4-羟基吲哚和4-甲氧基吲哚的合成

目的 寻找操作方便、反应路线短且成本低的工艺路线。方法 通过取代酚的醚化，再在苯环上直接引入腈乙基，然后水解、环合等反应，直接生成吲哚衍生物。结果 采用氢的亲核取代反应(VNS)，直接制得4-羟基吲哚和4-甲氧基吲哚，操作方便，反应路线短且成本较低。结论 4-羟基吲哚和4-甲氧基吲哚的收率分别达57．4％和28．8％，是值得研究推广的新工艺。     

4-去氧-4β-芳甲磺酰胺基-4′-去甲鬼臼脂素的合成及体外抑制肿瘤细胞活性

目的　寻找高效低毒的鬼臼脂素类抗肿瘤药物。方法和结果　设计合成了4-增碳侧链的磺酰胺基鬼臼脂素衍生物(1-15),均为新化合物。并对这些化合物进行了体外抑制KB细胞和L1210白血病细胞活性试验。结论　化合物2,3,8,9,11和12有显著的体外抑制肿瘤细胞活性。     

Synthetic approaches to peptide analogues containing 4, 4-difluoro-L-proline and 4-keto-L-proline

An improved synthesis of 4, 4-difluoro-L-proline is described. A key step in this synthesis involves the fluorination of Z-4-keto-L-proline benzyl ester, using diethylaminosulfur trifluoride (DAST), to give the corresponding Z-4, 4-difluoro-L-proline benzyl ester. Preparation of dipeptide derivatives containing 4, 4-difluoro-L-proline has been accomplished by initial synthesis of the corresponding 4-keto-L-proline dipeptide derivatives, which were then fluorinated with DAST. A one-step synthesis of Boc-4-keto-L-proline from Boc-4-hydroxy-L-proline by chromium trioxide oxidation is reported. These synthetic procedures should facilitate the preparation of a variety of peptide analogues containing 4, 4-difluoro-L-proline and 4-keto-L-proline.     

4-烷硫基-4-脱氧-4′-去甲表鬼臼毒素的合成和抗肿瘤活性

对4’-去甲表鬼臼毒素的C₄位进行化学修饰,合成和筛选了10个4-烷硫基-4-脱氧-4’-去甲表鬼臼毒素衍生物以进一步研究C₄位不同的原子和取代基与活性之间的关系及寻找结构简单、活性更强的抗肿瘤新药。4’-去甲表鬼臼毒素与硫醇在三氟化硼·乙醚或三氟乙酸存在下生成相应的硫醚,也可用硫醇与4β-溴-4-脱氧-4’-去甲表鬼臼毒素反应生成相应的硫醚。在体外筛选中,化合物10和12抑制L1210白血病细胞的活性与依托泊甙相当或更强,化合物9,10,12和15抑制KB细胞的活性与依托泊甙相当或更强。     

4-酰硫基-4-脱氧-4-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性

为研究4’-去甲表鬼臼毒素的C₄位不同原子及不同取代基类型同活性之间的关系,寻找活性高、毒性低的抗肿瘤新药,合成了11个4-酰硫基-4-脱氧-4’-去甲表鬼臼毒素,衍生物并进行了抗肿瘤活性试验。4-巯基-4-脱氧-4’-去甲表鬼臼毒素和不同的羧酸在二乙氧基磷酰氰酯存在下得相应的硫酯。该类化合物在L1210白血病细胞和KB细胞的体外抑制试验中普遍表现出抑制活性。化合物10的活性与依托泊甙相当。其余活性比依托泊甙差。与相应的C₄位酰氨基的4’-去甲表鬼臼毒素衍生物相比,活性明显弱。提示氮取代的衍生物活性更好。     

4-Phenyl- and 4-heteroaryl-4-anilidopiperidines. A novel class of analgesic and anesthetic agents

