Medazepam
Encyclopedia
Medazepam is a drug which is a benzodiazepine
derivative. It possesses anxiolytic
, anticonvulsant
, sedative
and skeletal muscle relaxant properties.
It is known by the following brand names: Nobrium, Rudotel, Raporan, Ansilan. Medazepam is a long acting benzodiazepine drug. The half-life of medazepam is 36 – 200 hours.
channel blockers and significantly inhibited depolarization-sensitive calcium uptake in experiments with cell components from rat brains. This has been conjectured as a mechanism for high dose effects against seizures in a study. It has major active benzodiazepine metabolites which gives it a more prolonged therapeutic effects after administration.
or analgesic
properties and are therefore unsuitable treatments for conditions such as depression, tension headaches and dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis
due to a lack of efficacy. The committee also recommended against benzodiazepines being used in the treatment of anxiety
or insomnia
in children. The committee was in agreement with the Institute of Medicine
(USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse
(USA) that there was little evidence that long term use of benzodiazepine hypnotics were benefitial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep promoting properties within 3 – 14 days of continuous use and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months continuous use due to the development of tolerance. The committee found that the regular use of benzodiazepines caused the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome
including symptoms such as anxiety
, apprehension, tremor
, insomnia
, nausea
, and vomiting
upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours on the cessation of a short acting benzodiazepine and within 3 – 10 days after the cessation of a more long acting benzodiazepine. Withdrawal effects could occur after treatment lasting only 2 weeks at therapeutic dose levels however withdrawal effects tended to occur with habitual use beyond 2 weeks and were more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition. The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short term use only. It was noted in the review that alcohol can potentiate the central nervous system
depressant effects of benzodiazepines and should be avoided. The central nervous system depressant effects of benzodiazepines may make driving or operating machinery dangerous and the elderly are more prone to these adverse effects. In the neonate high single doses or repeated low doses have been reported to produce hypotonia
, poor sucking, and hypothermia
in the neonate and irregularities in the fetal heart. Benzodiazepines should be avoided in lactation
. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion
, toxic psychosis, convulsions, or a condition resembling delirium tremens
. Abrupt withdrawal from lower doses may cause depression, nervousness
, rebound insomnia, irritability
, sweating
, and diarrhoea.
(5.1.40), has been suggested to be synthesized in various ways. The first is the
reduction of the carbonyl group in diazepam by lithium aluminum hydride.
The second way of making medazepam consists of the initial reduction of the carbonyl
group by lithium aluminum hydride into 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-
2-one—the first intermediate product in the synthesis of diazepam—which is synthesized by the cyclocondensation of 2-amino-5-chlorobenzophenone with glycine
ethyl ester into 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine, and the subsequent methylation of the secondary amine nitrogen atom of the resulting product by methyl iodide, using sodium hydride
as a base.
The third method of making medazepam consists of a new way of making 7-chloro-2,3-
dihydro-5-phenyl-1H-1,4-benzodiazepine, which consists in heterocyclization of
1-(2,5-dichlorophenyl)-1-phenylimine with ethylenediamine. The starting 1-(2,5-
dichlorophenyl)-1-phenylimine is synthesized by the reaction of 2,5-dichlorobenzonitrile
with phenylmagnesium bromide
.
Finally, a method of making medazepam from 4-chloro-N-methylaniline is suggested. The
last is reacted with ethyleneimine in the presence of aluminum chloride, giving N-
(4-chlorophenyl)-N-methylethylenediamine. Acylation
of the resulting product
with benzoyl chloride
gives the respective amide
, which cyclizes into the desired
medazepam using phosphorus oxychloride.
See also:
Various modifications of the described methods have been suggested.
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
derivative. It possesses anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
, sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
and skeletal muscle relaxant properties.
It is known by the following brand names: Nobrium, Rudotel, Raporan, Ansilan. Medazepam is a long acting benzodiazepine drug. The half-life of medazepam is 36 – 200 hours.
Pharmacology
Benzodiazepine drugs including medazepam increase the inhibitory processes in the cerebral cortex by allosteric modulation of the GABA receptor. Benzodiazepines may also act via micromolar benzodiazepine binding sites as Ca2+Calcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
channel blockers and significantly inhibited depolarization-sensitive calcium uptake in experiments with cell components from rat brains. This has been conjectured as a mechanism for high dose effects against seizures in a study. It has major active benzodiazepine metabolites which gives it a more prolonged therapeutic effects after administration.
The Committee on the Review of Medicines
The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence and benzodiazepine withdrawal problems and other adverse effects. The committee found that benzodiazepines do not have any antidepressantAntidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
or analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
properties and are therefore unsuitable treatments for conditions such as depression, tension headaches and dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
due to a lack of efficacy. The committee also recommended against benzodiazepines being used in the treatment of anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
or insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
in children. The committee was in agreement with the Institute of Medicine
Institute of Medicine
The Institute of Medicine is a not-for-profit, non-governmental American organization founded in 1970, under the congressional charter of the National Academy of Sciences...
(USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse
National Institute on Drug Abuse
The National Institute on Drug Abuse is a United States federal-government research institute whose mission is to "lead the Nation in bringing the power of science to bear on drug abuse and addiction."-History:...
(USA) that there was little evidence that long term use of benzodiazepine hypnotics were benefitial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep promoting properties within 3 – 14 days of continuous use and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months continuous use due to the development of tolerance. The committee found that the regular use of benzodiazepines caused the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
including symptoms such as anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, apprehension, tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours on the cessation of a short acting benzodiazepine and within 3 – 10 days after the cessation of a more long acting benzodiazepine. Withdrawal effects could occur after treatment lasting only 2 weeks at therapeutic dose levels however withdrawal effects tended to occur with habitual use beyond 2 weeks and were more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition. The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short term use only. It was noted in the review that alcohol can potentiate the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
depressant effects of benzodiazepines and should be avoided. The central nervous system depressant effects of benzodiazepines may make driving or operating machinery dangerous and the elderly are more prone to these adverse effects. In the neonate high single doses or repeated low doses have been reported to produce hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, poor sucking, and hypothermia
Hypothermia
Hypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
in the neonate and irregularities in the fetal heart. Benzodiazepines should be avoided in lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion
ConFusion
ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
, toxic psychosis, convulsions, or a condition resembling delirium tremens
Delirium tremens
Delirium tremens is an acute episode of delirium that is usually caused by withdrawal from alcohol, first described in 1813...
. Abrupt withdrawal from lower doses may cause depression, nervousness
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, rebound insomnia, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
, sweating
Sweating
Perspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
, and diarrhoea.
Chemistry
7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine(5.1.40), has been suggested to be synthesized in various ways. The first is the
reduction of the carbonyl group in diazepam by lithium aluminum hydride.
- E. Reeder, L.H. Sternbach, (1963).
The second way of making medazepam consists of the initial reduction of the carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
group by lithium aluminum hydride into 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-
2-one—the first intermediate product in the synthesis of diazepam—which is synthesized by the cyclocondensation of 2-amino-5-chlorobenzophenone with glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
ethyl ester into 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine, and the subsequent methylation of the secondary amine nitrogen atom of the resulting product by methyl iodide, using sodium hydride
Sodium hydride
Sodium hydride is the chemical compound with the empirical formula NaH. It is primarily used as a strong base in organic synthesis. NaH is representative of the saline hydrides, meaning it is a salt-like hydride, composed of Na+ and H− ions, in contrast to the more molecular hydrides such as...
as a base.
- S. Inaba, H. Nagata, (1971).
- G.A. Archer, E. Fells, L.H. Sternbach, (1964).
The third method of making medazepam consists of a new way of making 7-chloro-2,3-
dihydro-5-phenyl-1H-1,4-benzodiazepine, which consists in heterocyclization of
1-(2,5-dichlorophenyl)-1-phenylimine with ethylenediamine. The starting 1-(2,5-
dichlorophenyl)-1-phenylimine is synthesized by the reaction of 2,5-dichlorobenzonitrile
with phenylmagnesium bromide
Phenylmagnesium bromide
Phenylmagnesium bromide, with the simplified formula , is a magnesium-containing organometallic compound. It is so commonly used that it is commercially available as a solution in diethyl ether or tetrahydrofuran . Phenylmagnesium bromide is a Grignard reagent...
.
- S. Inaba, H.Nagata, (1969).
Finally, a method of making medazepam from 4-chloro-N-methylaniline is suggested. The
last is reacted with ethyleneimine in the presence of aluminum chloride, giving N-
(4-chlorophenyl)-N-methylethylenediamine. Acylation
Acylation
In chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....
of the resulting product
with benzoyl chloride
Benzoyl chloride
Benzoyl chloride, also known as benzenecarbonyl chloride, is an organochlorine compound with the formula C6H5COCl. It is a colourless, fuming liquid with an irritating odour...
gives the respective amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
, which cyclizes into the desired
medazepam using phosphorus oxychloride.
- K.H. Heinrich, (1967).
- K.H. Heinrich, (1967).
See also:
- Wunsch, K. H.; Dettmann, H.; Schonberg, S.; Chem. Ber. 1969, 102, 3891.
Various modifications of the described methods have been suggested.
- S. Inaba, K. Ishizumi, T. Okamoto, H. Yamamoto, Chem. Pharm. Bull., 20, 1628 (1972).
- M. Mihalic, V. Sunjic, F. Kajfez, M. Zinic, J. Heterocycl. Chem., 14, 941 (1977).
See also
- BenzodiazepineBenzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
- Benzodiazepine dependenceBenzodiazepine dependenceBenzodiazepine dependence or benzodiazepine addiction is a condition during which a person is dependent on benzodiazepine drugs. Dependence can be either a psychological dependence, physical dependence, or a combination of the two...
- Benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
- Long term effects of benzodiazepinesLong term effects of benzodiazepinesThe long-term effects of benzodiazepines include drug dependence as well as the possibility of adverse effects on cognitive function, physical health, and mental health. There are significant risks associated with the long-term use of benzodiazepines. However, not all people experience problems...