Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-02-03
2004-03-23
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S547000
Reexamination Certificate
active
06710041
ABSTRACT:
The invention described herein relates to compounds for the preparation of medicaments useful for the treatment of psychiatric and neurological disorders, to processes for their preparation and to pharmaceutical compositions containing them as active ingredients. In particular, the invention described herein relates to compounds with a pyrrolobenzothiazepine structure with typical and a typical antipsychotic activity that can be formulated in pharmaceutical compositions intended for the treatment of acute and chronic psychotic states.
BACKGROUND TO THE INVENTION
The involvement of dopamine and of the dopaminergic neurons in a variety of psychiatric and neurological disorders, has now been extensively documented (E. R. Kandel, J. H. Schwartz, in “
Principles of Neural Science” Neurology”,
Elsevier Science Publishing Co. New York, 1985).
Among the various pathologies concerned, schizophrenia is characterised by a complex symptomatology caused by abnormal neurotransmission of the main dopaminergic pathways of the central nervous system. The states of hallucination and deliria, described as positive symptoms, are due to increased activity of the mesolimbic dopaminergic pathway, while the cognitive deficits and states of social isolation, indicated as negative symptoms, are attributed to reduced dopaminergic neurotransmission in the frontal cortex.
The condition of hyperactivation of dopaminergic neurotransmission which underlies the acute and chronic psychotic states of schizophrenia, acute psychoses of unknown aetiology, and the forms of psychosis and agitation that form part of the symptomatology of other diseases, is counteracted from a therapeutic point of view by the use of classic antipsychotic agents, otherwise called neuroleptics, the most representative of which are chlorpromazine (phenothiazine class) and haloperidol (butyrophenone class).
Chlorpromazine was the first product to prove distinctly effective in the treatment of psychoses. This compound, initially used as a sedative, proved capable of improving the condition of psychotic patients, in that it was capable of inducing a particular indifference to environmental stimuli without altering the state of vigilance of the subjects using it. Thanks to the enormous commercial success of chlorpromazine, a search began in the '50s for new neuroleptic agents and this soon led to the identification of other antipsychotic products belonging to many chemical classes.
The therapeutic efficacy of the neuroleptics is related to their ability to modulate the dopaminergic neurotransmission of the central nervous system, via blockade of the dopamine receptors.
Their antipsychotic potency is directly proportional to their ability to bind and block dopamine receptors of subtype D
2
in the cerebral areas involved in abnormal functional dopaminergic neurotransmission. Moreover, psychopharmacology studies show that the dopaminergic hyperactivity that affects the mesolimbic pathway also involves the receptor subtypes D
1
and D
3
. Consequently, the antipsychotic potency of a neuroleptic may also depend on its ability to interact with these receptors, which are densely distributed on the neuronal endings in this pathway (J. Schwartz, Giro B., M. P. Martres & P. Sokoloff “
Neuroscience”
4, 99-108; 1992).
From the clinical point of view, the antipsychotic efficacy of the numerous neuroleptic agents present on the market is qualitatively equivalent in all cases. They differ only in their potency, in the sense that, whereas some of them are effective at doses of only a few mg, others need to be administered at much higher doses.
The real differences between the various neuroleptic agents depend on their ability to favour the occurrence of unwanted side effects such as arterial hypotension, sedation and, above all, severe motor abnormalities, some of which are among the most frequent manifestations associated with the clinical efficacy of the treatment. Whereas the former are due to the ability of the product to interact with the alpha-1 adrenergic and H
1
histaminergic receptors, respectively, the latter, common to all neuroleptic agents, are due to blockade of the D
2
receptors of the nigrostriatal dopaminergic system.
Pharmacological and clinical studies have shown that the simultaneous administration of neuroleptics and products with selective antagonist activity on serotoninergic 5-HT
2a
receptors can increase the antipsychotic efficacy of the former and attenuate the occurrence of extrapyramidal symptoms as compared to treatment with neuroleptic agents alone (G. F. Busatto and R. W. Kerwin “
Journal of Psychopharmacology”
11(1), 3-12; 1997).
Further developments in this sense have led to the generation of drugs with a mixed antagonist component, i.e. which are active on different receptors.
Clozapine (8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) is an antipsychotic agent capable of simultaneously antagonising dopamine on D
2
receptors and serotonin on 5-HT
2
receptors. This new action profile, called “atypical”, allows schizophrenia to be treated with a lower incidence of extrapyramidal symptoms (
J. Med. Chem.,
39, 1996, pp. 1172-1188).
Unfortunately, the occurrence of cases of agranulocytosis has limited the therapeutic use of this drug (
Lancet.
1975, 2, 657).
Octoclothepine (8-chloro-10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepine) is a compound partly endowed with “atypical” activity. Its pharmacological activity has been studied in relation to the optical isomers of this compound (
J. Med. Chem.,
1991, 34, 2023-2030): a slightly greater effect on schizophrenia by the (S) form is unfortunately associated with a greater incidence of extrapyramidal effects, so that its use has been withdrawn from clinical trials. The (R) isomer presents a more “atypical” profile, with fewer side effects, but also an inferior general potency. Moreover, the two isomers prove to be endowed with the same activity as 5-HT
2
and D
1
antagonists.
In view of the studies cited above, the need for antipsychotic agents with substantial therapeutic activity and without side effects remains unsatisfied. In particular, the search continues for antipsychotic agents which present greater neuroleptic activity, a lower incidence of extrapyramidal effects and minimal side effects (agranulocytosis; neutropaenia; sedation; weigh gain; costipation; urinary retention; dryness; hypotension).
ABSTRACT OF THE INVENTION
It has now been found that compounds of the 9-amino-substituted pyrrolo[2,1-b][1,3]benzothiazepine class, particularly formula (I) compounds
where:
R=H, Cl, Br, F, I, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, C
1
-C
4
alkyl, C
5
-C
6
cycloalkyl;
R
1
=C
1
-C
4
dialkylamine, where the alkyl groups can be the same or different from one another, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl, 4-alkyl-1-homopiperazinyl;
R
2
=H, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, C
1
-C
4
alkyl, CHO, CH═NOH;
R
3
=H, CHO;
are endowed with antipsychotic activity.
One object of the invention described herein therefore consists in the formula (I) compounds indicated here above and their pharmaceutically acceptable salts.
Another object of the invention described herein consists in processes for the preparation of formula (I) compounds.
A further object of the invention described herein is the use of said compounds as medicaments useful as antipsychotic agents for the treatment of psychiatric and neurological disorders, particularly disorders related to increased activity of the mesolimbic dopaminergic pathway and/or mesocortical dopaminergic hypofunction such as schizophrenia in its positive and negative symptoms.
Still another object of the present invention is the use of said compounds as medicaments, in particular as antipsychotic agents, for the treatment of psychosis, such as schizophrenia, paranoid states, manic-depressive states, affective disorders, social withdrawal, personality regression, hallucin
Campiani Giuseppe
Di Cesare Assunta
Mastroianni Domenico
Minetti Patrizia
Nacci Vito
Kifle Bruck
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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