The incorporation of the 4-phenylpiperidine pharmacophore found in morphine into 4-anilidopiperidines related to fentanyl (1) led to a novel class of potent opioid analgesic and anesthetic agents with a favorable pharmacological profile. The synthesis, analgesic activity, and anesthetic properties of a series of 4-phenyl-4-anilidopiperidines (13-29) are discussed. Isosteric replacement of the phenyl by various heteroaryl substituents extended the series to include 4-heteroaryl-4-anilidopiperidines (30-53). Within this group, 1-[2-(1H-pyrazol-1-yl)ethyl]-4-(4-methylthiazol-2-yl)-4-(N- phenylpropionamido)piperidine (48), exhibited high analgesic potency, short duration of action, rapid recovery of motor coordination following anesthetic doses, and greater cardiovascular and respiratory safety during anesthesia as compared with opioids fentanyl (1) and alfentanil (2) currently in clinical use. Such analgesics could be of great utility to clinicians in the expanding outpatient surgical arena and for patient-controlled analgesia and computer assisted continuous infusion pain control techniques.     

Il-4r expression in AIDS-KS cells and response to rhIL-4 and IL-4 toxin (DAB389-IL-4)

Interleukin-4 (IL-4) is a pleiotropic cytokine affecting growth and differentiation of various cell types as well as regulating other cytokines. To study the effect of IL-4 on AIDS-related Kaposi's sarcoma (AIDS-KS) cells, we first examined the tumor cells for IL-4 receptor (IL-4R) expression. KS cells express a single 4 kB IL-4R-specific mRNA and 1828 ± 408 high affinity IL-4 binding sites per cell with a dissociation constant (Kd) of 154 ± 37 pM. Addition of recombinant human IL-4 (rIL-4) minimally inhibited AIDS-KS cell growth and expression of IL-6. We then studied the effects of a chimeric fusion toxin DAB₃₈₉-IL-4 which exerts cellular toxicity only on cells expressing IL-4R. DAB₃₈₉-IL-4 inhibited protein synthesis in AIDS-KS cells at low concentrations (IC₅₀ of 5 × 10^-11 M). This effect was abrogated by neutralizing antibody to IL-4 (25D2). We conclude that KS cells express a functional IL-4R and this receptor could serve as a target for novel therapy with agents such as DAB₃₈₉-IL-4.     

Synthesis and anti-HIV activity of 4'-azido- and 4'-methoxynucleosides.

A series of nucleosides were synthesized in which the 4'-hydrogen was substituted with either an azido or a methoxy group. The key steps in the syntheses of the 4'-azido analogues were the stereo- and regioselective addition of iodine azide to a 4'-unsaturated nucleoside precursor followed by an oxidatively assisted displacement of the 5'-iodo group. The 4'-methoxynucleosides were made via epoxidation of 4'-unsaturated nucleosides with in suit epoxide opening by methanol. Reaction-mechanism considerations, empirical conformation rules, NMR-based conformational calculations, and NOE experiments suggest that the 4'-azidonucleosides prefer a 3'-endo (N-type) conformation of the furanose moiety. When evaluated for their inhibitory effect on HIV in A3.01 cell culture, all the 4'-azido-2'-deoxy-beta-D-nucleosides exhibited potent activity. IC50's ranged from 0.80 microM for 4'-azido-2'-deoxyuridine (6c) to 0.003 microM for 4'-azido-2'-deoxyguanosine (6e). Cytotoxicity was detected at 50-1500 times the IC50's in this series. The 4'-methoxy-2'-deoxy-beta-D-nucleosides were 2-3 orders of magnitude less active and less toxic than their azido counterparts. Modifications at the 2'- or 3'-position of the 4'-substituted-2'-deoxynucleosides tended to diminish activity. Further evaluation of 4'-azidothymidine (6a) in H9, PBL, and MT-2 cells infected with HIV demonstrated a similar inhibitory profile to that of AZT. However, 4'-azidothymidine (6a) retained its activity against HIV mutants which were resistant to AZT.     

