Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-01
2003-02-11
Chang, Ceila (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S365700, C548S375100
Reexamination Certificate
active
06518295
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of derivatives of aryl(or heteroaryl)azolylcarbinols of general formula (I), as well as their physiologically acceptable salts, in the manufacture of medicaments, useful in human and/or veterinary therapy, for the treatment of disorders that are mediated by an excess of substance P, and especially disorders of the central nervous system such as anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfuntion, drug addiction, cognitive disorders, locomotive disorders, etc.
BACKGROUND OF THE INVENTION
Substance P is a peptide, a tachykinin, that can be isolated from brain tissue and the gastrointestinal tract. In the brain, substantia nigra and the basal ganglions contain relatively high concentrations of substance P.
There is evidence suggesting that substance P functions as a neurotransmitter. In the basal ganglions, substance P is synthesised in the medium sized striatal neurones with spinae, which project the substantia nigra pars reticulate. Studies on the receptor distribution indicate that the receptors NK
1
are found in the striate at a relatively high density, but are to all extents and purposes absent from the substantia nigra. However, the substantia nigra contains one of the highest levels of tissue substance P in the central nervous system. Although this seems to indicate that receptor and ligand are unpaired, substance P can interact with the receptors in the striate by release of from collateral local axons of the striatonigral neurones. The terminals containing substance P have been shown to make synaptic contact with the cholinergic cell bodies in the striate. In the striate, the receptors NK
1
seem to be expressed mainly by cholinergic inter-neurones, although a small population of non-cholinergic striatal neurones can also express these receptors. Furthermore, stimulation of the NK
1
receptors by substance P has been shown to increase the release of acetylcholin (Ach), both in vitro and in vivo. As a consequence, an anatomical circuit has been described in which substance P, released locally in the striate from the collateral axons of the striatonigral neurones can bind to the NK
1
receptors of the striatal cholinergic inter-neurones to stimulate the release of acetylcholine (J. J. Anderson,
J.Pharmacol. Exp. Ther
., 1995, 274, 928-936).
Substance P has also been implicated in the pathophysiology of several neuropsychiatric disorders such as, schizophrenia, manic depressive psychosis, sexual dysfunction, drug addiction, cognitive disorders, locomotive disorders, or with depression (M. Bianchi,
Inflamm. Res
., 1995, 44 (11), 466-469). Similarly, a clear relation between depressive states and levels of substance P can be supposed, since the products that act as inhibitors of substance P have a clear anti-depressive component when studied in various laboratory animal models.
On the other hand, there is also a relation between the anxiety processes (anxiolisis/anxiogenesis) with the levels of substance P. It has been demonstrated that products that act as antagonists of the NK
1
receptor display anxiolytic activity in a social interaction trial (S. File,
Pharmacol. Biochem. Behav
., 1997, 58 (3), 747-752), with little tendency towards the development of tolerance. Similarly, administration of substance P is an anxiogenic agent when studied in the elevated-plus-maze trial (R. M. Teixeira,
Eur.J. Pharmacol
., 1996, 31 (1), 7-14), and substance P receptor blockers have the opposite effect. It can therefore be deduced that the levels of substance P play an important role in the expression of anxiety.
In our patents EP 289380 and ES 9800793 we have described carbinol derivatives of general formula (I)
wherein Ar represents a benzene ring or a substituted or unsubstituted thiopheno ring, R1 represents a hydrogen atom or a lower alkyl group (C
1
-C
4
); R2 represents a dialkylaminoalkyl or azahetercyclylalkyl radical and Het represents an azol, as well as their physiologically acceptable salts, which are claimed for the treatment of pain.
In our patents PCT/EP 96105596, ES 9701538, ES 9701728 and ES 9800793 we have also described several procedures for preparing enantiomerically pure compounds of general formula (I).
