Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-21
2003-06-03
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S184000, C544S182000
Reexamination Certificate
active
06573263
ABSTRACT:
The present invention relates to new substituted imidazotriazinones, processes for their preparation, and their use for the production of medicaments, in particular for improving perception, concentration power, learning power and/or memory power.
Phosphodiesterases (PDEs) play an essential role in the regulation of the intracellular cGMP and cAMP levels. Of the previously described phosphodiesterase isoenzyme groups PDE 1 to PDE 10 (Beavo and Reifsnyder
Trends in Pharmacol. Sci.
1990, 11, 150-155; Sonderling and Beavo
Curr. Opin. Cell Biol.
2000, 12, 174-179), the PDEs 1, 2, 5, 9 and 10 are mainly responsible for the metabolism of cGMP. On account of the varying distribution of these cGMP-metabolizing PDEs in the tissue, selective inhibitors should raise the cGMP levels in the corresponding tissue, depending on the tissue distribution of the appropriate isoenzyme.
The particular feature of PDE 2 lies in its positive cooperative kinetics with respect to the substrate cGMP. It was postulated that small amounts of cGMP bind to the so-called cGMP-binding domain and thereby bring about activation of the enzyme. By this means, the affinity of the catalytic domain to cGMP and cAMP is also increased (Martins et al.
J. Biol. Chem.
1982, 257, 1973-1979). Therefore PDE 2 can hydrolyse and thereby also control both second messenger systems by means of small amounts of cGMP.
PDE 2 has been isolated from various tissues, for example from heart, adrenal gland, liver, platelets and in particular brain. In the brain, PDE 2 mRNA is expressed strongly in the cortex, the basal ganglia and in the hippocampus (Sonnenburg et al.
Biol. Chem.
1991, 266, 17655-17661). The sequence of the human isoform PDE 2A3 was reported by Rosman et al.
Gene
1997, 191, 89-95. Of the tissues investigated, the expression of PDE 2A was demonstrated strongly therein in the brain and heart and more weakly in liver, skeletal muscle, kidney and pancreas.
U.S. Pat. No. 4,278,673 discloses imidazopyrimidinones having cAMP PDE-inhibitory action for the treatment of asthma and bronchitis.
WO-A-99/67244 and WO-A-99/24433 disclose 7-alkyl-2-phenyl-imidazotriazinones having PDE 5-inhibiting action for the treatment of vascular diseases.
EP-A-0 771 799, WO-A-98/40384 and WO-A-00/12504 describe purinone, allopurinol and triazolopyrimidinone derivatives, their inhibitory action on cGMP-metabolizing PDEs and their suitability for the treatment of vascular diseases.
The present invention relates to compounds of the general formula (I),
in which
R
1
denotes phenyl, naphthyl, quinolinyl or isoquinolinyl, each of which can be substituted up to three times identically or differently by radicals selected from the group consisting of (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, halogen, cyano, —NHCOR
8
, —NHSO
2
R
9
, —SO
2
NR
10
R
11
, —SO
2
R
12
, and —NR
13
R
14
,
in which
R
8
, R
10
, R
11
, R
13
and R
14
independently of one another are hydrogen or (C
1
-C
4
)-alkyl, and
R
9
and R
12
independently of one another are (C
1
-C
4
)-alkyl, or
R
10
and R
11
together with the adjacent nitrogen atom form an azetidin-1-yl, pyrrol-1-yl, piperid-1-yl, azepin-1-yl, 4-methyl-piperazin-1-yl or morpholin-1-yl radical, or
R
13
and R
14
together with the adjacent nitrogen atom form an azetidin-1-yl, pyrrol-1-yl, piperid-1-yl, azepin-1-yl, 4-methyl-piperazin-1-yl or morpholin-1-yl radical,
R
2
and R
3
independently of one another denote hydrogen or fluorine,
R
4
denotes (C
1
-C
4
)-alkyl,
R
5
denotes (C
1
-C
3
)-alkyl,
R
6
denotes hydrogen or methyl,
R
7
denotes phenyl, thiophenyl, furanyl, each of which can be substituted up to three times identically or differently by radicals selected from the group consisting of (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, halogen and cyano, or (C
5
-C
8
)-cycloalkyl,
L denotes carbonyl or hydroxymethanediyl, and
M denotes (C
2
-C
5
)-alkanediyl, (C
2
-C
5
)-alkenediyl or (C
2
-C
5
)-alkinediyl,
and their physiologically tolerable salts.