Anticonvulsant activity of some 4-methoxy- and 4-chlorobenzanilides

A series of mono-, di-, and trimethylated derivatives of 4-chloro- and 4-methoxybenzanilide was synthesized and evaluated for anticonvulsant activity. This series was prepared in the course of studies designed to examine the relationship between anticonvulsant effects and benzamide structure. The compounds were tested in mice against seizures induced by maximal electroshock (MES) and pentylenetetrazole (scMet), as well as with the rotorod assay for neurologic deficit. In mice dosed intraperitoneally, 4-methoxy-2, 6-dimethylbenzanilide (4) showed a median anticonvulsant potency (ED50) of 18.58 mg/kg in the MES test and a median toxicity (TD50) of 133.72 mg/kg in the rotorod toxicity assay, yielding a protective index (PI = TD50/ED50) of 7.2. In mice dosed orally with 4, the anti-MES ED50 was 27.40 mg/kg and the TD50 dose was determined to be 342.58 mg/kg, resulting in a protective index of 12.5.     

Role of cyclooxygenase products in the lung action of leukotrienes A4, B4, C4, D4 and E4

Leukotrienes (LT) LTA4, LTB4, LTC4, LTD4 and LTE4 induced marked contractions of guinea pig lung parenchymal strips mounted in organ baths. These contractions were inhibited differentially (40-50% for LTA4, LTC4, LTD4 and LTE4, and 90% for LTB4) by indomethacin (20 micrograms.ml-1; 55.9 microM). Two novel inhibitors of thromboxane synthetase (OKY-1581 and OKY-046) reduced the myotropic activity of the lung strips and the release of prostaglandins and thromboxanes from the perfused guinea pig lungs stimulated by LTB4 and LTD4. The release of cyclooxygenase products prostaglandin F2 alpha, thromboxane B2 and 12-hydroxyheptadecatrienoic acid by guinea pig lungs following stimulation with LTB4 and LTD4 was also measured by gas chromatography-mass spectrometry. The role of prostaglandins and thromboxanes in the lung actions of leukotrienes was confirmed using a cascade superfusion system and classical organ baths. Although prostaglandins and thromboxanes contribute to the contractile effect of LTB4 on the guinea pig lung whereas they may play a lesser role in the action of the peptidoleukotrienes (approx. 40-50%), stimulation of their release by the peptidoleukotrienes is many times more effective than by LTB4.     

Inhibition of leukotriene B4 in neutrophils by lipoxins A4 and B4.

Lipoxins are derived from the oxygenation products of arachidonic acid in human leukocytes. They have exhibited selective biological effects different from those of other eicosanoids. We have examined the effect of lipoxin A4 and B4 (LXA4, LXB4) on the production of leukotriene B4 (LTB4) in human neutrophils. Cultured human polymorphonuclear leukocytes were preincubated with LXA and B and their ability to inhibit LTB4 generation was assessed after incubation with calcium ionophore A23187. We found that the pretreatment of neutrophils with lipoxins inhibit the release of LTB4 by A23187 stimulated PMNs. Our data suggests that LXA4 and B4 can contribute to immunosuppression in an inflammatory state via the inhibition of LTB4 synthesis.     

4-Aetaminophenol and 4-hydroxyphenylsalicylamide synthesized by reductive acylation of 4-nitrophenol on palladium catalysts

The possibility of obtaining paracetamol (4-acetamidophenol) and oxaphenamide (4-hydroxyphenylsalicylamide) by means of a single-stage reductive acylation of 4-nitrophenol on palladium catalysts has been studied. Using this single-stage reaction under mild conditions (organic solvents; temperature, 45°C; hydrogen pressure, 1 bar) the target compounds were obtained with a yield of 70–90% for paracetamol and 41–63% for oxaphenamide. Metal — polymer catalyst systems have proved to be more active and selective than the traditional heterogeneous Pd/C catalysts. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 12, pp. 37–39, December, 2005.     

我国OTC药品营销的4P和4C战略

目的我国医药行业的蓬勃发展离不开科学技术的支撑,更离不开科学的经营管理与有效的市场营销活动。随着我国市场经济的不断完善,医药企业面临的营销环境也在不断变化。本文就如何结合我国医药行业营销实践不断更新营销理念,在OTC药品营销工作中合理运用4P理论和4C理论进行相关探讨。在分析对比两者的区别与联系基础上提出了应该采用优势互补的OTC药品营销战略组合的观点。