Benzodiazepines

By | March 6, 2012

Alprazolam

• The compound was patented in 1969 by Upjohn Co.

• First launched by Pfizer in 1983 for the treatment of anxiety

• Approval in the USA for the treatment of panic disorder with or without agoraphobia in 2003

Clonazepam

• First described in 1963 as sedative, muscle relaxant and anticonvulsant

• Parenteral formulation patented in 1963 by Hoffmann-La Roche Inc.

• Registered in 1975 by Roche in US for the prophylactic management of Lennox-Gastaut syndrome and akinetic and myoclonic seizures

• First launched in 1975 by Roche for the treatment of epilepsy or panic disorder

• Approval in the US as a generic medication in 1997

• Launched in 2003 by RocheSolvay in a lyophilized wafer that desintegrates when exposed to saliva and thus enhances the ease of administration without altering the pharmacology

Diazepam

• The muscle-relaxant action of diazepam was first described in 1955

• First launched by Roche in 1961 for the management of anxiety disorders

• Launched in 1963 by Roche for the treatment of acute alcohol withdrawal, epilepsy and muscle spasm and cerebral spasticity

• Licensed to Shire in 2003 and to Valeant in 2005

Lorazepam

• Compound patent filed in 1961 by American Home Products Corp.

• First launched by Wyeth Pharmaceuticals in 1972 for the treatment of anxiety

• Launched by Wyeth Pharmaceuticals in 1977 for the management of status epilepticus and for preoperative uses in anesthesia

• To date, there is no report of an enantioselective synthesis for lorazepam although pure enantiomers of the corresponding methyl ester, obtained by HPLC resolution on chiral stationary phases, showed significant differences in their binding to benzodiazepine receptors isolated from bovine brains

Lormetazepam

• The compound was patented in 1961 by American Home Products Corp.

• Launched by Schering AG/Wyeth Pharmaceuticals in 1980 for the treatment of sleep disorders

• Resolution of racemic lormetazepam by high-performance liquid chromatography is extensively described in the literature, but no enantioselective synthesis has been described for this compound. To date, there are no data of the activity of the enantiomers

Midazolam

• The compound patent was filed in 1974 by Hoffman-La Roche

Midazolam is considered as a fast-acting benzodiazepine, with a short elimination half-life. It is reported to be quite addictive, as should be expected given its potent anxiolytic properties and rapid onset of action

• Unlike other benzodiazepines midazolam is water soluble because the imidazole ring is open at pH values below 4. However, when it is injected and the pH is 7.4, the imidazole ring closes and it becomes much more lipid soluble, facilitating its rapid uptake into nerve tissue. This, and the fact that it has a pKa of 6.15 and is therefore predominantly unionized (>90%) at physiological pH, accounts for its rapid onset of action and its high protein binding in the blood (up to 97%)

• Launched in 1982 for sedation condition, by Astellas Pharma / Roche

Brotizolam

• The compound patent was filed in 1974 by Boehringer

• First launched by Boehringer Ingelheim in 1984 for the treatment of sleep disorders and in 1989 for the treatment of insomnia

• Launched by Boehringer Ingelheim in Spain for the treatment of anxiety

Etizolam

• The compound patent was filed in 1971 by Yoshitomi Pharmaceutical Industries

• First launched by Fournier Pierrel Farma in 1989 for the treatment of anxiety and insomnia

Ethyl loflazepate

• The compound patent was filed by Hoffmann-La Roche in 1969

• Launched by Sanofi-Aventis in 1982 for the treatment of anxiety

Chlordiazepoxide hydrochloride

• Chlordiazepoxide was the first benzodiazepine to be synthesized and made commercially available. The compound patent was filed by Hoffmann-LaRoche in 1958

• Launched by Roche in 1960 for the treatment of anxiety

Oxazepam

• The compound patent was filed by American Home Products in 1961

• Launched by Wyeth Pharmaceuticals in 1966 for the treatment of anxiety

• Oxazepam is a metabolite of diazepam. It is commonly prescribed for anxiety disorders with associated tension, irritability, and agitation. It is also prescribed for drug and alcohol withdrawal, and for anxiety associated with depression

Medazepam

• The compound patent was filed by Hoffmann-La Roche in 1961

• Launched by Roche in 1968 for the treatment of anxiety

Prazepam

• The compound was patented in 1963 by Warner-Lambert Pharmaceutical Co.

• Prazepam exhibits potent anti-anxiety and sedative activity without undesirable side-effects such as hypnosis

• Launched in 1980 by Pfizer for the treatment of anxiety

• Prazepam was withdrawn in 1993 in the United States for the treatment of anxiety

Bromazepam

• The compound patent was filed in 1961 by Hoffmann-La Roche Inc.

• Launched in 1975 for the treatment of anxiety by Roche

• Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. Due to its relatively short half-life and duration of action (8 to 12 hours), withdrawal symptoms may be more severe and more frequently encountered as with long acting benzodiazepines

Clobazam

• Patented in 1966 by Roussel-UCLAF

• Launched in 1975 by Sanofi-Aventis for the treatment of anxiety, delirium tremens and as adjunctive treatment of epilepsy

Nordazepam

• Patented in 1959 by Hoffmann-La Roche

• Launched in 1973 for the treatment of sleep disorders by Ravizza

• Launched in 1985 for the treatment of anxiety by Bouchara

• Nordazepam is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, and medazepam

Ketazolam

• Patented in 1968 by Upjohn

• Clinical trials demonstrate that ketazolam is at least equivalent, and in some respects even superior, to diazepam with fewer and less severe side-effects

• Launched in 1987 for the treatment of generalized anxiety by Novartis

Halazepam

• Patented in 1966 by Scherico

• Launched in 1982 for the management of anxiety disorders and short-term relief of symptoms of anxiety by Schering-Plough.

• Nordazepam possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It is a trifluoromethyl derivative of nordazepam. While its structure may be similar to chlordiazepoxide and diazepam, it has both less toxicity and less tendency to cause paradoxical hostility and aggression than either of them

Clorazepate dipotassium

• The compound patent was filed in 1964 by CM Industries

• Launched in 1968 for the treatment of anxiety by Sanofi-Aventis

• Clorazepate is principally prescribed in the treatment of alcohol withdrawal and epilepsy, although it is also a useful anxiolytic because of its long half-life

• Some chiral stationary phases have been used for the separation of clorazepate enantiomers by liquid chromatography, but any enantioselective synthesis has been described for this compound to date

Clotiazepam

• The compound patent was filed in 1970 by Yoshitomi Pharmaceutical Industries

• Launched in 1979 by Mitsubishi Pharma and Esteve for the treatment of anxiety

Tofizopam

• The compound patent was filed in 1966 by Egyesult Gyogyszervegyeszeti Gyar

• Launched by Toyama for the treatment of anxiety

• Like other benzodiazepines, tofizopam possesses anxiolytic properties but not anticonvulsant, sedative, skeletal muscle relaxant, motor skill-impairing or amnestic properties. While it may not be an anticonvulsant itself, it has been shown to enhance the anticonvulsant action of other 1,4-benzodiazepines

• Tofizopam is not approved for sale in the United States or Canada. However, Vela Pharmaceuticals of New Jersey is developing the D- enantiomer (dextofisopam) as a treatment for irritable bowel syndrome

• Levotofisopam (S-enantiomer) is in phase I trials for the treatment of anxiety, epilepsy and postmenopausal syndrome (Vela Pharmaceuticals). The enantiomers have been isolated by chiral chromatography

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