Diazepam derivatives

This protocol was also applied to diazepam derivatives 6 [49]. When these compounds were treated with /V- be n z v I o x vc ar bon vI -1.- pro line acid chloride and tetrahydrofuroyl chloride, the expected spirocyclic systems 7 (Scheme 2) were obtained in good yields. In the case of the /V-benzyloxycarbonyl-i.-praline acid chloride, the reaction was carried out at room temperature, while the process involving the tetrahydrofuroyl chloride needed to be performed in refluxing toluene. This higher temperature was the likely cause of the loss of selectivity observed in the latter case, in which a 10 1 mixture of diastereoisomers was obtained. 

Given the conditions and the requirements for the initial symptomatic treatment of mass casualties, the diazepam derivative avizafone in autoinjectors and/or midazolam for intramuscular injection should be sufficient. In view of lo-razepam s reported efficacy in treatment of status epilepticus, it is recommended that more experimental studies are performed on the efficacy of lorazepam, and also in controlling nerve-agent-induced seizures and convulsions. 

In a new procedure, several 3-substituted diazepam derivatives (124) have been prepared, in moderate to good yields, by allowing metallated diazepams (123) to react with alkyl iodides, carbonyl compounds, or esters. Two equivalents of lithium di-isopropylamide (LDA) were required to produce an equilibrium concentration of (123) that was sufficiently high for synthetic use. ... 

Synthesis of bioactive heterocycbc ferrocene derivatives 13QN143. Synthesis of biologically active diazepam derivatives 12MR0285. Synthesis of complex bioactive molecules 12MI10. 

Review on synthesis of biologically active diazepam derivatives 12MRO 285. 

As with many variables in the procedure, patient sedation is largely a personal preference. Despite the agents to be utilized, it is important that the operator become completely familiar and comfortable with one or more agents. A popular practice is combining a sedative agent with a narcotic, thus achieving optimal sedation, anesthesia, and analgesic effect. A popular combination is the use of a diazepam derivative with a semisynthetic narcotic. 

Diazepam and phenolic diazepam derivatives were significant metabolites of medazepam in dog, rat and man. ... 

A water-soluble phosphine derivative of diazepam allows for more convenient parenteral tranquilizer therapy and avoids some complications due to blood pressure lowering caused by the propylene glycol medium otherwise required for administration. Fosazepam (82) is prepared from benzodiazepine by sodium hydride-mediated alkylation with chioromethyldimethyl phosphine... 

Diphenylhydantoin (23), diazepam (24), phenacemide (25), and ethylphenacemide (26) are all potent anticonvulsants 41 . The first two drugs, though chemically unrelated, have similarities in their three-dimensional structures 42). The other two open-chain acetylurea derivatives 25 and 26 in the crystalline state bear striking stereochemical... 

Unfortunately, the pharmacology of chloride channels is poorly developed. Specific and highly useful inhibitors or modulators (e.g. strychnine, picrotoxin, diazepams) are only available for ligand-gated chloride channels (but these are covered in a different chapter). There are several chloride channel inhibitors such as the stilbene-disulfonates DIDS and SITS, 9-antracene-carboxylic acid (9-AC), arylaminobenzoates such as DPC and NPPB, niflumic acids and derivates, sulfony-lureas, and zinc and cadmium. All of these inhibitors, however, are not veiy specific. Several of these inhibitors (e.g. DIDS) inhibit many chloride channels only partially even at millimolar concentrations and have effects on other types of transport proteins. 

A variety of drugs have been developed that act as sedatives, antidepressants, or stimulants some of these are effective in treating psychiatric disorders. Many of these drugs are weak bases. Examples are barbiturates such as phenobarbital, tranquilizers like diazepam (Valium), and amphetamines derived from phenylethylamine. 

A number of benzodiazepine derivatives were evaluated to probe the selective binding of diazepam to the templated MIP. Samples of 20 and 50 ng of each drug were prepared in 1 mL of toluene. 

Both toxins are isoxazole derivatives. In the mushroom, as well as in the eater, ibotenic acid (Figure 3.6a) is decarboxylated to muscimol (Figure 3.6b), which seems to be the active species. Muscimol is an agonist of GABA, and acts on the CNS in a way similar to diazepam. In animal experiments, both ibotenic acid and muscimol caused a decrease in muscle tone and motor activity, and an increase in brain levels of serotonine, but did not affect the cerebellar content of GABA. For a recent review on ibotenic acid and muscimol see Michelot and Melendez-Howell (2003). 

Diazepam From a chemical point of view, diazepam, 7-chloro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one (5.1.2), is the most simple of all of the examined derivatives of l,4-benzodiazepin-2-ones. Various ways for the synthesis of diazepam from 2-amino-5-chlorobenzophenone have been proposed. The first two ways consist of the direct cyclocondensation of 2-amino-5-chlorobenzophenone or 2-methylamino-5-chlorobenzophenone with the ethyl ester of glycine hydrochloride. The amide nitrogen atom of the obtained 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one (5.1.1), is methylated by dimethylsulfate, which leads to the formation of diazepam (5.1.2). 

The third way for the synthesis emanates from 2-methylamino-5-chlorobenzophenone (5.1.5), which is acylated by chloracetic acid chloride, forming 2-chloracetylmethylamido-5-chlorbenzophenone (5.1.6). Reaction of this product with hexamethylenetetramine replaces the chlorine atom in the chloracetyl part of the molecule, giving a hexamethyl-enetetramino derivative of 2-aminoacetyhnethylamido-5-chlorbenzophenone, which upon hydrolysis in an hydrochloric acid ethanol solution undergoes cyclocondensation and gives diazepam (5.1.2) [6,7]. 

As already noted, there are drugs found among benzodiazepine derivatives that have expressed anxiolytic action and that lack or have poorly expressed sedative-hypnotic effects, which are called daytime tranquilizers. Medazepam, a representative of the daytime tranquilizers, is a drug that differs from diazepam only in the absence of a carbonyl group in the seven-membered azepine ring. 

From the chemical point of view, formally, antiepileptic drugs could be classified as derivatives of hydantoins (phenytoin, mephenytoin, ethotoin), barbiturates (phenobarbital, mephobarbital, and primidone), succinimides (ethosuximide, methosuximide, phensux-imide), benzodiazepines (diazepam, chlorodiazepoxide, clonazepam, lorazepam), oxazo-lidines (trimethadione, paramethadione), and also valproic acid, carbamazepine, and acetazolamide. 

AA Omran, K Kitamura, S Takegami, A-AY El-Sayed, M Abdel-Mottaleb. Determination of partition coefficients of diazepam and flurazepam between phosphatidylcholine bilayer vesicles and water by second derivative spectro-photometric method. J Pharm Biomed Anal 25 319-324, 2001. 

Midazolam (Versed), diazepam (Valium), and lo-razepam (Ativan) are benzodiazepine derivatives that are useful in anesthesia. Midazolam is the most popular of these agents for the induction of anesthesia. Its popularity is related to its aqueous solubility and to its short duration of action, which permits a prompt return of psychomotor competence. Unlike midazolam, lor-azepam and diazepam are not water soluble and must be formulated in propylene glycol the latter is irritating to the vasculature on parenteral administration. 

---