泼尼松 | 53-03-2

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 肾上腺皮质激素类药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 泼尼松
• 中文别名: 强的松；强的松,去氢可的松；去氢可的松
• 英文名称: Prednison
• 英文别名: prednisone；(8S,9S,10R,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,9,12,14,15,16-octahydrocyclopenta[a]phenanthrene-3,11-dione
• CAS: 53-03-2
• 化学式: C₂₁H₂₆O₅
• mdl: MFCD00003608
• 分子量: 358.434
• InChiKey: XOFYZVNMUHMLCC-ZPOLXVRWSA-N

物化性质

• 熔点：
  236-238 °C(lit.)
• 比旋光度：
  169 º (c=0.5, dioxane)
• 沸点：
  410.86°C (rough estimate)
• 密度：
  1.1121 (rough estimate)
• 闪点：
  >200℃
• 溶解度：
  几乎不溶于水，微溶于乙醇(96%)和二氯甲烷。它显示多态性(5.9)。
• 物理描述：
  Prednisone is an odorless white crystalline powder. (NTP, 1992)
• 颜色/状态：
  Crystals
• 气味：
  Odorless
• 味道：
  Persistent bitter after-taste
• 蒸汽压力：
  3.82X10-13 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Stable under recommended storage conditions.

• 旋光度：
  Specific optical rotation: +172 deg at 25 °C/D (dioxane); max absorption (methanol): 238 nm (e = 15,500)
• 分解：
  Hazardous decomposition products formed under fire conditions - Carbon oxides.
• 碰撞截面：
  181.8 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.666
• 拓扑面积：
  91.7
• 氢给体数：
  2
• 氢受体数：
  5

ADMET

代谢

泼尼松被代谢为17α,21-二羟基-孕甾-1,4,6-三烯-3,11,30-三酮（M-XVII）、20α-二氢-泼尼松（M-V）、6β-羟基-泼尼松（M-XII）、6α-羟基-泼尼松（M-XIII）或20β-二氢-泼尼松（M-IV）。20β-二氢-泼尼松被代谢为17α,20ξ,21-三羟基-5ξ-孕-1-烯-3,11-二酮（M-XVIII）。泼尼松可逆地代谢为[泼尼松龙]。泼尼松龙被代谢为Δ6-泼尼松龙（M-XI）、20α-二氢-泼尼松龙（M-III）、20β-二氢-泼尼松龙（M-II）、6α-羟基-泼尼松龙（M-VII）或6β-羟基-泼尼松龙（M-VI）。6α-羟基-泼尼松龙被代谢为6α,11β,17α,20β,21-五羟基孕甾-1,4-二烯-3-酮（M-X）。6β-羟基-泼尼松龙被代谢为6β,11β,17α,20β,21-五羟基孕甾-1,4-二烯-3-酮（M-VIII）、6β,11β,17α,20α,21-五羟基孕甾-1,4-二烯-3-酮（M-IX）和6β,11β,17α,21-四羟基-5ξ-孕-1-烯-3,20-二酮（M-XIV）。MVIII代谢为6β,11β,17α,20β,21-五羟基-5ξ-孕-1-烯-3-酮（M-XV）然后到MXIV，而MIX代谢为6β,11β,17α,20α,21-五羟基-5ξ-孕-1-烯-3-酮（M-XVI）然后到MXIV。这些代谢物及其葡萄糖醛酸苷主要通过尿液排出。

Prednisone is metabolized to 17α,21-dihydroxy-pregnan-1,4,6-trien-3,11,30-trione (M-XVII), 20α-dihydro-prednisone (M-V), 6βhydroxy-prednisone (M-XII), 6α-hydroxy-prednisone (M-XIII), or 20β-dihydro-prednisone (M-IV). 20β-dihydro-prednisone is metabolized to 17α,20ξ,21-trihydroxy-5ξ-pregn-1-en-3,11-dione(M-XVIII). Prednison is reversibly metabolized to [prednisolone]. Prednisolone is metabolized to Δ6-prednisolone (M-XI), 20α-dihydro-prednisolone (M-III), 20β-dihydro-prednisolone (M-II), 6αhydroxy-prednisolone (M-VII), or 6βhydroxy-prednisolone(M-VI). 6αhydroxy-prednisolone is metabolized to 6α,11β,17α,20β,21-pentahydroxypregnan-1,4-diene-3-one (M-X). 6βhydroxy-prednisolone is metabolized to 6β,11β,17α,20β,21-pentahydroxypregnan-1,4-diene-3-one (M-VIII), 6β,11β,17α,20α,21-pentahydroxypregnan-1,4-diene-3-one (M-IX), and 6β,11β,17α,21-tetrahydroxy-5ξ-pregn-1-en-3,20-dione (M-XIV). MVIII is metabolized to 6β,11β,17α,20β,21-pentahydroxy-5ξ-pregn-1-en-3-one (M-XV) and then to MXIV, while MIX is metabolized to 6β,11β,17α,20α,21-pentahydroxy-5ξ-pregn-1-en-3-one (M-XVI) and then to MXIV. These metabolites and their glucuronide conjugates are excreted predominantly in the urine.

