CN1131861C - 哌嗪衍生物及其制备方法 - Google Patents
哌嗪衍生物及其制备方法 Download PDFInfo
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- CN1131861C CN1131861C CN00135330A CN00135330A CN1131861C CN 1131861 C CN1131861 C CN 1131861C CN 00135330 A CN00135330 A CN 00135330A CN 00135330 A CN00135330 A CN 00135330A CN 1131861 C CN1131861 C CN 1131861C
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明提供了通式(B)的化合物及其可药用酸加成盐以及其制备方法。
Description
本申请系1996年7月19日提交的96195610一案的分案申请。
技术领域
本发明涉及新的哌嗪衍生物，它们的制备方法，它们的应用和含有它们的药物组合物。这种新的化合物用作5-HT1A结合剂，尤其是作为5-HT1A拮抗剂。
背景技术
EP-A-0512755公开了下面的通式化合物及其可药用酸加成盐：
其中：
A是2-4个碳原子的亚烷基，其选择性地被一个或多个低级烷基取代，
Z是氧或硫，
R是氢或低级烷基，
R1是单或二环芳基或杂芳基，
R2单或二环杂芳基，和
R3是氢，低级烷基，环烷基，环烯基，环烷基(低级)烷基，芳基，芳基(低级)烷基，杂芳基，杂芳基(低级)烷基，式-NR4R5基团[其中R4是氢，低级烷基，芳基或芳基(低级)烷基和R5是氢，低级烷基，-CO(低级)烷基，芳基，CO芳基，CO(低级)烷基，环烷基，或环烷基-(低级)烷基，或R4和R5与它们连结的氮原子一起表示饱和的杂环，其可以含有其他杂原子]或式OR6基团[其中R6是低级烷基，环烷基，环烷基(低级)烷基，芳基，芳基(低级)烷基，杂芳基或杂芳基(低级)烷基]。
该化合物作为5-HT1A结合剂，尤其是5-HT1A拮抗剂，例如，用于治疗CNS疾病，例如焦虑而被公开。
发明内容
我们现在发现，落入式(I)范围，但是在EP-A-0512755中没有具体被公开的化合物，及其可药用盐具有特别有用的性质，使得该化合物通过口服途径给药特别适用于作为治疗CNS疾病的5-HT1A拮抗剂。
本发明的新化合物是下面通式的化合物及其可药用酸加成盐：
式(A)化合物含有不对称碳原子，因此它可以存在不同的立体异构体形式，例如作为外消旋体或旋光异构体形式。优选的化合物是：
R-N-[1-[2-[1-[4-[5-(2，3-二氢[1，4]苯并二氧杂环己烯基)]哌嗪基]丙基]-N-(2-哌啶基)-环己基甲酰胺(下文中称为化合物A1)及其可药用酸加成盐。
我们已经发现，本发明的新化合物是有效的5-HT1A结合剂，其效能与EP-A-0512755中公开的最有效的化合物的类似。新化合物选择性地结合5-HT1A受体，其选择程度比它们结合其他受体，如α1受体要大得多。通过标准的药理学方法试验证明，新化合物是5-HT1A拮抗剂。出乎意料的是，我们发现，新化合物通过口服途径给药是特别有效的5-HT1A拮抗剂。当通过口服途径给药时，作为5-HT1A拮抗剂，新化合物比EP-A-0512755的最有效的化合物要更有效许多倍。本发明的5-HT1A拮抗剂可以用于治疗哺乳动物，尤其是人类的CNS疾病，如精神分裂症(和其他精神病如妄想狂和mano-抑郁症)和焦虑(例如综合焦虑疾病，恐慌性攻击和强迫观念与行为疾病)。该5-HT1A拮抗剂也可以用作抗抑郁药，治疗低血压和作为睡眠/觉醒循环调节剂，增强行为和/或性功能剂和作为识别增强剂。与在EP-A-512755中公开的一类化合物相比，本发明新化合物的增加的口服生物利用度是特别有利的，该化合物用小得多剂量通过口服给药产生类似的治疗效果。
具体实施方式
下面的表I和II总结了EP-A-512755中公开的化合物和本发明新化合物通过口服途径的5-HT1A受体结合活性，α1受体结合活性，结合选择性(即5-HT1A结合与α1-结合的比率)和5-HT1A拮抗剂活性。
表I
1 2 3 4 5 6
| 现有技术化合物(EP-0512755的实施例序号) | 5HT1A结合IC50(nM) | α1结合IC50(nM) | 比率5HT1A/α1 | 5-HT1A-拮抗剂活性MEDmg/kg口服 | 5-HT1A-拮抗剂比率* |
| 3 | 2.2 | 230 | 105 | 1 | 4.2 |
| 5 | 12 | 230 | 19.2 | ＞10 | |
| 6 | 60 | 245 | 4 | ||
| 8 | 90 | 140 | 2.5 | ||
