硝基芳烃用NaBH4－SbCl3或NaBH4－BiCl3还原成伯胺

硝基芳烃用ＮａＢＨ４－ＳｂＣｌ３或ＮａＢＨ４－ＢｉＣｌ３还原成伯胺ＲｅｎＰＤ等［ＳｙｎＣｏｍｍｕｎ，１９９５；２５：３７９９］硝基芳烃于乙醇中加ＮａＢＨ４－ＳｂＣｌ３或ＮａＢＨ４－ＢｉＣｌ３室温反应可得相应的伯胺。１１例收率８０％～９５％。［金恰摘周...     

2－咪唑甲醛、2－咪唑羧酸及其乙酯的廉价改良合成法

２－咪唑甲醛、２－咪唑羧酸及其乙酯的廉价改良合成法ＧａｌｅａｚｚｉＥ等［ＪＯｒｇＣｈｅｍ，１９９５，６０：１０９０］ＧＨＣｌ２ＣＮ制得的亚胺酯（ＣＨＣｌ２ＣＯＣＨ３）与氨基乙醛缩二甲醇８０℃反应得到相应的乙脒［ＣＨＣｌ２ＣＮＨＣＨ２ＣＨ（ＯＣＨ３）２...     

Vilsmeier－Haack反应制备2，4－二羟基苯甲醛

Ｖｉｌｓｍｅｉｅｒ－Ｈａａｃｋ反应制备２，４－二羟基苯甲醛ＭｅｎｄｅｌｓｏｎＷＬ等［ＳｙｎＣｏｍｍｕｎ，１９９６；２６：６０３］间苯二酚和ＰＯＣｌ３／ＤＭＦ／ＣＨ３ＣＮ或（ＣＯＣｌ）２／ＤＭＦＣＨ３ＣＮ在０℃下反应得中间产物，续在５０℃水中水解得纯产...     

羧烷基化合成萘普生工艺改进

１－溴－２－甲氧基萘与０－对在苯磺酰乳酸乙酯（１）在无水氯化铝催化下化Ｆｒｉｅｄｅｌ－Ｃｒａｆｔｓ反应，还原脱溴直接合成ｄｌ－１ａ萘普生（３），以上反应均在“一锅”内完成，收率达９５。     

酯在AlCl_3－PhNMe_2作用下高效水解成酸

酯在ＡｌＣｌ_３－ＰｈＮＭｅ_２作用下高效水解成酸ＡｋｉｙａｍａＴ．［ＳｙｎＣｏｍｍｕｎ，１９９４；２４：２１７９］酯和ＡｌＣｌ３－ＰｈＮＭｅ２室温反应下，多种酯基均可水解成酸，分子中一些官能团不受影响，适用于脱去保护的酯基，１６例收率除一例４７％外为...     

α－氯甲基酮的简便制法

α－氯甲基酮的简便制法ＲｉｅｋｅＲＤ等［ＳｙｎＣｏｍｍｕｎ，１９９５；２５：３９２３］ＲＢｒ与ＲｉｅｋｅＺｎ（在ＴＨＦ中用萘基锂还原ＺｎＣｌ２制得）的加成复合物，在ＣｕＣＮ·ＬｉＢｒ存在下于－３５℃与氯乙酞氯直接反应可得高收率的α－氯甲基酮化合物，此...     

苯并咪唑-2-磺酸和2-氯苯并咪唑的大量制备

（取代）２－巯基苯并咪唑用过碳酸钠水溶液作氧化剂，制备（取代）苯并咪唑－２－磺酸，３例收率６５％～９２％。如继与在ＰＯＣｌ３中的ＰＣｌ５反应，即得高收率的（取代）２－氯苯并咪唑，３例收率８０％～８４％。苯并咪唑-2-磺酸和2-氯苯并咪唑的大量制备@丁健     