来源:DrugBank

代谢

在一项研究中，口服泼尼松后，血浆泼尼松龙的浓度在60到120分钟之间达到峰值，然后呈指数下降。在快速静脉注射类固醇后，血浆泼尼松龙的浓度在10到20分钟内达到峰值。血浆泼尼松龙浓度随时间的变化通过双相指数消失曲线表示，先是快速分布相，然后是较慢的衰减相。口服泼尼松后达到的血浆泼尼松龙浓度与静脉给药后第二相的浓度范围相同。

In one study after an oral dose of prednisone, the plasma prednisolone concentration peaked between 60 and 120 min and then declined exponentially. After rapid iv injection of steroid, the plasma prednisolone concentration peaked within 10 to 20 min. An initial rapid distribution phase succeeded by a slower decay phase was expressed by a biphasic exponential disappearance curve of the plasma prednisolone concentration versus time. Plasma prednisolone concentrations achieved with an oral dose of prednisone were in the same range as those obtained during the second phase after iv administration.

来源:Hazardous Substances Data Bank (HSDB)

代谢

11-氧代还原为11alpha-羟基组通过酶11beta-羟基脱氢酶将泼尼松转换为泼尼松龙，其生物活性形式。这一反应主要发生在肝脏，即使在肝脏疾病存在的情况下，也可能顺利进行。

Reduction of the 11-oxo to the 11alpha-hydroxyl group by the enzyme 11beta-hydroxydehydrogenase converts prednisone to prednisolone, its biologically active form. This reaction takes place mainly in the liver, and may proceed satisfactorily even in the presence of liver disease

来源:Hazardous Substances Data Bank (HSDB)

代谢

在体外，泼尼松被肝脏、肺和肾脏组织转化为泼尼松龙。相反，泼尼松龙被肾脏组织转化为泼尼松。

In vitro, prednisone is converted to prednisolone by liver, lung and renal tissue. Conversely, prednisolone is converted to prednisone by renal tissue.

来源:Hazardous Substances Data Bank (HSDB)

代谢

这项工作的目的是评估这些皮质类固醇对几种细胞色素P450（包括P450 1A2、2D6、2E1和3A）表达的影响，以及对人肝细胞中环孢霉素A氧化酶活性的影响。为此，将来自肝叶切除术的人肝细胞在无血清培养基中，在胶原蛋白包被的培养皿中培养96-144小时，在此期间，细胞在缺乏或存在50-100 uM皮质类固醇、利福平或地塞米松的条件下。为了更接近当前的临床方案，肝细胞培养还与皮质类固醇和环孢霉素A或酮康唑（一种选择性细胞色素P450 3A的抑制剂）共同处理。在这些培养物中平行测量环孢霉素A氧化酶活性、肝细胞内环孢霉素A氧化代谢产物的滞留、细胞色素P450蛋白和相应信息的积累，以及这些细胞色素P450的新合成和半衰期。我们从七个不同的肝细胞培养物中获得的结果表明：1)地塞米松和泼尼松，而不是泼尼松龙或甲泼尼龙，是细胞色素P450 3A的诱导剂，在蛋白质和mRNA积累水平上，以及主要由这些细胞色素P450催化的环孢霉素A氧化酶活性方面；2)尽管皮质类固醇在人肝中已知主要由细胞色素P450 3A代谢，但环孢霉素或酮康唑部分或完全抑制这些细胞色素P450，并没有影响这些分子的诱导效率；3)皮质类固醇不影响细胞色素P450 3A的半衰期，也不影响其他形式的细胞色素P450的积累，包括1A2、2D6和2E1；4)长期用环孢霉素处理细胞并不影响细胞色素P450 3A的积累；5)皮质类固醇是人肝微粒体中环孢霉素A氧化酶的竞争性抑制剂，地塞米松、泼尼松龙、泼尼松和甲泼尼龙的Ki值分别为61 + 或 - 12、125 + 或 - 25、190 + 或 - 38、210 + 或 - 42 uM；6)长期用皮质类固醇处理细胞并不影响环孢霉素氧化代谢产物从细胞中的排泄。

