N-(2,2,2-三氟乙基)-9-(4-[4-[4’-(三氟甲基)[1,1’-联苯]-2-甲酰氨基]哌啶-1-基]丁基)-9H-芴-9-甲酰胺 | 182431-12-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 中文名称: N-(2,2,2-三氟乙基)-9-(4-[4-[4’-(三氟甲基)[1,1’-联苯]-2-甲酰氨基]哌啶-1-基]丁基)-9H-芴-9-甲酰胺
• 中文别名: N-(2,2,2-三氟乙基)-9-(4-[4-[4'-(三氟甲基)[1,1'-联苯]-2-甲酰氨基]哌啶-1-基]丁基)-9H-芴-9-甲酰胺
• 英文名称: 9-[4-[4-[[[4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide
• 英文别名: lomitapide；N-(2,2,2-trifluoroethyl)-9-(4-(4-(4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamido)piperidin-1-yl)butyl)-9H-fluorene-9-carboxamide；N-(2,2,2-trifluoroethyl)-9-[4-[4-[[2-[4-(trifluoromethyl)phenyl]benzoyl]amino]piperidin-1-yl]butyl]fluorene-9-carboxamide
• CAS: 182431-12-5
• 化学式: C₃₉H₃₇F₆N₃O₂
• 分子量: 693.732
• InChiKey: MBBCVAKAJPKAKM-UHFFFAOYSA-N

物化性质

• 熔点：
  142°C(lit.)
• 沸点：
  778.2±60.0 °C(Predicted)
• 密度：
  1.34±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 蒸汽压力：
  9.74X10-21 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable if stored as directed; avoid strong oxidizing agents. /Lomitapide mesylate/[Selleck Chemicals; Material Safety Data Sheet: N-(2,2,2-trifluorethyl)-9-[4-[4-[[[4'-(trifluoromethyl)
• 分解：
  Thermal decomposition may produce toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides. /Lomitapide mesylate/[Selleck Chemicals; Material Safety Data Sheet: N-(2,2,2-trifluorethyl)-9-[4-[4-[[[4'-(trifluoromethyl)
• 解离常数：
  pKa1 = 9.02 (primary amine); pKa2 = 10.35 (secondary amine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  8.6
• 重原子数：
  50
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  61.4
• 氢给体数：
  2
• 氢受体数：
  9

ADMET

代谢

洛米他派主要通过CYP3A4代谢为其无活性的代谢物M1和M3。CYP酶中，CYP1A2、2B6、2C8、2C19对洛米他派的代谢程度较低。

Lomitapide is mainly metabolized by CYP3A4 to it's inactive metabolites, M1 and M3. CYP enzymes that metabolize lomitapide to a minor extent include CYP 1A2,2B6,2C8,2C19.

来源:DrugBank

代谢

洛米他派由肝脏广泛代谢。代谢途径包括氧化、氧化N-脱烷基化、葡萄糖苷酸结合和哌啶环开环。细胞色素P450（CYP）3A4将洛米他派代谢为其主要代谢物M1和M3，可在血浆中检测到。氧化N-脱烷基化途径将洛米他派分子分解为M1和M3。M1是保留哌啶环的部分，而M3在体外保留洛米他派分子的其余部分。CYPs 1A2、2B6、2C8和2C19可能在一定程度上将洛米他派代谢为M1。M1和M3在体外不抑制微囊体甘油三酯转移蛋白的活性。

