cyclopenta-1,3-diene;titanium(2+);dichloride | 1271-19-8

• 物质功能分类: 有机原料 - 有机金属类化合物 - 有机钛
• 分子结构分类: 有机化合物 - 碳氢化合物 - 芳香烃
• 英文名称: cyclopenta-1,3-diene;titanium(2+);dichloride
• CAS: 1271-19-8
• 化学式: C10H10Cl2Ti-2
• 分子量: 248.96
• InChiKey: MKNXBRLZBFVUPV-UHFFFAOYSA-L

物化性质

• 熔点：
  260-280 °C (dec.)(lit.)
• 沸点：
  355.52°C (estimate)
• 密度：
  1.6 g/mL at 25 °C(lit.)
• 溶解度：
  微溶于H2O、苯；溶于氯仿、乙醇、甲苯
• LogP：
  -1.35 at 20℃
• 物理描述：
  Titanocene dichloride appears as red to red-orange crystals. (NTP, 1992)
• 颜色/状态：
  Bright red acicular crystals from toluene
• 稳定性/保质期：

  STABLE IN DRY AIR; SLOWLY HYDROLYZED IN MOIST AIR

• 分解：
  When heated to decomposition it emits toxic fumes of /hydrogen chloride/.

计算性质

• 辛醇/水分配系数(LogP)：
  4.19
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  0
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

毒理性

• 人类毒性摘录

通过吸入有毒...

TOXIC BY INHALATION ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

外周血参数（红细胞压积、红细胞计数、网织红细胞、白细胞和血小板计数、血液分类计数）在单次注射细胞毒素剂钛ocene二氯化物；（ED90, 40 mg/kg；LD10, 60 mg/kg）和顺铂（ED90, 10 mg/kg）后进行了分析。尽管顺铂将网织红细胞和嗜多色红细胞数量降低到接近零的水平，但钛ocene二氯化物对骨髓提供年轻红细胞的供应没有明显影响；在使用钛ocene二氯化物或顺铂后，红细胞计数和红细胞压积值从未降低。在白细胞的情况下，使用钛ocene二氯化物治疗后，白细胞计数没有超出正常范围，而在使用顺铂后，观察到低于对照值的减少。最后，使用钛ocene二氯化物和顺铂后，循环血小板的数量也暂时降低到控制范围以下。结果表明，钛ocene二氯化物仅引起轻微的骨髓毒性，血小板是唯一受影响的可逆细胞。因此，钛ocene二氯化物的骨髓抑制作用显然甚至比顺铂的还要小。

Peripheral blood parameters (hematocrit, counts of red blood cells, reticulocytes, white blood cells and platelets, differential blood count) were analyzed after single injections of the cytostatic agents titanocene dichloride; (ED90, 40 mg/kg; LD10, 60 mg/kg) and cisplatin (ED90, 10 mg/kg). Whereas cisplatin depressed the number of reticulocytes and polychromatophilic erythrocytes to near zero level, titanocene dichloride did not obviously affect the supply of young erythrocytes from bone marrow; red blood cell count and hematocrit values were never reduced after application either of titanocene dichloride or of cisplatin. In the case of leukocytes, white blood cells count did not leave the normal range after treatment with titanocene dichloride, whereas a diminution under control values was observed after application of cisplatin. Finally, the number of circulating platelets transiently decreased beneath control range as well after application of titanocene dichloride as of cisplatin. The results indicate an only slight myelotoxicity induced by titanocene dichloride, the platelets being the only cells affected in a reversible manner. Thus, myelosuppression by titanocene dichloride is apparently even less pronounced than in the case of cisplatin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

在给雌性小鼠单次注射抗癌药物钛ocene二氯的ED90（40 mg/kg）和LD10（60 mg/kg）剂量后，通过分析给药后30分钟至16天内的各种血液化学参数和尿液组成，研究了器官毒性的模式。尽管电解质、血尿素氮、肌酐、总胆红素和胆固醇的血清水平没有改变，但天冬氨酸脱氢酶、谷氨酰胺-草酰乙酸转氨酶和谷氨酸-丙酮酸转氨酶的血清浓度显著且同时增加，指向肝实质细胞损伤；即使在LD10剂量下，这些病变在钛ocene二氯给药后的8天和16天内显然是可逆的。此外，钛ocene二氯给药后，葡萄糖浓度立即降低，显然刺激了调节性的胰高血糖素和皮质醇的输出；这些效果在钛ocene二氯给药后的4至8天内也是可逆的。在目前的研究中，没有显示出钛ocene二氯诱导的肾毒性的迹象。