从替告吉宁合成表雄酮

替告吉宁（Ｉ）α－甲基吡啶，醋酐ＨＣｌ经常压裂解，用ＣｒＯ３室温氧化水解得稀醇酮（Ⅱ）（Ⅱ）经过肟化反应得烯醇酮肟（Ⅲ）（Ⅲ）、ＰｏＣｌ３吡啶在苯中重排，水解得表雄酮（Ⅳ）。     

氯化镧对兔颈上交感神经节突触传递的影响

以蔗糖间隙法观察镧（Ｌａ３＋）对离体兔颈上交感神经节突触传递的影响。由顺向刺激诱发的复合神经节动作电位（ＡＰｃ），Ｎ电位（相当于快兴奋性突触后电位），以及后超极化和Ｐ电位（相当于慢抑制性突触后电位），被用作突触反应的指标。在浓度为２０，４０，８０和１６０μｍｏｌ·Ｌ－１时，ＬａＣｌ３减小ＡＰｃ和Ｎ波的幅度，而以ＬａＣｌ３灌流后，对节前神经干的动作电位并无明显影响。后超极化及Ｐ电位先有增大，继而也被抑制。ＬａＣｌ３（４０μｍｏｌ·Ｌ－１）可减弱无钙Ｋｒｅｂｓ液对ＡＰｃ的抑制效应。高钙（１０ｍｍｏｌ·Ｌ－１）则可拮抗ＬａＣｌ３对ＡＰｃ的抑制作用。４－氨基吡啶（０．１ｍｍｏｌ·Ｌ－１）可逆转ＬａＣｌ３对ＡＰｃ的抑制效应。外源性乙酰胆碱引起的神经节去极化，被ＬａＣｌ３所抑制。结果提示，Ｌａ３＋可通过突触前及突触后机制抑制颈上交感神经节的突触传递。     

用NaBH_4－BiCl_3选择性还原α，β－不饱和酯的双键

用ＮａＢＨ_４－ＢｉＣｌ_３选择性还原α，β－不饱和酯的双键ＲｅｎＰＤ等［ＳｙｎＣｏｍｍｕｎ，１９９５，２ｓ：３３９５］还原反应在１５℃、９５％乙醇中进行。ＢｉＣｌ３和ＮａＢＨ４用量不同，收率也不同。所列６例底物，乙酯的还原收率在９０％以上，远较甲酯为...     

A comparison of the effects of nabumetone vs meloxicam on serum thromboxane B2 and platelet function in healthy volunteers

AIMS: To compare the effects of nabumetone and meloxicam, two cyclo-oxygenase-2 (COX-2) preferential nonsteroidal anti-inflammatory drugs (NSAIDs), on platelet COX-1 activity and platelet function. METHODS: Twelve healthy volunteers (3 male, 9 female, median age 22 years) participated in an open, randomized, cross-over trial of nabumetone 1000 mg twice daily vs meloxicam 7.5 mg twice daily during 1 week with 2 weeks wash-out. After a second 2 week wash-out period, one dose of indomethacin 50 mg was given as a positive control to check for NSAID induced inhibition of platelet function. COX-1 inhibition was measured as percentage inhibition of serum TXB2 generation in clotting whole blood, and as closure time with use of the platelet function analyser PFA-100. Data are reported as median with range. Paired variables were analysed using Wilcoxons signed rank test. RESULTS: TXB2 levels decreased significantly after all three medications, but percentage inhibition after nabumetone and indomethacin (88% and 97%, respectively) was significantly higher than after meloxicam (63%) (P<0.05). Closure times increased significantly after administration of all three medications (P<0.05). Increases in closure time after administration did not differ between nabumetone and meloxicam (24% and 14%, respectively), but were significantly larger after indomethacin administration (63%) (P<0.01). CONCLUSIONS: In the maximum registered dosage, nabumetone inhibits thromboxane production much more than meloxicam, signifying less COX-2 selectivity of the former. However, both nabumetone and meloxicam cause only minor impairment in platelet function in comparison with indomethacin and the difference between them is not significant.     