| 11 | 1 | 197 | 197 | 10 | |
| 17 | 3.1 | 63 | 19.3 | 1 | 7.6 |
| 20 | 4.1 | 385 | 93.9 | ＞10 | |
| 30 | 14 | 74 | 5.3 | 10 | |
| 33 | 1.4 | 125 | 89.3 | 10 | 7.0 |
| 46 | 2.3 | 798 | 346.9 | 3 | |
| 47 | 4.9 | 64 | 13 | 3-10 | |
| 48 | 6.4 | 126 | 19.7 | ||
| 49 | 2.7 | 1403 | 519.6 | 10 | |
| 50 | 4 | 40 | 10 | ||
| 51 | 3.7 | 46 | 12.4 | ＜10 | |
| 52 | 147 | ||||
| 53 | 8 | 558 | 69.8 | 10 | |
| 54 | 175 | ||||
| 55 | 2.3 | 688 | 299.1 | 1 | 3.2 |
| 56 | 2.7 | 56 | 20.7 | ||
| 57 | 12.7 | 281 | 22.1 | ||
| 58 | 16 | 28 | 1.75 | 1-3 | |
| 59 | 67 | ||||
| 60 | 3 | 312 | 104 | 0.3 | 7.4 |
| 61 | 18 | 136 | 7.1 | ||
| 62 | 10 | 144 | 14.4 | ||
| 63 | 131 | ||||
| 64 | 35 | ||||
| 65 | 13 | 115 | 8.8 | ||
| 66 | 1.8 | 28 | 15.5 |
表II
1 2 3 4 5 6
| 本发明化合物 | 5-HT1A结合IC50(nM) | α1结合IC50(nM) | 5-HT1A/α1比率 | 5-HT1A拮抗剂活性MED mg/kg口服 | 5-HT1A拮抗剂比率* |
| A1 | 4.3 | 625 | 145 | 1 | 20 |
*(ED50拮抗剂@3mg/kg口服)/ED50载体
根据B.S.Alexander和M.D.Wood的方法，《药学和药理学杂志)》，1988，40，888-891，在鼠海马膜匀浆中测试化合物的5-HT1A结合亲和力(第2栏)。
根据A.L.Marrow等的方法，《分子药理学杂志》(Mol.Pharmacol.)，1986，29，321，测试化合物的α1结合亲和力(第3栏)。
通过选择性的5-HT1A受体激动剂，8-OH-DPAT，诱导鼠‘8-OH-DPAT综合症’的能力测试5-HT1A受体拮抗剂活性(第5和6栏)，其中鼠‘8-OH-DPAT综合症’的特征是平伸展体姿，前爪踩和过多运动(hyperlocomotion)。8-OH-DPAT综合症在试验激动剂经过外侧尾静脉静脉内(i.v)给药之后0-5分钟时间内以有(明确的综合症应答)和没有(不明确的或没有综合症应答)记分。
在初步评价以后。选择对数级的试验激动剂的剂量范围，包括期望的ED50。第一个动物接受接近所期望的ED50的试验激动剂剂量。如果动物产生响应(出现综合症)，下一个动物接受范围内的下一个最低剂量级，如果动物不产生应答(没有综合症或综合症不明显)，则下一个动物接受所选择范围内的下一个最高剂量级。该方法重复至少10个动物，并且连续地将动物进行试验。
在将8-OH-DPAT静脉内给药之前60分钟将试验拮抗剂口服(p.o.)给药。使用如上面描述的连续的高/低方法为不同的预处理组测定8-OH-DPAT的ED50值。
最低有效剂量(MEDs)作为最低的测试剂量得到，其中拮抗剂的ED50值和载体预处理组的置信限度没有重叠。
对选择性的5-HT1A受体激动剂，8-OH-DPAT的应答用诱导8-OH-DPAT综合症的ED50值表示，该值使用连续的高/低分析按静脉内给药测定。5-HT1A拮抗剂活性通过试验化合物与载体预处理相比的对抗8-OH-DPAT的应答，即增加诱导8-OH-DPAT综合症的ED50的能力测定。比率表示按用3mg/kg p.o.试验化合物预处理的8-OH-DPAT的ED50值(ED50拮抗剂)除以按用载体预处理的8-OH-DPAT的ED50值(ED50载体)。
即比率＝(ED50拮抗剂@3mg/kg p.o.)/(ED50载体)
通过计算相同剂量，即3mg/kg p.o.的所有化合物的比率，可以将它们在该剂量的效果作直接比较。因此比率越大，5-HT1A拮抗剂和载体预处理的ED50值之间的差别越大，因此拮抗剂效果越强。总之，该比率越大，口服给药的5-HT1A拮抗剂越有效。
