Synthesis and Pharmacological Properties of 1-Aryl-4-(3′4′,5′-trimethoxybenzoyl)piperazines

A series of 1-aryl-4-(3′,4′,5′-trimethoxybenzoyl)piperazines (IIa - IIg) having structures containing 3,4,5-trimethoxybenzoyl fragments were synthesized and characterized. Compounds IIa and IIc - IIg demonstrated weak anxiolytic properties and moderately decreased the spontaneous motor activity in rats. Compound IIb exhibited anxiolytic activity comparable with that of buspirone but, in contrast to this reference drug, increased the motor activity of test animals. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 5, pp. 12 – 14, May, 2005.     

7-(4′-氨基丁基)-茶碱的合成

为制备茶碱FPIA试剂盒中荧光素标记抗原,作者设计合成了其重要中间体7-(4′-氨基丁基)-茶碱。后者是经茶碱钠与N-(4′-溴丁基)-邻苯二甲酰亚胺缩合,再经肼解后得到的。     

3(3′-甲基-4′-取代苯基-1′,3′-丁二烯基)吲哚类衍生物的合成及其抗癌活性

目的　研究 3 (3′ 甲基 4′ 取代苯基 1′ ,3′ 丁二烯基 )吲哚类衍生物的合成及其抗癌活性。方法　通过亲电取代、羟醛缩合、选择性还原、相转移Wittig反应和水解反应合成目的化合物 ,利用几种药理模型进行抗癌和抗炎活性筛选。结果　设计合成了 11个 3 (3′ 甲基 4′ 取代苯基 1′ ,3′ 丁二烯基 )吲哚化合物 ,均为新化合物。生物活性实验结果表明 ,化合物 8对HL 6 0 ,HCT 8和Bel740 2癌细胞株有效 ,且在浓度为 10 -5mol·L-1时 ,其抗炎抑制率可达 10 0 %。结论　化合物 8显示了抑癌作用和抗炎活性 ,值得进一步研究。     

3-(3′-甲基-4′-取代苯基-1′,3′-丁二烯基)吲哚类衍生物的合成及其抗癌活性

目的　研究3-(3′-甲基-4′-取代苯基-1′,3′-丁二烯基)吲哚类衍生物的合成及其抗癌活性。方法　通过亲电取代、羟醛缩合、选择性还原、相转移Wittig反应和水解反应合成目的化合物,利用几种药理模型进行抗癌和抗炎活性筛选。结果　设计合成了11个3-(3′-甲基-4′-取代苯基-1′,3′-丁二烯基)吲哚化合物,均为新化合物。生物活性实验结果表明,化合物8对HL-60,HCT-8和Bel7402癌细胞株有效,且在浓度为10^-5mol·L^-1时,其抗炎抑制率可达100％。结论　化合物8显示了抑癌作用和抗炎活性,值得进一步研究。     

2′,4′-二氟-α-(1H-1,2,4-三唑-1-基)苯乙酮的合成

２′,４′－二氟－α－（１Ｈ－１,２,４－三唑－１－基）苯乙酮（１）是合成氟康唑的关键中间体。文献报道的合成方法是先将１Ｈ－１,２,４－三唑（３）与ＮａＨＣＯ３在甲苯中回流,然后滴加α－氯－２′,４′－二氟苯乙酮（２）,于１１０°Ｃ反应４ｈ,收率仅８．７％［１］。作者通过提高三唑的投料量,可使收率提高到３０％,但操作仍甚繁琐;后设计相转移催化的三唑烷基化方法,以ＴＥＢＡ作为固－液相转移催化剂,Ｋ２ＣＯ３为缚酸剂,ＣＨ２Ｃｌ２为溶剂,常温反应即可制备目标化合物,收率提高到８２．６％。新的方法具有操…     

3′-(4-(Benzyloxy)phenyl)-1′-phenyl-5-(heteroaryl/aryl)-3,4-dihydro-1′H,2H-[3,4′-bipyrazole]-2-carboxamides as EGFR kinase inhibitors: Synthesis,anticancer evaluation,and molecular docking studies

Pyrazoline-linked carboxamide derivatives were designed, synthesized, and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer activity, and apoptotic and cardiomyopathy toxicity. Compounds 6m and 6n inhibit EGFR kinase at a concentration of 6.5 ± 2.91 and 3.65 ± 0.54 µM, respectively. Some of these compounds showed effects on proliferation, which were also then evaluated against four different human cancer cell lines, that is, MCF-7 (breast cancer), A549 (non-small-cell lung tumor), HCT-116 (colon cancer), and SiHa cells (cancerous tissues of the cervix uteri). The results showed that certain synthetic compounds showed significant inhibitor activity; compounds 6m and 6n were more cytotoxic than doxorubicin against A549 cancer cells, with IC₅₀ values of 10.3 ± 1.07 and 4.6 ± 0.57 µM, respectively. Additionally, compounds 6m and 6n induced apoptosis in A549 cancer cells, as evidenced by 4′,6-diamidino-2-phenylindole (DAPI) staining and phase-contrast microscopy. Potency to induce apoptosis by compound 6n was further confirmed by fluorescence-activated cell sorting using Annexin V-FITC and propidium iodide labeling. Compound 6n showed normal cardiomyocytes with no marked sign of pyknotic nuclei in cardiomyopathy and also normal histological appearance of the renal cortex when compared with that of control. Results of molecular docking studies suggested that compounds 6m and 6n can bind to the hinge region of the adenosine triphosphate-binding site of EGFR kinase, like the standard drug erlotinib. Therefore, the present study suggests that compounds 6m and 6n have potent in vitro antitumor activities against the human non-small-cell lung tumor cell line A549, which can be further explored in other cancer cell lines and in animal studies.     

