具有上述定义，和
X代表卤素，优选碘，或者
[B]当D/E代表式-CH2-O-CO基团时，使式(VII)的2-氨基-2-丁烯-4-交酯
与通式(VIII)的亚苄基化合物在惰性溶剂中在乙酸存在下反应，
其中R和R1具有上述定义，得到通式(IX)化合物：
其中R和R1具有上述定义，然后用常规试剂进行烷基化反应，当其中的R1＝H时，用常规方法水解酯化合物。
5.含有至少一种权利要求1的通式(I)化合物的药物。
6.药物的制备方法，其特征在于将至少一种权利要求1的通式(I)化合物转化为合适的给药形式，若必要的话，加入常用的助剂和赋形剂。
7.用于治疗疾病的权利要求1的通式(I)化合物。
8.权利要求1的通式(I)化合物在制备治疗中枢神经系统疾病的药物中的用途。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4430092.1 | 1994-08-25 | ||
| DE4430092A DE4430092A1 (de) | 1994-08-25 | 1994-08-25 | 2,3-Cyclisch kondensierte 1,4-Dihydropyridine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
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| CN1127250A true CN1127250A (zh) | 1996-07-24 |
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| CN95116650A Pending CN1127250A (zh) | 1994-08-25 | 1995-08-24 | 2，3-桥连的1，4-二氢吡啶类化合物及其制法和其药用 |
Country Status (15)
| Country | Link |
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| US (1) | US6121284A (zh) |
| EP (1) | EP0705830A1 (zh) |
| JP (1) | JPH0859622A (zh) |
| KR (1) | KR960007594A (zh) |
| CN (1) | CN1127250A (zh) |
| AU (1) | AU3011095A (zh) |
| CA (1) | CA2156672A1 (zh) |
| CZ (1) | CZ217495A3 (zh) |
| DE (1) | DE4430092A1 (zh) |
| FI (1) | FI953956A (zh) |
| HU (1) | HU218209B (zh) |
| IL (1) | IL115029A0 (zh) |
| NO (1) | NO953321L (zh) |
| PL (1) | PL310147A1 (zh) |
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| US6265417B1 (en) | 1997-12-18 | 2001-07-24 | Abbott Laboratories | Potassium channel openers |
| US6593335B1 (en) | 1997-12-18 | 2003-07-15 | Abbott Laboratories | Potassium channel openers |
| JP2002528452A (ja) * | 1998-10-28 | 2002-09-03 | アボット・ラボラトリーズ | ジヒドロピリジン化合物および使用方法 |
| MXPA02008615A (es) * | 2000-03-03 | 2003-04-14 | Abbott Lab | Abridores de canales de potasio de dihidropirazolona triciclica y dihidroisoxazolona triciclica. |
| US6538004B2 (en) | 2000-03-03 | 2003-03-25 | Abbott Laboratories | Tricyclic dihydropyrazolone and tricyclic dihydroisoxazolone potassium channel openers |
| US20050075359A1 (en) * | 2003-03-14 | 2005-04-07 | Rikako Kono | Large conductance calcium-activated K channel opener |
| EP1663227A2 (en) * | 2003-09-10 | 2006-06-07 | Synta Pharmaceuticals Corporation | Dihydropyridine compounds for treating or preventing metabolic disorders |
| US8916550B2 (en) * | 2005-05-09 | 2014-12-23 | Hydra Biosciences, Inc. | Compounds for modulating TRPV3 function |
| EP1888575A2 (en) * | 2005-05-09 | 2008-02-20 | Hydra Biosciences, Inc. | Compounds for modulating trpv3 function |
| US9233926B2 (en) * | 2008-09-17 | 2016-01-12 | Sanford-Burnham Medical Research Institute | Compounds for stem cell differentiation |
| EP2348855A4 (en) * | 2008-09-17 | 2013-01-09 | Burnham Inst Medical Research | SMALL MOLECULE COMPOUNDS FOR THE DIFFERENTIATION OF STEM CELLS |