将表现出最好的5-HT1A亲和力和5-HT1A/α1选择性的EP-A-512755的化合物进行5-HT1A拮抗剂活性试验(第5栏)，将表现出最好的5-HT1A拮抗剂活性(第5栏)的化合物进一步用第6栏的方法进行试验。其结果明显显示本发明化合物(A1)具有良好的5-HT1A结合亲和力和5-HT1A/α1选择性，并且与在EP-A-512755中一般性公开的一类化合物相比，本发明化合物作为5-HT1A拮抗剂显示出出乎预料增加的口服给药活性。作为一种说明，将化合物A1的口服5-HT1A拮抗剂比率(比率20)与最接近于现有技术中公开的结构的化合物，即具有7.6比率的实施例17的化合物的比率比较。
化合物A1不仅出人意料的比化合物17口服更有效，而且比比率为19.3的现有技术化合物具有好得多选择性，即比率是145。
本发明化合物可以通过已知的方法从已知的原料或可以通过常规方法制备的原料制备。例如化合物可以通过在EP-A-0512755中公开的通用方法制备。
一种制备本发明化合物的方法包括用环己烷甲酸或其酰化衍生物将下式的胺酰基化：
酰化衍生物的实例包括酰卤(例如酰氯)，叠氮化物，酸酐，咪唑化物(imidazolides)(例如从羰基二咪唑得到的物质)，从碳化二亚胺如二烷基碳化二亚胺尤其是环己基碳化二亚胺得到的活化的酯或O-酰基脲。
通式(B)的原料酰胺是新化合物并且由本发明提供。其可以通过公开于EP-A-0512755中通用途径例如下面例举的途径制备：
(其中Hal是卤素，尤其是氯或溴)。还原反应可以用例如配合的金属氢化物，例如氢化铝锂进行。
在制备式B起始物料的另一方法中，将下式的氧杂噻唑烷-2，2-二氧化物：
与1-(2，3-二氢-1，4-苯并二氧杂环己烯-5-基)哌嗪反应。制备亚砜的反应和方法用下面的反应路线说明：(其中X是离去基团，优选氯，溴或氟)。
上面反应路线中的某些方法步骤和反应路线中的某些新的中间体在John Wyeth & Brother Limited的名称为“制备哌嗪衍生物的新方法和中间体”的公开的PCT申请WO95/33725(PCT/GB95/01256)中提出保护要求。该申请要求了1994年6月3日递交的英国专利申请9411108.5的优先权。
制备本发明化合物的另一方法包括用烷基化试剂将下式的酰胺烷基化：
其中烷基化试剂提供下式基团：烷基化试剂可以是，例如，下式化合物：其中X1是离去基团如卤素或烷基-或芳基-磺酰氧基。制备本发明化合物的另一方法包括将下式化合物：
用下式化合物烷基化：
(其中X1如上面定义的)。
进行上面描述的方法可以以游离碱或酸加成盐的形式得到本发明化合物。如果本发明化合物以酸加成盐的形式得到，其游离碱可以通过碱化酸加成盐的溶液得到。相反，如果该方法的产物是游离碱，其酸加成盐，尤其是可药用酸加成盐，可以根据从碱化合物制备酸加成盐的常规方法，通过在适当的有机溶剂中用酸处理溶液得到。
酸加成盐的实例是那些由无机酸或有机酸形成的形式，这些酸是如硫酸，盐酸，氢溴酸，磷酸，酒石酸，富马酸，马来酸，柠檬酸，乙酸，甲酸，甲磺酸，对-甲苯磺酸，草酸和琥珀酸。
本发明化合物的旋光形式可以通过外消旋体的拆分或通过不对称合成或使用容易得到的手性前体得到。
本发明还提供了含有本发明化合物或其可药用酸加成盐以及与之结合的可药用载体的药物组合物。本领域中已知的任何适当的载体可以用于制备药物组合物。在该组合物中，载体通常是固体或液体或者是固体或液体的混合物。
固体形式的组合物包括粉剂，颗粒剂，片剂，胶囊(例如硬和软明胶胶囊)，栓剂和阴道栓剂。固体载体可以是，例如，也可以用作调味剂，润滑剂，增溶剂，悬浮剂，填料，glidants，压片助剂，粘合剂或片剂崩解剂的一种或多种物质；其也可以是包囊材料。在粉剂中，载体是细分的固体，其与细分的活性组分混合。在片剂中，活性组分以适当的比例与具有所需的压缩性质的载体混合，并且被压缩成所需的形状和大小。粉剂和片剂优选含有至高达99％，例如从0.03-99％，优选1-80％的活性组分。适当的固体载体包括，例如，磷酸钙，硬脂酸镁，滑石，蔗糖，乳糖，糊精，淀粉，明胶，纤维素，甲基纤维素，羧甲基纤维素钠，聚乙烯基吡咯烷，低熔点蜡和离子交换树脂。
术语“组合物”包括活性成分与作为载体的包囊材料做成胶囊的制剂，其中活性成分(有或没有其他载体)用载体包裹，载体因此与活性成分相结合。类似情况包括扁形胶囊剂。
液体形式组合物包括，例如，溶液剂，悬浮剂，乳化剂，糖浆，酏剂和加压组合物。例如，活性成分可以溶于或悬浮于可药用液体载体如水，有机溶剂，它们的混合物或可药用油或脂肪中。液体载体可以含有其他适当的药物添加剂如增溶剂，乳化剂，缓冲剂，防腐剂，调味剂，调味剂，悬浮剂，增稠剂，着色剂，粘度调节剂，稳定剂或渗透-调节剂。适当的用于口服和非肠道给药的液体载体实例包括水(尤其是含有如上面的添加剂，例如纤维素衍生物，优选羧甲基纤维素钠溶液)，醇(例如甘油和二元醇)和它们的衍生物，和油(例如馏分椰子油和花生油)。用于非肠道给药的载体也可以是油性酯如油酸乙酯和肉豆蔻酸异丙酯。消毒液体载体用于非肠道给药的消毒液体形式组合物。
