Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-27
2002-02-05
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S243000
Reexamination Certificate
active
06344471
ABSTRACT:
The present invention relates to novel 2-aminocarbonyl-5(2H)-isoxazolones as selective ligands of a high-affinity binding site of diisopropyl fluorophosphate (DFP) on brain membranes for the prophylaxis and treatment of disorders of the central nervous system, in particular cognitive disorders, depression, schizophrenia and anxiety.
Studies with the so-called Morris test, an animal model for learning and memory, have shown that diisopropyl fluorophosphate (DFP) has an enhancing effect on learning and memory processes (
J. Pharmacol. Exp. Ther
. 1996, 278, 697-708). The optimum dosage of DFP for the procognitive effect in young adult rats is 0.03 mg/kg, administered orally. An increase of the dose above this value does not lead to a further increase in learning performance, but to a return to the control level and, when increased even further, to a deterioration of the cognitive performance compared to control animals. DFP does indeed inhibit cholinesterase; however, a significant cholinesterase inhibition in the brain of rats ex vivo is achieved only at dosages of ≧3 mg/kg orally, i.e. at dosages which are higher by a factor of about 100 than the active dose in the learning test. Cholinesterase inhibitors such as tacrine or physostigmine, which differ structurally from phosphoric acid esters, show no improvement of cognitive learning ability in this animal model.
The discrepancy between the cognitively stimulating dosages on the one hand and acetylcholinesterase-inhibiting dosages on the other hand indicates that a second mechanism of action, which is more sensitive for DFP than cholinesterase, is involved.
In the spinal cord of chicken, a high-affinity binding site for DFP has been identified (
Biochem. Pharmacol
. 1994, 48, 2073-2079), which differs from the catalytically active centres of acetylcholinesterase and butyrylcholinesterase. The function of the novel high-affinity binding site for DFP has hitherto not been known.
For the first time, it has now been found that high-affinity specific binding sites for DFP are present in membranes of the mammal brain. They were demonstrated in membranes of the cerebral cortex of rat, calf and man.
Surprisingly, the high-affinity binding site for DFP is not a known molecular target of DFP. In particular, the competition profile of the binding site does not agree with that of acetylcholinesterase, butyrylcholinesterase, neuropathy target esterase, prolylendopeptidase and dipeptidyl peptidase II. Moreover, selective ligands for 84 known neurotransmitter receptors, enzymes and ion channels of the mammal brain were tested in vitro for [
3
H]DFP competition. None of the compounds showed any affinity, not even at very high concentrations which were already physiologically irrelevant.
In addition to DFP, only the known acetylcholinesterase inhibitor dichlorvos binds to the high-affinity DFP binding site.
Accordingly, cerebral tissue preparations of mammals, preferably of rat, calf or human, are suitable for finding ligands of the high-affinity DFP binding site.
The high-affinity DFP binding site is isolated by customary methods from cerebral tissue of mammals, preferably by homogenization and centrifugation of the tissue, and resuspension of the precipitate.
The ligand is then generally added in various concentrations to this mixture and preincubated.
To measure binding, DFP is added, and the mixture is incubated. The DFP is usually labelled, preferably radioactively labelled. DFP is added in concentrations of less than 50 nM, preferably in a concentration of 0.1 -20 nM, very particularly preferably 5-15 nM.
Ligands are usually understood as meaning modulators, i.e. substances which influence the activity of the binding site. The modulators can act agonistically or antagonistically on the binding site.
Binding sites in the context of the invention are endogenous proteins, preferably enzymes or receptors.
The learning- and memory-enhancing effect of DFP described above is explained by the properties of the novel high-affinity binding site for DFP. Accordingly, substances which influence this binding site like DFP should also have the cognition-enhancing effect of DFP. Such substances are therefore suitable both for therapeutic and preventive treatment of cognitive disorders in general, in particular of dementias of the Alzheimer type.
