Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-14
2002-08-27
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S377000, C548S225000, C548S233000, C548S235000
Reexamination Certificate
active
06441013
ABSTRACT:
The invention relates to sulfonyloxazolamines of the general formula I
in which
R
1
, R
2
each independently of one another are H, A, —(CH
2
)
n
—Ar or alkenyl having 2 to 6 C atoms,
R
1
and R
2
together are also a mononuclear saturated heterocycle having 1 to 2 N, O and/or S atoms,
Z, is H, A, CF
3
, NO
2
, Hal OH, OA, NH
2
, NHA or NA
2
,
A is alkyl having 1 to 6 C atoms,
Ar is phenyl which is mono- or di-substituted by Z,
Hal is F, Cl, Br or I,
n is 1 or 2,
or their physiologically acceptable salts or solvates as therapeutic active compounds.
The invention furthermore relates to the use of the sulfonyloxazolamines of the general formula I as therapeutic active compounds.
The invention also relates to the use of the sulfonyloxazolamines of the general formula I for the production of pharmaceutical preparations in the control of disorders of the central nervous system.
Some compounds of the general formula I are known from various earlier publications. Thus, the preparation of the compounds of the formula I is described in V. A. Chervonyi et al.,
Ukr. Khim. Zh
. (Russ. Ed.) 1991, 57(4), 415-418 or V. A. Chervonyi et al.,
Zh. Org. Khim
. 1988, 24 (2), 453-4 corresponding to V. A. Chervonyi et al.,
J. Org. Chem. USSR
(Engl. transl.) 1988, 24, 401. More detailed publications with respect to the pharmacological efficacy of the compounds of the formula I are not available in the prior art.
The invention was based on the object of finding novel useful properties of sulfonyloxazolamines, in particular those which confirm the compounds to be therapeutic active compounds and/or can lead to the use of the sulfonyloxazolamines as therapeutic active compounds and/or to the production of pharmaceutical preparations.
It has been found that the compounds of the formula I and their pharmacologically active salts surprisingly have a selective affinity for 5-HT6 receptors, together with good tolerability. They exhibit 5-HT6-antagonistic or 5-HT6 agonistic actions.
5-HT6 receptors form a subfamily of 5-HT receptors. The neurotransmitter 5-hydroxytryptamine (5-HT), also known as serotonin, is an important regulating neurotransmitter in the brain, whose actions are assisted by a a family of receptors which, at the current level of knowledge, contain 13 G protein-coupled receptors and an ion channel.
The greatest density of the serotonin S-HT6 receptors in the brain is found in the olfactory tubercle, in the nucleus accumbens, in the striatum, in the dentate gyrus and in the CA1-3 regions of the hippocampus. These regions are involved to a particular extent in psychiatric disorders such as, for example, schizophrenia or depression. Moreover, At is known from animal experiments that the administration ox 5-HT6 antisense oligonucleotides causes a behavioural syndrome which corresponds to that of dopamine agonists. Furthermore, hyperactivity of the dopaminergic neurotransmitter system in schizophrenia (dopamine hypothesis of schizophrenia) is pathophysiologically confirmed. However, dysfunctions of the dopamine system in various forms of depression have been demonstrated. Of the established or alternatively newer therapeutics which are employed in clinical practice for the treatment of these psychiatric disorders, a large number moreover bind to the 5-HT6 receptor. The atypical neuroleptics (e.g. clozapine) and the tricyclic antidepressants (e.g. amitriptyline) may be mentioned here in particular.
Moreover, it was found in animal experimental investigations that 5-HT6 receptors in the brain control cholinergic neurotransmission. Cholinergics are employed in disorders with memory disturbances such as, for example, Alzheimer's disease.
For these reasons, it can be concluded that there is an involvement of the 5-HT6 receptor in psychiatric and neurological disorders such as, preferably, schizophrenia, depression and Alzheimer's.
The compounds of the formula I and their physiologically acceptable salts are therefore suitable as therapeutic active compounds for disorders of the central nervous system. The compounds of the formula I and their physiologically acceptable salts or solvates are particularly suitable for the treatment of psychoses, schizophrenia, manic depression (B. L. Roth et al.,
J. Pharmacol. E. Ther
. 1994, 268, 1403-1410), depression (D. R. Sibley et al.,
Mol. Pharmacol
. 1993, 43, 320-327), neurological disorders (A. Bourson et al.,
J. Pharmacol. Exp. Ther
. 1995, 274, 173-180), memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease (A. J. Sleight et al.,
Neurotransmissions
1995, 11, 1-5), bulimia, anorexia nervosa or other eating disorders, compulsive acts or of premenstrual syndrome.
The invention relates to the compounds of the formula I or their physiologically acceptable salts or solvates as therapeutic active compounds.
The invention relates to the use of compounds of the formula I or their physiologically acceptable salts or solvates as therapeutic active compounds.
The invention furthermore relates to the use of compounds of the formula I or their physiologically acceptable salts or solvates as therapeutic active compounds or disorders of the central nervous system.
Solvates of the compounds of the formula I are understood as meaning adducts of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual force of attraction. Solvates are, for example, mono- or dihydrates or alcoholates.
For all radicals which occur more than once, such as, for example, Z, it holds true that their meanings are independent of one another.
Above and below, the radicals and parameters R
1
, R
2
, Z and n have the meanings indicated in the formulae I to VI, if not expressly stated otherwise.
In the above formulae, A is alkyl, is linear or branched, and has 1 to 6, preferably 1, 2, 3 or 4, C atoms. A is preferably methyl, furthermore ethyl, propyl, butyl, isobutyl, sec-butyl or tert-butyl, in addition also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl or hexyl. Methyl is particularly preferred.
Alkenyl is preferably allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl, in addition is preferably 4-pentenyl, isopentenyl or 5-hexenyl. Allyl is particularly preferred for alkenyl.
Ar is preferably phenyl which is mono- or disubstituted by Z, where Z can be X, A, CF
3
, NO
2
, Hal, OH, OA, NE
2
, NHA or NA
2
.
Ar is therefore preferably phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-ter-butylphenyl, o-, m- or p-aminophenyl, o-, m- or p-N,N-dimethylaminophenyl, o-, m- or p-nitrophenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m-, p-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromopheryl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl.
Phenyl, o- or p-methylphenyl, o- or p-chlorophenyl, p-bromophenyl, p-methoxyphenyl or 2,4-dichlorophenyl is particularly preferred for Ar.
In —(CH
2
)
n
—Ar, Ar has one of the preferred meanings indicated beforehand, where n can be 1 or 2. Benzyl is particularly preferred for —(C
2
)
n
—Ar.
Hal is preferably fluorine, chlorine or bromine.
Z is H, A, CF
3
, NO
2
, Hal, OH, OA, NH
2
, NHA or NA
2
, where A and Hal have one of the preferred meanings indicated beforehand. H, methyl, chlorine, bromine or methoxy is particularly preferred for Z.
n is preferably 1 or 2, particularly preferably 1.
R
1
and R
2
are, independently of one another, H, A —(CH
2
)
n
—Ar or alkenyl having 2 to 6 C atoms, where A, Ar, alkenyl and n have one of the, preferred or particularly preferred meanings indicated beforehand.
In addition, R
1
and R
2
together are also a mononuclear saturated he
Barnickel Gerhard
Bartoszyk Gerd
Böttcher Henning
Cezanne Bertram
Greiner Hartmut
McKane Joseph K.
Merck Patent GmbH
Saeed Kamal
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