消毒溶液或悬浮液的液体药物组合物可以通过，例如，肌内，腹膜内或皮下注射使用。消毒溶液也可以通过静脉内给药。当化合物是口服活性化合物时，其可以以液体或固体组合物形式给药。
优选的药物组合物是以单位剂量形式，例如片剂或胶囊。采用这些形式时，组合物可以再分成含有适当数量的活性成分的单位剂量形式；单位剂量形式可以是包装组合物，例如包装的粉剂，小瓶，安瓿，预罐装的注射器或含有液体的扁形胶囊剂。单位剂量形式可以是，例如，胶囊或片剂本身，或者可以是适当数量的以包装形式的任何该组合物。根据具体的需要和活性成分的活性，在组合物单位剂量中的活性成分的数量可以在0.5毫克或更少至750毫克或更多的范围内变化或调节。
本发明还提供了本发明化合物用于生产治疗哺乳动物CNS疾病的药物的用途。
下面的实施例说明本发明。
实施例1
(R)-N-[1-[2-[1-[4-[5-(2，3-二氢[1，4]苯并二氧杂环己烯基)]]哌嗪基]]丙基]-N-(2-吡啶基)环己烷甲酰胺
在冰/水冷却下，将三乙胺(0.85ml，0.6g，6mmol)和环己烷基羰基氯(0.74ml，0.81g，5.5mmol)滴入(R)-2-[1-[4-[5-(2，3-二氢[1，4]苯并二氧杂环已烯基)]]哌嗪基]-N-(2-吡啶基)丙胺(1.77g，5.0mmol)在二氯甲烷(10ml)中的搅拌着的溶液中。[通过将(S)-5-甲基-3-吡啶-2-基[1，2，3]氧杂异噻唑烷-2，2-二氧化物与1-(2，3-二氢-1，4-苯并二氧杂环己烷-5-基)哌嗪反应制备(R)-2-[1-[4-[5-(2，3-二氢[1，4]苯并二氧杂环己烯基)]]哌嗪基]-N-(2-吡啶基)丙胺]。在0℃搅拌悬浮液1小时，加入二氯甲烷(25ml)。溶液用水(25ml)洗涤，干燥(硫酸钠)，真空浓缩得到橙色泡沫。粗产物用硅胶色谱分离，用乙酸乙酯：已烷(2∶3→1∶0)洗脱得到(R)-N-[1-[ 2-[1-[4-[5-(2，3-二氢[1，4]苯并二氧杂环己烯基)]]哌嗪基]]丙基]-N-(2-吡啶基)环己烷甲酰胺游离碱，为白色泡沫(2.09g)。将该泡沫溶于甲醇(100ml)，溶液用醚中的氯化氢酸化，真空浓缩。加入乙腈，浓缩溶液，剩余物用乙酸乙酯研磨得到标题化合物，为二盐酸盐水合物(2.25g)，熔点：120-220℃。(C27H36N4O3.2HCl.2H2O的测定值：：C，58.7；H，7.5；N，9.8；计算值：C，58.4；H，7.3；N，10.1％)；[α]28 D+26°(c1.0，在甲醇中)。
Claims (2)
1.式(B)化合物或其盐：
2.一种制备权利要求1的化合物的方法，其中将式(D)的氧杂异噻唑烷-2，2-二氧化物或其盐：
与1-(2，3-二氢-1，4-苯并二氧杂环己烯-5-基)哌嗪反应。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9514901.9 | 1995-07-20 | ||
| GBGB9514901.9A GB9514901D0 (en) | 1995-07-20 | 1995-07-20 | Piperazine derivatives |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96195610A Division CN1077889C (zh) | 1995-07-20 | 1996-07-19 | 哌嗪衍生物和它们作为5－ht1a拮抗剂的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1309127A CN1309127A (zh) | 2001-08-22 |
| CN1131861C true CN1131861C (zh) | 2003-12-24 |
Family
ID=10778004
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96195610A Expired - Fee Related CN1077889C (zh) | 1995-07-20 | 1996-07-19 | 哌嗪衍生物和它们作为5－ht1a拮抗剂的应用 |
| CN00135330A Expired - Fee Related CN1131861C (zh) | 1995-07-20 | 2000-12-05 | 哌嗪衍生物及其制备方法 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96195610A Expired - Fee Related CN1077889C (zh) | 1995-07-20 | 1996-07-19 | 哌嗪衍生物和它们作为5－ht1a拮抗剂的应用 |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0839146B1 (zh) |
