Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-16
2001-01-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252160, C514S258100, C544S118000, C544S124000, C544S131000, C544S262000
Reexamination Certificate
active
06174884
ABSTRACT:
The present invention relates to 1,5-dihydro-pyrazolo[3,4-d]-pyrimidinone derivatives, to a process for their preparation, and to their use in medicaments, in particular for the treatment of cardiovascular and cerebrovascular diseases, diseases of the peripheral vessels, and diseases of the urogenital system.
Phosphodiesterases (PDEs) play an important role in the regulation of the intracellular cGMP and cAMP level. Amongst the phosphodiesterase isoenzyme groups PDE I to PDE V which have been described to date [Nomenclature of Beavo and Reifsnyder (cf. Beavo, J. A. and Reifsnyder, D. H.: Trends in Pharmacol. Sci 11, 150-155 (1990)], the Ca-calmodulin-activated PDE I, the cGMP-stimulateable PDE II and the cGMP-specific PDE V are essentially responsible for the cGMP metabolism. Due to the different distribution of these cGMP-metabolizing PDEs in the tissue, selective inhibitors should, depending on the distribution in the tissue of the isoenzyme in question, increase the c-GMP levels in the tissue in question. This may lead to a specific antiaggregatory, antispastic, vasodilatory and/or antiarrhythmic action.
Moreover, U.S. Pat. No. 5,294,612, U.S. Pat. No. 4,211,731, U.S. Pat. No. 3,211,732, WO 96/28448 and WO 96/28429 disclose 6-heterocyclyl-pyrazolo[3,4-d]pyrimidin-3-one and 6-substituted pyrazolo[3,4-d]pyrimidin-4-ones, which can be employed for hypertension, angina and heart diseases.
The present invention now relates to 1,5-dihydro-pyrazolo[3,4-d]-pyrimidinone derivatives of the general formula (I)
in which
A and D together represent a radical of the formula
where
R
2
represents aryl which has 6 to 10 carbon atoms and which is optionally up to trisubstituted by identical or different substituents from the series consisting of nitro, cyano, hxdroxyl, trifluoromethyl, halogen, carboxyl, or by straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each of which has up to 6 carbon atoms or
hydrogen, trifluoromethyl, cyano, carboxyl, or straight-chain or branched alkoxy or alkoxycarbonyl, each of which has up to 8 carbon atoms, or straight-chain or branched alkyl which has up to 8 carbon atoms and which is optionally substituted by hydroxyl,
R
1
represents straight-chain or branched acyl having up to 4 carbon atoms, or
represents straight-chain or branched alkyl having up to 10 carbon atoms, optionally substituted by hydroxyl, azido or by a group of the formula —NR
3
R
4
or —OSO
2
R
5
where
R
3
and R
4
are identical or different and
represent hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or
R
3
and R
4
together with the nitrogen atom form a 5 or 6-membered saturated heterocycle which can optionally contain a further hetero atom selected from the series consisting of S or O or a radical —NR
6
where
R
6
represent hydrogen or straight-chain or branched alkyl is up to 4 carbon atoms
and
R
5
represents phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
E represents a straight-chain or branched alkylene or alkenylene chain, each of which has up to 6 carbon atoms which are optionally substituted by hydroxyl, or
represents the C═O group,
L and V are identical or different and represent aryl having 6 to 10 carbon atoms or a 5- to 7-membered aromatic, optionally benzo-fused, heterocycle which has up to 3 hetero atoms from the series consisting of S, N and/or O which are optionally up to trisubstituted by identical or different substituents from the series consisting of halogen, hydroxyl, nitro, trifluoromethyl, carboxyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, each of which has up to 6 carbon atoms, or by a group of the formula —(W)
a
—NR
7
R
8
where
a is a number 0 or 1,
W is a radical of the formula —CO or —SO
2
,
R
7
and R
8
are identical or different and have the abovementioned meaning of R
3
and R
4
,
and/or the cycles are optionally substituted by aryl having 6 to 10 carbon atoms or by a 5- to 7-membered aromatic, optionally benzo-fused, heterocycle having up to 3 hetero atoms from the series consisting of S, N and/or O, which, in turn, are optionally up to disubstituted by identical or different substituents from the series consisting of halogen, hydroxyl, nitro, carboxyl, trifluoromethyl or by straight-chain or branched alkyl, alkox or alkoxycarbonyl, each of which has up to 5 carbon atoms, or by a group of the formula —(W′)
b
—NR
9
R
10
where
b has the abovementioned meaning of a and is identical to this meaning or different from it,
R
9
and R
10
have the abovementioned meaning of R
3
and R
4
and are identical to this meaning or different from it,
W′ has the abovementioned meaning of W and is identical to this meaning or different from it,
or
L represents a radical of the formula
or
V represents methyl,
T represents a radical of the formula —CH
2
—X—Y—
where
X represents a bond or an oxygen or sulphur atom or the —NH-group,
Y represents a straight-chain or branched alkylene chain having up to 9 carbon atoms,
and the tautomers and salts of these.
The substances according to the invention may also be present as salts. Preferred within the scope of the invention are physiologically acceptable salts.
Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preferred are salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthaline disulphonic acid.
Equally, physiologically acceptable salts may be metal salts or ammonium salts of the compounds according to the invention which have a free carboxyl group. Especially preferred examples are sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The compounds of the general formula (I) according to the invention can occur in various stereochemical forms which relate to each other either like image and mirror image (enantiomers) or which do not relate to each other like image and mirror image (diastereomers). The invention relates not only to the antipodes, but also to the racemic forms and the diastereomer mixtures. The racemic forms and the diastereomers can be separated in a known manner to give the stereoisomerically uniform constituents.
Within the scope of the invention, heterocycle generally represents a saturated or unsaturated 5- to 7-membered, preferably 5- to 6-membered, heterocycle which can contain up to 3 hetero atoms from the series consisting of S, N and/or O. Examples which may be mentioned are: pyridyl, thienyl, indonyl furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Pyridyl, thienyl, indolyl and furyl are preferred.
Preferred compounds of the general formula (I) are those
in which
A and D together represent a radical of the formula
where
R
2
represents phenyl which is optionally up to disubstituted by identical or different substituents from the series consisting of nitro, cyano, hxdroxyl, trifluoromethyl, fluorine, chlorine, bromine, carboxyl or by straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each of which has up to 5 carbon atoms, or
hydrogen, trifluoromethyl, cyano, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl, each of which has up to 6 carbon atoms, or straight-chain or branched alkyl which has up to 6 carbon atoms and which is optionally substituted by hydroxyl,
R
1
represents straight-chain or branched acyl having up to 6 carbon atoms, or
straight-chain or branched alkyl which has up to 8 carbon atoms and which is optionally substituted by hydroxyl,
Bischoff Erwin
Haning Helmut
Keldenich Jorg
Niewohner Ulrich
Rosentreter Ulrich
Bayer Aktiengesellschaft
Norris McLaughlin & Marcus P.A.
Raymond Richard L.
LandOfFree
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