Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-26
2002-05-21
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S551000
Reexamination Certificate
active
06391870
ABSTRACT:
The present invention relates to the field of antipsychotic drugs, in particular to polycondensated heterocycles with a pyrrolo[2,1-b][1,3]benzothiazepine structure.
STATE OF THE ART
The intervention of dopamine and dopaminergic neurons in the pathology of a variety of psychiatric and neurological disorders has been amply documented (Caine, D. B., Therapeutics and Neurology; Blackwell Scientific Publications, Oxford 1980, p. 281). In addition, it is also known that drugs which are active on dopamine receptors may play an important role in the therapy of such disorders; there is therefore considerable interest in the effects of dopamine agonist and antagonist compounds on dopaminergic receptors, particularly with a view to their therapeutic implications.
Chlorpromazine and aloperidol have long been the treatment of choice for acute and chronic schizophrenia. It has been postulated that these drugs relieve the positive symptoms of the disease by blocking dopaminergic transmission in certain areas of the brain. Chlorpromazine and aloperidol are defined as “typical neuroleptic agents”: their action is characterised by remission of the symptoms of schizophrenia, accompanied, however, by unwanted extrapyramidal collateral symptoms (motor disorders, catalepsy, hyperprolactinaemia, etc.). The elimination of these adverse effects therefore constitutes an important objective in the development of new neuroleptic therapies.
Clinical trials have demonstrated that not only dopamine antagonists but also 5-HT
2
antagonist compounds are capable of improving the symptoms of schizophrenia, in particular, it has been observed that the co-administration of 5-HT
2
antagonists and “typical” antipsychotic agents reduces the incidence of extapyramridal symptoms as compared to treatment with neuroleptic agents alone (Psychopharmacol., 99, 1989, S18-S27; Niemegeers et al. in 5-HT
2
Receptor Antagonists in Schizophrenia, Racagni Ed., Elsevier Publishers, 1991, Vol. 1, pp. 535-537).
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 D2 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).
Octoclothepin (8-chloro-10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin) 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 and a lower incidence of extapyramidal effects.
It has now surprisingly been found that polycondensated heterocycles with a pyrrolo[2,1-b][1,3]benzothiazepine are endowed with an interesting pharmacological profile as antipsychotic activity.
ABSTRACT OF THE INVENTION
The present invention describes polycondensated heterocycles with a pyrrolo[2,1-b][1,3]benzothiazepine structure. As compared to known antipsychotic agents, the compounds according to the invention present substantial activity associated with a simultaneous reduction in unwanted extrapyramidal symptoms. The compounds object of the invention described herein can be formulated in pharmaceutical compositions for the treatment of psychoses such as, for example, schizophrenia.
Accordingly, it is an object of the present invention polycondensated heterocycles with a pyrrolo[2,1-b][1,3]benzothiazepine structure as disclosed in the formula (I) below.
Another object of the present invention is a process for the preparation of said compounds.
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, or hallucinations.
In its industrial aspects, the present invention provides pharmaceutical compositions comprising at least a compound of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The invention described herein relates to new derivatives with a neuroleptic action, corresponding to the following structural formula (I):
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
=dialkylamine, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl
R
2
=hydrogen, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio;
and the pharmaceutically acceptable salts thereof.
The formula (I) derivatives possess a chiral carbon atom in position 9 on the benzothiazepine ring. The invention described herein comprises both the formula (I) derivative in racemic form and the single (R) and (S) isomers, separately.
In formula (I), R preferably represents bromine, chlorine, fluorine or hydrogen, more preferably chlorine or fluorine; R
1
preferably a 4-methylpiperazinyl group; and R
2
preferably hydrogen.
Preferred derivatives according to the invention are the products:
(±)-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine, hereinafter referred to as (±)-3a;
(±)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine, hereinafter referred to as (±)-3b (ST1455);
(+)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine, particularly preferred, hereinafter referred to as (+)-3b (ST1460)
(±)-7-fluoro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine, hereinafter referred to as (3c) (ST1456);
(±)-7-fluoro-9-(4-ethylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine (4c) (ST1457);
(±)-7-fluoro-9-[4-(2′-hyroxyethylpiperazin-1-yl]-9,10-dihydropyrrolo[2,1b][1,3]benzothiazepine (5c) (ST1458);
The invention described herein also relates to new, effective methods of synthesis to obtain the new pyrrolo[2,1-b][1,3]benzothiazepine structures. One of the problems encountered was that of realising a cyclisation method that made it possible to obtain the particular formula (I) tricyclic system with high yields.
The various synthesis methods described herein include a cyclisation reaction of a derivative comprising a phenyl group and a pyrrole group, where the cyclisation leads to the formation of a [1,3] thiazepine ring. The result of said cyclisation reaction is preferably a pyrrolobenzothiazepinone, which can be transformed into a formula (I) derivative by substituting the keto group on the thiazepine ring with a group selected from the definitions given above for the radical R
1
.
A process for the synthesis of formula (I) products is illustrated in Scheme 1A in its essential steps, and in Scheme 1B in detail.
With reference to Scheme 1B, the process involves the react
Campiani Giuseppe
Di Cesare Maria Assunta
Minetti Patrizia
Nacci Vito
Kifle Bruck
Nixon & Vanderhye
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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