Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-21
2004-01-27
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S233200, C514S218000, C514S212080, C540S599000, C540S575000, C544S184000, C544S058600, C544S112000
Reexamination Certificate
active
06683081
ABSTRACT:
The present relates to novel triazolotriazinones, to processes for preparing them and to their use as medicaments, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.
J. Heterocycl. Chem. (1993), 30(5), 1341-9, J. Heterocycl. Chem. (1984), 21(3), 697-9 and Nucleosides Nucleotides (1995), 14(7), 1601-12 describe 6-amino-triazolotriazinones which have an antiviral effect.
J. Med. Chem. (1986), 29(11), 2231-5 also describes 6-amino-triazolotriazinones as nucleoside analogs having an antitumor effect. Triazolotriazinones having the substituents described in the present invention and having an inhibitory effect against cGMP-metabolizing phosphodiesterases have not been disclosed.
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 dysfunctions.
The present invention now relates to triazolotriazinones of the general formula (I),
in which
R
1
represents straight-chain or branched alkyl having up to 6 carbon atoms or represents (C
3
-C
8
)-cycloalkyl,
R
2
represents hydrogen or represents straight-chain or branched alkyl having up to 6 carbon atoms,
R
3
and R
4
are identical or different and represent hydrogen or (C
1
-C
6
)-alkoxy or represent (C
1
-C
6
)-alkyl which is optionally substituted, up to 3 times, identically or differently, by hydroxyl, (C
1
-C
5
)-alkoxy or phenoxy or by radicals of the formulae —O—CO—NR
5
R
6
, —NR
7
R
8
or
in which
R
5
, R
6
, R
7
and R
8
are identical or different and denote hydrogen, (C
1
-C
6
)-alkyl or phenyl, or
R
7
and R
8
, together with the nitrogen atom to which they are bonded, form a 5- to 6-membered, saturated heterocycle which can additionally contain a further heteroatom from the series S and O,
and/or (C
1
-C
6
)-alkyl is, for its part, optionally substituted by phenyl which is optionally substituted, up to 3 times, identically or differently, by hydroxyl, (C
1
-C
6
)-alkoxy or halogen or by (C
1
-C
6
)-alkyl which, for its part, is in turn substituted by hydroxyl or (C
1
-C
6
)-alkoxy, or phenyl is optionally substituted by radicals of the formulae —SO
2
—NR
9
R
10
or —NR
11
R
12
, in which
R
9
, R
10
, R
11
and R
12
are identical or different and denote hydrogen, (C
1
-C
6
)-alkyl or phenyl, or
R
11
and R
12
, together with the nitrogen atom to which they are bonded, form a 5- to 6-membered, saturated heterocycle which can additionally contain a further heteroatom from the series S and O, or
R
3
represents hydrogen or (C
1
-C
6
)-alkyl, and
R
4
represents radicals of the formula
or represents phenyl which is optionally substituted, up to 3 times, identically or differently, by halogen, (C
1
-C
6
)-alkoxy or hydroxyl or by a radical of the formula
or by (C
1
-C
6
)-alkyl which, for its part, can be substituted by hydroxyl or (C
1
-C
6
)-alkoxy, or
R
3
and R
4
, together with the nitrogen atom to which they are bonded, form a radical of the formula
in which
R
13
denotes hydrogen, (C
1
-C
6
)-alkoxycarbonyl, (C
3
-C
6
)-cycloalkyl, pyridyl, pyrimidyl or (C
1
-C
6
)-alkyl which is optionally substituted by hydroxyl,
R
14
and R
15
are identical or different and denote hydrogen, hydroxyl or (C
1
-C
6
)-alkyl which is optionally substituted by hydroxyl or by a radical of the formula —P(O)(OR
18
)(OR
19
), in which
R
18
and R
19
are identical or different and denote hydrogen or (C
1
-C
6
)-alkyl, or
R
14
and R
15
together form a radical of the formula ═N—OH,
R
16
and R
17
are identical or different and denote hydrogen or (C
1
-C
6
)-alkyl which is optionally substituted by hydroxyl,
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 and/or (C
3
-C
6
)-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
6
)-Alkyl represents a straight-chain or branched alkyl radical having from 1 to 6 carbon atoms. 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.
Within the context of the invention, (C
1
-C
6
)-alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl radical having from 1 to 6 carbon atoms. Those which may be mentioned by way of example are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. Preference is given to a straight-chain or branched alkoxycarbonyl radical having from 1 to 4 carbon atoms. Particular preference is given to a straight-chain or branched alkoxycarbonyl radical having from 1 to 3 carbon atoms.
In general, halogen 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, fury
Bischoff Erwin
Dembowsky Klaus
Es-Sayed Mazen
Haning Helmut
Lampe Thomas
Bayer Aktiengesellschaft
Ford John M.
Pellegrino Susan M.
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