The pattern of organ toxicity after single injections of the antitumor agent titanocene dichloride in ED90 (40 mg/kg) and LD10 (60 mg/kg) doses to female mice was investigated by analyzing various blood chemical parameters and the composition of urine at intervals between 30 min and 16 days after administration. Whereas the serum levels of electrolytes, blood urea nitrogen, creatinine, total bilirubin and cholesterol did not alter, marked and simultaneous increase in serum concentrations of the enzymes gultamate dehydrogenase, glutamine-oxaloacetic transaminase and glutamic-pyruvic transaminase occurred pointing to cellular damage within liver parenchyma; these lesions were apparently reversible within 8 and 16 days after application of titanocene dichloride even at the LD10 dose. Moreover, glucose concentration decreased immediately after titanocene dichloride administration, obviously stimulating a regulative output of glucagon and cortisol; these effects were also reversible within 4 to 8 days after titanocene dichloride administration. No hints to nephrotoxicity induced by titanocene dichloride became manifest in the present study.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

单次应用毒理学等效剂量的具有细胞抑制活性的金属配合物二氯钛ocene，对小鼠肾脏的形态外观和功能行为的影响通过使用光镜和电子显微镜、测定血液滞留值和尿液分析进行了分析。钛的二氯化合物仅引起轻微的形态学改变，例如在给予LD50剂量后，近端肾小管细胞中空泡化增加；肾脏内从未出现过严重的病理损伤。

The effect of a single application of toxicologically equivalent doses of the cytostatically active metal complexes titanocene dichloride, upon the morphologic appearance and the functional behavior of the kidneys was analyzed in mice by use of light and electron microscopy, by determination of blood retention values and by urine analysis. The dichlorides of titanium caused only slight morphologic alterations such as increased vacuolation in the proximal tubular cells even after administration of LD50 doses; severe pathologic injuries within the kidneys were always lacking.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

抗肿瘤药物二氯 titanocene 的致畸和胚胎毒性作用在给怀孕小鼠单次剂量二氯 titanocene (30 或 60 毫克/千克) 后进行了研究，给药时间为妊娠的第 8、10、12、14 或 16 天。在第 18 天通过剖腹产取出胎儿，并检查外部、内部和骨骼畸形以及毒性现象。最显著的结果是在妊娠第 10 天和第 12 天应用二氯 titanocene 后，许多胎儿出现腭裂（30 毫克/千克的胎儿中有 10%；60 毫克/千克的有 40-50%）。除了部分胎儿出现额外的肋骨畸形外，没有发现其他畸形。另一方面，二氯 titanocene 的胚胎毒性影响显著，导致每窝活胎数量减少，妊娠第 8 天至第 16 天应用二氯 titanocene 后，平均胎儿体重明显且剂量依赖性地减少，骨骼骨化明显迟缓。

The teratogenic and embryotoxic effects of the antitumor agent titanocene dichloride were investigated after application of single doses of titanocene dichloride (30 or 60 mg/kg) to pregnant mice on days 8, 10, 12, 14, or 16 of gestation. The fetuses were removed on day 18 by caesarian section and examined for external, internal and skeletal malformations as well as for toxic phenomena. The most striking result was the occurrence of cleft palate in numerous fetuses (10% of the fetuses, 30 mg/kg; 40-50%; 60 mg/kg) after titanocene dichloride application on days 10 and 12. Besides the additional appearance of costal malformations in some fetuses, no other malformations were recognizable. On the other hand, the embryotoxic influence titanocene dichloride was significant and caused diminution of the number of live fetuses per litter, marked and dose dependent reduction of mean fetal body weight after titanocene dichloride application on day 8 through day 16 and distinct retardation of skeletal ossification.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在当前研究中，通过电子光谱成像技术在超微结构水平上确定了小鼠肝脏中钛的亚细胞分布，这是在施用治疗性剂量（ED100；ED = 有效剂量）和毒性剂量（LD25；LD = 致死剂量）的抗癌剂二氯钛ocene后24小时和48小时进行的。在24小时时，钛主要积累在衬砌肝窦的内皮细胞和库普弗细胞的细胞质中。钛在肝细胞的核仁和常染色质中被检测到，与磷和氧一起包装成颗粒。一天后，钛仍然存在于内皮细胞和库普弗细胞的细胞质包涵体中，而在48小时时，在肝细胞核仁中只观察到少量的钛沉积。此时，钛主要以高度浓缩的颗粒形式积累在常染色质和核仁周围的异染色质中。发现钛在肝细胞的细胞质中，被纳入可能代表溶酶体的细胞质包涵体中。有时这些包涵体位于胆管附近，偶尔将其内容物挤入胆管腔内。这一观察结果表明，含有钛的代谢物主要通过胆汁排出。这些结果证实了电子光谱成像是一种适用于确定生物组织中轻、中重量元素的亚细胞分布的适当方法。可以从当前研究的发现中推断出钛ocene复合物或钛ocene代谢物的细胞作用模式。