Lomitapide is metabolized extensively by the liver. The metabolic pathways include oxidation, oxidative N-dealkylation, glucuronide conjugation, and piperidine ring opening. Cytochrome P450 (CYP) 3A4 metabolizes lomitapide to its major metabolites, M1 and M3, as detected in plasma. The oxidative N-dealkylation pathway breaks the lomitapide molecule into M1 and M3. M1 is the moiety that retains the piperidine ring, whereas M3 retains the rest of the lomitapide molecule in vitro. CYPs 1A2, 2B6, 2C8, and 2C19 may metabolize lomitapide to a small extent to M1. M1 and M3 do not inhibit activity of microsomal triglyceride transfer protein in vitro.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：洛米他派是一种白色至灰白色的粉末。洛米他派被用作低脂饮食和其他降脂治疗的辅助手段，包括在可用的情况下降低低密度脂蛋白胆固醇（LDL-C）、总胆固醇（TC）、载脂蛋白B（apo B）和非高密度脂蛋白胆固醇（non-HDL-C）在患有纯合子家族性高胆固醇血症（HoFH）的患者中的水平。人类暴露和毒性：关于洛米他派过量影响的数据非常有限。在临床研究中，给人受试者最大剂量的洛米他派是200毫克，单次给药，没有不良反应。在怀孕期间不应使用洛米他派，因为给孕妇使用洛米他派可能会对胎儿造成伤害。洛米他派还可能在患有罕见遗传性疾病的患者中引起腹泻和吸收不良，包括乳糖不耐症、拉普乳糖酶缺乏和葡萄糖-半乳糖吸收不良；因此，应避免在此类患者中使用洛米他派。洛米他派有导致肝毒性的风险。洛米他派可能导致转氨酶升高和肝脂肪变性。目前尚不清楚洛米他派相关的肝脂肪变性在多大程度上促进了转氨酶的升高。尽管尚未报告有肝功能障碍或肝衰竭的病例，但人们担心洛米他派可能会诱导脂肪肝炎，这种病可以在几年内进展为肝硬化。因此，不应给中度或重度肝功能损害（Child-Pugh B级或C级）的患者或患有活动性肝脏疾病的患者使用，包括血清转氨酶浓度持续升高的情况。在一组包括使用原代人淋巴细胞的体外细胞遗传学分析的研究中，洛米他派没有表现出遗传毒性潜力。动物研究：在为期两年的小鼠饮食致癌性研究中，洛米他派的剂量为0.3、1.5、7.5、15或45 mg/kg/天。在雄性小鼠中，剂量低至1.5 mg/kg/天，在雌性小鼠中低至7.5 mg/kg/天，肝脏腺瘤和癌的发生率有统计学意义的增加。在雄性小鼠中，剂量低至15 mg/kg/天时，小肠癌的发生率显著增加，而在雌性小鼠中，腺瘤和癌的合并发生率在剂量低至15 mg/kg/天时显著增加。在大鼠的两年研究中，没有药物相关的肿瘤发生率显著增加。在 rats、兔子和雪貂中进行了繁殖研究。从妊娠第6天到器官形成期间，给怀孕的大鼠口服灌胃剂量为0.04、0.4或4 mg/kg/天的洛米他派，当暴露量大于或等于人类最大推荐剂量（MRHD）（60毫克）的两倍时，会出现胎儿畸形。胎儿畸形包括脐疝、腹裂、肛门闭锁、心脏形状和大小的改变、肢体扭转、尾部的骨骼畸形以及颅骨、脊椎和骨盆骨骼的迟缓。从妊娠第12天到器官形成期间，给怀孕的雪貂口服灌胃剂量为1.6、4、10或25 mg/kg/天的洛米他派，当暴露量从低于MRHD的人体暴露量到MRHD的5倍时，会出现母体毒性和胎儿畸形。胎儿畸形包括脐疝、内翻或短肢、爪子上缺失或融合的指、腭裂、眼睑睁开、低耳位和尾巴弯曲。在兔子的研究中，从妊娠第6天到器官形成期间，暴露量高达MRHD-BSA（基于体表面积）的3倍没有出现不良反应。然而，暴露量等于或大于MRHD-BSA的6倍时，会导致胚胎-胎儿死亡。在大鼠中，洛米他派在剂量高达5 mg/kg/天的情况下对生育力没有影响，估计该剂量的系统暴露量是人类的4倍（雌性）和5倍（雄性）以上，基于AUC。在一组包括体外细菌反向突变（Ames）研究和大鼠口服微核研究的实验中，洛米他派没有表现出遗传毒性潜力。