We have now discovered that the compound of general formula (I), as well as their physiologically acceptable salts, are especially useful in the manufacture of medicaments, useful in veterinary and/or human therapy, for the treatment of disorders that are mediated by an excess of substance P, especially certain disorders of the central nervous system such as anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfunction, drug addiction, cognitive disorders, locomotive disorders, etc.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the use of derivatives of aryl(or Ieteroaryl)azolylcarbinol of general formula (I)
where
Ar is a phenyl or thienyl radical, unsubstituted or optionally substituted by 1, 2 or 3 identical or different substituents, selected from the group composed of fluorine, chlorine, bromine, methyl, trifluoromethyl and methoxy;
R1 is a hydrogen atom, a cyclohexyl group, an N-methylpiperidyl group, a phenyl group, a vinyl group or a C
1
-C
4
alkyl group;
R2 is a hydrogen atom or di(C
1
-C
4
alkyl)amino (C
2
-C
3
alkyl), (C
1
-C
2
alkyl)azaheterocyclyl (C
2
-C
3
alkyl), or azaheterocyclyl (C
2
-C
3
alkyl); and
Het is a heterocyclic azotic five-membered ring that contains from one to three nitrogen atoms, unsubstituted or optionally substituted by 1 or 2 identical or different substituents selected from the group composed of fluorine, chlorine, bromine, a C
1
-C
12
alkyl group, a benzyl radical, a cyano C
2
-C
3
alkyl) radical, a carboxyalkyl (C
2
-C
3
alkyl) radical, a methoxycarbonyl (C
2
-C
3
alkyl) radical, a hydroxy (C
2
-C
3
alkyl) radical, an amino (C
2
-C
3
alkyl) radical, a di(C
1
-C
4
alkyl)amino (C
2
-C
3
alkyl) radical and an azaheterocyclyl (C
2
-C
3
alkyl) radical; or one of its physiologically acceptable salts, in the manufacture of a medicament for the treatment of disorders that are produced by an excess of substance P, and specially disorders of the central nervous system involving substance P receptors such as anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfuntion, drug dependency, cognitive disorders, locomotive disorders, etc., in mammals, including man.
The term “C
1
-C
4
alkyl group” represents a straight or branched radical that is derived from a saturated hydrocarbon of from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and terc-butyl for example.
The term “di(C
1
-C
4
alkyl)amino (C
2
-C
3
alkyl), (C
1
-C
2
alkyl)azaheterocyclyl (C
2
-C
3
alkyl), or azaheterocyclyl (C
2
-C
3
alkyl)” represents an alkyl radical of two or three carbon atoms joined to a diC
1
-C
4
alkyl)amine or to a (C
1
-C
2
alkyl)azaheterocycle or to an azaheterocycle, respectively, such as dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidylethyl, N-ethylpiperidylethyl, N-methylpyrrolidinylethyl, morpholinylpropyl, pyrrolidinylalkyl, etc.
The term “cyano (C
2
-C
3
alkyl)” represents an alkyl radical of two or three carbon atoms joined to a cyano functional group.
The term “carboxy(C
2
-C
3
alkyl)” represents an alkyl radical of two or three carbon atoms joined to a carboxyl functional group.
The term “methoxycarbonyl(C
2
-C
3
alkyl)” represents an alkyl radical of two or three carbon atoms joined to a methoxycarbonyl functional group.
The term “hydroxy(C
2
-C
3
alkyl)” represents an alkyl radical of two or three carbon atoms joined to a hydroxyl functional group.
The term “amino(C
2
-C
3
alkyl)” represents an alkyl radical of two or three carbon atoms joined to an amino functional group.
The compounds of general formula (I) can be synthesised according to the procedures described in patents EP 289380 or ES 9800793. The compounds of general formula (I) have a stereogenic centre and the invention relates both t
Frigola-Constansa Jordi
Merce-Vidal Ramón
Chang Ceila
Laboratorios del Dr. Esteve S.A.
Wright Sonya
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