In the present study, the subcellular distribution of titanium in the liver of mice was determined 24 and 48 hr after application of a therapeutic (ED100; ED = effective dose) and a toxic (LD25; LD= lethal dose) dose (60 and 80 mg/kg, respectively) of the antitumor agent titanocene dichloride by electron spectroscopic imaging at the ultrastructural level. At 24 hr titanium was mainly accumulated in the cytoplasm of endothelial and Kupffer cells, lining the hepatic sinusoids. Titanium was detected in the nucleoli and the euchromatin of liver cells, packaged as granules together with phosphorus and oxygen. One day later titanium was still present in cytoplasmic inclusions within endothelial and Kupffer cells, whereas in hepatocyte nucleoli only a few deposits of titanium were observed at 48 hr. At this time titanium was mainly accumulated in the form of highly condensed granules in the euchromatin and the perinucleolar heterochromatin. It was found in the cytoplasm of liver cells, incorporated into cytoplasmic inclusion bodies which probably respresent lysosomes. Sometimes these inclusions were situated near bile canaliculi and occasionally extruded their content into the lumen of bile capillaries. This observation suggests a mainly biliary elimination of titanium containing metabolites. These results confirm electron spectroscopic imaging to be an appropriate method for determining the subcellular distribution of light and medium weight elements within biological tissues. Insights into the cellular mode of action of titanocene complexes or titanocene metabolites can be deduced from the findings of the present study.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

含有钛的代谢物通过胎盘进入胚胎腔室的情况是通过分析在妊娠第10、12、14或16天给予孕鼠单一剂量的抗肿瘤剂二氯钛ocene（60 mg/kg）后1小时至24小时不同间隔期的胚胎/胎儿中的钛含量来研究的。在妊娠第10、12或14天给药后，钛浓度与未处理的胚胎相比并未升高。只有在妊娠第16天，即器官发生结束后，给药后4-24小时内在胎儿腔室内可检测到少量的钛，超出对照组数值2到3倍。这些结果解释了在胚胎器官发生期间给予孕鼠治疗剂量的二氯钛ocene后，发育中的胚胎器官为何没有组织学病变，以及新生儿为何没有出现多种致畸效应。

The passage of titaniun containing metabolites across the placenta into the embryonal compartment was investigated by analyzing the titanium content in embryos/fetuses at various intervals between 1 hr and 24 hr after treatment of pregnant mice with single doses of the antitumor agent titanocene dichloride (60 mg/kg) on days 10, 12, 14 or 16 of gestation. After treatment on days 10, 12 or 14, the titanium concentrations were not elevated in comparison to untreated embryos. Only on day 16, beyond the end of organogenesis, small amounts of titanium were detectable in the fetal compartment 4-24 hr after substance application, exceeding the control values by ranging between 2 and 3. These results explain the absence of histologic lesions in developing embryonal organs and the lack of multiple teratogenic effects in new-borns after application of therapeutic doses of titanocene dichloride to pregnant mice during the embryonal organogenesis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

钛的药代动力学和器官分布在单次腹腔注射抗癌剂双氯钛ocene（60 mg/kg）治疗剂量后的不同时间点直至96小时进行了分析。在24小时和48小时时，在肝脏和肠道中发现了最高的器官浓度，积累了80-90 mg钛/kg干重，对应的肝脏/血液和肠道/血液比率为8-9。

The pharmacokinetics and organ distribution of titanium were analyzed at various intervals up to 96 hr after a single ip injection of a therapeutic dose of the antitumor agent titanocene dichloride (60 mg/kg). Highest organ concentrations were found in the liver and the intestine where 80-90 mg titanium/kg dry weight were accumulated at 24 and 48 hr, corresponding to liver/blood and intestine/blood ratios of 8-9.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