... The aim of this work was to evaluate the effects of these corticosteroids on the expression of several forms of cytochromes p450, including p450 1A2, 2D6, 2E1, and 3A, and on cyclosporin A oxidase activity in human liver. For this purpose, human hepatocytes prepared from lobectomies were maintained in culture in a serum-free medium, in collagen-coated dishes, for 96-144 hr, in the absence or presence of 50-100 uM corticosteroids, rifampicin, or dexamethasone. To mimic more closely the current clinical protocol, hepatocyte cultures were also co-treated with corticosteroids and cyclosporin A or ketoconazole (a selective inhibitor of cytochromes p450 3A). Cyclosporin A oxidase activity, intracellular retention of cyclosporin A oxidized metabolites within hepatocytes, accumulation of cytochromes p450 proteins and corresponding messages, and de novo synthesis and half-lives of these cytochromes p450 were measured in parallel in these cultures. Our results, obtained from seven different hepatocyte cultures, showed that 1) dexamethasone and prednisone, but not prednisolone or methylprednisolone, were inducers of cytochrome p450 3A, at the level of protein and mRNA accumulation, as well as of cyclosporin A oxidase activity, known to be predominantly catalyzed by these cytochromes p450; 2) although corticosteroids are known to be metabolized in human liver, notably by cytochrome p450 3A, partial or total inhibition of this cytochromes p450 by cyclosporin or ketoconazole, respectively, did not affect the inducing efficiency of these molecules; 3) corticosteroids did not affect the half-life of cytochrome p450 3A or the accumulation of other forms of cytochromes p450, including 1A2, 2D6, and 2E1; 4) chronic treatment of cells with cyclosporin did not affect cytochrome p450 3A accumulation; 5) corticosteroids were all competitive inhibitors of cyclosporin A oxidase in human liver microsomes, with Ki values of 61 + or - 12, 125 + or - 25, 190 + or - 38, and 210 + or - 42 uM for dexamethasone, prednisolone, prednisone, and methylprednisolone, respectively; and 6) chronic treatment of cells with corticosteroids did not influence the excretion of oxidized metabolites of cyclosporin from the cells.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：泼尼松是一种具有持久苦味的白色结晶粉末。它是一种糖皮质激素、抗炎药和抗肿瘤药。人类暴露和毒性：在连续使用治疗剂量时，泼尼松会在人体内产生深远和多样的代谢效应。大剂量使用时，它可能诱发心脏并发症。此外，它会改变人体对各种刺激的免疫反应；发生的改变包括淋巴细胞减少、单核细胞减少和迟发型超敏皮肤试验的抑制。可能会出现液体和电解质紊乱，包括钠和液体潴留，这可能导致充血性心力衰竭和高血压。大剂量使用时，可能会出现钾丢失、低钾性碱中毒和钙排泄增加。糖皮质激素在孕妇使用时可能会对胎儿造成损害。一项回顾性研究对260名在怀孕期间接受药理剂量糖皮质激素的妇女进行了研究，发现2例腭裂、8例死胎、1例自然流产和15例早产。另一项研究报告在86次分娩中发生2例腭裂。在接受每天3毫克/千克体重泼尼松单独治疗28天，然后以0.5-1毫克/千克体重治疗18-120个月的患者的周围淋巴细胞中，没有检测到染色体损伤。动物研究：在大鼠和小鼠中进行了致癌性研究。在处理过的雄性中，20只中有7只发生了肿瘤，其中3只是垂体肿瘤，1只是乳腺肿瘤；18只雌性大鼠中有16只发生了肿瘤，其中8只是乳腺癌，5只是垂体癌，2只是肾上腺癌，1只是肝癌。雌性的总体肿瘤发生率是对照组的1.5-2倍。然而，在小鼠中，处理过的雄性的肿瘤发生率为19只中的4只（21%），包括2只淋巴肉瘤和2只肺肿瘤，处理过的雌性的肿瘤发生率为27只中的8只（30%），包括4只肺肿瘤，2只淋巴肉瘤和2只子宫肿瘤。这些发生率与对照组相比没有显著增加。从大鼠怀孕的第11天开始，每天给予2.5或5毫克的泼尼松，直到分娩，据报道会抑制胎儿胸腺和脾的生长。泼尼松在大肠杆菌中不具有诱变性，在给予大鼠时也没有引起染色体损伤。生态毒性研究：使用轮虫Brachionus calyciflorus和两种甲壳类动物，即枝角类Daphnia magna和背甲目Thamnocephalus platyurus，进行了急性毒性试验。对绿藻Pseudokirchneriella subcapitata和甲壳类动物Ceriodaphnia dubia进行了慢性毒性试验。结果显示泼尼松的急性和慢性毒性较低。一些光产物对C. dubia具有高毒性效应。

