Tricyclic piperazines

According to a hypothesis launched by Larionov et al in the 1960s, some new nitrogen mustard derivatives were developed. They contain metabolites and heterocyclic structures as carriers of the cytotoxic chloroethylamine groups. By this way the synthesis of aliylating metabolites started melphalan (sarcolysine) as L- or DL-phenylalanine derivative prospidine with a tricyclic piperazine moiety and chlorambucil as butyric acid derivative. It was proven that each alkylating metabolite has its own spectrum of selective antitumor activity. 

Adverse Neurological Effects Many neurological syndromes, particularly involving the extrapyramidal motor system, occur following the use of most antipsychotic drugs, especially with the high-potency D -receptor antagonists (tricyclic piperazines and butyrophenones). Acute adverse extrapyramidal effects are less likely with aripiprazole, clozapine, quetiapine, thioridazine, and ziprasidone, or low doses of olanzapine or risperidone. 

The iV-( -nitrophcnyl)pipcrazinc-2-carbonitrilc 251 (Y = NBOC) was reductively cyclized to the tricyclic /V-oxides 252 (Y = NBOC) either by catalytic hydrogenation, or by electrochemical reduction. Electrochemical reduction gave lower yield. Compounds 251 were prepared by electrochemical cyanation of the iV-(o-nitrophenyl)piperazine 250. The jV-oxides 252 were further hydrogenated to the 2,3,4,4 ,5,6-hexahydro-l//-pyrazino[l,2- ]quinoxaline 253 (Y = NBOC) (Scheme 46) <2001EJ0987>. 

FIGURE 8. MM2-85 calculated lp—N—C—H rotational potential curve (C in the tricyclic ring system) for 68, with a pseudoequatorial piperazine ring. The conformations A (dashed line) and B (solid line) are defined in Scheme 6. Reproduced with permission from Reference 108... 

Nuclei for tricyclic antidepressants and tranquilizers, for example clomacran (89) (64USP3131190), almost invariably contain the three rings fused in a linear array. An exception to this general rule is fantridone (90), an antidepressant obtained by alkylation of the anion of phenanthridone with 3-chloro-iV,iV-dimethylpropylamine (68BRP1135947). Similar activity is shown by a relatively simple quinoline derivative (91), which is derived from 2-chloroquinoline and piperazine (70GEP2006638). 

Table 19. Tricyclic Nonpeptide FTIs 8-Chlorobenzocycloheptapyridine Substituted Piperazine and Piperidine Analogues...

Amoxapine Dibenzoxazepine ring piperazine Less potent than other tricyclics dopamine... 

There is a more clear-cut cause-and-effect relation in the parkinsonian symptoms that occasionally occur with high-dosage tricyclic therapy in susceptible individuals (particularly elderly women). Because of its piperazine side-chain and structural resemblance to the phenothia-zines, amoxapine has antidopaminergic properties that appear to produce typical dystonic reactions (88), but other tricyclic antidepressants may also be implicated in producing the full range of so-called extrapyramidal syndromes, including akathisia, dystonic reactions, parkinsonism, and tardive dyskinesia. Case reports have been described before (SEDA-16, 9 SEDA-17, 18 SEDA-18, 18). In the reports of tardive dyskinesia the problem is often that these patients have taken many different drugs. 

As previously noted (SEDA-4, 21 SEDA-5, 17), amoxapine has a tricyclic nucleus with a modified piperazine side chain and is closely related to the neuroleptic drug loxapine. In animals, amoxapine has no antisero-tonergic properties and less anticholinergic activity than prototype drugs. Peak plasma concentrations are achieved in less than 2 hours, and the half-lives of the parent drug and its two active metabolites are 8, 6, and 30 hours respectively. 

Nitro-piperazin-1 -yl-N- (tricycle [3.3.1. ] dec-1 -ylmetbyl-benzamide bydrogen chloride... 

Aryl Piperazines/Piperidines. There are two major structural classes that confer concomitant 5-HT and Dg antagonism. These are the aiyl piperidines/piperazines and some tricyclic systems. One of the first clinical studies to assess the role of serotonergic blockade in antipsychotic therapy was conducted on se-toperone (129), a 5-HT2/D2 antagonist that showed promising results but was later discontinued because of bioavailability issues (588). 

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