Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-06
2003-11-04
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...
C548S542000, C548S544000, C548S546000, C548S550000
Reexamination Certificate
active
06642267
ABSTRACT:
BACKGROUND AND SUMMARY OF THE INVENTION
The invention relates to substituted 1,5-dihydropyrrol-2-one derivatives, processes for their preparation, medicaments comprising these compounds, and the use of these compounds for the preparation of medicaments.
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 into nociception.
Conventional opioids, such as e.g. 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 e.g. 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 bonding 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 e.g. 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, such as 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, tinnitus aurium or perinatal asphyxia.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that substituted 1,5-dihydropyrrol-2-one derivatives of the following general formula I, as NMDA antagonists, selectively attack the glycine bonding 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, tinnitus aurium or perinatal asphyxia. The compounds and derivatives of formula I moreover have a pronounced analgesic and/or anxiolytic action.
The present invention therefore provides substituted 1,5-dihydropyrrol-2-one derivatives of the general formula I:
wherein
X represents O, S or NR
7
;
the radical R
1
represents H, OR
11
, SR
11
, COR
8
, CSR
8
, NR
9
R
10
, COOR
8
, CONR
9
R
10
, CSNR
9
R
10
, COCOR
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 radicals R
2
, R
3
, which are identical or different, represent H, F, Cl, Br, CF
3
, OR
11
, SR
11
, NR
9
NR
10
, 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
11
, SR
11
, COR
8
, COOR
8
, COCOR
8
, CONR
9
R
10
, CSNR
9
R
10
, 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
5
, R
6
, which are identical or different, represent H, O, OH, OR
11
, SR
11
, COR
8
, CSR
8
, COOR
8
, COCOR
8
, CONR
9
R
10
, CSNR
9
R
10
, a C
1-10
-alkyl, preferably a C
1-6
-alkyl, an aryl or a heteroaryl radical, or represent an aryl radical bonded via C
1-6
-alkylene group, preferably an aryl radical bonded via a C
1-3
-alkylene group or R
5
and R
6
together denote the group ═O;
the radical R
7
represents H, OR
11
, SR
11
, COR
8
, COOR
8
, COCOR
8
, CONR
9
R
10
, CSNR
9
R
10
, 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
8
represents H, OR
11
, SR
11
, NR
9
R
10
, 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
9
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;
the radical R
10
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;
the radical R
11
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,
with the proviso that
the racemates
of 1-methyl-3-acetamino-5-ethoxymethylenetetramic acid,
of 3-acetamino-5-ethoxymethylenetetramic acid,
of &agr;-acetylamino-&ggr;-benzylthiomethylenetetramic acid
of the acetamide of N-[2,5-dihydro-2-oxo-4-[(phenylmethyl)thio]-5-[[(phenylmethyl)thio]methylene]-1H-pyrrol-3-yl],
of the acetamide of N-[2,5-dihydro-2-oxo-1-(phenylmethyl)-4-[(phenylmethyl)thio]-5-[[(phenylmethyl)thio]methylene]-1H-pyrrol-3-yl],
of the benzamide of N-[2,5-dihydro-2-oxo-1-(phenylmethyl)-4-[(phenylmethyl)thio]-5-[[(phenylmethyl)thio]methylene]-1-H-pyrrol-3-yl],
of the acetamide of N-[2,5-dihydro-1-methyl-2-oxo-4-[(phenylmethyl)thio]-5-[[(phenylmethyl)thio]methylene]-1H-pyrrol-3-yl],
of the propanamide of N-[2,5-dihydro-1-methyl-2-oxo-4-[(phenylmethyl)thio]-5[[(phenylmethyl)thio]methylene]-1H-pyrrol-3-yl],
and the geometric isomers
of the acetamide of N-[2,5-dihy
Poschen-Rieder Hermann
Przewosny Michael
Stachel Hans-Dietrich
Crowell & Moring LLP
Gruenenthal GmbH
McKane Joseph K.
Saeed Kamal
LandOfFree
Substituted 1,5-dihydropyrrol-2-one derivatives active as... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted 1,5-dihydropyrrol-2-one derivatives active as..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted 1,5-dihydropyrrol-2-one derivatives active as... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3140748