IDENTIFICATION AND USE: Lomitapide is a white to off-white powder. Lomitapide is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). HUMAN EXPOSURE AND TOXICITY: Very few data are available on the effects of overdose to lomitapide. The maximum dose administered to human subjects in clinical studies was 200 mg lomitapide, as a single dose, without adverse consequences. Lomitapide should not be used during pregnancy because lomitapide may cause fetal harm when administered to a pregnant woman. Lomitapide may also cause diarrhea and malabsorption in patients with rare hereditary disorders, including galactose intolerance, the Lapp lactase deficiency, and glucose-galactose malabsorption; therefore, use of lomitapide should be avoided in such patients. Lomitapide causes a risk of hepatotoxicity. Lomitapide can cause elevations in transaminases and hepatic steatosis. To what extent lomitapide-associated hepatic steatosis promotes the elevations in transaminases is unknown. Although cases of hepatic dysfunction or hepatic failure have not been reported, there is concern that lomitapide could induce steatohepatitis, which can progress to cirrhosis over several years. Therefore, it should not be administered to patients with moderate or severe hepatic impairment (Child-Pugh class B or C) or patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations. Lomitapide did not exhibit genotoxic potential in a battery of studies, including an in vitro cytogenetics assay using primary human lymphocytes. ANIMAL STUDIES: In a 2-year dietary carcinogenicity study in mice, lomitapide was administered at doses of 0.3, 1.5, 7.5, 15, or 45 mg/kg/day. There were statistically significant increases in the incidences of liver adenomas and carcinomas in males at doses as low as 1.5 mg/kg/day and in females at as low as 7.5 mg/kg/day. Incidences of small intestinal carcinomas in males and combined adenomas and carcinomas in females were significantly increased at doses as low as 15 mg/kg/day. In 2 year studies in rats, there were no statistically significant drug-related increases in tumor incidences. Reproduction studies were conducted in rats, rabbits and ferrets. Oral gavage doses of 0.04, 0.4, or 4 mg/kg/day lomitapide given to pregnant rats from gestation day 6 through organogenesis were associated with fetal malformations at greater than or equal to 2-times human exposure at the maximum recommended human dose (MRHD) (60 mg) based on plasma AUC comparisons. Fetal malformations included umbilical hernia, gastroschisis, imperforate anus, alterations in heart shape and size, limb malrotations, skeletal malformations of the tail, and delayed ossification of cranial, vertebral and pelvic bones. Oral gavage doses of 1.6, 4, 10, or 25 mg/kg/day lomitapide given to pregnant ferrets from gestation day 12 through organogenesis were associated with both maternal toxicity and fetal malformations at exposures that ranged from less than the human exposure at the MRHD to 5-times the human exposure at the MRHD. Fetal malformations included umbilical hernia, medially rotated or short limbs, absent or fused digits on paws, cleft palate, open eye lids, low-set ears, and kinked tail. In rabbits, exposures up to 3 times the MRHD based on body surface area (BSA) (MRDH-BSA) from gestational day 6 through organogenesis were not associated with adverse effects. However, exposure equal to or greater than 6 times the MRHD-BSA resulted in embryo-fetal death. Lomitapide had no effect on fertility in rats at doses up to 5 mg/kg/day at systemic exposures estimated to be 4-times (females) and 5-times (males) higher than in humans at 60 mg based on AUC. Lomitapide did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) and an oral micronucleus study in rats.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

洛米他派与治疗过程中血清转氨酶中度升高有关，34%的患者出现血清转氨酶水平超过正常上限3倍的情况。还报告了转氨酶升高超过10倍ULN的情况，这可能需要停药。尽管ALT升高的频率较高，但血清胆红素和碱性磷酸酶水平的升高是罕见的，且没有出现黄疸的明显急性肝损伤的报告。长期使用洛米他派可能会伴随血清转氨酶水平的波动和肝脏脂肪的积累。在某些情况下，肝脏脂肪的增加是从基线水平开始的。

Lomitapide is associated with a moderately high rate of serum aminotransferase elevations during therapy, levels above 3 times the upper limit of normal (ULN) occurring in 34% of patients. Aminotransferase elevations above 10 times ULN have also been reported which can necessitate drug discontinuation. Despite the frequency of ALT elevations, however, increases in serum bilirubin and alkaline phosphatase levels are rare and there have been no reports of clinically apparent acute liver injury with jaundice. Chronic therapy with lomitapide can be associated with fluctuations in serum aminotransferase levels and accumulation of liver fat. In some instances, the increase in liver fat is from baseline levels of

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

使用期间对哺乳的影响：目前没有关于在哺乳期间使用洛米他派的相关已发表信息。由于担心对婴儿脂质代谢的干扰和可能的致瘤性，洛米他派在哺乳期间不应使用。 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发表信息。 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发表信息。