(C
1
-C
4
)-Alkyl and (C
1
-C
3
)-alkyl in the context of the invention represent a straight-chain or branched alkyl radical having 1 to 4 and 1 to 3 carbon atoms respectively. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, i-, s-, t-butyl. Methyl and ethyl are preferred.
(C
2
-C
5
)-Alkanediyl in the context of the invention represents a straight-chain or branched alkanediyl radical having 2 to 5 carbon atoms. Examples which may be mentioned are ethylene, propane-1,3-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1,3-diyl, butane-2,4-diyl, pentane-2,4-diyl. A straight-chain (C
2
-C
5
)-alkane-1,&ohgr;-diyl radical is preferred. Examples which may be mentioned are ethylene, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl. Propane-1,3-diyl and butane-1,4-diyl are particularly preferred.
(C
2
-C
5
)-Alkenediyl in the context of the invention represents a straight-chain or branched alkenediyl radical having 2 to 5 carbon atoms. Examples which may be mentioned are ethene-1,2-diyl, ethene-1,1-diyl, propene-1,1-diyl, propene-1,2-diyl, prop-2-ene-1,3-diyl, propene-3,3-diyl, propene-2,3-diyl, but-2-ene-1,4-diyl, pent-2-ene-1,4-diyl. A straight-chain (C
2
-C
5
)-alkene-1,&ohgr;-diyl radical is preferred. Examples which may be mentioned are ethene-1,2-diyl, prop-2-ene-1,3-diyl, but-2-ene-1,4-diyl, but-3-ene-1,4-diyl, pent-2-ene-1,5-diyl, pent-4-ene-1,5-diyl. Prop-2-ene-1,3-diyl, but-2-ene-1,4-diyl and but-3-ene-1,4-diyl are particularly preferred.
(C
2
-C
5
)-Alkinediyl in the context of the invention represents a straight-chain or branched alkinediyl radical having 2 to 5 carbon atoms. Examples which may be mentioned are ethine-1,2-diyl, ethine-1,1-diyl, prop-2-ine-1,3-diyl, prop-2-ine-1,1-diyl, but-2-ine-1,4-diyl, pent-2-ine-1,4-diyl. A straight-chain (C
2
-C
5
)-alkene-1,&ohgr;-diyl radical is preferred. Examples which may be mentioned are ethine-1,2-diyl, prop-2-ine-1,3-diyl, but-2-ine-1,4-diyl, but-3-ine-1,4-diyl, pent-2-ine-1,5-diyl, pent-4-ine-1,5-diyl. Prop-2-ine-1,3-diyl, but-2-ine-1,4-diyl and but-3-ine-1,4-diyl are particularly preferred.
(C
1
-C
4
)-Alkoxy in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy. Methoxy and ethoxy are preferred.
(C
5
-C
8
)-Cycloalkyl in the context of the invention represents cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The following may preferably be mentioned are: cyclopentyl, cyclohexyl or cycloheptyl.
Halogen in the context of the invention in general represents fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine and chlorine are particularly preferred.
Preferred salts in the context of the invention are physiologically acceptable salts of the compounds according to the invention.
Physiologically acceptable salts of the compounds according to the invention can be acid addition salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Salts which may be mentioned are, however, also salts with customary bases, such as, for example, alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methyl-piperidine.
The compounds according to the invention can exist in stereoisomeric forms, which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invent
Böss Frank-Gerhard
Grosser Rolf
Hendrix Martin
König Gerhard
Niewöhner Ulrich
Balasubramanian Venkataraman
Bayer Aktiengesellschaft
Chiu Jerrie L.
Raymond Richard L.
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