血清中皮质醇、醛固酮、黄体酮和儿茶酚胺的浓度在给非怀孕和怀孕小鼠（妊娠第10天进行治疗）单次剂量施用二氯 titanocene（60 mg/kg）后30分钟、1、2、4、8、24和48小时进行测定。Titanocene dichloride 在物质应用后1-2小时内，使怀孕和非怀孕小鼠的血清皮质醇浓度增加5-6倍。血清中的醛固酮、黄体酮和儿茶酚胺水平不受 titanocene dichloride 治疗的影响。推测血清中皮质醇的增加是由于施用 titanocene dichloride 后肾上腺迅速释放皮质醇，从而间接介导小鼠腭裂的诱导。

The serum concentrations of cortisol, aldosterone, progesterone and catecholamines were determined 30 min, 1, 2, 4, 8, 24 and 48 hr after application of single doses of titanocene dichloride (60 mg/kg) to non-pregnant and to pregnant mice (treatment on day 10 of gestation). Titanocene dichloride induced 5-6 fold increases in serum cortisol concentration of pregnant as well as of non-pregnant mice within 1-2 hr after substance application. The serum levels of aldosterone, progesterone and catecholamines were not influenced by treatment with titanocene dichloride. It is supposed that the augmentation of cortisol in the serum is due to a rapid release of cortisol from the suprarenal glands after application of titanocene dichloride thus mediating indirectly the induction of cleft palate in mice.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• TSCA：
  Yes
• 危险等级：
  8
• 危险品标志：
  Xi,T
• 安全说明：
  S26,S36/37/39,S45,S6,S7/8
• 危险类别码：
  R61,R40,R33,R37/38,R34
• WGK Germany：
  3
• 海关编码：
  29310095
• 危险品运输编号：
  UN3261
• 危险类别：
  8
• RTECS号：
  XR2050000
• 包装等级：
  II
• 危险性防范说明：
  P201,P261,P280,P305+P351+P338,P405,P501
• 危险性描述：
  H302,H332,H315,H319,H341,H335

制备方法与用途

二氯二茂钛简介

二氯二茂钛是一种化学式为(η5-C5H5)2TiCl2的有机钛化合物，常写为Cp2TiCl2。这种茂金属在有机金属化学和有机合成中是常用的试剂。其性质为亮红色固体，在空气中会缓慢水解。与二茂铁形成的“三明治”结构不同，由于四个配体围绕一个金属中心，它形成四面体结构。此外，该化合物具有一定的抗肿瘤活性，并已作为化疗药物进入临床试验。

背景

双环戊二烯二氯化钛主要用作烯烃共聚及均聚催化剂。在国际市场上，已有几套装置用于生产其作为烯烃均聚催化剂的装置。而作为其用量较大的SBS催化加氢的催化剂，其市场需求与SBS催化加氢转化为SEBS的市场需求密切相关。

制备

二氯二茂钛的制备过程如下：在氮气保护下，加入镁粉、蒽和四氢呋喃溶液，滴加几滴碘甲烷。在一定温度下搅拌后获得黄绿色液体。随后将其放入超声波振荡器中振荡4小时，得到活化的蒽镁橙黄色沉淀。接下来，在60℃温度下，滴加环戊二烯和四氯化钛溶液，20分钟后冷却至室温，进行过滤，并用二氯甲烷洗涤滤渣。将洗涤后的滤液与过滤液合并浓缩，冰浴结晶后得到红色双环戊二烯二氯化钛晶体。此法制备的收率约为65%。

用途 高效加氢催化剂

二氯二茂钛是一种高效的加氢催化剂，主要用于烯烃聚合及加氢反应中。此外，在医药领域，它作为一种高效低毒的活性物质也被广泛使用。

具体应用

• 用于丁苯嵌段共聚物加氢
• 在苯甲醛和溴甲基丙烯酸合成α-γ-丁内酯
• 苯甲醛与丙烯酸溴甲酯通过一锅法制备α-亚甲基-γ-丁内酯

反应信息

• 作为反应物：
  描述：

  cyclopenta-1,3-diene;titanium(2+);dichloride 在 锌 氩 、 锌 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 bis(cyclopentadienyl)titanium (III) chloride
  参考文献：
  名称：

