Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-04
2004-10-12
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S212080, C514S236200, C540S524000, C544S112000
Reexamination Certificate
active
06803365
ABSTRACT:
The present invention relates to novel imidazo[1,3,5]triazinones, to processes for preparing them and to their use as medicaments, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.
The synthesis of imidazo[1,3,5]triazinones is described in J. Org. Chem. (1979), 44(10), 1740-2; in J. Org. Chem. (1979), 44(22), 3835-9; in J. Org. Chem. (1981), 46 (18), 3681-5 and J. Chem. Res. Synop. (1994), (3), 96-7. These publications did not report any biological effect.
Imidazo[1,3,5]triazinones which possess antiviral and/or antitumor effect are described in Nucleosides Nucleotides (1987), 6(4), 663-78; in Eur. J. Med. Chem. (1992), 27(3), 259-66; in J. Heterocycl. Chem. (1993), 30(5), 1341-9; in J. Med. Chem. (1995), 38(18), 3558-68 and Biorg. Med. Chem. Lett. (1996), 6(2), 185-8. The compounds which are mentioned in these literature references were for the most part prepared as guanine or guanosine analogs and are therefore as a rule substituted in the 2 position by —NH
2
, —SH or —H. None of the compounds which are described contains a phenyl ring or a substituted phenyl ring in the 2 position. None of the compounds which are described has been reported to have an inhibitory effect on phosphodiesterases.
The compounds according to the invention are potent inhibitors of cyclic guanosine 3′,5′-monophophate-metabolizing phosphodiesterases (cGMP-PDEs). In accordance with the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990), these phosphodiesterases are the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.
An increase in the concentration of cGMP can lead to therapeutic, antiaggregatory, antithrombotic, antiproliferative, antivasospastic, vasodilatory, natriuretic and diuretic effects. It can exert an effect on the short-term or long-term modulation of vascular and cardiac inotropy, cardiac rhythm and stimulus conduction in the heart (J. C. Stoclet, T. Keravis, N. Komas and C. Kugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100). Inhibition of the cGMP-PDEs can also strengthen erection. These compounds are therefore suitable for treating erectile dysfunction.
The present invention now relates to novel imidazo[1,3,5]triazinones of the general formula (I)
in which
R
1
represents straight-chain or branched alkyl having up to 4 carbon atoms,
R
2
represents straight-chain or branched alkyl having up to 4 carbon atoms or represents (C
3
-C
8
)-cycloalkyl,
R
3
represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R
4
and R
5
are identical or different and represent hydrogen, (C
1
-C
6
)-alkoxy or hydroxyl or represent (C
1
-C
8
)-alkyl which is optionally substituted, up to 3 times, identically or differently, by hydroxyl or (C
1
-C
6
)-alkoxy or by radicals of the formulae
in which
R
6
and R
7
are identical or different and denote hydrogen or (C
1
-C
6
)-alkyl,
and/or, for its part, (C
1
-C
8
)-alkyl is optionally substituted by phenyl or phenoxy which, for their part, are optionally substituted, once to three times, identically or differently, by halogen, hydroxyl, (C
1
-C
6
)-alkoxy or (C
1
-C
6
)-alkyl or by a radical of the formula —SO
2
NR
8
R
9
,
in which
R
8
and R
9
are identical or different and denote hydrogen or (C
1
-C
6
)-alkyl,
or
R
4
represents hydrogen or methyl,
and
R
5
represents radicals of the formulae
or
represents phenyl which is optionally substituted, up to 3 times, identically or differently, by halogen, acetyl or (C
1
-C
6
)-alkoxy or by radicals of the formulae
—NR
10
R
11 or —CH
2
—P(O)(OR
12
)(OR
13
)
in which
R
10
and R
11
are identical or different and denote hydrogen or (C
1
-C
4
)-alkyl,
R
12
and R
13
are identical or different and denote hydrogen or (C
1
-C
6
)-alkyl,
or
R
4
and R
5
, together with the nitrogen atom to which they are bonded, form radicals of the formulae
in which
R
14
and R
15
are identical or different and denote hydroxyl, hydrogen or (C
1
-C
4
)-alkyl which is optionally substituted by hydroxyl,
or
R
14
denotes hydrogen,
and
R
15
denotes a radical of the formula
or
R
14
and R
15
together form a radical of the formula ═N—O—CH
3
,
R
16
denotes hydrogen or (C
1
-C
6
)-alkyl which is optionally substituted by hydroxyl, or denotes a 5-to 6-membered, aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O,
and the salts, N-oxides and isomeric forms thereof.
The compounds according to the invention can exist in stereoisomeric forms which either relate to each other as image and mirror image (enantiomers) or which do not relate to each other as image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers or their respective mixtures. The racemic forms, as well as the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.
The substances according to the invention can also be present as salts. Within the context of the invention, preference is given to physiologically harmless salts.
Physiologically harmless salts can be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acid, such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid or benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
Physiologically harmless salts can equally well be metal or ammonium salts of the compounds according to the invention. Particular preference is given, for example, to sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia, or to organic amines, such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
(C
3
-C
8
)-Cycloalkyl represents cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Those which may be mentioned as being preferred are: cyclopropyl, cyclopentyl and cyclohexyl.
(C
1
-C
8
)-Alkyl, (C
1
-C
6
)-alkyl and (C
1
-C
4
)-alkyl represents a straight-chain or branched alkyl radical having from 1 to 8, from 1 to 6 and from 1 to 4 carbon atoms, respectively. Those which may be mentioned by way of example are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Preference is given to a straight-chain or branched alkyl radical having from 1 to 4 carbon atoms. Particular preference is given to a straight-chain or branched alkyl radical having from 1 to 3 carbon atoms.
(C
1
-C
6
)-Alkoxy represents a straight-chain or branched alkoxy radical having from 1 to 6 carbon atoms. Those which may be mentioned by way of example are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy. Preference is given to a straight-chain or branched alkoxy radical having from 1 to 4 carbon atoms. Particular preference is given to a straight-chain or branched alkoxy radical having from 1 to 3 carbon atoms.
Halogen generally represents fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine and bromine. Particular preference is given to fluorine and chlorine.
A 5-to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, O and/or N represents, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Preference is given to pyridyl, pyrimidyl, pyridazinyl, furyl and thienyl.
Preference is given to compounds according to the invention of the general formula (I),
in which
R
1
represents methyl or ethyl,
R
2
represents straight-chain or branched alkyl having up to 3 carbon atoms or represents (C
3
-C
6
)-cycloalkyl,
R
3
represents straight-chain or branched alkyl having up to 3 carbon atoms,
R
4
and R
5
are identical or different
Bischoff Erwin
Dembowsky Klaus
Es-Sayed Mazen
Haning Helmut
Lampe Thomas
Bayer Aktlengesellschaft
Pellegrino Susan M.
Raymond Richard L.
LandOfFree
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