Synthesis of some new 3,5-diamino-4-(4′-fluorophenylazo)-1-aryl/heteroarylpyrazoles as antimicrobial agents

Synthesis of some new 3,5-diamino-4-(4′-fluorophenylazo)-1-aryl/heteroarylpyrazoles (5a–5i) was achieved by the treatment of aryl/heteroarylhydrazines 4a–4i with 2-[(4-fluorophenyl)hydrazono]malononitrile 3 in refluxing ethanol. The structure of the compounds was established on the basis of IR, NMR (¹H and ¹³C) and mass spectral studies. All the nine synthesized compounds were screened for their in vitro antimicrobial activity against two Gram-positive (Staphylococcus aureus, Bacillus subtilis), two Gram-negative bacteria (Escherichia coli, Klebesiella aerogenes) and three pathogenic fungi (Aspergillus niger, Candida albicans, and Saccharomyces cerevisiae).     

Metabolism of the platelet-activating factor antagonist (±)-trans-2-(3′-methoxy-5′-methylsulphonyl-4′-propoxyphenyl)-5-(3″, 4″,5″-trimethoxyphenyl)tetrahydrofuran (L-659,989) in rhesus monkeys

1. The plasma concentration, main route of metabolism and excretion of ³H-L-659,989 were studied in male and female rhesus monkeys by dosing either i.v. or orally at 10 mg/kg.

2. The percentage of the AUC for the plasma radioactivity concentration-time curve of oral vs i.v. dosed monkeys was 78% for males and 90% for females, indicating that the dose was well absorbed.

3. The bioavailability of the drug was low (≤10%) for all monkeys, probably due to rapid first pass metabolism. The drug was metabolized predominantly at the C-4′-propoxy side-chain. The two major plasma metabolites were identified as the 4′-2-(hydroxy)propoxy metabolite (³H-trans-4′-HP) and the 4′-hydroxy metabolite (³H-4′-hydroxy) which was isolated as a 2:1 mixture of (±)trans:(±)cis.

4. Approx, 80% of the radiolabelied dose was excreted equally in the urine and faeces in 96h, with the largest percentage of the Initiated dose (31.4%) in the 0-24h urine.

5. The major metabolites in the excreta were the (±)trans(±)cis mixture of ³H-4′-hydroxy and the glucuronide conjugate of ^3H-trans-4′-hydroxy. The glucuronide conjugate of ³H-trans-4′-hydroxy was excreted in the urine of i.v. and orally dosed monkeys and represented an average of 21% and 5.1% of the dose, respectively. ³H-4′-Hydroxy was excreted in both the urine and faeces, accounting for. 0.1% and 7.4% of the dose in i.v. and orally dosed monkeys, respectively.     

Synthesis and smooth muscle-selective relaxant activity of a piperidine analogue: 1-(4′-fluorophenacyl)-4-hydroxy-4-phenyl-piperidinium chloride

The antispasmodic and vasodilator activities of a newly synthesized piperidine derivative (1-(4'-fluorophenacyl)-4-hydroxy-4-phenyl-piperidinium chloride) were studied in vitro. The test compound exhibited a dose-dependent relaxant effect on the spontaneous and K+ (75 mM)-induced contractions of isolated rabbit jejunum with respective EC50 values of 0.01 mM (0.01-0.02, 95% Cl) and 0.30 mM (0.17-0.56). The Ca++ channel blocking (CCB) activity was confirmed when the test compound (0.1-0.2 mM) shifted the Ca++ dose-response curves to the right, similar to that produced by verapamil (0.1-1.0 microM), a standard CCB. In the isolated rabbit aorta, the test compound showed a dose-dependent vasodilator effect on K+ (75 mM)-induced contractions with an EC50 value of 0.08 mM (0.02-0.26) while also suppressed the norepinephrine (1 microM) control peak responses with EC50 value of 0.08 mM (0.05-0.13, n=5). When tested in Langendorff perfused rabbit heart preparation, the test compound exhibited a negligible inhibitory effect on the rate or force of atrial and ventricular contractions when tested up to 5 mM. The results show smooth muscle-selective relaxant effect of the test compound on intestinal and vascular preparations mediated possibly via blockade of voltage and receptor-operated Ca++ channels.     

