Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-07
2004-03-02
Seaman, D. Margaret (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S311000, C546S089000, C546S165000
Reexamination Certificate
active
06699877
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives, to a process for their preparation, their use for the preparation of pharmaceutical compositions and pharmaceutical compositions containing these compounds.
The treatment of chronic and non-chronic painful conditions is extremely important in medicine. There is a worldwide need for effective treatment of pain for patient-oriented and target-oriented treatment of chronic and non-chronic painful conditions, this concept being interpreted as the successful and satisfactory treatment of pain for the patient. This is manifested by the large number of scientific studies which have appeared recently in the field of applied analgesics and basic research in nociception.
Conventional opioids such as morphine are very effective in the therapy of strong to very strong pain. However, their use is limited by the known side effects, for example respiratory depression, vomiting, sedation, constipation and tolerance development. Furthermore, they are less effective for neuropathic or incidental pain suffered inter alia by tumor patients.
Opioids deploy their analgesic effect by binding to membrane receptors belonging to the family known as G-protein-coupled receptors (GPRC). The biochemical and pharmacological characterization of subtypes of these receptors has now raised hopes that subtype-specific opioids have a different profile of effects and side effects from, for example morphine. Further pharmacological investigations have in the meantime made the discovery of a plurality of subtypes of these opioid receptors (&mgr;
1
, &mgr;
2
, &kgr;
1
, &kgr;
2
, &kgr;
3
, &dgr;
1
and &dgr;
2
) possible. There are further receptors and ion channels which participate substantially in the pain development and pain transmission system. The NMDA (N-methyl-D-as partate) ion channel is particularly important: a substantial proportion of synaptic communication takes place through it. The exchange of calcium ions between the neuronal cell and its environment is controlled by this channel.
Information about the physiological significance of ion channel-selective substances has been obtained through the development of patch clamp technology. The effect of NMDA antagonists on the influx of calcium ions into the interior of the cell can thus be clearly demonstrated. It has also been found that these substances have an independent antinociceptive potential (for example, ketamine). It is important here that the mechanism of action is quite different, for example, from opiates, as NMDA antagonists intervene directly in the crucial calcium balance of the cells during the transmission of pain. It has therefore been possible, for the first time, to treat the neuropathic forms of pain successfully.
Various NMDA antagonists, which were tetrahydroquinoline derivatives in this case, have already been described in J. Med. Chem. (1992) 35, 1954-1968, J. Med. Chem. (1992) 35, 1942-1953 and Med. Chem. Res. (1991) 1; 64-73 and patent applications EP 386 839, WO 97/12879 A1, WO 98/07704 A1 and WO 98/42673 A1. A large number of possible indications, including the treatment of pain, have been mentioned, in particular, in the patent applications. However, the effectiveness and usefulness of these substances are still uncertain, so there is a need for further substances here.
DESCRIPTION OF THE INVENTION
One object of the invention was to provide analgesically acting substances, in particular NMDA antagonists, suitable for treating pain, in particular also chronic and neuropathic pain. In addition, these substances should have the fewest possible side effects such as nausea, vomiting, dependency, respiratory depression or constipation.
The invention accordingly relates to substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of general formula I, in the form of their racemates, enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of an individual enantiomer or diastereomer; their bases and/or salts of physiologically acceptable acids,
wherein
either
R
1
and R
2
together, respectively singly or multiply substituted or unsubstituted, form
—(CH
2
)
n
— with n=3-10,
—CH═CH—CH
2
—,
—CH═CH—CH
2
—CH
2
—,
—CH
2
—CH═CH—CH
2
—,
—CH
2
—CH═CH—CH
2
—CH
2
—,
—CH
2
—CH
2
—CH═CH—CH
2
—CH
2
—,
—O—CH
2
—CH
2
—,
—O—CH
2
—CH
2
—CH
2
—,
—CH
2
—O—CH
2
—,
—CH
2
—CH
2
—O—CH
2
—,
R
3
is selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C
1
-C
18
alkyl, C
2
-C
18
alkenyl or C
2
-C
18
alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C
3
-C
8
cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by N, S or O, respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
R
4
is selected from
R
4a
or ZR
4a
wherein Z is respectively branched or unbranched, singly or multiply substituted or unsubstituted C
1
-C
6
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkinyl, and R
4a
is selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C
1
-C
12
alkyl, C
2
-C
12
alkenyl or C
2
-C
12
alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C
3
-C
8
cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
C(O)R
9
, C(O)OR
9
, C(S)R
9
, C(S)OR
9
or SO
2
)R
9
with R
9
selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C
3
-C
8
cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl, in particular phenethyl, 1-adamantyl, 2-adamantyl, 1-naphthyl or 2-naphthyl 2-,3- or 4-pyridyl; thiazolyl;
SR
10
with R
10
selected from
respectively singly or multiply substituted or unsubstituted aryl or heteroaryl,
C(O)NR
11
R
12
, C(O)NR
11
NR
12
R
13
, C(NR
11
)NR
12
R
13
, C(S)NR
11
R
12
or C(S)NR
11
NR
12
R
13
, wherein R
11
, R
12
and R
13
, independently of one another, are selected from
H; respectively branched or unbranched, singly or multiply substituted or un-substituted C
1
-C
18
alkyl, C
2
-C
18
alkenyl or C
2
-C
18
alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C
3
-C
8
cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N, respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl;
R
5
, R
6
, R
7
and R
8
, independently of one another, are selected from
H, F, Cl, Br, I, CN, NO
2
; respectively branched or unbranched, singly or multiply substituted or unsubstituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkinyl;
OR
14
, OC(O)R
14
, OC(S)R
14
, C(O)R
14
, C(O)OR
14
, C(S)R
14
, C(S)OR
14
, SR
14
, S(O)R
14
or S(O
2
)R
14
, wherein R
14
is selected from
H; respectively branched or unbranched, singly or multiply substituted or unsubstituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkinyl; saturated or unsaturated, singly or multiply substituted or unsubstituted C
3
-C
8
cycloalkyl, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; respectively singly or multiply substituted or unsubstitued alkyl aryl or alkyl heteroaryl; respectively singly or multiply substituted or unsubstituted aryl or heteroa
Bloms-Funke Petra
Englberger Werner
Gerlach Matthias
Jagusch Utz-Peter
Maul Corinna
Crowell & Moring LLP
Gruenenthal GmbH
Seaman D. Margaret
LandOfFree
Substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid... 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 1,2,3,4-tetrahydroquinoline-2-carboxylic acid..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3229612