Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-23
2002-12-10
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06492407
ABSTRACT:
The invention relates to the use of triazolones as pharmaceutical compositions, particularly pharmaceutical compositions with a neuroprotective activity, as well as new triazolones and processes for preparing them.
Triazolones are known from the prior art and are disclosed, for example, by published German applications DE 19521162 and DE 3631511 and also by European Patent applications EP 270 061 and EP 208 321. The compounds disclosed therein are effective pesticides and may be used in particular as insecticides and acaricides.
The present invention, by contrast, discloses triazolones which can be used as pharmaceuticals, particularly pharmaceutical compositions with a neuroprotective activity. Surprisingly, it has been found that the compounds according to the invention have an affinity for or an effect on various types of receptors and exhibit a neuroprotective activity.
Tests in vitro and in vivo have shown that the cell damage and loss of function occurring in the brain as a result of hypoglycaemia, hypoxia, anoxia, global and focal ischaemia, cranial brain trauma, brain oedema, and intercranial pressure are due in some measure to an increased synaptic activity and hence increased release of transmitters. Apart from glutamate, histamine and serotonin are of particular importance as neurotransmitters. Moreover, the concentrations of calcium and sodium ions in particular are changed.
It is known that after systemic administration of glutamate neurones are destroyed in mouse brains (S. M. Rothman and T. W. Olney, Trends in Neurosciences 10 (1987) 299). This finding leads one to conclude, inter alia, that glutamate plays a part in neurodegenerative diseases (R. Schwarcz and B. Meldrum, The Lancet 11 (1985) 140). Moreover, substances such as for example quisqualic acid, cainic acid, ibotenic acid, glutamic acid, N-methyl-D-aspartic acid (NMDA) and &agr;-amino-3-hydroxy-5-methyl-4-isooxazolpropionic acid (AMPA) are known as exogenous or endogenous neurotoxins.
Brain lesions which may be induced by such substances are comparable with those which occur in conjunction with epilepsy and other neurodegenerative disorders, e.g., Huntington's disease and Alzheimer's disease. Substances and ions which inhibit the activity of the glutamate receptor and the ion channel connected to this receptor, e.g., competitive and non-competitive antagonists of excitatory amino acids, protect brain cells from hypoxic or ischaemic damage. These findings show that the glutamate receptors play an important part in mediating ischaemic damage.
It has been found that, surprisingly, the triazolones according to the invention have an antagonistic effect on the AMPA receptor. Moreover, these compounds exhibit a high affinity for the following type of receptor: “Na
+
channel site 2” binding site. In view of these findings the compounds according to the invention may be used to treat neurodegenerative disorders and cerebral ischaemia of various origins.
The invention relates to the use of triazolones of general formula (I) as pharmaceutical compositions, particularly as pharmaceutical compositions with a neuroprotective activity,
wherein:
R
1
denotes C
6
-C
10
-aryl, preferably phenyl, which may optionally be substituted directly or via a C
1
-C
4
-alkylene bridge by one or more of the groups halogen, nitro, —CF
3
, —CN, —OR
4
, —COOR
4
, —OCOR
4
, —SR
5
, —SO
2
R
5
, —OSO
2
R
5
, —NR
6
R
7
, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, or C
2
-C
4
-alkynyl;
R
1
denotes a C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl or C
2
-C
6
-alkynyl group, which may optionally be substituted by phenyl, —NR
6
R
7
, halogen, nitro, —CF
3
, —CN, or —OR
4
;
R
2
denotes a C
6
-C
10
-aryl, preferably phenyl, which may optionally be substituted directly or via a C
1
-C
4
-alkylene bridge by one or more of the groups halogen, nitro, —CF
3
, —CN, —OR
4
, —COOR
4
, —OCOR
4
, —SR
5
, —SO
2
R
5
, —OSO
2
R
5
, —NR
6
R
7
, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, or C
2
-C
4
-alkynyl;
R
2
denotes a C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, or C
2
-C
6
-alkynyl group, which may optionally be substituted by phenyl, —NR