  Fused heterocyclic imido and amido compounds

  摘要：

  本发明涉及融合的环状化合物，以及使用这些化合物治疗核激素受体相关疾病，如癌症和免疫障碍的方法，以及含有该式化合物的制药组合物。本发明还涉及融合的杂环亚胺和酰胺化合物及其立体异构体，其化学式如下所示。其中，G、L、Z1、Z2、Q1、Q2、A1、A2、Y'和W'在本文中有定义。

  公开号：

  US07470797B2
• 作为产物：
  描述：

  dilithium 、 四氯化钛 、 甲苯 在 甲苯 、 正戊烷 作用下， 反应 30.0h， 以gives 1.85 g of the titanocene dichioride as a brown-beige powder的产率得到cyclopenta-1,3-diene;titanium(2+);dichloride
  参考文献：
  名称：

  Process for the preparation of polyolefins

  摘要：

  本发明涉及一种聚烯烃的制备方法，该方法通过在立体刚性的金属茂化合物存在下聚合至少一种烯烃，所述金属茂化合物包含至少两个取代或未取代的环戊二烯基配体，通过单环或多环环系统相互连接，其中至少一个环戊二烯基配体与单环或多环环系统融合。

  公开号：

  US05565534A1
• 作为试剂：
  描述：

  5-乙烯基双环[2.2.1]庚-2-烯 、 三乙基铝 在 cyclopenta-1,3-diene;titanium(2+);dichloride 作用下， 反应 5.0h， 以to produce 134.7 g of 5-ethylbicyclo[2. 2. 1]hept-2-ene having the purity of 98.9%的产率得到5-乙基双环(2.2.1)-2-庚烯
  参考文献：
  名称：

  Method for preparing resin having light color

  摘要：

  制备轻色树脂的方法包括以下步骤：在Ziegler催化剂的存在下，氢化式为（1）的化合物，其中l、m和n分别为0≤l≤3、0≤m≤8和l≤n≤3的整数，R1和R6分别表示氢原子或具有1至3个碳原子的碳氢基团，具有或不具有R5和R6形成环，以获得式为（2）的诺伯烯化合物，其中l、m、n和R1和R6与上述相同；并聚合诺伯烯化合物以得到轻色树脂。

  公开号：

  US04908420A1

文献信息

• Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
  申请人：——

  公开号：US20040077605A1

  公开（公告）日：2004-04-22

  Fused cyclic compounds, methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds.

  熔合环状化合物，使用这种化合物治疗与核激素受体相关的疾病，如癌症和免疫障碍的方法，以及含有这种化合物的制药组合物。
• N-oxides of morpholine derivatives and their use as therapeutic agents
  申请人：Merck Sharp & Dohme Limited

  公开号：US05610159A1

  公开（公告）日：1997-03-11

  ##STR1## The present invention relates to morpholine derivatives of the formula (I) and pharmaceutically acceptable salts thereof wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9a, R.sup.9b, X, Y, Z and Het are as defined in the specification; m is 0 or 1; and n is 0 or 1, where the sum total of n+m is 1 or 2. The compounds are of particular use in the treatment of pain, inflammation, migraine, emesis and postherpetic neuralgia.

  本发明涉及公式(I)的吗啡啶衍生物及其药学上可接受的盐，其中R.sup.1，R.sup.2，R.sup.3，R.sup.4，R.sup.5，R.sup.6，R.sup.7，R.sup.9a，R.sup.9b，X，Y，Z和Het如规范中所定义；m为0或1；n为0或1，其中n+m的总和为1或2。这些化合物特别适用于治疗疼痛、炎症、偏头痛、恶心和带状疱疹后神经痛。
• Polymorphic form of a tachykinin receptor antagonist
  申请人：Merck & Co., Inc.

  公开号：US20010041702A1

  公开（公告）日：2001-11-15

  This invention is concerned with a novel polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)-ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine which is a tachykinin receptor antagonist useful in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, pain or migraine, asthma, and emesis. The instant polymorphic form has advantages over the other known forms of 2-(R)-(1-(R)-(3,1-bis(trifluoro-methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations.

