... Zopiclone & zolpidem are used primarily as hypnotics. Both are extensively metabolized; N-demethylation, N-oxidation, & decarboxylation of zopiclone occur, & zolpidem undergoes oxidation of methyl groups & hydroxylation of a position on the imidazolepyridine ring system. ... Since CYP3A4 has been reported to play an important role in metab of zolpidem, possible interactions with drugs which are substrates &/or inhibitors of that CYP isozyme should be considered. /Salt not specified/
Chlorpromazine, haloperidol, imipramine, & cimetidine have little effect on zolpidem toxicokinetics, although potentiation of the sedative effect of zolpidem was observed when it was given in combination with chlorpromazine & imipramine. No pharmacodynamic interactions have been observed with concomitant admin of cimetidine or ranitidine. /Salt not specified/
This study was undertaken to determine whether there are pharmacokinetic (PK) interactions between zolpidem, a hypnotic, & sertraline, an antidepressant. 28 healthy female volunteers received a single dose of zolpidem alone & 5 consecutive dose(s) of zolpidem 10 mg in the presence of chronic doses (19 days) of sertraline 50 mg. Using HPLC, plasma levels of zolpidem, sertraline, & N-desmethylsertraline were determined at different times throughout the study & PK parameters derived. Compared to zolpidem alone, the /half life/ of the first dose of zolpidem in the presence of sertraline was reduced, the Cmax of the fifth zolpidem dose in the presence of sertraline was significantly increased, & its Tmax was significantly reduced. After 5 doses of zolpidem, the AUC of sertraline (-60%) & the Cmax of N-desmethylsertraline (+13%) were changed. There were no next-day effects of zolpidem on the Digit Symbol Substitution Test, & both drugs were well tolerated. Overall, coadministration of sertraline 50 mg & zolpidem 10 mg appears to be safe in healthy females but could result in a shortened onset of action & increased effect of zolpidem. /Salt not specified/
... The inhibitory effect of ritonavir on the biotransformation of the hypnotic agents triazolam & zolpidem was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer study subjects received 0.125 mg triazolam or 5.0 mg zolpidem concurrent with low-dose ritonavir (4 doses of 200 mg), or with placebo. ... Ritonavir was a potent in vitro inhibitor of triazolam hydroxylation but was less potent as an inhibitor of zolpidem hydroxylation. In the clinical study, ritonavir reduced triazolam clearance to <4% of control values (p<.005), prolonged elimination half-life (41 versus 3 hrs; p<.005), & magnified benzodiazepine agonist effects such as sedation & performance impairment. In contrast, ritonavir reduced zolpidem clearance to 78% of control values (p<.08), & slightly prolonged elimination half-life (2.4 versus 2.0 hrs; NS). Benzodiazepine agonist effects of zolpidem were not altered by ritonavir. ... Short-term low-dose admin of ritonavir produces a large & significant impairment of triazolam clearance & enhancement of clinical effects. In contrast, ritonavir produced small & clinically unimportant reductions in zolpidem clearance. The findings are consistent with the complete dependence of triazolam clearance on CYP3A activity, compared with the partial dependence of zolpidem clearance on CYP3A. /Salt not specified/
The objective was to evaluate possible pharmacokinetic & pharmacodynamic interactions for repeated nightly zolpidem dosing with fluoxetine. 29 healthy female volunteers (mean age, 25.6 yrs) received zolpidem (10 mg) & fluoxetine (20 mg) in the following open design: zolpidem on night 1 followed by 1 washout day, a daily morning dose of fluoxetine on days 3-27, & a morning dose of fluoxetine plus an evening dose of zolpidem on days 28-32. Plasma levels of zolpidem, fluoxetine, & norfluoxetine were determined at the transitions from one regimen to the next. Morning psychomotor tests were performed on days 1, 2, 28, 29, & 33. Steady-state plasma concns of fluoxetine/norfluoxetine were reached by day 24 of fluoxetine dosing. No significant differences in any pharmacokinetic parameters for fluoxetine & norfluoxetine were observed between day 27 & day 32. There were no significant differences in AUC, maximal plasma concn, or time to maximal concn parameters for zolpidem plasma concns among nights 1, 28, & 32. There was a statistically significantly increased /half life/ for zolpidem on night 32, compared with night 28 (3.64 & 3.29 hr, respectively). There were no significant differences in the next-morning Digit Symbol Substitution Test performance at any time in the study. Both zolpidem & fluoxetine were well tolerated alone or during coadministration. These findings indicate the absence of clinically significant pharmacokinetic or pharmacodynamic interactions between fluoxetine & zolpidem (5 consecutive doses) when the drugs are coadministered to healthy women. Therefore, based on these observations, short-term cotherapy with fluoxetine (20 mg) & zolpidem (10 mg) appears safe. /Salt not specified/
Treatment should be largely symptomatic & supportive, similar to that following a benzodiazepine overdose. ... Tracheal protection must be provided. Activated charcoal was used in one patient, but there are no systematic studies supporting its use. Extracorporeal methods of treatment (hemodialysis, hemoperfusion) would probably not be useful in the clinical setting (high protein binding, rapid onset of action & elimination, availability of an effective antidote). In a controlled study flumazenil ... rapidly reversed the decr in alertness, psychometricity, & electroencephalographic changes induced by zolpidem. In one overdose patient who had ingested 300 mg of zolpidem followed by coma, pinpoint pupils, & respiratory depression requiring assisted ventilation, iv flumazenil ... was followed by arousal of the patient, correction of the miosis, & normalization of the respiratory pattern & blood gas analysis. Naloxone appears to be ineffective in diminishing coma or respiratory acidosis. Repeated doses of flumazenil may be required. /Salt not specified/