◉ Summary of Use during Lactation:No relevant published information exists with the use of lomitapide during breastfeeding. Because of a concern with disruption of infant lipid metabolism and possible tumorigenicity, lomitapide should not be used during breastfeeding. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

洛米他派与强效（例如，波塞普韦、克拉霉素、康尼伐坦、茚地那韦、伊曲康唑、酮康唑、洛匹那韦/利托那韦、奈法唑酮、奈非那韦、泊沙康唑、利托那韦、沙奎那韦、特拉普韦、泰利霉素、替普那韦/利托那韦、伏立康唑）或中等效力CYP3A4抑制剂（例如，阿瑞匹坦、阿塔那韦、西普罗氟沙星、克唑替尼、达鲁那韦/利托那韦、地尔硫卓、红霉素、氟康唑、福沙那韦、伊马替尼、维拉帕米）的联合使用是禁忌的。如果无法避免与中等或强效CYP3A4抑制剂联合使用，在CYP3A4抑制剂治疗期间应中断洛米他派治疗。

Concomitant use of lomitapide with potent (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, voriconazole) or moderate CYP3A4 inhibitors (e.g., aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) is contraindicated. If concomitant use with moderate or potent CYP3A4 inhibitors cannot be avoided, lomitapide therapy should be interrupted during the course of treatment with the CYP3A4 inhibitor.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

洛米他派与CYP3A4抑制剂联合使用可能会导致洛米他派全身暴露量增加。当强力CYP3A4抑制剂酮康唑（每天两次，每次200毫克，连续9天）与洛米他派（每天一次，每次60毫克）同时给药时，洛米他派的峰血浆浓度和血浆浓度-时间曲线下面积（AUC）分别增加了15倍和27倍。至少在1名患者中，将强力CYP3A4抑制剂克拉霉素添加到洛米他派治疗中，开始使用强力CYP3A4抑制剂几天内，ALT和AST浓度分别增加到正常上限（ULN）的24倍和13倍。洛米他派与中等强度CYP3A4抑制剂联合使用尚未进行研究；然而，评估洛米他派与强力及弱力CYP3A4抑制剂联合使用的药代动力学研究结果表明，中等强度CYP3A4抑制剂可能会增加洛米他派的暴露量。

Concomitant use of lomitapide with inhibitors of CYP3A4 may result in increased systemic exposure to lomitapide. When the potent CYP3A4 inhibitor ketoconazole (200 mg twice daily for 9 days) was administered concomitantly with lomitapide (60 mg once daily), peak plasma concentration and area under the plasma concentration-time curve (AUC) of lomitapide were increased by 15- and 27-fold, respectively. When the potent CYP3A4 inhibitor clarithromycin was added to lomitapide therapy in at least 1 patient, ALT and AST concentrations were increased to 24 and 13 times the upper limit of normal (ULN), respectively, within days of initiating the potent CYP3A4 inhibitor. Concomitant use of lomitapide with moderate inhibitors of CYP3A4 has not been studied; however, results of pharmacokinetic studies evaluating concomitant use of lomitapide with potent and weak CYP3A4 inhibitors suggest that moderate CYP3A4 inhibitors will likely increase lomitapide exposure.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

在健康患者中，单次服用60毫克洛米他派的达峰时间大约为6小时。洛米他派的绝对生物利用度大约为7%。

In healthy patients, time to maximum lomitapide concentration is about 6 hours with a single dose of 60 mg. Lomitapide has an approximate absolute bioavailability of 7%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约52.9-59.5%通过尿液排出，33.4-35.1%通过粪便排出。

About 52.9-59.5% is eliminated by the urine and 33.4-35.1% is eliminated by the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

稳态分布容积约为985-1292升。

The steady state volume of distribution is about 985-1292 L.