Moreover, the antimicrobial and antileukaemic effect of 1-(1-amninocarbonyl)-2,1-benzisoxazol-3(1H)-ones is known (
J. Med. Chem
. 1984, 27, 1212-1215). The synthesis of 2-aminocarbonyl-3-methyl-5(2H)-isoxazolone has also been described (
Can. J. Chem
. 1981, 59, 175-179).
The present invention relates to compounds of the general formula (I)
in which
R
1
and R
2
are identical or different and
represent (C
1
-C
8
)-alkyl which is optionally interrupted by an oxygen or sulphur atom or by a radical NR
5
and which is optionally mono- or polysubstituted by radicals selected from the group consisting of (C
1
-C
4
)-alkoxy, (C
1
-C
3
)-perfluoroalkoxy, halogen and NR
6
R
7
,
represent (C
3
-C
8
)-cycloalkyl which is optionally interrupted by an oxygen or sulphur atom or by a radical NR
8
and which is optionally mono- or polysubstituted by radicals selected from the group consisting of (C
1-C
4
)-alkoxy, (C
1
-C
3
)-perfluoroalkoxy, halogen and NR
9
R
10
,
represent aryl-(CH
2
)
m
,
in which
R
5
, R
6
, R
7
, R
8
, R
9
and R
10
are identical or different and independently of one another represent hydrogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-acyl, (C
1
-C
4
)-alkoxy-carbonyl, carbamoyl, mono- or di-(C
1
-C
4
)-alkyl-amino-carbonyl, and
m represents 0, 1, 2 or 3, or
R
1
represents hydrogen, aryl-S(O)
n
, (C
1
-C
4
)-alkoxy, aryl-O or halogen and
R
2
is as defined above, and
in which
n represents 0, 1 or 2, or
R
1
and R
2
together with the adjacent carbon atoms form a 5- to 10-membered monounsaturated carbocycle which is optionally interrupted by an oxygen or sulphur atom or by a radical NR
11
and which is optionally mono- or polysubstituted by radicals selected from the group consisting of (C
1
-C
4
)-alkoxy, (C
1
-C
3
)-perfluoroalkoxy, halogen or NR
12
R
13
,
in which
R
11
, R
12
and R
13
are identical or different and independently of one another have the meaning mentioned for R
5
,
R
3
and R
4
are identical or different and independently of one another
represent (C
1
-C
8
)-alkyl which is optionally interrupted by an oxygen or sulphur atom or by a radical NR
14
and which is optionally mono- or polysubstituted by radicals selected from the group consisting of (C
3
-C
6
)-cycloalkyl, (C
1
-C
4
)-alkoxy, halogen and NR
15
R
16
,
represent (C
3
-C
8
)-cycloalkyl which is optionally interrupted by an oxygen or sulphur atom or by a radical NR
17
and which is optionally mono- or polysubstituted by radicals selected from the group consisting of (C
1
-C
4
)-alkoxy, halogen and NR
18
R
9
,
represent aryl-(CH
2
)
p
,
in which
R
14
, R
15
, R
16
, R
17
, R
18
and R
19
are identical or different and independently of one another have the meaning mentioned for R
5
, and
represents 0 or 1, or
R
3
and R
4
together with the nitrogen atom form a saturated or partially unsaturated 3- to 10-membered mono- or bicyclic heterocycle which optionally contains up to two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and which is optionally substituted by radicals selected from the group consisting of (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, hydroxyl, halogen, COOR
20
, aryl-Y and NR
21
R
22
,
in which
R
20
represents hydrogen or (C
1
-C
4
)-alkyl,
Y represents a bond, CH
2
, CO or CHOH, and
R
21
and R
22
are identical or different and independently of one another have the meaning mentioned for R
5
, and
X represents oxygen or sulphur,
and salts thereof,
except for 2-aminocarbonyl-3-methyl-5(2H)-isoxazolone.
Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particular preference is given, for example, to salts with hydrochloric acid,
Böss Frank
Ergüden Jens
Fürstner Chantal
Lensky Stephan
Riedl Bernd
Bayer Aktiengesellschaft
Chiu Jerrie L.
Gerstl Robert
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