Substituted pyrrolidine-2,3,4-trione 3-oxime derivatives...

Details Substituted pyrrolidine-2,3,4-trione 3-oxime derivatives... Substituted pyrrolidine-2,3,4-trione 3-oxime derivatives...

2002-02-06

2004-04-06

Rotman, Alan L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S546000, C548S547000

Reexamination Certificate

active

06716872

ABSTRACT:

BACKGROUND AND SUMMARY OF THE INVENTION
The invention relates to substituted pyrrolidine-2,3,4-trione 3-oxime derivatives, processes for their preparation, pharmaceutical compositions comprising these compounds, and methods for using these compounds for the preparation of pharmaceutical compositions and for the treatment of various diseases or conditions.
The treatment of chronic and non-chronic states of pain is of great importance in medicine. There is a worldwide demand for pain treatments which have a good efficacy. The urgent need for action in respect of patient-relevant and target-orientated treatment of chronic and non-chronic states of pain, this being understood as meaning successful and satisfactory pain treatment for the patient, is documented in the large number of scientific works which have recently appeared in the field of applied analgesia and fundamental research on nociception.
Conventional opioids, such as morphine, have a good action in the treatment of severe to very severe pain. However, their use is limited due to the known side effects, e.g. respiratory depression, vomiting, sedation, constipation, addiction, dependency and development of tolerance. They can therefore be administered over a relatively long period of time or in relatively high dosages only with particular safety precautions, such as specific prescription instructions (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York 1990). Furthermore, they have a relatively low efficacy for some states of pain, in particular neuropathic and incidental pain.
Opioids display their analgesic action by binding to receptors on the membrane which belong to the family of so-called G protein-coupled receptors. In addition, there are further receptors and ion channels which are considerably involved in the system of pain formation and pain conduction, such as the N-methyl-D-aspartate (NMDA) ion channel, via which a considerable part of the communication of synapses proceeds and through which the calcium ion exchange between a neuronal cell and its environment is controlled.
Knowledge of the physiological importance of ion channel-selective substances has been acquired by the development of the patch clamp technique, with which the action of NMDA antagonists on the calcium balance inside the cell can be demonstrated.
An object on which the invention is based was to provide new compounds which are suitable for pain treatment or for anxiolysis. Furthermore, these compounds should have as few as possible of the side effects of opioid analgesics, e.g. nausea, vomiting, dependency, respiratory depression or constipation. Further objects were to provide new active compounds for treatment of inflammatory and/or allergic reactions, depressions, drug and/or alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory tract diseases, coughing, mental illnesses, epilepsy, schizophrenia, Alzheimer's disease, Huntington's disease, Parkinson's disease, cerebral ischaemias, cerebral infarctions, psychoses caused by increased amino acid levels, apoplexies, cerebral oedemas, hypoxia, anoxia, AIDS dementia, encephalomyelitis, Tourette's syndrome or perinatal asphyxia.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that substituted pyrrolidine-2,3,4-trione 3-oxime derivatives of the following general formula I, as NMDA antagonists, selectively attack the glycine binding site and are suitable for treatment of inflammatory and/or allergic reactions, depressions, drug and/or alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory tract diseases, coughing, mental illnesses, epilepsy, schizophrenia, Alzheimer's disease, Huntington's disease, Parkinson's disease, cerebral ischaemias, cerebral infarctions, psychoses caused by increased amino acid levels, apoplexies, cerebral oedemas, hypoxia, anoxia, AIDS dementia, encephalomyelitis, Tourette's syndrome or perinatal asphyxia, and which moreover have a pronounced analgesic or anxiolytic action.