IDENTIFICATION AND USE: Prednisone is white crystalline powder with a persistent bitter after-taste. It is glucocorticoid, anti-inflammatory agent and antineoplastic agent. HUMAN EXPOSURE AND TOXICITY: Prednisone causes profound and varied metabolic effects when used at therapeutic doses, given on a continuous basis. When given in large doses it can induce cardiac complications. In addition, it modifies the body's immune response to diverse stimuli; among the changes that occur are lymphopenia, monocytopenia and suppression of delayed hypersensitivity skin tests. Fluid and electrolyte disturbances may occur, including sodium and fluid retention, which may lead to congestive heart failure and hypertension. With large doses, potassium loss, hypokalemic alkalosis, and increased calcium excretion may occur. Glucocorticoids may cause fetal damage when administered to pregnant women. One retrospective study of 260 women who received pharmacologic dosages of glucocorticoids during pregnancy revealed 2 instances of cleft palate, 8 stillbirths, 1 spontaneous abortion, and 15 premature births. Another study reported 2 cases of cleft palate in 86 births. No chromosomal damage was detected in peripheral lymphocytes of patients treated with 3 mg/kg bw per day prednisone alone for 28 days and then with 0.5-1 mg/kg bw per day for 18-120 months. ANIMAL STUDIES: Carcinogenicity studies have been conducted in rats and mice. Of treated males, 7/20 developed tumors, among which were 3 pituitary tumors and 1 tumor of the breast; 16/18 female rats developed tumors, 8 of the breast, 5 of the pituitary, 2 of the adrenal and 1 of the liver. The overall tumor incidence in females was 1.5-2-fold higher than that in controls. However in mice, the tumor incidence in treated males was 4/19 (21%), with 2 lymphosarcomas and 2 lung tumors, and that in treated females was 8/27 (30%), with 4 lung tumors, 2 lymphosarcomas and 2 uterine tumors. These incidences were not significantly greater than those in controls. Prednisone given to rats from the 11th day of pregnancy until parturition at daily doses of 2.5 or 5 mg was reported to inhibit the growth of the fetal thymus and spleen. Prednisone was not mutagenic in Escherichia coli, and it caused no chromosomal damage when administered to rats. ECOTOXICITY STUDIES: The rotifer Brachionus calyciflorus and two crustaceans, the cladoceran Daphnia magna and the anostracan Thamnocephalus platyurus, were used to perform acute toxicity tests. Chronic toxicity tests have been performed on the alga Pseudokirchneriella subcapitata and the crustacean Ceriodaphnia dubia. The results showed low acute and chronic toxicity of prednisone. Some of the photoproducts had high toxic effects on C. dubia.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

泼尼松是一种糖皮质激素受体激动剂。它首先在肝脏中被代谢为其活性形式，泼尼松龙。泼尼松龙穿过细胞膜并与特定的细胞质受体以高亲和力结合。其结果包括抑制炎症部位的白细胞浸润，干扰炎症反应介质的功能，抑制体液免疫反应，以及减少水肿或瘢痕组织。糖皮质激素的抗炎作用被认为涉及磷脂酶A2抑制蛋白，即脂皮质素，它们控制强效炎症介质如前列腺素和白三烯的生物合成。泼尼松可以刺激胃液的各种成分的分泌。抑制促肾上腺皮质激素的产生可能导致内源性糖皮质激素的抑制。泼尼松具有轻微的盐皮质激素活性，通过刺激钠进入细胞和细胞内钾的丢失。这在肾脏中尤为明显，其中快速的离子交换导致钠潴留和高血压。