Nabumetone in elderly patients with osteoarthritis: economic benefits versus ibuprofen alone or ibuprofen plus misoprostol

Nonsteroidal anti-inflammatory drugs (NSAIDs) vary in their potential to produce gastropathy. We compared the 3-month direct medical costs, including those associated with treating NSAID-induced adverse events, of nabumetone, ibuprofen, or ibuprofen plus misoprostol in 171 elderly patients with osteoarthritis. Total direct medical costs per patient treated were $US183 for nabumetone, $US252 for ibuprofen, and $US270 for ibuprofen plus misoprostol. Differences resulted from higher costs associated with treatment of drug-related adverse events with ibuprofen, and higher drug acquisition prices with the combination regimen. Sensitivity analyses demonstrated that direct costs with nabumetone approached those for the other 2 regimens if the price of nabumetone increased by 60%, the probability of lesion formation with nabumetone increased 4-fold, the probability of a lesion greater than 0.5cm being symptomatic and needing treatment was 31%, or the price of misoprostol decreased by 50%. Although this study found more lesions because of mandated endoscopies than might be recognised or treated in clinical practice, the results suggest an economic benefit of nabumetone.     

Effects of NSAIDs on cryoprobe-induced gastric ulcer healing in rats

BACKGROUND: Failure of ulcer healing may be critically important to the development of serious gastrointestinal complications in patients on long-term NSAIDs. AIM: To determine the effect of indometacin, celecoxib, a cyclooxygenase-2-specific inhibitor, and nabumetone, a pro-drug, on ulcer healing rates in the rat. METHODS: Gastric ulcers were induced using a cryoprobe. An NSAID or a vehicle control was administered to groups of eight rats for 3 or 6 days (2 mg/kg indometacin, 9 mg/kg celecoxib or 40 mg/kg nabumetone). The ulcer area was measured and epithelial proliferation at the ulcer margins was measured histochemically. The effect of the drugs on intestinal prostaglandin levels was also assessed. RESULTS: The mean ulcer sizes in the four groups on day 3 were comparable. On day 6, control animals and those receiving nabumetone showed significant ulcer healing (P < 0.02), while the mean ulcer sizes in the indometacin (P < 0.01) and celecoxib (P < 0.02) groups were significantly larger than those in the control group. Higher doses of nabumetone (160 mg/kg), however, impaired healing. Intestinal prostaglandins were reduced (P < 0.01) only in indometacin-treated animals. The epithelial proliferation index was significantly lower among indometacin- (P=0.02) and celecoxib-treated (P=0.03) animals compared to controls at day 3. CONCLUSIONS: Celecoxib and indometacin both decreased the epithelial proliferative response and delayed healing of cryoprobe-induced gastric ulcers. In contrast, nabumetone impaired ulcer healing only at very high doses.     

Effect of nabumetone treatment on vascular responses of the thoracic aorta in rat experimental arthritis

Nabumetone is a nonsteroidal anti-inflammatory (NSAI) drug which is known to cause less gastrointestinal damage than other NSAI drugs. This study was performed to evaluate whether nabumetone treatment might alter the vascular aberrations related to inflammation in a rat model of adjuvant-induced arthritis. Nabumetone treatment (120 or 240 mg x kg(-1) x day(-1), orally) was initiated on the 15th day of adjuvant inoculation and continued for 14 days. Arthritic lesions, vascular contractile and relaxant responses and gastroduodenal histopathological preparations were evaluated 29 days after adjuvant inoculation. The contractile responses of aortic rings to phenylephrine and KCl were increased in grade 2 arthritic rats. In grade 3 arthritis only the phenylephrine contractility was decreased. The relaxant responses to acetylcholine and sodium nitroprusside were decreased in grades 2 and 3. In healthy rats, nabumetone did not change the vascular responses. After treatment of arthritic rats with nabumetone, both the contractile and relaxant response of the aortic rings returned to normal, and arthritic score and paw swelling were reduced. Gastroduodenal histopathology did not show erosions or ulcers in any of the groups. In conclusion, nabumetone improved the systemic signs and vascular alterations in experimental arthritis without showing any gastrointestinal side effects.     