A peak blood level of 200 ng/mL was reached 30 min after oral admin of 20 mg zolpidem. After oral admin zolpidem is rapidly & completely absorbed from the GI tract. Although some first-pass biotransformation of the drug results in a bioavailability of about 70%, after doses of 7-20 mg, zolpidem is 92% bound to plasma proteins. The apparent volume of distribution after a 5 mg iv dose was 0.5 L/kg. Brain concns reach one third to one half of those achieved in the plasma. Zolpidem is completely metabolized. <1% of an admin dose is excreted unchanged in the urine. Three metabolites have been identified but have no pharmacologic activity after an 8 mg iv dose. Systemic clearance of zolpidem was 0.26 L/kg/g & the elimination half-life was 1.5 hr. /Salt not specified/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
唑吡坦在母乳中的排泄量占给药剂量的0.004%至0.019%。/未指明盐类/
The excretion of zolpidem in breast milk represents 0.004 to 0.019% of an admin dose. /Salt not specified/
Zolpidem is eliminated almost entirely by conversion to inactive products in the liver, largely through oxidation of the methyl groups on the phenyl & imidazopyridine rings to the corresponding carboxylic acids. Its half-life in plasma is approx 2 hr in individuals with normal hepatic blood flow or function. This value may be increased twofold or more in those with cirrhosis, & it also tends to be greater in older patients; adjustment of dosage often is necessary in both categories of patients. Although little or no unchanged zolpidem is found in the urine, the elimination of the drug is slower in patients with chronic renal insufficiency, largely owing to an incr in its apparent volume of distribution. /Salt not specified/
Solid dispersions & physical mixtures of Zolpidem in polyethylene glycol 4000 (PEG 4000) & 6000 (PEG 6000) were prepared with the aim to incr its aqueous solubility. ... Physical determinations/revealed/ no drug-polymer interactions ... Both solubility & dissolution rate of the drug in these formulations were increased. Each individual dissolution profile of PEG based formulation fitted Baker-Lonsdale & first order kinetic models. Finally, significant differences in ataxic induction time were observed between Zolpidem orally administered as suspension of drug alone & as solid dispersion or physical mixture. These formulations, indeed, showed almost 2- to 3-fold longer ataxic induction times suggesting that, in the presence of PEG, the intestinal membrane permeability is probably the rate-limiting factor of the absorption process. /Salt not specified/
我们开发了唑吡坦及其氟化类似物 1-3 的高效微波辅助三步合成。该程序依赖于易于获得且价格低廉的起始材料的利用。与传统加热系统相比，我们的协议在产品的产量和纯度方面表现出卓越的性能。值得注意的是，与油浴加热系统相比，完成反应所需的总时间要短得多。最后，我们对唑吡坦酒石酸盐 I 的制备进行了详细研究，并使用偏光显微镜评估了其粒径。我们的目标是选择合适的方法来产生可接受的粒度，因为固体大小直接影响生物流体中的溶解度和进一步的生物利用度。
Process for the preparation of 2-phenyl-imidazo [1, 2-a] pyridine-3-acetamides
申请人：DINAMITE DIPHARMA S.p.A.
公开号：US20020019528A1
公开（公告）日：2002-02-14
A process for the preparation of 2-phenyl-imidazo[1,2-a]pyridine-3 -acetamides comprises the reaction of a 2-phenyl-imidazo[1,2-a]pyridine with an oxalic ester reactive derivative, followed by reduction of the carbonyl group and reaction with an amine.
Processes for the preparation of imidazo[1,2-a] pyridine derivatives
申请人：Sridharan Ramasubramanian
公开号：US20060084806A1
公开（公告）日：2006-04-20
A process for the preparation of imidazo[1,2-a]pyridine derivatives of the formula I:
wherein R is hydrogen, halogen or a C
1
-C
4
alkyl group; R
1
and R
2
are independently hydrogen, a straight or branched C
1
-C
6
alkyl group which is unsubstituted or substituted by one or more halogen atoms, hydroxyl, N(C
1
-C
4
alkyl)
2
, carbamoyl or C
1
-C
4
alkoxy radicals, a C
1
-C
6
alkyl hydroxy group, a C
3
-C
6
cycloalkyl radical, a benzyl radical, a phenyl radical or R
1
and R
2
together with the nitrogen atom to which they are bonded are joined together to form a substituted or unsubstituted heterocyclic group optionally containing one or more additional heterocyclic atoms; and R
3
and R
4
are independently hydrogen, halogen or a C
1
-C
4
alkyl group, or a pharmaceutically acceptable salt thereof, the process comprising (a) reacting an imidazo[1,2-a]pyridine carboxylic acid of the formula II
wherein R, R
3
and R
4
have the aforestated meanings with a halogenating agent in the absence of a solvent to form an acid halide intermediate and (b) reacting the acid halide intermediate with an amine of the formula HNR
1
R
2
wherein R
1
and R
2
have the aforestated meanings to form the compound of formula I.
[EN] PROCESS FOR THE SYNTHESIS OF ZOLPIDEM<br/>[FR] PROCEDE POUR LA SYNTHESE DE ZOLPIDEM
申请人：RANBAXY LAB LTD
公开号：WO2005010002A1
公开（公告）日：2005-02-03
The present invention relates to processes for the preparation of zolpidem of Formula V as shown in the accompanying drawings or pharmaceutically acceptable salts thereof from N, N-dimethyl-3-(4-methyl) benzoyl propionamide of Formula II. The process includes (a) reacting N,N-dimethyl-3-(4-methyl) benzoyl propionamide of Formula II with bromine to get the bromo amide of Formula III; (b) condensing the bromo amide of Formula III with 2-amino-5-methylpyridine of Formula IV to get the zolpidem base of Formula V; and (c) converting zolpidem base of Formula V to its hemitartarate salt of Formula VII.