Prednisone is a glucocorticoid receptor agonist. It is first metabolized in the liver to its active form, prednisolone. Prednisolone crosses cell membranes and binds with high affinity to specific cytoplasmic receptors. The result includes inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of inflammatory response, suppression of humoral immune responses, and reduction in edema or scar tissue. The antiinflammatory actions of corticosteroids are thought to involve phospholipase A2 inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes. Prednisone can stimulate secretion of various components of gastric juice. Suppression of the production of corticotropin may lead to suppression of endogenous corticosteroids. Prednisone has slight mineralocorticoid activity, whereby entry of sodium into cells and loss of intracellular potassium is stimulated. This is particularly evident in the kidney, where rapid ion exchange leads to sodium retention and hypertension.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

泼尼松

Compound:prednisone

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服泼尼松的Tmax为2小时，而缓释制剂的Tmax为6-6.5小时。5毫克剂量的泼尼松的AUC为572毫升/分钟/1.73平方米，20毫克剂量的泼尼松的AUC为1034毫升/分钟/1.73平方米，50毫克剂量的泼尼松的AUC为2271毫升/分钟/1.73平方米。关于泼尼松Cmax的数据不易获得。

Oral prednisone has a Tmax of 2 hours, while the delayed-release formulation has a Tmax of 6-6.5 hours. A 5mg dose of prednisone has an AUC of 572mL/min/1.73m2, a 20mg dose of prednisone has an AUC of 1034mL/min/1.73m2, and a 50mg dose of prednisone has an AUC of 2271mL/min/1.73m2. Data regarding the Cmax of prednisone is not readily available.

来源:DrugBank

吸收、分配和排泄

• 消除途径

泼尼松主要通过尿液以硫酸盐和葡萄糖醛酸苷的形式排出体外。

Prednisone is excreted mainly in the urine as sulfate and glucuronide conjugates.

来源:DrugBank

吸收、分配和排泄

• 分布容积

关于泼尼松的分布体积的数据不易获得。然而，0.15mg/kg剂量的泼尼松龙的分布体积为29.3升，而0.30mg/kg剂量的分布体积为44.2升。

Data regarding the volume of distribution for prednisone is not readily available. However, a 0.15mg/kg dose of prednisolone has a volume of distribution of 29.3L, while a 0.30mg/kg dose has a volume of distribution of 44.2L.

来源:DrugBank

吸收、分配和排泄

• 清除

关于泼尼松龙的清除数据并不容易获得。以5.5µg/h/kg的速率输注泼尼松龙的平均清除率为0.066±0.12L/h/kg，而以0.15±0.03L/h/kg的速率输注的平均清除率为0.15L/h/kg。

Data regarding the clearance of prednisone is not readily available. A 5.5µg/h/kg infusion of prednisolone has an average clearance of 0.066±0.12L/h/kg, while a 0.15±0.03L/h/kg infusion has an average clearance of 0.15L/h/kg.

来源:DrugBank

吸收、分配和排泄

静脉注射（3）H-泼尼松到猴子后30分钟，泼尼松的浓度在肾脏中最高。该药物也存在于肝脏、脾脏、肺、小肠、血清和胆汁中。泼尼松龙的浓度在肝脏中最高的。它也存在于肾脏、胰腺、脾脏、肺、小肠、血清和胆汁中。

Thirty minutes after iv administration of (3)H-prednisone to a monkey, the concentration of prednisone was highest in the kidney. The drug was also found in the liver, spleen, lung, small intestine, serum and bile. The concentration of prednisolone was highest in the liver. It was also found in the kidney, pancreas, spleen, lung, small intestine, serum and bile.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S36/37/39,S45
• 危险品运输编号：
  NONH for all modes of transport
• WGK Germany：
  3
• 海关编码：
  2937210000
• 危险类别码：
  R63
• RTECS号：
  TU4154100

制备方法与用途

根据提供的信息,泼尼松的主要用途和特点包括:

1. 用于治疗体内严重感染性疾病,如中毒性菌痢、中毒性肺炎等。

2. 具有抗炎、抗过敏作用,可用于以下疾病:

• 中毒型细菌性痢疾
• 风湿性疾病
• 过敏性疾病
• 肾病综合征
• 某些血液病

3. 用于内科急症抢救:

• 重症感染
• 大手术后
• 器官移植术前术后

4. 可以与化疗药物联合使用,改善病人的一般情况。

5. 在神经科方面,研究发现小剂量泼尼松可有效控制视神经脊髓炎(NMO)的复发。

6. 老年患者长期使用需谨慎,易发生高血压和骨质疏松等问题。

7. 妊娠期妇女应权衡利弊使用,哺乳期妇女不宜大剂量给药。

8. 对儿童和青少年需按体重、年龄调整用药量,避免影响生长发育。

9. 长期大量应用时需补充蛋白质饮食,注意观察不良反应并逐渐减量停药。

反应信息

• 作为反应物：
  描述：

  泼尼松 在 potassium carbonate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 生成
  参考文献：
  名称：

  利用闭环复分解反应合成新型抗炎甾体大环化合物

  摘要：

  通过使用闭环易位反应从容易获得的抗炎类固醇（如泼尼松龙，6-甲基泼尼松龙和16-甲基泼尼松龙）合成了一类新的13和16元类固醇大环化合物。

  DOI：

  10.1016/j.tetlet.2014.12.048
• 作为产物：
  描述：

  醋酸泼尼松 在 potassium carbonate 、 溶剂黄146 作用下， 以 乙醇 、 水 为溶剂， 以68.5%的产率得到泼尼松
  参考文献：
  名称：

  一种泼尼松的制备方法

  摘要：

  本发明公开了一种泼尼松的制备方法，属于药物的制备加工技术领域。该方法以醋酸氢化可的松为起始原料，经氧化、生物发酵脱氢、水解三个步骤，制备得到本发明所述的泼尼松。本发明所述泼尼松的制备方法通过改进传统工艺的不足，实现了目的产品纯度高，质量稳定性好，收率高，生产成本低，反应条件温和，避免了使用剧毒的氰试剂，本发明方法操作简便，适于工业化生产，具有广阔的市场前景。

  公开号：

  CN111777654B

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
  申请人：——

  公开号：US20020143182A1

  公开（公告）日：2002-10-03

  The invention relates to certain heterocyclic compounds useful for the treatment of cancer and other diseases, having the Formula (I): 1 wherein: (a) m is an integer 0 or 1; (b) R 12 is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic, a substituted heterocyclic, a heteroaryl, a substituted heteroaryl, an aryl or a substituted aryl residue; (c) Ar 3 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (d) Ar 4 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (e) R 5 is hydrogen, hydroxy, alkyl or substituted alkyl; (f) - - - - - represents a bond present or absent; and (g) W, X, Y and Z are independently or together C(O)—, C(S), S, O, or NH; or a pharmaceutically acceptable salt thereof.

  该发明涉及某些对治疗癌症和其他疾病有用的杂环化合物，其具有以下式（I）： 1 其中： (a) m是整数0或1； (b) R12是烷基，取代烷基，环烷基，取代环烷基，杂环基，取代杂环基，杂芳基，取代杂芳基，芳基或取代芳基残基； (c) Ar3是芳基，取代芳基，杂芳基或取代杂芳基残基； (d) Ar4是芳基，取代芳基，杂芳基或取代杂芳基残基； (e) R5是氢，羟基，烷基或取代烷基； (f) - - - - - 代表存在或不存在的键；以及 (g) W、X、Y和Z独立或一起是C(O)、C(S)、S、O或NH；或其药学上可接受的盐。
• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• Cobalamin conjugates for anti-tumor therapy
  申请人：Weinshenker M. Ned

  公开号：US20050054607A1

  公开（公告）日：2005-03-10

  The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.

  本发明提供了一种适用于治疗肿瘤相关疾病的钴胺素-药物结合物。钴胺素通过可切割的连接剂间接共价结合到抗肿瘤药物上，还可以通过一个或多个可选的间隔物。钴胺素通过其核糖环的5'-OH与第一间隔物或可切割连接剂共价结合。药物通过其现有或添加的功能基团与可切割连接剂的第二间隔物结合。在给药后，结合物与转钴胺素（其任何同工异构体）形成复合物。然后，该复合物结合到细胞膜上的受体并被细胞摄取。一旦进入细胞，细胞内酶将切割结合物，从而释放药物。根据结合物的结构，特定类别或类型的细胞内酶影响切割。由于生长细胞对钴胺素的需求量较高，肿瘤细胞通常摄取结合物的比例高于正常非生长细胞。本发明的结合物与相应的游离药物相比，具有较低的全身毒性和增强的疗效。

表征谱图