  这项发明涉及一种新的多晶型化合物2-(R)-(1-(R)-(3,5-双三氟甲基苯基)-乙氧基)-3-(S)-(4-氟苯基)-4-(3-(5-氧代-1H,4H-1,2,4-三唑基)甲基吗啡啶，它是一种缓激肽受体拮抗剂，可用于治疗或预防中枢神经系统疾病、炎症性疾病、疼痛或偏头痛、哮喘和呕吐等疾病。这种多晶型具有比已知的其他形式的2-(R)-(1-(R)-(3,1-双三氟甲基苯基)乙氧基)-3-(S)-(4-氟苯基)-4-(3-(5-氧代-1H,4H-1,2,4-三唑基)甲基吗啡啶更好的热力学稳定性和适合用于制药配方的优点。
• Substituted morpholine derivatives and their use as therapeutic agents
  申请人：Merck Sharp & Dohme Limited

  公开号：US05612337A1

  公开（公告）日：1997-03-18

  The present invention relates to compounds of formula (I), wherein R.sup.1 is hydrogen, halogen, C.sub.1-6 C alkyl, C.sub.1-6 alkoxy, CF.sub.3, NO.sub.2, CN, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, CO.sub.2 R.sup.a, CONR.sup.a R.sup.b, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or C.sub.1-4 alkyl substituted by C.sub.1-4 alkoxy, where R.sup.a and R.sup.b are hydrogen or C.sub.1-4 alkyl; R.sup.2 is hydrogen, halogen, C .sub.1-6 alkyl, C.sub.1-6 alkoxy substituted by C.sub.1-4 alkoxy or CF.sub.3 ; R.sup.3 is hydrogen, halogen or CF.sub.3 ; R.sup.4 is selected from the definitions of R.sup.1 ; R.sup.5 is selected from the definitions of R.sup.2 ; R.sup.6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by .dbd.O, .dbd.S or a C.sub.1-4 alkyl group, and optionally substituted by an aminoalkyl group; R.sup.9a and R.sup.9b are hydrogen or C.sub.1-4 alkyl, or R.sup.9a and R.sup.9b are joined to form a C.sub.5-7 ring; X is C.sub.1-4 alkylene optionally substituted by oxo; and Y is a C.sub.1-4 alkyl group optionally substituted by hydroxyl; with the proviso that if Y is C.sub.1-4 alkyl, R.sup.6 is substituted at least by an aminoalkyl group; and pharmaceutically acceptable salts and prodrugs thereof. The compounds are of particular use in the treatment of pain, inflammation, migraine and emesis.

  本发明涉及式(I)的化合物，其中R.sup.1是氢、卤素、C.sub.1-6烷基、C.sub.1-6烷氧基、CF.sub.3、NO.sub.2、CN、SR.sup.a、SOR.sup.a、SO.sub.2R.sup.a、CO.sub.2R.sup.a、CONR.sup.aR.sup.b、C.sub.2-6烯基、C.sub.2-6炔基或C.sub.1-4烷基，其被C.sub.1-4烷氧基取代，其中R.sup.a和R.sup.b是氢或C.sub.1-4烷基；R.sup.2是氢、卤素、C.sub.1-6烷基、被C.sub.1-4烷氧基取代的C.sub.1-6烷氧基或CF.sub.3；R.sup.3是氢、卤素或CF.sub.3；R.sup.4是从R.sup.1的定义中选择的；R.sup.5是从R.sup.2的定义中选择的；R.sup.6是一个含有2或3个氮原子的5元或6元杂环，可以选择地被.dbd.O、.dbd.S或C.sub.1-4烷基取代，并可以选择地被氨基烷基取代；R.sup.9a和R.sup.9b是氢或C.sub.1-4烷基，或者R.sup.9a和R.sup.9b结合形成一个C.sub.5-7环；X是可选择地被氧代取代的C.sub.1-4烷基；而Y是可选择地被羟基取代的C.sub.1-4烷基，但前提是如果Y是C.sub.1-4烷基，则R.sup.6至少被一个氨基烷基取代；以及其药学上可接受的盐和前药。这些化合物在治疗疼痛、炎症、偏头痛和恶心方面特别有用。
• Morpholine and thiomorpholine tachykinin receptor antagonists
  申请人：Merck & Co., Inc.

  公开号：US20020002164A1

  公开（公告）日：2002-01-03

  Substituted heterocycles of the general structural formula: 1 are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis, and calcium channel blockers useful in the treatment of cardiovascular conditions such as angina, hypertension or ischemia.

  通用结构式1的替代杂环可作为缓激肽受体拮抗剂，用于治疗炎症性疾病、疼痛或偏头痛、哮喘和呕吐，以及钙通道阻滞剂，用于治疗心血管疾病，如心绞痛、高血压或缺血。