| JP (1) | JP4166824B2 (zh) |
| KR (1) | KR100447002B1 (zh) |
| CN (2) | CN1077889C (zh) |
| AR (1) | AR003451A1 (zh) |
| AT (1) | ATE196294T1 (zh) |
| AU (1) | AU700546B2 (zh) |
| BR (1) | BR9609694A (zh) |
| CA (1) | CA2227386C (zh) |
| DE (1) | DE69610316T2 (zh) |
| DK (1) | DK0839146T3 (zh) |
| ES (1) | ES2150684T3 (zh) |
| GB (1) | GB9514901D0 (zh) |
| GR (1) | GR3034408T3 (zh) |
| HU (1) | HUP9802447A3 (zh) |
| IL (1) | IL122981A (zh) |
| MX (1) | MX9800483A (zh) |
| NZ (1) | NZ313231A (zh) |
| PT (1) | PT839146E (zh) |
| WO (1) | WO1997003982A1 (zh) |
| ZA (1) | ZA966048B (zh) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19730989A1 (de) * | 1997-07-18 | 1999-01-21 | Merck Patent Gmbh | Piperazin-Derivate |
| US6271234B1 (en) * | 1997-08-01 | 2001-08-07 | Recordati S.A., Chemical And Pharmaceutical Company | 1,4-disubstituted piperazines |
| IT1293804B1 (it) | 1997-08-01 | 1999-03-10 | Recordati Chem Pharm | Diarilalchilpiperazine attive sulle basse vie urinarie |
| US6399614B1 (en) | 1997-08-01 | 2002-06-04 | Recordati S.A. Chemical And Pharmaceutical Company | 1-(N-phenylaminoalkyl)piperazine derivatives substituted at position 2 of the phenyl ring |
| US20060223824A1 (en) | 2000-11-28 | 2006-10-05 | Wyeth | Serotonergic agents |
| US6469007B2 (en) * | 2000-11-28 | 2002-10-22 | Wyeth | Serotonergic agents |
| US20060287335A1 (en) | 2000-11-28 | 2006-12-21 | Wyeth | Serotonergic agents for treating sexual dysfunction |
| EP1408976B3 (en) | 2001-07-20 | 2010-08-25 | Psychogenics Inc. | Treatment for attention-deficit hyperactivity disorder |
| CN1982307A (zh) * | 2002-03-12 | 2007-06-20 | 惠氏公司 | 合成手性n－芳基哌嗪的方法 |
| AU2003220110B2 (en) | 2002-03-12 | 2009-04-09 | Wyeth | Process for making chiral 1,4-disubstituted piperazines |
| US7361773B2 (en) | 2002-03-12 | 2008-04-22 | Wyeth | Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines |
| US7091349B2 (en) | 2002-03-12 | 2006-08-15 | Wyeth | Process for synthesizing N-aryl piperazines with chiral N′-1-[benzoyl(2-pyridyl)amino]-2-propane substitution |
| ES2334836T3 (es) * | 2002-03-12 | 2010-03-16 | Wyeth | Preparacion de 2-((2,3-dihidro-benzo(1,4)dioxin-5-il)-(2-hidroxietil)-amino)-etanol y productos intermedios correspondientes. |
| US20050209245A1 (en) * | 2004-03-19 | 2005-09-22 | Wyeth | Process for preparing N-aryl-piperazine derivatives |
| TW200800959A (en) | 2005-06-10 | 2008-01-01 | Wyeth Corp | Piperazine-piperidine antagonists and agonists of the 5-HT1a receptor |
| MX2007015772A (es) | 2005-06-17 | 2008-02-22 | Wyeth Corp | Compuestos utiles como inhibidores de serotonina y agonistas y antagonistas de 5-ht-1a. |
| TW200808741A (en) * | 2006-06-09 | 2008-02-16 | Wyeth Corp | 6-methoxy-8-[4-(1-(5-fluoro)-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline hydrochloric acid salts |
| TW200901974A (en) | 2007-01-16 | 2009-01-16 | Wyeth Corp | Compounds, compositions, and methods of making and using them |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU645681B2 (en) * | 1991-05-02 | 1994-01-20 | John Wyeth & Brother Limited | Piperazine derivatives |
| DE69527787T2 (de) * | 1994-06-03 | 2003-01-02 | John Wyeth & Brother Ltd., Maidenhead | Verfahren und zwischenprodukte zur herstellung von piperazinderivaten |
-
1995
- 1995-07-20 GB GBGB9514901.9A patent/GB9514901D0/en active Pending
-
1996
- 1996-07-10 AR ARP960103516A patent/AR003451A1/es active IP Right Grant
- 1996-07-16 ZA ZA9606048A patent/ZA966048B/xx unknown
- 1996-07-19 BR BR9609694A patent/BR9609694A/pt not_active Application Discontinuation
- 1996-07-19 EP EP96924983A patent/EP0839146B1/en not_active Expired - Lifetime
- 1996-07-19 IL IL12298196A patent/IL122981A/xx not_active IP Right Cessation
- 1996-07-19 CN CN96195610A patent/CN1077889C/zh not_active Expired - Fee Related
- 1996-07-19 AU AU65249/96A patent/AU700546B2/en not_active Ceased
- 1996-07-19 KR KR10-1998-0700371A patent/KR100447002B1/ko not_active Expired - Fee Related