Comparative biotransformation and disposition studies of nabumetone in humans and minipigs using high-performance liquid chromatography with ultraviolet,fluorescence and mass spectrometric detection

The disposition of the non-steroidal anti-inflammatory drug (NSAID) nabumetone after a single oral dose administration of nabumetone tablets to humans and minipigs was investigated. Nabumetone is a prodrug, which is metabolized in the organism to the principal pharmacodynamically active metabolite -- 6-methoxy-2-naphthylacetic acid (6-MNA), and some other minor metabolites (carbonyl group reduction products, O-desmethylation products and their conjugates with glucuronic and sulphuric acids). Standards of the above-mentioned metabolites were prepared using simple synthetic procedures and their structures were confirmed by NMR and mass spectrometry. A simple HPLC method for the simultaneous determination of nabumetone, 6-MNA and the other metabolites was developed, validated and used for xenobiochemical and pharmacokinetic studies in humans and minipigs and for distribution studies in minipigs. Naproxen was chosen as the internal standard (I.S.), both UV (for higher concentrations) and fluorescence detection (for very low concentrations) were used. The identity of the nabumetone metabolites in biological samples was confirmed using HPLC-MS experiments. Pharmacokinetics of nabumetone, 6-MNA and 6-HNA (6-hydroxy-2-naphthylacetic acid) in human and minipig plasma was evaluated and compared. The concentration levels of nabumetone metabolites in urine, bile and synovial fluid were also evaluated.     

Role of carbonyl reducing enzymes in the phase I biotransformation of the non-steroidal anti-inflammatory drug nabumetone in vitro

1.?Nabumetone is a clinically used non-steroidal anti-inflammatory drug, its biotransformation includes major active metabolite 6-methoxy-2-naphtylacetic acid and another three phase I as well as corresponding phase II metabolites which are regarded as inactive. One important biotransformation pathway is carbonyl reduction, which leads to the phase I metabolite, reduced nabumetone.

2.?The aim of this study is the determination of the role of a particular human liver subcellular fraction in the nabumetone reduction and the identification of participating carbonyl reducing enzymes along with their stereospecificities.

3.?Both subcellular fractions take part in the carbonyl reduction of nabumetone and the reduction is at least in vitro the main biotransformation pathway. The activities of eight cytosolic carbonyl reducing enzymes – CBR1, CBR3, AKR1B1, AKR1B10, AKR1C1-4 – toward nabumetone were tested. Except for CBR3, all tested reductases transform nabumetone to its reduced metabolite. AKR1C4 and AKR1C3 have the highest intrinsic clearances.

4.?The stereospecificity of the majority of the tested enzymes is shifted to the production of an (+)-enantiomer of reduced nabumetone; only AKR1C1 and AKR1C4 produce predominantly an (?)-enantiomer. This project provides for the first time evidence that seven specific carbonyl reducing enzymes participate in nabumetone metabolism.     

Evaluation of hydroxyimine as cytochrome P450-selective prodrug structure

Hydroxyimine derivatives of ketoprofen (1) and nabumetone (2) were synthesized and evaluated in vitro and in vivo as cytochrome P450-selective intermediate prodrug structures of ketones. 2 released nabumetone in vitro in the presence of isolated rat and human liver microsomes and in different recombinant human CYP isoforms. Bioconversion of 2 to both nabumetone and its active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), was further confirmed in rats in vivo. Results indicate that hydroxyimine is a useful intermediate prodrug structure for ketone drugs.     