来源:DrugBank

吸收、分配和排泄

稳态下洛米他派的平均分布体积为985-1292升。洛米他派与血浆蛋白的结合率为99.8%。

The mean lomitapide volume of distribution at steady state is 985-1292 liters. Lomitapide is 99.8% plasma-protein bound.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

单次口服60毫克Juxtapid后，健康志愿者中洛米他派的tmax约为6小时。洛米他派的绝对生物利用度大约为7%。洛米他派的药代动力学大约是剂量成正比的，适用于10-100毫克口服单次剂量。

Upon oral administration of a single 60-mg dose of Juxtapid, the lomitapide tmax is around 6 hours in healthy volunteers. The absolute bioavailability of lomitapide is approximately 7%. Lomitapide pharmacokinetics is approximately dose-proportional for oral single doses from 10-100 mg.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 储存条件：
  -20°C

制备方法与用途

生物活性

Lomitapide（AEGR-733, BMS-201038）是一种强效的微粒体甘油三酯转移蛋白（MTP）抑制剂，用于治疗家族性高胆固醇血症。

靶点

Target	Value
MTP

体外研究

Lomitapide 是一种口服的 MTP 抑制剂，适用于霍夫曼氏家族性高胆固醇血症（HoFH）患者的治疗。HoFH 是一种罕见的高胆固醇血症形式，可能导致早发动脉粥样硬化疾病。Lomitapide 肝脏代谢通过细胞色素 P-450（CYP）同工酶 3A4，并与包括阿托伐他汀和辛伐他汀在内的 CYP3A4底物相互作用。

体内研究

单独使用 Lomitapide 或与其他降低血脂的疗法联合使用，可显著降低低密度脂蛋白胆固醇（LDL-C）浓度，平均降幅超过 50%。Lomitapide 可能引起严重的胃肠道不良反应，并增加肝脂肪水平。50 毫克洛米塔普胶囊的生物利用度为 7.1%，其半衰期平均为 39.7 小时。单次剂量 Lomitapide 可分别在 0.3 和 1 公斤/千克剂量下，使血清甘油三酯降低 35% 和 47%。多次剂量治疗后，Lomitapide 也能导致甘油三酯（71%-87%）、游离脂肪酸（33%-40%）和 LDL-C（26-29%）的剂量依赖性下降。

反应信息

• 作为反应物：
  描述：

  N-(2,2,2-三氟乙基)-9-(4-[4-[4’-(三氟甲基)[1,1’-联苯]-2-甲酰氨基]哌啶-1-基]丁基)-9H-芴-9-甲酰胺 、 甲烷磺酸 以 醋酸异丙酯 为溶剂， 反应 1.0h， 以90%的产率得到甲磺酸洛美他派
  参考文献：
  名称：

  甲磺酸洛美他派晶型III

  摘要：

  本发明提供了一种甲磺酸洛美他派的晶型III，该结晶形式的X‑射线衍射图具有包括在衍射角2θ：9.912度、11.584度、14.651度、15.444度、17.416度、21.154度、21.984度的衍射峰，2θ误差为±0.2度。本发明的制备工艺稳定可控，能够适应于工业化生产，得到的晶型III稳定性良好，能够满足生产运输储存的药用要求；纯度较高，杂质含量较少，不含有或仅含有较低含量的残留溶剂，符合国家药典规定的有关医药产品残留溶剂的限量要求，因而本发明的结晶可以较好地作为医药活性成分使用。

  公开号：

  CN105523994B
• 作为产物：
  描述：

  4-三氟甲基-联苯-2-甲酸 在 20% palladium hydroxide-activated charcoal 、 potassium carbonate 作用下， 以 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 、 乙腈 、 环己烯 为溶剂， 反应 26.5h， 生成 N-(2,2,2-三氟乙基)-9-(4-[4-[4’-(三氟甲基)[1,1’-联苯]-2-甲酰氨基]哌啶-1-基]丁基)-9H-芴-9-甲酰胺
  参考文献：
  名称：

  [EN] PROCESS FOR THE PREPARATION OF LOMITAPIDE
  [FR] PROCÉDÉ DE PRÉPARATION DE LOMITAPIDE

  摘要：

  本发明涉及一种制备具有可接受杂质水平的高纯度洛米他派或其药用可接受盐的方法。

  公开号：

  WO2016071849A1

文献信息

• [EN] IMIDE AND ACYLUREA DERIVATIVES AS MODULATORS OF THE GLUCOCORTICOID RECEPTOR<br/>[FR] DÉRIVÉS IMIDE ET ACYLURÉE UTILISÉS COMME MODULATEURS DU RÉCEPTEUR DE GLUCOCORTICOÏDES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2015027021A1

  公开（公告）日：2015-02-26

  Novel non-steroidal compounds are provided which are useful in treating diseases or disorders associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-KB activity, including metabolic and inflammatory and immune diseases or disorders, having the structure of formula (I): an enantiomer, diastereomer, or tautomer thereof, or a pharmaceutically-acceptable salt thereof, in which the variables are as defined in the specification.