The present invention therefore provides compounds of the general formula I
wherein
the radical R
1
represents H, OR
8
, COR
5
, CSR
5
, NR
6
R
7
, COOR
5
, CONR
6
R
7
, CSNR
6
R
7
, a C
1-10
-alkyl, preferably a C
1-6
-alkyl, an aryl or a heteroaryl radical or represents an aryl radical bonded via a C
1-6
-alkylene group, preferably an aryl radical bonded via a C
1-3
-alkylene group,
the radicals R
2
, R
3
, which are identical or different, represent H, F, Cl, Br, CF
3
, OR
8
, SR
8
, a C
1-10
-alkyl, preferably a C
1-6
-alkyl, an aryl or a heteroaryl radical or represent an aryl radical bonded via a C
1-6
-alkylene group, preferably an aryl radical bonded via a C
1-3
-alkylene group,
the radical R
4
represents H, OH, OR
8
, SR
8
, COR
5
, COOR
5
, COCOR
5
, CONR
6
R
7
, CSNR
6
R
7
, preferably OH or OR
8
, a C
1-10
-alkyl, preferably a C
1-6
-alkyl, an aryl or a heteroaryl radical or represents an aryl radical bonded via a C
1-6
-alkylene group, preferably an aryl radical bonded via a C
1-3
-alkylene group,
the radical R
5
represents H, a C
1-10
-alkyl, preferably a C
1-6
-alkyl, an aryl or a heteroaryl radical or represents an aryl radical bonded via a C
1-6
-alkylene group, preferably an aryl radical bonded via a C
1-3
-alkylene group,
the radicals R
6
, R
7
, which are identical or different, represent H, OR
8
, COR
5
, COOR
5
, a C
1-10
-alkyl, preferably a C
1-6
-alkyl, an aryl or a heteroaryl radical or represent an aryl radical bonded via a C
1-6
-alkylene group, preferably an aryl radical bonded via a C
1-3
-alkylene group,
the radical R
8
represents a C
1-10
-alkyl, preferably a C
1-6
-alkyl, an aryl or a heteroaryl radical or represents an aryl radical bonded via a C
1-6
-alkylene group, preferably an aryl radical bonded via a C
1-3
-alkylene group,
in the form of their racemates, enantiomers, diastereomers or a corresponding base or a corresponding physiologically tolerated salt.
Alkyl radicals are also understood as meaning branched, unbranched or cyclic hydrocarbons which are unsubstituted or at least monosubstituted, preferably by F, Cl, Br, CN, NO
2
, CHO, SO
2
C
1-6
-alkyl, SO
2
CF
3
, OR
5
, NR
6
R
7
, COR
5
, COOR
5
, COCOR
5
, CONR
6
R
7
or CSNR
6
R
7
, where the radicals R
5
to R
7
have the meaning according to the general formula I. If these alkyl radicals contain more than one substituent, these can be identical or different. The alkyl radicals are preferably methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, neopentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
An aryl radical is also understood as meaning phenyl radicals which are unsubstituted or at least monosubstituted by OH, F, Cl, Br, CF
3
, CN, NO
2
, CHO, SO
2
C
1-6
-alkyl, SO
2
CF
3
, OR
5
, NR
6
R
7
, COR
5
, COOR
5
, COCOR
5
, CONR
6
R
7
, CSNR
6
R
7
, a C
1-6
-alkyl radical, a C
1-6
-alkoxy radical, a C
2-6
-alkylene radical, a heterocyclyl radical and/or a phenyl radical, wherein the radicals R
5
to R
7
have the meaning according to the general formula I. The term can also denote an optionally substituted naphthyl radical. The phenyl radicals can also be fused with further rings.
A heteroaryl radical is also understood as meaning 5- or 6-membered unsaturated heterocyclic compounds which are optionally provided with a fused-on aryl radical and contain at least one heteroatom, preferably nitrogen and/or oxygen and/or sulfur.
The heteroaryl radical is preferably furan, thiophene, pyrrole, pyridine, pyrimidine, quinoline, isoquinoline, phthalazine or quinazoline.
The following substituted pyrrolidine-2,3,4-trione 3-oxime derivatives are particularly preferred:
5-(methoxyphenylmethylene)-pyrrolidine-2,3,4-trione 3-oxime
5-(bromophenylmethylene)-pyrrolidine-2,3,4-trione 3-oxime
5-benzylidene-pyrrolidine-2,3,4-trione 3-oxime,
5-(2-chlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime
5-(4-chlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime
5-(2,3-dichlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime
5-(2,4-dichlorob

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