Dibenzodiazepines

H-Dibenzo[d,/][l,3]diazepine, 5,7-dihydroxy-synthesis, 7, 605 Dibenzodiazepines synthesis, 7, 605... 

The dibenzodiazepine 4 is produced by the thermal elimination of hydrogen fluoride from the diphenyldiazene derivative 3.150,151... 

The dibenzodiazepines 5 are hydrogenated to the 5,6-dihydro compounds by hydrazine/Raney nickel.149,153 The process is reversed by heating with mercury(II) oxide in diethyl ether.153... 

The optically active diaminobitolyl 2, which owes its chirality to restricted rotation, was converted into the optically active dibenzodiazepine 4 by way of its monobenzoyl derivative... 

The (mcthylsulfanyl)dibenzodiazepine 19 reacts with the hydrochlorides of primary or secondary amines to yield, after basification, 5/f-dibenzo[c ,/][l, 3]diazepin-6-amines 20.175... 

V-[2-(Acylamino)phenyl]-A-alkylarylamincs 1 cyclize in phosphoryl chloride or in polyphos-phoric acid to the dibenzodiazepines 2. Selected example are given, exact yields were not reported.44 309... 

The other dibenzodiazepines were prepared by the PPA method as follows The diphenylamine derivative was heated with ten times its weight of PPA at 150-160 C for 3.5 h, the resulting solution was poured into ice-water, the mixture was made alkaline with coned NH, and the product was extracted with Et20. The extract was dried and evaporated in vacuo. 

Dibenzodiazepines are reduced to the 10,11-dihydro compounds by catalytic hydrogenation or with lithium aluminum hydride.44 ... 

The other way of synthesis of clozapine is from 8-chloro-10,ll-dihydro-5H-dibenzo[b,e]l, 4-diazepin-ll-thione, which is alkylated at the sulfur atom of the dibenzodiazepine ring by 4-nitrobenzylchloride in the presence of potassium fert-butoxide, giving iV-methyl derivative (6.5.8). Reaction of this with A-methylpiperazine gives the desired clozapine (6.5.7) [59]. 

Mechanism of Action A dibenzodiazepine derivative that interferes with the binding of dopamine at dopamine receptor sites binds primarily at nondopamine receptor sites. Therapeutic Effect Diminishes schizophrenic behavior. 

Mechanism of Action A dibenzodiazepine derivative that interferes with the binding of dopamine at postysnaptic receptor sites in brain. Strong anticholinergic effects. Therapeutic Effect Suppresses locomotor activity, produces tranquilization. Pharmacokinetics Onset of action occurs within 1 hr. Metabolized to active metabolites 8-hydroxyloxapine, 7-hydroxyloxapine, and 8-hydroxyamoxapine. Excreted in urine. Half-life 4 hr... 

Clozapine Dibenzodiazepine 25-900 Low 100 Treatment-resistant illnesses Schizophrenia Bipolar disorder Autistic disorder Kumra et ah, 1996 Kowatch et ah, 1995 Zuddas et ah, 1996... 

These are the most widely used routes to 1,3-diazepines and provide easy access to the monocyclic system, 1,3- and 2,4-benzodiazepines, and dibenzodiazepines by the reactions of (113)-(116) (and their derivatives) respectively with 1,1-bis-electrophilic reagents. The use of aldehydes produces the rather unstable fully saturated —NHCH2NH— linkage and has been rarely applied to the synthesis of monocyclic systems. (67AHC(8)2l, p. 40) but provides useful syntheses of 1,3-benzodiazepines, e.g. (117) (67AHC(S)2l, p. 43), and 2,4-benzodiazepines, e.g. (118) (68CRV747, p.783). A 5,7-dihydroxy-6fT-dibenzo[[Pg.605]

Dibenzodiazepine Clozapine Very low Medium Very low Low Medium... 

Dibenzodiazepine Clozapine May benefit treatment-resistant patients little extrapyramidal toxicity May cause agranulocytosis in up to 2% of patients dose-related lowering of seizure threshold... 

Benzodiazepines are used as hypnotics because they have the ability to increase total sleep time. They demonstrate minimal cardiovascular effects, but do have the ability to increase heart rate and decrease cardiac output. Most CNS depressants, including the benzodiazepines, exhibit the ability to relax skeletal muscles. Clozapine, a dibenzodiazepine, is used in the treatment of schizophrenia. It has both sedative and antipsychotic actions, and is the only FDA-approved medication indicated for treatment-resistant schizophrenia, and for reducing the risk of suicidal behavior in patients with schizophrenia. This drug can have potentially life-threatening side effects, but appears to have no abuse potential and will not be considered further. 

A variety of drugs that block DA receptors are available for clinical use, and even more for experimental purposes. These drugs, also referred to as neuroleptics, include phenothiazines (e.g., chlorpromazine), thioxanthenes (e.g., chlorprothixene), butyrophenones (e.g., haloperidol), diphenylbutylpiperidines (e.g., pimozide), and dibenzodiazepines (e.g., clozapine). The major medical applications for these drugs are in the treatment of severe psychiatric illnesses, certain movement disorders, emesis and intractable hiccough. 

Clozapine, a tricyclic dibenzodiazepine derivative, was the first atypical AP to be approved by the FDA in 1989. It was originally thought that increased affinity to the 5HT2A receptor, in combination with a lower or no affinity to the D2 receptors, might define a compound as an atypical AP [12, 13], However, studies have shown that... 

Phenothiazines and related drugs, e.g., chlorpromazine (Largactil/ Thorazine). Some tricyclic antidepressants, e.g., amitriptyline Dibenzodiazepine derivatives and thienobenzodiazepines, e.g., clozapine, olanzapine Benzodiazepines, e.g., diazepam (Valium), nitrezepam (Librium) and lorazepam Barbiturates Opiates... 

Beside clozapine, only the 2-Cl-dibenzoxazepine loxapine (launched in 1975 by Wyeth) and 2-Cl-dibenzothiepine zotepine (launched in 1982 by Fujisawa) were introduced into clinical practice for the treatment of schizophrenia. Interestingly, in contrast with other dibenzodiazepines, all of which have a piperazinyl substitution at position-11, zotepine (which is a dibenzothiepine) has a 2-dimethylami-noethoxy-substitution at the same position. 

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