  提供了一种新型的非类固醇化合物，可用于治疗与糖皮质激素受体、AP-1和/或NF-KB活性调节相关的疾病或紊乱，包括代谢性、炎症性和免疫性疾病或紊乱，其结构如下式（I）：其对映体、二对映体或互变异构体，或其药用可接受盐，其中变量如规范中所定义。
• [EN] IMIDAZOLE-DERIVED MODULATORS OF THE GLUCOCORTICOID RECEPTOR<br/>[FR] MODULATEURS DU RÉCEPTEUR GLUCOCORTICOÏDE DÉRIVÉS DE L'IMIDAZOLE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2015027015A1

  公开（公告）日：2015-02-26

  Novel non-steroidal compounds are provided which are useful in treating diseases or disorders associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-kB activity, including metabolic and inflammatory and immune diseases or disorders, having the structure of formula (I): an enantiomer, diastereomer, or tautomer thereof, or a prodrug ester thereof, or a pharmaceutically-acceptable salt thereof, in which the variables are as defined in the specification.

  提供了一种新型的非类固醇化合物，可用于治疗与糖皮质激素受体、AP-1和/或NF-kB活性调节相关的疾病或紊乱，包括代谢性、炎症性和免疫性疾病或紊乱，其结构如下式（I）：其对映体、二对映体或互变异构体，或其前药酯，或其药用可接受盐，其中变量如规范中所定义。
• Triamide-substituted heterobicyclic compounds
  申请人：Pfizer Inc.

  公开号：US20030187053A1

  公开（公告）日：2003-10-02

  The invention relates to triamide MTP/ApoB inhibitors of the formula 1 1 wherein R 1 -R 8 are as defined in the specification, as well as pharmaceutical compositions and uses thereof, and processes for preparing the compounds. The compounds of the invention are useful for the treatment of obesity and lipid disorders.

  本发明涉及三酰胺MTP/ApoB抑制剂，其化学公式为1，其中R1-R8如说明书所述，以及包含这些化合物的药物组合物及其用途，以及制备这些化合物的方法。本发明的化合物可用于治疗肥胖和脂质紊乱。
• Microsomal triglyceride transfer protein inhibitor
  申请人：Pfizer Inc

  公开号：US20040132745A1

  公开（公告）日：2004-07-08

  The present invention provides inhibitors of microsomal triglyceride transfer protein (MTP) and/or apolipoprotein B (Apo B) secretion having Formula (I) which are useful for the treatment of obesity and related diseases, as well as prevention and treatment of atherosclerosis and its clinical sequelae, for lowering serum lipids, and in the prevention and treatment of related diseases. The invention further relates to pharmaceutical compositions comprising the compounds of the present invention and to methods of treating obesity, atherosclerosis, and related diseases and/or conditions with the compounds of the present invention, either alone or in combination with other medicaments, including lipid-lowering agents. 1

  本发明提供了具有公式(I)的微粒体甘油三酯转运蛋白（MTP）和/或载脂蛋白B（Apo B）分泌抑制剂，用于治疗肥胖及相关疾病，以及预防和治疗动脉粥样硬化和其临床后遗症，降低血清脂质，以及预防和治疗相关疾病。本发明还涉及包含本发明化合物的药物组合物，以及使用本发明化合物单独或与其他药物（包括降脂药）联合治疗肥胖、动脉粥样硬化和相关疾病/状况的方法。
• Novel phenyl-substituted imidazolidines, process for preparation thereof, medicaments comprising said compounds and use thereof
  申请人：JAEHNE Gerhard

  公开号：US20110178134A1

  公开（公告）日：2011-07-21

  The invention relates to compounds of formula (I) wherein the groups have stated meanings, and to their physiologically compatible salts. Said compounds are suitable, for example, as anti-obesity drugs and for treating cardiometabolic syndrome.

  本发明涉及具有所述意义的公式（I）的化合物，以及它们的生理相容性盐。所述化合物适用于例如作为抗肥胖药物和治疗心血管代谢综合征。