1-乙酰基-4-(4-羟基苯基)哌嗪的合成

目的对抗真菌药酮康唑的重要中间体1-乙酰基-4-(4-羟基苯基)哌嗪的合成工艺进行研究。方法以六水合哌嗪和对氯硝基苯为原料合成目标化合物,并对工艺进行探索。结果得到目标化合物,总产率优于现行路线。结论该路线有希望用于工业化生产。     

2β-(4′-甲基- 1′-哌嗪基)- 3α-羟基-16,17-取代-5α-雄甾烷的合成

为了寻找心血管系统药物,以表雄酮为原料,合成了7个16,17位取代的目标化合物:2β-(4’-甲基-1’-哌嗪基)-3α-羟基-5α-雄甾-17-酮、2β-(4’-甲基-1’-哌嗪基)-3α,17β-二羟基-5α-雄甾烷、2β-(4’-甲基-1’-哌嗪基)-3α-羟基-16α-溴-5α-雄甾-17-酮、2β-(4’-甲基-1’-哌嗪基)-3α,16α-二羟基-17-氧-5α-雄甾烷、2β-(4’-甲基-1’-哌嗪基)-3α,16α-二羟基-17-肟-5α-雄甾烷、2β-(4’-甲基-1’-哌嗪基)-3α,16α-二羟基-17β-氨基-5α-雄甾烷和2β—(4’-甲基-1’-哌嗪基)-3α,17β-二羟基-16β-氨基-5α-雄甾烷。初步药理试验结果表明它们都有不同程度的抗心律失常活性。     

1-乙酰-4-(4-羟基苯基)哌嗪合成的改进

二乙醇胺经溴化、环合一锅合成 N-(4-甲氧苯基)哌嗪氢溴酸盐(3),解决了劳动保护问题。酰化收率经改进从26%提高至70%以上,总收率26.4%,适合工业生产。     

Phase I trial of 1-(2′-deoxy-2′-fluoro-1-beta-D-arabinofuranosyl)-5-methyluracil (FMAU) terminated by severe neurologic toxicity

Summary FMAU (1-[2-deoxy-2-fluoro-l--D-arabinofuranosyl]-5-methyluracil) a newly synthesized fluorinated nucleoside, has potent in vitro antiviral and antileukemic activity and is active in murine leukemia lines resistant to cytosine arabinoside. In the initial phase I trial neurotoxicity, characterized by extrapyramidal dysfunction, was found to be the dose-limiting toxic effect, and a dosage of 32 mg/m₂/day for 5 days was suggested for phase II studies. We report a second phase I study of FMAU using this schedule. Mild, transient neurologic dysfunction was encountered in patients treated at the starting dose of 4 mg/m₂/day × 5 days and became severe and irreversible in two patients who received the highest cumulative doses administered at the 8 mg/m₂/day × 5 days level. Both severely affected patients died. Severe neurotoxicity developed and progressed in these patients despite serial neurologic examinations, including detailed neuropsychologic tests implemented in an effort to detect early neurotoxicity. Because of these findings, further study of this drug as an antileukemic agent cannot be recommended. If it is to be used as an antiviral agent, further phase I study at lower doses is advised.     

p-Toluenesulfonic acid-catalyzed solvent-free synthesis and biological evaluation of new 1-(4′,6′-dimethylpyrimidin-2′-yl)-5-amino-4H-3-arylpyrazole derivatives

A solvent-free quick synthesis of 1-(4′,6′-dimethylpyrimidin-2′-yl)-5-amino-4H-3-arylpyrazoles (3) was accomplished by grinding 2-hydrazino-4,6-dimethylpyrimidine (1) and β-ketonitriles (2) in the presence of p-Toluenesulfonic acid as a catalyst. Subsequently, 5-aminopyrazoles (3) were converted to their corresponding N-acetamide (4) and N-trifluoroacetamide (5) derivatives by treating (3) with acetic anhydride/acetic acid and trifluoroacetic anhydride/trifluoroacetic acid, respectively. The newly synthesized compounds were fully characterized using IR, NMR (¹H, ¹³C, and ¹⁹F), mass spectral studies, and elemental analyses. All of the fifteen compounds were screened for their in vitro antibacterial activity against two Gram-positive and two Gram-negative pathogenic bacteria such as Bacillus pumilus, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, respectively. Additionally, nine of these compounds were screened for their cytotoxicity against the human Caucasian promyelocytic leukemia (HL-60) cell line using the alamarBlue^® assay. Preliminary results reveal that compounds 3a, 3b, 3d, 5a, and 5d are showing moderate-to-significant cytotoxic and antibacterial activity.     

N-(4-氯-3-甲基苯基)-N′-甲基脲的合成

用铁粉还原、水汽蒸馏的方法制得4－氯－3－甲基苯胺，再以1，2，4－三氯苯为溶剂，与N－甲基脲直接缩合合成N－（4－氯－3－甲基苯基）－N′-甲基脲，该新方法优化了反应条件，可获得60％及67％的转化率和收率，且未反应的原料可回收套用。     

(R)-( )-和(S)-(-)-β,β′-联萘酚的制备

手性试剂(R)-( )-和(S)-(—)-β,β′-联萘酚[( )-1和(—)-1]由于能制得高纯度的对映体,光学性质稳定,且具有很强的面不对称性,在不对称合成中易生成高比例 ee 值的产物。已成功地应用于不对称还