- 1996-07-19 HU HU9802447A patent/HUP9802447A3/hu unknown
- 1996-07-19 JP JP50642797A patent/JP4166824B2/ja not_active Expired - Fee Related
- 1996-07-19 WO PCT/GB1996/001714 patent/WO1997003982A1/en not_active Ceased
- 1996-07-19 DK DK96924983T patent/DK0839146T3/da active
- 1996-07-19 CA CA002227386A patent/CA2227386C/en not_active Expired - Fee Related
- 1996-07-19 MX MX9800483A patent/MX9800483A/es unknown
- 1996-07-19 PT PT96924983T patent/PT839146E/pt unknown
- 1996-07-19 AT AT96924983T patent/ATE196294T1/de not_active IP Right Cessation
- 1996-07-19 NZ NZ313231A patent/NZ313231A/en unknown
- 1996-07-19 ES ES96924983T patent/ES2150684T3/es not_active Expired - Lifetime
- 1996-07-19 DE DE69610316T patent/DE69610316T2/de not_active Expired - Lifetime
-
2000
- 2000-09-14 GR GR20000402093T patent/GR3034408T3/el not_active IP Right Cessation
- 2000-12-05 CN CN00135330A patent/CN1131861C/zh not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| KR100447002B1 (ko) | 2004-12-04 |
| HUP9802447A2 (hu) | 1999-08-30 |
| EP0839146B1 (en) | 2000-09-13 |
| JPH11509544A (ja) | 1999-08-24 |
| ZA966048B (en) | 1998-01-16 |
| MX9800483A (es) | 1998-04-30 |
| GB9514901D0 (en) | 1995-09-20 |
| PT839146E (pt) | 2000-12-29 |
| IL122981A (en) | 2001-01-28 |
| DE69610316T2 (de) | 2001-03-29 |
| IL122981A0 (en) | 1998-08-16 |
| AR003451A1 (es) | 1998-08-05 |
| NZ313231A (en) | 2001-03-30 |
| ATE196294T1 (de) | 2000-09-15 |
| CN1077889C (zh) | 2002-01-16 |
| CN1190968A (zh) | 1998-08-19 |
| ES2150684T3 (es) | 2000-12-01 |
| CA2227386A1 (en) | 1997-02-06 |
| AU6524996A (en) | 1997-02-18 |
| DE69610316D1 (de) | 2000-10-19 |
| GR3034408T3 (en) | 2000-12-29 |
| CA2227386C (en) | 2006-05-16 |
| AU700546B2 (en) | 1999-01-07 |
| KR19990029067A (ko) | 1999-04-15 |
| BR9609694A (pt) | 1999-03-23 |
| JP4166824B2 (ja) | 2008-10-15 |
| WO1997003982A1 (en) | 1997-02-06 |
| CN1309127A (zh) | 2001-08-22 |
| DK0839146T3 (da) | 2000-11-20 |
| HUP9802447A3 (en) | 1999-11-29 |
| EP0839146A1 (en) | 1998-05-06 |
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