A placebo-controlled study of interaction between nabumetone and acenocoumarol

AIMS: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients treated with oral anticoagulants is generally discouraged due to the risk of interactions that could increase the risk of bleeding complications. Available data suggest the NSAID, nabumetone, does not produce such an interaction. We investigated whether nabumetone would interact with acenocoumarol, an oral anticoagulant widely used in some European countries. METHODS: A double-blind, randomized, placebo-controlled study was conducted evaluating nabumetone (1-2 g daily for up to 4 weeks) in osteoarthritis patients with thromboembolic risk previously stabilized on acenocoumarol. The primary efficacy end point was the proportion of patients whose International Normalized Ratio (INR) remained within established margins and whose acenocoumarol dose was not changed. Fifty-six patients were randomized to receive nabumetone (n=27) or placebo (n=29). RESULTS: Eighteen patients in each group (67% for nabumetone and 62% for placebo) completed the study without showing INR or acenocoumarol dose changes, and were considered as study successes. Nine patients (33%) with nabumetone and 11 (38%) with placebo were considered study failures in the intention-to-treat analysis (one patient on nabumetone and four on placebo did not complete the study due to reasons not related to INR and acenocoumarol dose changes). No significant differences were found between groups with regard to study successes. There were two minor bleeding complications, one in each group. Six patients per group presented with eight adverse experiences in each group. CONCLUSIONS: Treatment with nabumetone did not alter INR levels compared with placebo in patients stabilized on oral acenocoumarol who require NSAID therapy. These results suggest that nabumetone does not produce a clinically relevant interaction with acenocoumarol. In orally anticoagulated patients without other associated risk factors, treatment with nabumetone for up to 4 weeks does not require increased monitoring of INR levels.     

Non-steroidal anti-inflammatory drug,nabumetone, prevents indometacin-induced gastric damage via inhibition of neutrophil functions

Nabumetone is a non-steroidal anti-inflammatory drug (NSAID). It works as a prodrug and is extensively metabolized to an active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA). It is well known that neutrophil infiltration and activation are critical in the pathogenesis of NSAID-induced gastric injury, and nabumetone shows less incidence of gastrointestinal irritancy. We examined the effects of nabumetone on neutrophil activation and on indometacin-induced gastric damage. In the indometacin-induced gastric mucosal injury, rats were treated with indometacin and then nabumetone or 6MNA was orally administered. Nabumetone prevented gastric damage accompanied by the reduction of neutrophil infiltration into gastric mucosa, but such an effect was not observed with 6MNA. Nabumetone reduced the formyl methionyl leucyl phenylalanine (fMLP)-induced respiratory burst of human neutrophils to 30% of the control level in-vitro, but 6MNA did not. In addition, nabumetone prevented the fMLP-induced migration of neutrophils. Nabumetone did not inhibit O2- generation in the xanthine-xanthine oxidase system. These results suggest that nabumetone prevents gastric damage induced by the active metabolite, 6MNA, via the suppression of neutrophil activation in gastric mucosa.     

Clinical update of the relative safety of nabumetone in long-term clinical trials

Objective To determine whether the pharmacological profile of nabumetone results in gastric safety, maintains haemostasis and is renally safe. Methods The data from seven double-blind trials and one large randomized clinical trial were pooled and subjected to Kaplan-Meier life tests to determine the frequency of perforations, ulcers and bleeds (PUBs). Two studies each examined haemostasis and renal effects in volunteers and patients. Results PUBs The cumulative frequency of PUBs with nabumetone was 0.03% in 4471 patients. The cumulative frequency with all other NSAIDs comparators ranged from 0.8 to 1.8%. Haemostasis The mean impedance increased with nabumetone and decreased following indomethacin in normal volunteers. In patients, nabumetone was equivalent to placebo in effect on bleeding time, PT and PPT. Renal effects In a triple cross-over study in an at-risk population of elderly hypertensive patients receiving ACE/diuretic, nabumetone had no effect on GFR or PGE. Conclusion The pharmacological profile of nabumetone results in gastric, renal and haemostasis safety.