6
R
7
, halogen, nitro, —CF
3
, —CN, or —OR
4
;
R
2
denotes a C-linked 5- or 6-membered saturated or unsaturated heterocycle, which may contain as heteroatoms 1, 2, 3, or 4 atoms selected from the group comprising oxygen, nitrogen, or sulfur and which may optionally be substituted by C
1
-C
6
-alkyl or benzyl;
R
3
denotes hydrogen or a C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, or C
2
-C
6
-alkynyl group, which may optionally be substituted by —NR
6
R
7
, halogen, nitro, —CF
3
, —CN, or —OR
4
;
R
4
denotes hydrogen, C
1
-C
4
-alkyl optionally substituted by halogen or —NR
6
R
7
, or a phenyl or benzyl group, which may optionally carry one or more methoxy groups;
R
5
denotes hydrogen, C
1
-C
4
-alkyl, phenyl, or benzyl, wherein the phenyl or benzyl group may optionally be mono- or polysubstituted by methoxy;
R
6
denotes hydrogen, C
3
-C
6
-cycloalkyl, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, or C
2
-C
6
-alkynyl, each of which may be mono- or polysubstituted by phenyl, benzyl, or —OR
4
;
R
6
denotes C
6
-C
10
-aryl, preferably phenyl, or benzyl, which may optionally be substituted by halogen, —OR
4
, C
1
-C
4
-alkyl, preferably —CH
3
, —SO
3
H, or —COOR
4
;
R
7
denotes hydrogen, C
3
-C
6
-cycloalkyl, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, or C
2
-C
6
-alkynyl, each of which may be mono- or polysubstituted by phenyl, benzyl, or —OR
4
;
R
7
denotes C
6
-C
10
-aryl, preferably phenyl, or benzyl, which may optionally be substituted by halogen, —OR
4
, C
1
-C
4
-alkyl, preferably —CH
3
, —SO
3
H, or —COOR
4
; or
R
6
and R
7
together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen, oxygen, or sulfur as further heteroatoms, whilst the heterocycle may be substituted by branched or unbranched alkyl group having 1 to 4 carbon atoms, may be substituted by phenyl or benzyl.
It is preferable to use compounds of general formula (I) as pharmaceutical compositions, particularly as pharmaceutical compositions with a neuroprotective activity, wherein
R
1
denotes phenyl, which may optionally be substituted directly or via a C
1
-C
4
-alkylene bridge by one or more of the groups fluorine, chlorine, bromine, nitro, —CF
3
, —CN, —OR
4
, —COOR
4
, —OCOR
4
, —NR
6
R
7
, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, or C
2
-C
4
-alkynyl;
R
1
denotes C
1
-C
4
-alkyl, which may optionally be substituted by phenyl;
R
2
denotes phenyl, which may optionally be substituted directly or via a C
1
-C
4
-alkylene bridge by one or more of the groups fluorine, chlorine, bromine, nitro, —CF
3
, —CN, —OR
4
, —COOR
4
, —OCOR
4
, —NR
6
R
7
, C
1
-C
4
-alkyl, C
2
-C
4
-alkynyl, or C
2
-C
4
-alkynyl;
R
2
denotes C
1
-C
4
-alkyl, which may optionally be substituted by phenyl;
R
2
denotes a C-linked 5- or 6-membered saturated or unsaturated heterocycle, which may contain as heteroatoms 1, 2, 3, or 4 atoms selected from the group comprising oxygen or nitrogen and which may optionally be substituted by C
1
-C
4
-alkyl or benzyl;
R
3
denotes hydrogen or a C
1
-C
4
-alkyl group, which may optionally be substituted by —NR
6
R
7
, fluorine, chlorine, bromine, nitro, —CF
3
, —CN, or —OR
4
;
R
4
denotes hydrogen, C
1
-C
4
-alkyl optionally substituted by halogen or —NR
6
R
7
, or a phenyl or benzyl group, which may optionally carry one or more methoxy groups;
R
6
denotes hydrogen, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, or C
2
-C
4
-alkynyl, each of which may be mono- or polysubstituted by phenyl, benzyl, or —OR
4
,
R
6
denotes phenyl or benzyl, which may optionally be substituted by halogen, OR
4
, C
1
-C
4
-alkyl, preferably —CH
3
, —SO
3
H, or —COOR
4
;
R
7
denotes hydrogen, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, or C
2
-C
4
-alkynyl, each of which may be mono- or polysubstituted by phenyl, benzyl, or —OR
4
,
R
7
denotes phenyl or benzyl, which may optionally be substituted by halogen, OR
4
, C
1
-C
4
-alkyl, preferably —CH
3
, —SO
3
H, or —COOR
4
; or
R
6
and R
7
together with the nitrogen atom form a saturated or unsaturated 5- or 6-m
Bechtel Wolf-Dietrich
Brenner Michael
Palluk Rainer
Weiser Thomas
Wienrich Marion
Bahar Mojdeh
Boehringer Imgelheim Pharma KG
Raymond Robert P.
Stempel Alan R.
Travers Russell
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