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| DE2003148A1 (de) | 1970-01-24 | 1971-07-29 | Bayer Ag | Neue 1,4-Dihydropyridinderivate |
| GB1430961A (en) | 1972-01-22 | 1976-04-07 | Yamanouchi Pharma Co Ltd | 1-substituted-1,4-dihyddrypyridine derivatives |
| US4021434A (en) * | 1972-01-22 | 1977-05-03 | Yamanouchi Pharmaceutical Co., Ltd. | Sodium β-[2,6-dimethyl-3,5-bis(ethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-1-yl]ethyl sulfate |
| DE3410645A1 (de) * | 1984-03-23 | 1985-09-26 | Bayer Ag, 5090 Leverkusen | L-alkylsubstituierte 1,4-dihydropyridinlactone, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln |
| DE3443678A1 (de) * | 1984-11-30 | 1986-06-05 | Bayer Ag, 5090 Leverkusen | Verfahren zur herstellung von 4-acyloxy-3-oxo-buttersaeureestern |
| DE3521761A1 (de) * | 1985-06-19 | 1987-01-02 | Bayer Ag | Neue 1,4-dihydropyridine, verfahren zur herstellung und ihre verwendung in arzneimitteln |
| DE3629545A1 (de) * | 1986-08-30 | 1988-03-10 | Bayer Ag | Dihydropyridinverbindungen, verfahren zu ihrer herstellung und ihre verwendung |
| DE4125271A1 (de) * | 1991-07-31 | 1993-02-11 | Bayer Ag | Neue n-alkylierte 1,4-dihydropyridindicarbonsaeureester |
-
1994
- 1994-08-25 DE DE4430092A patent/DE4430092A1/de not_active Withdrawn
-
1995
- 1995-08-14 EP EP95112764A patent/EP0705830A1/de not_active Withdrawn
- 1995-08-17 AU AU30110/95A patent/AU3011095A/en not_active Abandoned
- 1995-08-18 US US08/516,804 patent/US6121284A/en not_active Expired - Fee Related
- 1995-08-18 JP JP7234704A patent/JPH0859622A/ja active Pending
- 1995-08-22 IL IL11502995A patent/IL115029A0/xx unknown
- 1995-08-22 CA CA002156672A patent/CA2156672A1/en not_active Abandoned
- 1995-08-23 PL PL95310147A patent/PL310147A1/xx unknown
- 1995-08-23 FI FI953956A patent/FI953956A/fi unknown
- 1995-08-24 KR KR1019950026300A patent/KR960007594A/ko not_active Application Discontinuation
- 1995-08-24 SK SK1044-95A patent/SK104495A3/sk unknown
- 1995-08-24 CN CN95116650A patent/CN1127250A/zh active Pending
- 1995-08-24 NO NO953321A patent/NO953321L/no unknown
- 1995-08-24 CZ CZ952174A patent/CZ217495A3/cs unknown
- 1995-08-25 HU HU9502503A patent/HU218209B/hu not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DE4430092A1 (de) | 1996-02-29 |
| NO953321D0 (no) | 1995-08-24 |
| HU218209B (hu) | 2000-06-28 |
| FI953956A0 (fi) | 1995-08-23 |
| SK104495A3 (en) | 1996-06-05 |
| AU3011095A (en) | 1996-03-07 |
| PL310147A1 (en) | 1996-03-04 |
| CZ217495A3 (en) | 1996-03-13 |
| CA2156672A1 (en) | 1996-02-26 |
| KR960007594A (ko) | 1996-03-22 |
| HUT74615A (en) | 1997-01-28 |
| FI953956A (fi) | 1996-02-26 |
| EP0705830A1 (de) | 1996-04-10 |
| IL115029A0 (en) | 1995-12-08 |
| HU9502503D0 (en) | 1995-10-30 |
| JPH0859622A (ja) | 1996-03-05 |
| NO953321L (no) | 1996-02-26 |
| US6121284A (en) | 2000-09-19 |
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